Ethiopan Pharmacology 2015

PHARMACOLOGY

Prepared by ; weku bedada (PhD Candidate)

Tusday ,May12,2015 Designed by YAYA 1

Pharmacology From pharmakon: ‘drug ’ and -logia: ‘the study of’ The study of the interactions that occur between a living

organism and chemicals that affect normal or abnormal biochemical function. Such interactions are explained by the two major principles; the pharmacokinetics and the pharmacodynamics.

Pharmacokinetics studies the effects of biological systems on the drugs and pharmacodynamics studies the effects of the drugs on biological systems.

A drug may be broadly defined as any chemical agent that affects biological system. If the chemical has medicinal properties, it is considered pharmaceutical.

The most important properties of an ideal drug are: effectiveness and safety.

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Body-drug interactions


Rudolf Buchheim• Rudolf Buchheim (1820–1879) was a

German pharmacologist .• He created the first pharmacological institute University

of Dorpat at 1845. • In 1867 he became professor of pharmacology

and toxicology at the University of Giessen.• Buchheim is remembered for his pioneer work in

experimental pharmacology. He introduced the bioassay to pharmacology, and created a methodology for determining the quantitative and medical aspects of chemical substances.

• A well-known student of his was chemist Oswald Schmiedeberg (1838–1921), who was to become the "founder of modern pharmacology".


Branches of Pharmacology• Clinical pharmacology: application of pharmacological

principles and methods in the medical clinic and towards patient care and outcomes

• Toxicology: Study of harmful or toxic effects of drugs (including those beneficial in lower doses).

• Pharmacogenetics: Clinical testing of genetic variation that gives rise to differing response to drugs

• Pharmacogenomics: Application of genomic technologies to new drug discovery and further characterization of older drugs

• Pharmacoepidemiology: Study of effects of drugs in large numbers of people

• Pharmacognosy: deals with the composition, use, and development of natural medicinal substances.


Sources of Drugs• Drugs are derived from a wide variety of different

sources, including plants, minerals, animals, synthetic and DNA sources.

• Plants e.g Quinidine from cinchona bark, digoxin from foxglove plant and morphine from opium poppy plant.

• Minerals e.g . Milk of magnesia (Mg) , Zinc oxide (Zn)• Animals: insulin from pancreas of the cow or pig• Synthetic: Acetylsalicylic acid(Aspirin) Meperidine,

Diphenoxylate, Co-Trimoxazole.• Recombinant DNA: Hepatitis B vaccine, insulin and the

growth hormone.


Discovery

Phase I

Preclinical

Phase II

Phase III

Approval

Post marketing surveillance

6 years 6 years 2 years

Preclinical Clinical Approval

Drug development - success rate by stageDrug development - success rate by stage

Safety and dosage (20-80 healthy volunteers)

Efficacy and side effects (100-300 patient volunteers)

Adverse reactions (1000-5000 patients)

Laboratory and animal testing

Target validation and lead discovery

(250 lead compounds)

(5 drug candidates)

(1 drug)

(>104 compounds)

5-10 years

Cost >$800m

Success 1 in 5,000


Drug names• Most drugs have three names; brand name, generic

name and chemical name.• Chemical name: derived using rules established by

the International Union of Pure and Applied Chemistry (IUPAC). These rules allow scientists all over the world to name structures the same way so that any other scientist will know what structure is being referred to based on the name.

• Since chemical names are usually long and complicated, the drugs are given a standard, shorter generic name.

• E.g. 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one for Diazepam ; N-acetyl-para-aminophenol for Acetaminophen


Drug names…• Brand names: trade name, properietry name• Brand name is chosen by the company that makes it.

The name is often chosen to be memorable for advertising, or to be easier to say or spell than some long generic name.

• The brand name is usually written most clearly on any packaging. However, you will always see the generic name written somewhere on the packet (often in small print).

• The original manufacturer of a drug receives a patent on the drug and is the only manufacturer who can produce and sell the drug during this patent period.

• E.g Valium for Diazepam,Bactrim for co-trimoxazole, Losec for co-trimoxazole


Drug names…• Generic names: official/non-proprietry names.

When patent protection expires on a drug, a bioequivalent version may be sold as a "generic" version of the brand name drug, typically at a significant discount below the brand name. Generic drugs are cheaper because the manufacturers have not had the expenses of developing and marketing a new drug.

• Generic drugs are copies of brand-name drugs that have exactly the same dosage, intended use, effects, side effects, route of administration, risks, safety, and strength as the original drug.

• Sometimes, generic versions of a drug have different colors, flavors, or combinations of inactive ingredients than the original medications. 10Tusday ,May12,2015 Designed by YAYA

Pharmacokinetics and Pharmacodynamics


Pharmacokinetics• “What the body does to the drug” .• The clinical application of is termed as Clinical

Pharmacokinetics• Clinical pharmacokinetics attempts to provide both a

quantitative relationship between dose and effect and a framework within which to interpret measurements of concentrations of drugs in biological fluids for the benefit of the patientLiberationAbsorptionDistributionMetabolismExcretion


Pharmacokinetics


Absorption from the GIT• Absorption from the GI tract is governed by factors such

as surface area, blood flow to the site of absorption, the physical state of the drug, its water solubility, and the drug's concentration at the site of absorption.

• Since most drug absorption from the GI tract occurs by passive diffusion, absorption is favored when the drug is in the nonionized and more lipophilic form.

• Drugs that are weak acids would be better absorbed from the stomach (pH 1 to 2) than from the upper intestine (pH 3 to 6), and vice versa for weak bases.

• Drugs that are destroyed by gastric secretions or that cause gastric irritation sometimes are administered in dosage forms with an enteric coating that prevents dissolution in the acidic gastric contents.


Absorption from the GIT…• The stomach has small surface area; by contrast, the villi

of the upper intestine provide an extremely large surface area (approximately 200 m2). Accordingly, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely nonionized in the stomach.

• Hence, any factor that accelerates gastric emptying will be likely to increase the rate of drug absorption, whereas any factor that delays gastric emptying is expected to have the opposite effect, regardless of the characteristics of the drug.


Routes of absorption• Enteral routes: Oral, Sublingual, Buccal and Rectal.• Pareneteral:Intravenous, Intramuscular, Subcutaneous,

Intra-arterial, Intradermal,Intraperitoneal etc• Pulmonary (Metered Dose Inhaler,Dry Powder Inhaler,

Nebulizer• Topical: Percutaneous, Ocular, Nasal,vaginal


Routes of Drug Administration


Oral Route Advantages:Convenient, cheapest, easy to useSafe and acceptable. Disadvantages: Less bioavailability (first pass effect: hepatic

metabolism of drug when absorbed and delivered through portal blood ).

Some drug is destroyed by gastric juices e.g. adrenaline, insulin, oxytocin

Slow; not preferred during emergency.Might cause gastric irritationMight be objectionable in taste. It might cause discoloration of teeth e.g. iron causes

staining, tetracyclines.18Tusday ,May12,2015 Designed by YAYA

Sublingual Route Involves tablets placed under the tongue or between

cheeks or Gingiva. The drug should be lipid soluble and small.

Advantages:Rapid absorption.Less first pass effect: Venous drainage from the mouth

is to the superior vena cava, bypassing the portal circulation.

Spitting out of the drug removes its effect Disadvantages: Inconvenient; Person may swallow the drug. Irritation of the mucous membrane might occur Might be unpleasant in taste. Examples: nitroglycerin, oxytocin, nifedipine.


Rectal Route Local or systemic actions after absorption. Advantages:Preferred in unconscious or uncooperative patients.Avoids nausea or vomitingLess first pass effect; the rectum's venous drainage is

two thirds systemic (middle and inferior rectal vein) and one third portal (superior rectal vein). Additionally, CYP3A4, is not present in high amount the lower intestine in contrast to the upper intestine.

Disadvantages:Generally not acceptable by the patients.Have 50% first pass metabolism.Examples: glycerin, Bisacodyl , IndomethacinRetention enema is diagnostic and is used for finding

the pathology of lower intestines. 20Tusday ,May12,2015 Designed by YAYA

Parenteral


Route…• Intravenous: drug delivery is controlled and achieved

with an accuracy and immediacy not possible by any other procedure. Also, certain irritating solutions can be given only in this manner because the drug, if injected slowly, is greatly diluted by the blood. Drugs in an oily vehicle must not be given by this route.

• Subcutaneous: involves administration into the subcutaneous tissue, a layer of fat located directly below the dermis and epidermis, collectively referred to as the cutis.

• Viscous formulations are not generally administered subcutaneously. Typical sites of SC injection include the arms, legs and abdomen.


Parenteral…• IM: involves administration into a muscle, usually the

gluteal (buttocks), vastus lateralis (lateral thigh) or deltoid (upper arm) muscles. The musculature resides below the subcutaneous tissue (which itself lies beneath the epidermis and the dermis).

• The volume of injection is small, usually 1–3 ml or up to 10 ml in divided doses.

• Absorption may be modulated to some extent by local heating, massage, or exercise.

• Faulty injection technique may lead to local muscle damage.


Parenteral…• Intradermal /Intracutaneous: made into the outer layer

of skin (dermis) and produce local effects. • Used mainly for local anesthesia and sensitivity tests,

such as allergy panels and tuberculin tests. • Intrasynovial/Intra-articular : are used for the relief of

joint pain or the local application of medication. • Intrathecal: has also been referred to as intraspinal,

subdural, subarachnoid, or lumbar injection. • Permits direct administration of medication into the

subarachnoid space of the spinal cord.• Intra-arterial: injected into an accessible artery.• This route requires specialist training to administer

therapeutic agents as if the artery is missed, possible damage to adjacent nerves may result.


Advantage : Parenteral• Fast: 15–30 seconds for IV, 3–5 minutes for IM and SC• Essential for drugs that offer poor bioavailability or those

that are rapidly degraded within the gastrointestinal tract (e.g. insulin and other peptides).

• For unconscious or uncooperative or for patients with nausea and vomiting (and additionally dysphagia).

• Local effects may be achieved using parenteral formulations, e.g. local anaesthesia.

• Parenteral formulations provide a means by which serious imbalances in electrolytes may be corrected (using infusion solutions).

• Total parenteral nutrition offers a means by which nutrition may be provided using specially formulated solutions that are infused into the patient.


Disadvantage : Parenteral• The manufacturing process is more complicated. Need

for strict asepsis• Skill of administration is required to ensure that the

dosage form is administered by the correct route. • Parenteral formulations are associated with pain on

administration. If not done properly, potentially fatal air boluses (bubbles) can occur.

• It is difficult to reverse the effects of drugs that have been administered parenterally, even immediately after administration.

• If needles are shared, there is risk of HIV and other infectious diseases.


Inhalation Route Gaseous and volatile agents and aerosols Rapid onset of action due to rapid access to circulation large surface area High blood flow AdvantagesFastest method, 7-10 secondsUsers can titrate the amount of drug they are receiving DisadvantagesMost addictive route since it hits the brain so quicklyParticles larger than 20 micron and the particles impact

in the mouth and throat. Smaller than 0.5 micron and they aren't retained.


Transport System• Passive diffusion: Drugs diffuse across a cell membrane

from a region of high concentration (eg, GI fluids) to one of low concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also depends on the molecule's lipid solubility, size, degree of ionization, and the area of absorptive surface.

• Facilitated diffusion is a process of passive transport aided by integral membrane proteins.

• Active transport is the movement of a substance against its concentration gradient. Active transport uses energy, unlike passive transport, which does not use any type of energy.


The Movement of Drugs Across Cell Barriers

Mechanism Direction Energy required Carrier Saturable

Passive diffusion Along gradient No No No

Facilitated diffusion Along gradient No Yes Yes

Active transport Against gradient Yes Yes Yes


Bioavailability: The fraction of the dose (F) that is absorbed and escapes any first-pass elimination.


Plasma drug concentration• t max. The time of peak plasma concentration, t max,

corresponds to the time required to reach maximum drug concentration after drug administration.

• C max. The peak plasma drug concentration, C max, represents the maximum plasma drug concentration obtained after oral administration of drug.

• AUC. The area under the plasma level–time curve, AUC, is a measurement of the extent of drug bioavailability. The AUC reflects the total amount of active drug that reaches the systemic circulation.

• Css. Drugs are administered in such a way as to maintain a steady state of a drug in the body ,i.e., just enough drug is given in each dose to replace the drug eliminated since the preceding dose. Thus, calculation of the appropriate maintenance dose is the primary goal. 31Tusday ,May12,2015 Designed by YAYA

Plasma drug concentration…• It takes approximately three to five half-lives to reach

steady-state concentrations during continuous dosing. In three half-lives, serum concentrations are at approximately 90% of their ultimate steady-state values.

• Therapeutic effects are delayed for drugs with longer t1/2. To reduce the onset time of the drug—a loading (priming) or initial dose of drug is given. The main objective of the loading dose is to achieve desired plasma concentrations, as quickly as possible.

• Elimination Half-Life(t1/2): the time required for drug blood levels to be reduced by 50%

• Clearance: may be defined as the volume of fluid cleared of drug from the body per unit of time. The units for clearance are mL/min or L/hr.


Plasma drug concentration

Single dose Multiple dose


Distribution• After a drug is absorbed into the bloodstream, it rapidly

circulates through the body. • Once absorbed, most drugs do not spread evenly

throughout the body. Drugs that dissolve in water (water-soluble drugs), such as atenolol , tend to stay within the blood and the fluid that surrounds cells (interstitial space). Drugs that dissolve in fat , such as the anesthetic drug halothane, tend to concentrate in fatty tissues.

• Some drugs leave the bloodstream very slowly, because they bind tightly to proteins circulating in the blood. Others quickly leave the bloodstream and enter other tissues, because they are less tightly bound to blood proteins.


Distribution…• The protein-bound part is generally inactive. As unbound

drug is distributed to tissues and its level in the bloodstream decreases, blood proteins gradually release the drug bound to them.

• A highly plasma protein bound drug (e.g., ibuprofen) will have a small Vd while a drug with high tissue protein binding (digoxin) will have a large Vd.

• In plasma, acidic drugs tend to bind mainly to albumin while basic compounds have greater affinity towards alpha acid glycoproteins.

• Due to the limitation in both the number and the type of binding sites 1) binding may be saturable and, 2) drugs may compete with one another for binding to the same site.


Volume of distribution(Vd)• It is defined as the hypothetical volume of plasma in

which the drug is dissolved. Vd is an indicative of the extent of distribution of a drug.

• The volume of distribution is more properly termed the apparent volume of distribution as it does not correlate to any actual body volume.

• It is obvious that Vd has no physiological meaning. Nevertheless, it is a very useful pharmacokinetic parameter. The larger the Vd, the greater is the extent of the distribution.

• Vd= total amount of drug adminstered drug blood plasma concentration• The units for Volume of Distribution are typically

reported in (ml or liter)/kg body weight36Tusday ,May12,2015 Designed by YAYA

Distribution…

Vd % Body Weight Extent of Distribution

5 7 Only in plasma

5-20 7-28 In extracellular fluids

20-40 28-60 In total body fluids.

>40 >56 In deep tissues; bound to peripheral tissues


Metabolism


Biotransformation (Metabolism) Many pharmaceuticals are lipophilic, which enables the

drug to pass across cell membranes. Unfortunately, the same chemical property that enhances bioavailability of drugs may also make renal excretion difficult.

Metabolism often converts lipophilic compounds into more readily excreted hydrophilic products. The rate of metabolism determines the duration and intensity of a drug's action.

Although the liver is quantitatively the most important organ in metabolizing drugs, every tissue in the body is capable of drug metabolism to some degree- skin, lungs, GIT, and kidneys.

Biotransformation reactions are classically divided into two main types: (phase I) and conjugation (phase II).


Metabolism… Phase I reactions (also termed nonsynthetic reactions)

may occur by oxidation, reduction, hydrolysis. These reactions typically involve a cytochrome P450 (often abbreviated CYP), NADPH and oxygen.

Results in drug inactivation (most of drugs), conversion of inactive drug into active metabolite, conversion of active drug into active metabolite, conversion to toxic metabolite.

Phase II (Synthetic) reactions: Functional group formed by phase I is masked by natural conjugates such as glucuronic acid, glutathione, sulphate, acetic acid, glycine or methyl group.

Sites on drugs where conjugation reactions occur include -COOH,-OH), NH2, and -SH groups.


CYP (Cytochrome P450 ) Families

• Multiple CYP gene families have been identified in humans, and the categories are based upon protein sequence homology

• Most of the enzymes are in CYP 1, 2, & 3 families . • Frequently, two or more enzymes can catalyze the same

type of oxidation, indicating redundant and broad substrate specificity.

• CYP3A4 is very common to the metabolism of many drugs; its presence in the GI tract is responsible for poor oral availability of many drugs.

• Percentage of drugs metabolized by CYP3A4-5:33%, CYP2D6:23%, CYP2C9:14%, CYP1A2:14%, CYP2C19:11%.


Factors affecting drug metabolism• Enzymes induction (phenobarbitone, phenytoin) and

enzyme inhibition (Cimetidine, erythromycin). This is very important in predicting drug-drug interactions

• Genetics variation: Isoniazid(Slow/fast acetylators). There will be high adverse effects in slow acetylators

• Nutrition state: low protein diet can decrease glycine.• Overdose:acetaminophen overdose causes hepatotoxicty• Age: children (immature enzyme), elders (organ

degeneration)• Gender: Diazepam metabolism is faster in women while

propranolol metabolism is faster in men.• Disease state: kidney and liver failure• Route of Administration: First pass hepatic effect in oral

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Excretion Drugs are eliminated from the body either unchanged by

the process of excretion or converted to metabolites. Renal excretion provides the most common mechanism

of drug excretion; this form of excretion relies on the hydrophilic character of a drug or metabolite.

It is the result of three processes: Filtration, active tubular secretion and passive re-absorption.

Most drugs cab be effectively filtered by Kidney. Penicillin is an example of a drug that is eliminated

largely by active transport in the proximal tubule. Drugs that are converted to polar metabolites by liver

will not be passively reabsorbed through tubules and thus excreted through urine.


Excretion… Drug reabsorption in the tubule can be enhanced or

inhibited by chemical adjustment of the urinary pH. E.g. Aspirin overdose is treated by administering sodium bicarbonate to alkalinize the urine.

Substances excreted in the feces are principally unabsorbed orally ingested drugs or drug metabolites excreted either in the bile or secreted directly into the intestinal tract and not reabsorbed. Excretion of drugs in breast milk is important not because of the amounts eliminated, but because the excreted drugs are potential sources of unwanted pharmacological effects in the nursing infant. Excretion from the lung is important mainly for the elimination of anesthetic gases.


Pharmacodynamics• Pharmacodynamics is used to describe the effects of a

drug on the body. It is often summarized as the study of what a drug does to the body.

• Understanding Pharmacodynamics can provide the basis for the rational therapeutic use of a drug and the design of new and superior therapeutic agents.

• Mechanism of action: the molecular interactions by which pharmacologic agents exert their effects.

• The majority of drugs:₋ mimic or inhibit normal physiological/biochemical

processes/ pathological processes ₋ inhibit vital processes of parasites and microbes.

• The desired activity of a drug is mainly due to interaction with receptors.


Effects of drugs• Therapeutic effect: desirable and beneficial effects of

drugs.• Adverse effect : harmful and undesired effect of drugs.

– An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect, and may result from an unsuitable or incorrect dosage or procedure, which could be due to medical error.

– Adverse effects may cause medical complications of a disease or procedure and negatively affect its prognosis.

– They may also lead to non-adherence with a treatment regimen.


Drug-Receptor Interaction• Therapeutic and toxic effects of drugs result from their

interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules' biochemical or biophysical activities.

• The component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug's observed effects is called receptor.

• Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce. 47Tusday ,May12,2015 Designed by YAYA

Receptor Theory• Receptor occupancy model: based on mass-action

kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium.

• In particular, the magnitude of the response is directly proportional to the amount of drug bound, and the maximum response would be elicited once all receptors were occupied at equilibrium

• Two-state receptor theory:describe the interaction between a ligand and its receptor, but also the active receptor (R*). It proposes that ligand binding results in a change in receptor state from an inactive to an active state based on the receptor's conformation. A receptor in its active state will ultimately elicit its biological response. 48Tusday ,May12,2015 Designed by YAYA

Drug-Receptor Interaction…• Receptors include receptors on the cell surface and

within the cell, as well as enzymes and other components that generate, amplify, coordinate, and terminate postreceptor signaling by chemical second messengers in the cytoplasm.

• Two major categories of receptors: Ligand gated (ionotropic) and G-protein coupled (metabotropic).

• Ligand-Gated Channels :regulate the flow of ions through plasma membrane channels.

• G-protein Coupled Receptors: act through increasing the intracellular concentrations of second messengers such as cyclic adenosine-3',5'-monophosphate (cAMP), calcium ion, or the phosphoinositides.


NE signal Transduction


Drug-Receptor Interaction…• Receptors are responsible for selectivity of drug action.

Changes in the chemical structure of a drug can dramatically increase or decrease a new drug's affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.

• Receptors mediate the actions of both pharmacologic agonists and antagonists.

• Agonists activate the receptor to signal as a direct result of binding to it.

• Antagonists bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor.


Drug-receptor interaction…• “Spare” receptors: receptors are said to be "spare" for a

given pharmacologic response if it is possible to elicit a maximal biologic response at a concentration of agonist that does not result in occupancy of the full complement of available receptors.

• Experimentally, spare receptors may be demonstrated by using irreversible antagonists to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response.

• “Orphan" receptors: receptors for which ligands are presently unknown; useful targets for the development of new drugs.


Drug-Receptor interaction…• Many receptors for drugs can be modeled as having two

conformational states that are in reversible equilibrium with one another. These two states are called the active state and the inactive state.

• Many drugs function as ligands for such receptors and affect the probability that the receptor exists preferentially in one conformation or the other. The pharmacologic properties of drugs are often based on their effects on the state of their cognate receptors.

• A drug that, upon binding to its receptor, favors the active receptor conformation is called an agonist; a drug that prevents activation of the receptor by agonist is referred to as an antagonist.


Drug-receptor interaction…• Affinity: a measure of the ability of the drug to bind to its

molecular target• Intrinsic activity : refers to the ability of a drug-receptor

complex to produce a functional response. It is used to distinguish the relative extent of pharmacologic response between different drug molecules that bind to the same receptor.

• Efficacy :Efficacy can be thought of as the state at which receptor-mediated signaling is maximal and, therefore, additional drug will produce no additional response.

• Potency: The potency of a drug is the concentration of drug needed to obtain a specific pharmacologic effect, such as the EC50 . More potent drug is the one that requires lower dose to cause same effect


Drug-Receptor interaction…• Chronic administration of a drug (e.g. organic nitrates)

causes a down-regulation or desensitization of receptors, which results in the rapid development of complete tolerance, a process known as tachyphylaxis.

• To avoid tachyphylaxis, it is necessary to interrupt therapy.


SEMILOG DOSE-RESPONSE CURVEEFFEC

T

POTENCYEFFICACY

ED50

Maximal Effect

Log [Dose]


Dose-Response Relationships


Drug-receptor interaction…• Therapeutic Index: In animal studies, the therapeutic

index is defined as the ratio of the TD50 to ED50. • Thus if TD50 = 500 mg and ED50 = 5 mg, the drug is 100-

fold more selective for the desired response and the therapeutic index is 100. The therapeutic index in humans is never known with great precision.


Dose-Response Curve• The pharmacodynamics of a drug can be quantified by

the relationship between the dose (concentration) of the drug and the organism's (patient's) response to that drug.

• One might intuitively expect the dose–response relationship to be related closely to the drug–receptor binding relationship, and this turns out to be the case for many drug–receptor combinations.

• Thus, a useful assumption at this stage of discussion is that the response to a drug is proportional to the concentration of receptors that are bound (occupied) by the drug.


Dose-Response Curve…• The hyperbolic shape of the curve becomes sigmoid

when plotted semi-logarithmically. Dose–response curves presented in this way are sigmoidal in shape and have three basic properties: threshold, slope, and maximal asymptote. These parameters characterize and quantitate the activity of the drug.


Dose-Response…• Graded Responses: is the situation in which a single

animal (or patient) gives graded responses to graded doses; that is,as the dose is increased, the response increases. With graded responses, one can obtain a complete dose–response curve in a single animal.

• Quantal dose-response: determining the dose of drug required to produce a specified magnitude of effect in a large number of individual patients or experimental animals and plotting the cumulative frequency distribution of responders versus the log dose. The specified quantal effect may be chosen on the basis of clinical relevance (e.g., relief of headache/death). It may also be used to generate information regarding the margin of safety of a drug (e.g. Therapeutic index).


Quantal


Drug receptor interaction…• Four types of related responses may occur at receptor:• Agonist: a drug molecule that interacts with the receptor

and elicits a maximal pharmacologic response. • Partial agonist: a drug that elicits a partial (below

maximal) response. Partial agonists produce a lower response, at full receptor occupancy, than do full agonists.

• Antagonist: an agent that elicits no response from the receptor, but inhibits the receptor interaction of a second agent. The primary action of antagonists is to prevent agonists (other drugs or endogenous regulatory molecules) from activating receptors.

• “Inverse agonists“: reduce receptor activity below basal levels.


Pharmacodynamic Drug-Drug Interactions• A drug–drug interaction occurs when one drug interacts

with or interferes with the action of another drug.• Drug–drug interactions can produce effects that are

additive, synergistic,or antagonistic.• An additive drug reaction occurs when the combined

effect of two drugs is equal to the sum of each drug given alone. E.g. heparin and alcohol

• Drug synergism occurs when drugs interact with each other and produce an effect that is greater than the sum of their separate actions. E.g Diazepam and alcohol.

• An antagonistic drug reaction occurs when one drug interferes with the action of another, causing neutralization or a decrease in effect of other drug.


Pharmacological Antagonists• Can be competitive (reversible or irreversible) or non-

competitive• The effect of a reversible antagonist can be overcome by

more drug (agonist). • The effect of irreversible antagonists cannot be overcome

by more drug (agonist). The antagonist bind to the receptor in an irreversible fashion, by forming a covalent bond with the receptor.

• In case of non-competitive(e.g. benzodiazepines), the antagonist drug binds allosterically to the receptor at different site from that of active site; but lead in to conformational change of the active.

• The primary action of antagonists is to prevent agonists from activating receptors.


Pharmacological Antagonism


Non-receptor antagonism• Not all of the mechanisms of antagonism involve

interactions of drugs or endogenous ligands at a single type of receptor, and some types of antagonism do not involve a receptor at all.

• Chemical antagonism: protamine can be used clinically to counteract the effects of heparin, an anticoagulant; in this case, one drug acts as a chemical antagonist of the other.

• Physiologic antagonism: physiologic antagonism between endogenous regulatory pathways mediated by different receptors. For example, histamine lead to increased bronchoconstriction ,an effect that is physiologically opposed by adrenaline. Histamine and adrenaline act on quite distinct receptor systems.


Adverse effects• The transfer of drugs across the placenta is of critical

importance because drugs may cause anomalies(teratogenicity) in the developing fetus.

• FDA has a categorized drug from "Category A" (safest) to "Category X" (known danger) based on their risk to fetus.

• A: Adequate and well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.

• B: Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women, or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. 69Tusday ,May12,2015 Designed by YAYA

Pregnancy category…• C: Animal studies have shown an adverse effect, and

there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted, and there are no adequate and well-controlled studies in pregnant women.

• D: Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

• X: Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or who may become pregnant. 70Tusday ,May12,2015 Designed by YAYA

Hypersensitivity/ allergic reaction• The presence of an antigen stimulates the antigen-

antibody response that in turn prompts the body to produce antibodies.

• Some allergic reactions occur within minutes (even seconds) after the drug is given; others may be delayed for hours or days.

• Anaphylactic shock is an extremely serious allergic drug reaction that usually occurs shortly after the administration of a drug to which the individual is sensitive.

• Symptoms include itching, various types of skin rashes, and hives (urticaria),difficulty breathing, wheezing, cyanosis, a sudden loss of consciousness, and swelling of the eyes, lips, or tongue.


Other common adverse effects• Carcinogenicity: the ability or tendency to produce

cancer• Mutagenicity: the capacity to induce mutations• Genotoxicity describes deleterious action on a cell's

genetic material affecting its integrity.• Idiosyncrasy: unusual or abnormal reaction to a drug. For

example, a patient may be given a drug to help him or her sleep (e.g., a hypnotic). Instead of falling asleep, the patient remains wide awake and shows signs of nervousness or excitement. This is not to be mistaken with idiopathic which implies that the cause is not known.


Pharmacology of peripheral nervous system


Autonomic Nervous System(ANS)• The autonomic nervous system, also called the visceral,

vegetative, or involuntary nervous system, is distributed widely throughout the body and regulates autonomic functions that occur without conscious control.

• The autonomic nervous system consists of two large divisions: (1) the sympathetic or thoracolumbar outflow and (2) the parasympathetic or craniosacral outflow.

• The neurotransmitter of all preganglionic autonomic fibers, most postganglionic parasympathetic fibers, and a few postganglionic sympathetic fibers is acetylcholine.

• The adrenergic fibers comprise the majority of the postganglionic sympathetic fibers; here the primary transmitter is norepinephrine (NE, noradrenaline)..

• The terms cholinergic and adrenergic describe neurons that liberate ACh or norepinephrine, respectively. 76Tusday ,May12,2015 Designed by YAYA

ANS…• In most instances, the sympathetic and parasympathetic

neurotransmitters can be viewed as physiological or functional antagonists. If one neurotransmitter inhibits a certain function, the other usually augments that function.

• Most viscera are innervated by both divisions of the autonomic nervous system, and the level of activity at any moment represents the integration of influences of the two components.

• Actions on male sexual organs are complementary and are integrated to promote sexual function.

• The control of peripheral vascular resistance is primarily, but not exclusively, due to sympathetic control of arteriolar resistance.


ANS …• The sympathoadrenal system can discharge as a unit, particularly

during rage and fright.• HR is accelerated; BP rises; blood flow is shifted from the skin and

splanchnic region to the skeletal muscles; blood glucose rises; the bronchioles and pupils dilate; and the organism is better prepared for "fight or flight.”

• The parasympathetic system is organized mainly for discrete and localized discharge.

• Concerned primarily with conservation of energy and maintenance of organ function during periods of minimal activity.

• Slows the HR, lowers the BP, stimulates gastrointestinal movements and secretions, aids absorption of nutrients, protects the retina from excessive light, and empties the urinary bladder and rectum.


Eye


Cardiovascular system


Lung and GIT


Urinary & Reproductive System


Liver


Neurotransmission

• The terms cholinergic and adrenergic were proposed originally by Dale to describe neurons that liberate ACh or norepinephrine, respectively.

• Nerve impulses elicit responses in smooth, cardiac, and skeletal muscles, exocrine glands, and postsynaptic neurons by liberating specific chemical neurotransmitters.

• A neurotransmitter is a substance released synaptically by one neuron onto another cell (neuron or neuroeffector) to produce some response - localized effect as opposed to systemic (hormone).


Cholinergic Transmission• Acetylcholine is synthesized in the nerve

terminal from acetyl-CoA (produced in mitochondria) and choline (transported across the cell membrane) by the enzyme choline acetyltransferase (ChAT).

• Release of transmitter stores from vesicles in the nerve ending requires the entry of calcium.

• Acts on Nicotnic (Nn, Nm) and Muscarnic (M1-M5)

• The action of acetylcholine in the synapse is normally terminated by metabolism to acetate and choline by the enzyme acetylcholinesterase in the synaptic cleft.


Adrenergic Transmission• Norepinephrine is synthesized

from amino acid tyrosine through the action of tyrosine hydroxylase, dopa decarboxylase and Dopamine -hydroxylase.

• Acts on ( 1,2) and (1-3) receptors

• NE that has been released is taken up by the selective NE transporter (NET);which is then concentrated in vesicles by vesicular monoamine transporter (VMAT).

• MAO and COMT also involve in termination of NE activity. 86Tusday ,May12,2015 Designed by YAYA

Directly acting : Choline esters• Acetylcholine: actions are diffuse, and hydrolysis is

rapid. Available as an ophthalmic surgical aid for the rapid production of miosis.

• Methacholine differs from ACh chiefly in its greater duration and selectivity for cardiac muscarnic receptors. It may be used for diagnosis of bronchial hyperreactivity.

• Bethanechol (methyl analog of carbachol): has mainly muscarinic actions, with prominent effects on motility of the GI tract and urinary bladder. It is completely resistant to hydrolysis by cholinesterases.

• Carbachol: Almost completely resistant to hydrolysis by cholinesterases. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia.


Directly acting : Natural alkaloids • Muscarine was first isolated from Amanita muscaria in

1869. It was the first muscarnic agonist ever studied and causes profound activation of the peripheral cholinergic nervous system that may end in convulsions and death.

• Pilocarpine, from the genus Pilocarpus, has a dominant muscarinic action; present clinical use is restricted largely to the employment of pilocarpine as a sialagogue (treatment of xerostomia) and miotic agent.

• Major contraindications include asthma, coronary insufficiency, and acid-peptic disease.

• Adverse effects: salivation, sweating, abdominal cramps, a sensation of tightness in the urinary bladder, difficulty in visual accommodation.


Indirect-Acting Cholinergic Drugs• Classified as reversible and irreversible.• Mechanism: prevention of hydrolysis of ACh by AChE at

sites of cholinergic transmission. 1.Reversible agents• Edrophonium, neostigmine, pyridostigmine, and

physostigmine (Physostigma venenosum, calabar bean)• Physostigmine is absorbed readily from the GI tract,

subcutaneous tissues, and mucous membranes. Neostigmine and pyridostigmine are absorbed poorly after oral administration.

• Used to diagnose and treat myasthenia gravis, (weakness and marked fatigability of skeletal muscle), and for reversal of non-depolarizing neuromuscular blockers.


Reversible…• Physostigmine, also called eserine, is an alkaloid

obtained from the Calabar or ordeal bean, the dried, ripe seed of Physostigma venenosum, a perennial plant found in tropical West Africa.

• The Calabar bean once was used by native tribes of West Africa as an "ordeal poison" in trials for witchcraft. A pure alkaloid was isolated by Jobst and Hesse in 1864 and named physostigmine.

• After basic research elucidated the chemical basis of the activity of physostigmine, scientists began systematic investigations of a series of substituted aromatic esters of alkyl carbamic acids. Neostigmine was introduced into therapeutics in 1931 for its stimulant action on the GI tract and subsequently was reported to be effective in the symptomatic treatment of myasthenia gravis. 90Tusday ,May12,2015 Designed by YAYA

Indirect-Acting Cholinergic Drugs….

• The similarity between the symptoms of myasthenia gravis and curare poisoning in animals suggested to Jolly that physostigmine, an agent known to antagonize curare, might be of therapeutic value. Forty years elapsed before his suggestion was given systematic trial.

• The edrophonium test for evaluation of possible myasthenia gravis is performed by rapid IV injection of 2 mg of edrophonium chloride, followed 45 seconds later by an additional 8 mg if the first dose is without effect; a positive response consists of brief improvement in strength.

• Excessive dose of anti-ChE results in a cholinergic crisis.


Indirect-Acting Cholinergic Drugs….

2. Irreversible Highly lipid soluble Organophosphate insecticides (malathion, parathion) or

nerve gases (sarin, tabun) Pralidoxime is used as antidote for irreversible

cholinesterase inhibitors. Certain phosphorylated AChEs can undergo a fairly rapid

process of "aging," so that within the course of minutes or hours they become completely resistant to the reactivators.


Muscarnic receptor antagonists• Muscarinic receptor antagonists prevent the effects of

ACh by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells; in peripheral ganglia; and in the CNS.

• The actions of most clinically available muscarinic receptor antagonists differ only quantitatively from those of atropine, considered as the prototype of the group.

1. Natural alkaloids: atropine, scopolamine2.Synthetic: Cyclopentolate , tropicamide, ipratropium,

pirenzepine, Benztropine, Trihexyphenidyl .


Atropine• Atropine and scopolamine are alkaloids of the

belladonna (Solanaceae) plants.• Compete with ACh and other muscarinic agonists for a

common binding site on the muscarinic receptor.• Because atropine has limited CNS effects, it is preferred

to scopolamine for most purposes.• Dilate the pupil (mydriasis) and paralyze

accommodation (cycloplegia). The wide pupillary dilation results in photophobia; the lens is fixed for far vision, near objects are blurred, and objects may appear smaller than they are.

• The dominant effect on heart is tachycardia.• Cause bronchodilation and inhibit secretions of the

nose, mouth, pharynx, and bronchi.94Tusday ,May12,2015 Designed by YAYA

Atropine• secretion, tone and motility of GI and urinary tract.• Dose-Response ladder: salivary and bronchial secretion

and sweating mydriasis & cycloplegia, HR micturition and tone and motility of the gut gastric motility and particularly secretion.

• Absorbed rapidly from the GIT. Systemic absorption of inhaled or orally ingested quaternary muscarinic receptor antagonists is minimal.

• Atropine has a half-life of ~4 hours; hepatic metabolism accounts for the elimination of about half of a dose; the remainder is excreted unchanged in the urine.


Atropine

Therapeutic uses• Symptomatic relief of acute rhinitis and treatment of

airway disease• Urinary urgency, PUD and Spasm• Examination of the eye and breaking of adhesions

between the iris and the lens.• Anticholinesterases Poisoning.Adverse effects• Tachycardia• Dry mouth• Blurred vision• Constipation• Urinary retention


Neuromuscular blockers(NMBs)• Curare has been used for centuries by the Indians along

the Amazon and Orinoco Rivers for immobilizing and paralyzing wild animals used for food; death results from paralysis of skeletal muscles.

• A localized paralytic action of curare was first described by Claude Bernard in the 1850s. Griffith and Johnson reported the first trial of curare for promoting muscular relaxation in general anesthesia in 1942.

• Gallamine is one of a series of synthetic substitutes for curare described by Bovet and coworkers in 1949.

• Classified as Non-depolarizing and Depolarizing.• Currently, only a single depolarizing agent is in clinical

use, whereas many non-depolarizing agents are available.


Non-depolarizing• Tubocurarine, pancuronium, atracurium, vecuronium• Combine with the NM receptor at the NMJ and thereby

competitively block the binding of ACh.• Small, rapidly moving muscles such as those of the eyes,

jaw, and larynx relax before those of the limbs and trunk. Ultimately, the intercostal muscles and finally the diaphragm are paralyzed, and respiration then ceases.

• Recovery of muscles usually occurs in the reverse order to that of their paralysis, and thus the diaphragm ordinarily is the first muscle to regain function

• Devoid of central effects following ordinary clinical doses because of their inability to penetrate the blood-brain barrier.


Non-depolarizing…• Tubocurarine might produce partial blockade probably at

autonomic ganglia and at the adrenal medulla, which results in a fall in blood pressure and tachycardia.

• Anti-ChE agents can be used in the treatment of overdosage with competitive blocking agents. Atropine is used concomitantly to prevent stimulation of muscarinic receptors and thereby to avoid slowing of the heart rate.

• The anti-ChE agents, however, are synergistic with the depolarizing blocking agents, particularly in their initial phase of action.

• Therapeutic use : an adjuvant in surgical anesthesia to obtain relaxation of skeletal muscle, particularly of the abdominal wall, to facilitate operative manipulations.

• Use: prolonged apnea, CV collapse, anaphylaxis99Tusday ,May12,2015 Designed by YAYA

Depolarizing blockers: Succinylcholine• Their initial action is to depolarize the membrane by

opening channels in the same manner as ACh.• However, they persist for longer durations at the

neuromuscular junction primarily because of their resistance to acetylcholinesterase.

• In such cases, the depolarizing agents produce initially the characteristic fasciculations and potentiation of the maximal twitch, followed by the rapid onset of neuromuscular block; termed a dual mechanism.

• No longer indicated for children 8 years of age and younger unless emergency intubation is necessary.


Adrenergic neurotransmission


Adrenergic Neurotransmission• The ultimate response of a target organ to

sympathomimetic amines is dictated not only by the direct effects of the agents, but also by the reflex homeostatic adjustments of the organism.

• A rise in arterial BP caused by stimulation of -receptors elicits compensatory reflexes that are mediated by the carotid-aortic baroreceptor system. As a result, sympathetic tone is diminished and vagal tone is enhanced.

• Conversely, when there is a fall in mean BP at the mechano-receptors of the carotid sinus and aortic arch, the baroreceptor reflex works to restore pressure by reducing vagal outflow and increasing sympathetic outflow to the heart and vessels.


Adrenergic Agonists Direct-acting agonists: act directly by binding to the

adrenergic receptors A feature of direct-acting sympathomimetic drugs is that

their responses are not reduced by prior treatment with reserpine or guanethidine.

Indirect-acting agonists: cause the release of NE from intra-neuronal storage vesicles by the virtue of being taken up by the pre-synaptic adrenergic neurons (e.g., amphetamine, tyramine)

Mixed-action agonists: acts by directly activating receptors and also enhancing release of neurotransmitter from storage vesicles; is not a substrate for COMT or MAO , can cross BBB. e.g. Ephedrine


Direct acting: -agonists Selective 1: Phenylephrine, xylometazoline Selective 2: Clonidine, Methyl Dopa Non-selective: Dopamine Pharmacologic effects of -agonists• Decrease NE release (α2 )• Elevate blood pressure (α1)• Vasoconstriction of the URT lowers congestion(α1).• leads to Mydriasis without loss of accommodation (α1).• Inhibits Insulin release (α1)• Increases contraction of pregnant human uterus (α1)-Methyldopa, an inhibitor of aromatic L-amino acid

decarboxylase and successively decarboxylated and hydroxylated in its side chain to form the putative "false neurotransmitter"-methylnorepinephrine which is α2-adrenergic receptors agonist.


Direct acting : -agonists Selective 2:Salbutamol, Salmeterol ,Ritodrine Selective 1: Dobutamine Non-selective: Dopamine, Isopreternol Pharmacologic effects of -agonists• Increase HR, Contractility, conduction velocity(1)• Relaxation of bronchiolar smooth muscle and

bronchodilation(2)• Causes contraction of ciliary muscles (2)• Inhibits uterine tone and contractions (2)• Renin release from juxtaglomerular area(that results in

production of Angiotensin I, and then Angiotensin II. Angiotensin II is potent vasoconstrictor and also causes Na and water retention through Aldosterone) (1).


Therapeutic uses adrenergic agonists• -agonists: eye disorder, nasal congestion, epistaxis,

anaphylactic shock, cardiac arrest, hypotension (1 agonists), hypertension(2 agonists)

• -agonists: Bronchial asthma and delay delivery in premature labor (2 agonists), heart failure (1 agonists)

Adverse effects of adrenergic agonists• Anxiety, restlessness and tremors, tachycardia,

palpitation, angina and arrhythmia• Eye irritation• Gangrene (vasoconstriction)


Mixed Agonist: Ephedrine

• Chemically related to EP and stimulates release of NE• It is not a substrate for COMT or MAO & hence has

long duration of action• It activates β2 as well as α- and β1-aderenergic

receptors • It is used to treat mild cases of asthma• It crosses BBB giving rise to CNS stimulant action• It is now replaced by more selective β2 agonists


Adrenergic antagonists Direct acting• - blockers: prazosin,phentolamine• -blockers: metoprolol, proporanolol• Mixed-blocker: labetalol,carvedilol Indirect acting• Storage depleters: Reserpine, Guanethedine


Alpha-Adrenergic Blockers Non-selective:• Phenoxybenzamine(irreversible)• Phentolamine (Reversible) Selective• Selective α1-blockers: Prazosin, Doxazosin• Selectivity for 1A blocker:Tamsulosin• Selective α2-blocker: Yohimbine Selectivity for 1A may favor blockade of receptors in

prostate. Therapeutic uses: Hypertension, Pheochromocytoma,

Benign prostatic Hyperplasia(BPH) Adverse Effects: First dose phenomenon, postural

hypotension, Reflex Tachycardia, Headache, and nasal stuffiness 111Tusday ,May12,2015 Designed by YAYA

Beta-Adrenergic Receptors Blockers Selective β1-blocker: Atenolol, metoprolol Selective β2- blocker: butoxamine Non-selective β blocker: Propranolol, Timolol Mixed α & β- blocker: labetalol, Carvedilol Therapeutic uses: CVS diseases, Thyrotoxicosis ,

Pheochromocytoma Adverse effects: Bradycardia, bronchospasm, Masking

symptoms of hypoglycemia, lipid disturbance, hypotension.


Indirect adrenergic antagonists• Guanethidine: is transported across the sympathetic

nerve membrane by uptake. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine. However, such agents can transiently stimulate the release of norepinephrine because of their capacity to displace the amine from storage sites.

• Reserpine: block the vesicular monoamine transporter (VMAT 2) and produces a slow, prolonged depletion of the adrenergic transmitter from adrenergic storage vesicles, where it is largely metabolized by intraneuronal MAO.


CNS pharmacology

Werku bedada


I. Sedative-Hypnotics• An effective sedative (anxiolytic) agent should reduce

anxiety and exert a calming effect. • The degree of central nervous system depression caused

by a sedative should be the minimum consistent with therapeutic efficacy.

• A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep.

• Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with many drugs in this class simply by increasing the dose.


Anxiolytics /Sedative-Hypnotics

1. Benzodiazepines

2. Barbiturates

3. BZ1 selective agonist: Zolpidem (anxiolytics)

4. 5-HT1A agonist: Buspirone (anxiolytics)


Benzodiazepines Alprazolam(12-15hrs) and chlordiazepoxide (15–40

hrs), clonazepam(23-28hrs) and diazepam ( 20–80hrs). Mechanism: increase in the frequency of chloride

channel-opening by promoting the binding of GABA to the GABAA receptors.

Sedatives, Hypnotics, Anxiolytics, Anticonvulsants, anesthetics and skeletal Muscle relaxants.

Decrease time to sleep onset and waking during the night

Cross the placental barrier and are secreted into breast milk. Metabolized extensively by cytochrome P450 enzymes; have many active metabolites.


Benzodiazepines…

Adverse Reactions: motor incoordination, amnesia, tolerance and mild dependence,

The criminal use of benzodiazepines in cases of "date rape" is based on their dose-dependent amnestic effects (flunitrazepam).

Antidote: Flumazenil binds with high affinity to specific sites on the GABAA receptor, where it competitively antagonizes the binding and allosteric effects of benzodiazepines and other ligands. It is given intravenously.

Use: anxiety, insomnia, epilepsy, anesthesia, spasticity


Barbiturates Phenobarbitone, pentobarbitone , thiopental. Were used extensively as sedative-hypnotic drugs; they

have been replaced largely by the much safer benzodiazepines.

Mechanism: increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels.

Can produce all degrees of depression of the CNS. Adverse effects: Oliguria or anuria, Strong physical

dependence and depression of the medullary centers. DDIs: Potent induction of liver enzymes. Use: Anxiety, Insomnia, Anesthesia, Epilepsy


GABA receptors• GABA receptors are divided into two types:

I. GABA- AII. GABA- B. – GABA- A receptors open chloride channels and are antagonized by

picrotoxin and bicuculline, which both cause generalized convulsions.

– GABA- B receptors, which can be selectively activated by the antispastic drug baclofen,are coupled to G proteins that either inhibit calcium channels or activate potassium channels.

• Inmost regions of the brain, IPSPs have a fast and slow component mediated by GABA-A and GABA-B receptors, respectively.

• Immunohistochemical studies indicate that a large majority of the localcircuit neurons synthesize GABA.

• A special class of local circuit neuron localized in the dorsal hornof the spinal cord also synthesizes GABA.

• These neurons form axoaxonic synapses with primarysensory nerve terminals and are responsible for presynaptic inhibition.


II. Antidepressants Depression is characterized by feelings of intense

sadness and despair, mental slowing and loss of concentration, pessimistic worry, lack of pleasure, self-deprecation, and variable agitation or hostility.

Evidence implicates alterations in NE , Serotonin (5-HT) and Dopamine ( DA).

As many as 10% -15% of individuals with severe depression, and up to 25% of those with bipolar disorder, display suicidal behavior at some time.

Lifetime risk for major depression is considerably higher, at 5% to 10%, and approximately twice the risk in women than in men.

Drugs: TCA (amytriptiline, Imipramine),SSRIs (Fluoxetine, Fluvoxamine), MOIs (Phenelzine, Selegiline) .


Tricyclic Antidepressants (TCAs)• Characteristic three ring nucleus• Mechanism: inhibit SERT and NET thus increasing the level of

5-HT and NE respectively.• Most are incompletely absorbed• High protein binding, high lipid solubility• All are metabolized in liver, High first pass effect. Drugs that

inhibit CYP2D6, such as SSRIs, may increase plasma exposures of TCAs

• “Therapeutic lag" lasting 3-4 weeks before a measurable therapeutic response becomes evident. This challenge is compounded by the early emergence of side effects.

• SEs:anticholinergic Ses (M), Orthostatic hypotension (1), Sedation(H1) and weight gain, Cardiac toxicity, Sexual dysfunction.


Selective Serotonin Reuptake Inhibitors Mechanism: reuptake of 5-HT. Better safety profile. Fluoxetine is the prototype drug in the family Fairly well absorbed and distributed t1/2 : 16-24 hrs ; norfluoxetine has t1/2 :8 days Drug interaction: Serotonin Syndrome (hyperthermia,

muscle rigidity, rapid changes in mental status and vital signs) if taken with MAO-Is.

Inhibitors of CYP3A4 and CYP2D6 Adverse effects: nausea, vomiting and delayed or

impaired orgasm, insomnia, agitation. Paroxetine is associated with an increased risk of

congenital cardiac malformations.124Tusday ,May12,2015 Designed by YAYA

III. Mood stabilizers

Used in bipolar disorder/manic-depressive disorder

Characterized by substantial mood fluctuations, a cycling between very low and very high moods.

Mania is characterized by excessive physical activity, rapidly changing ideas, and impulsive behavior.

Can have additional disorders (psychosis, anxiety).

A deficiency of monoaminergic

transmission in the CNS might

cause depression, whereas an

excess may result in mania.

Drugs: Lithium, Valproate,

Carbamazepine, aripiprazole

Combination therapy often

required


Lithium Carbonate• Cornerstone for the treatment and prophylaxis of mania.• Mechanism: develops a relatively small gradient across

biological membranes and therefore cannot maintain membrane potentials (inhibit release of NE and DA).

• Complete absorption occurs in about 8 hours, with peak plasma concentrations occurring 2 to 4 hours after an oral dose. Distribute in total body water like Na. Excreted through kidney. Optimal Serum levels:0.5 and 1.0 mEq/L.

• Li+ competes with Na+ for reabsorption, and Li+ retention can be increased by Na+ loss related to diuretic use, or febrile, diarrheal, or other GI illness.

• SEs: tremor, convulsions, nephrotoxicity, hypothyroidism, arrhythmias, coma and death

• Pregnancy category D: tricuspid valve malformation.126Tusday ,May12,2015 Designed by YAYA

Pharmacology of SchizophreniaPharmacology of Schizophrenia


Schizophrenia A symptom of mental illnesses characterized by a

distorted or non-existent sense of reality. Schizophrenia is a neurodevelopmental disorder with

complex genetics and incompletely understood pathophysiology. Certain environmental exposures confer an increased risk of developing schizophrenia, including fetal second-trimester viral and nutritional insults, birth complications, and substance abuse in the late teen or early adult years.

Positive symptoms : Hallucinations, delusions, disorganized speech and agitated behavior.

Negative symptoms :apathy, avolition, alogia,cognitive deficits: deficits in working memory, processing speed, social cognition, and problem solving


Neurotransmitter changes Dopamine theory : drugs that increase DA activity, such

as levodopa (a precursor), amphetamines (releasers of DA), and apomorphine (a direct DA receptor agonist) aggravate schizophrenia. DA receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs

Serotonin theory : atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia.

Glutamate theory: antagonists of the NMDA receptor such as phencyclidine, when administered to nonpsychotic subjects, produce much more "schizophrenia-like" symptoms than do DA agonists.


Dopamine tract Innervation Function D-antagonist effects

Mesolimbic Limbic areas Arousal, memory, motivation

Psychosis relief

Mesocortical Cortex

Cognition, communication, social functions, stress response

Psychosis relief

Nigro-striatal StriatumExtrapyramidal system, movement coordination

Movement disorders

Tubero-infundibular Pituitary gland Prolactin regulation Hyperprolactinemia

Dopamine pathways


I. Typical Antipsychotics Mechanism: D2 receptors antagonism High potency (e.g. Haloperidol, Fluphenazine) and low potency(e.g.

Chlorpromazine, Thioridazine). The high potency antipsychotics have fewer autonomic effects but greater

extrapyramidal effects due to excessive D2 blockade. Low-potency have high affinities for H1(sedation), M (anticholinergic effects), and 1(hypotension)

receptors. Generally more effective against positive than the negative symptoms. Choice usually based on tolerability of side effects 4-6wk until full response ;70-80% of patients respond. t1/2 of most antipsychotics is long (15-30 hours) Metabolized by liver and excreted in the urine.


Typical antipsychotics… Adverse effects• Parkinson-like symptoms(catalepsy)• Acute dystonia: sustained muscular contraction • Akathisia : continuous motor restlessness• Tardive dyskinesia: involuntary movements in

face/tongue and limbs months or years later.• Neuroleptic malignant syndrome: characterized by

hyperthermia, severe muscular rigidity, autonomic instability, changing levels of consciousness.

• Gynecomastia, galactorrhea• Anticholinergic side-effects, orthostatic hypotension,

sedation, weight gain.• QTc prolongation (e.g., thioridazine)


MANAGEMENT OF EPS

• Dystonia and parkinsonism: anticholinergic &

antiparkinsonian drugs• Neuroleptic malignant syndrome: muscle relaxants,

DA agonists, supportive therapy• Akathisia: benzodiazepines, -blockers• Tardive dyskinesia: increase neuroleptic dose; switch

to Clozapine


II. Atypical Antipsychotics• Clozapine, Olanzapine, Risperidone, Aripiprazole• Mechanism: D2 and 5-HT2 in cortical and limbic areas• The newest, aripiprazole, appears to be a partial agonist

of D2 receptors. • Effective against positive and negative symptoms.• Clinically effective doses of atypical agents show

markedly reduced EPS risk (or nearly absent in the case of quetiapine and clozapine) compared to typical antipsychotic agents.

• There has been increased concern over metabolic effects: weight gain, hypertriglyceridemia, and new-onset type 2 DM, and diabetic ketoacidosis

• Risk of agranulocytosis with clozapine requires continual monitoring.


Antiparkinson’s Drugs


Parkinson’s Disease First described by James Parkinson in 1817 as paralysis

agitans, or the "shaking palsy. Arvid Carlsson, Eric Kandel, and Paul Greengard won

the Nobel Prize in Physiology and Medicine in 2000 for work with the neurotransmitter dopamine and its effects in Parkinson's disease.

Symptoms– Bradykinesia– Rigidity– Tremor– Postural instability

136

James Parkinson(1755-1824)Tusday ,May12,2015 Designed by YAYA

Pathophysiology• The pathological hallmark of PD is a loss of the

pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies.

• The D1 and D2 proteins are abundant in the striatum and are the most important receptor sites with regard to the causes and treatment of PD.

• Most symptoms do not appear until striatal DA levels decline by at least 70-80%

• Without treatment, PD progresses over 5 to 10 years to a rigid, akinetic state in which patients are incapable of caring for themselves.


Pharmacologic Agents Dopaminergic agents1. Dopamine precursor: L-DOPA2. D2 agonists: bromocriptine ,pramipexole3. MAOI: selegiline 4. COMTI: tolcapone, entacapone Glutamate antagonist: amantadine Antimuscarnics : Trihexyphenidyl, Benztropine


Levodopa Levodopa

Dopamine

Selegiline

Tolcapone BromocriptinePramipexole

D2-receptors

(-)

(+)

Dopaminergic Drugs

MAO-B

COMT(-)


1. Levodopa• A prodrug that is converted to dopamine by DOPA

decarboxylase and can cross the blood-brain barrier.• When administered orally, levodopa is absorbed rapidly

from the small intestine. Concentrations of the drug in plasma usually peak between 0.5 and 2 hours after an oral dose. The half-life in plasma is 1-3 hrs.

• To assure that adequate concentrations of levodopa reach the CNS, and to reduce peripheral toxicity, L-dopa is administered with Carbidopa, and Benserazide a decarboxylase inhibitor that do not cross the BBB.

• Adverse effects:“On/off" effect, Motor complications ,Nausea, Hallucinations and confusion.


2. Dopamine Agonists Durations of action (8-24 hrs) substantially longer than

that of levodopa and are useful in the management of dose-related fluctuations in motor state.

Two types: older ergot derivatives(Bromocriptine) and newer non-ergot derivatives (Pramipexole).

Bromocriptine is also used for treatment of hyperprolactinemia. Initial treatment with bromocriptine may cause profound hypotension, so they should be initiated at low dosage.

Pramipexole can be initiated more quickly, achieving therapeutically useful doses in a week or less. Generally cause less GIT disturbance than do the ergot derivatives.


• Benefit parkinsonism by blocking ACh receptors in the CNS, thereby partially redressing

the imbalance created by decreased dopaminergic activity.

• Also produce modest improvement in tremor, rigidity, hypersalivation, muscular stiffness

and leg cramp, but little in bradykinesia, which is the most disabling symptom of

Parkinson’s disease.

Adverse effects: xerostomia, blurred vision, constipation,

urine retention, Tachycardia, confusion.

3. Antimuscarnics


Anti-seizure drugs


Epilepsy• Electrophysiological analyses of individual neurons

during a seizure demonstrate that the neurons undergo depolarization and fire action potentials at high frequencies.

• Pharmacological studies disclosed that antagonists of the GABA or agonists of glutamate trigger seizures.

• Drug mechanism: Na+ channels, GABA-mediated inhibition, T current Ca2+ channel

• Classified into partial (simple/complex) seizures and generalized (absence, myoclonic, and tonic-clonic) seizures. A simple partial seizure is associated with preservation of consciousness.

• Therapy is symptomatic. Available drugs inhibit seizures, but neither effective prophylaxis nor cure is available.


Classes of Anti-epileptic drugs

Older drugs• Phenytoin• Carbamazepine• Ethosuximide• Valproic Acid• Phenobarbital• Diazepam

Newer drugs• Lamotrigine• Topiramate• Gabapentin• Tiagabine• Vigabatrin


Phenytoin• Effective against all types of seizures, except absence.• Mechanism: Na+ channels inactivation.• Control of seizures generally is obtained with

concentrations above 10 g/ml, while toxic effects develop at concentrations around 20 g/ml.

• The low aqueous solubility of phenytoin hindered its intravenous use and led to production of fosphenytoin, a water-soluble prodrug.

Plasma half-life ranges 6-24 hrs at plasma concentrations . Metabolized by CYPs.

Adverse effects : Hypersensitivity, Cardiac arrhythmias, gingival hyperplasia, osteomalacia, and megaloblastic anemia,hirsutism

Pregnancy category D146Tusday ,May12,2015 Designed by YAYA

Carbamazepine• Useful in all seizures except absence.• Produce therapeutic responses in manic-depressive

patients. Further, it has antidiuretic effects. • Mechanism: Na+ channels inactivation.• Absorbed slowly and erratically. Peak concentrations

usually are observed 4-8 hours after PO; distributes rapidly into all tissues

• Hepatic CYP3A4 is primarily responsible for biotransformation of Carbamazepine.

• Acute intoxication with Carbamazepine can result in stupor or coma, hyperirritability, convulsions, and respiratory depression.

• A late complication is retention of water


Valproic acid• Absence, myoclonic, partial, and tonic-clonic seizures.• Mechanism: Na+ channels inactivation, T-current Ca2+

inactiation, GABA actiation.• Absorbed rapidly and completely after oral

administration. Peak concentration in 1 to 4 hrs. The t1/2 is approximately 15 hrs; hepatic metabolism.

• The most common side effects are anorexia, nausea, and vomiting in ~16% of patients. Effects on the CNS include sedation, ataxia, and tremor.

• Rash, alopecia, and stimulation of appetite have been observed occasionally and weight gain has been seen with chronic valproic acid treatment in some patients.

• Elevation of hepatic transaminases in plasma is observed in up to 40% of patients.


Ethosuximide• Primary agent for the treatment of absence seizures.• Inhibits Ca2+ currents (T currents) in thalamic neurons• Absorption is complete, with peak conc in 3 hours. The

t1/2 averages 40- 50 hrs.• Approximately 25% of the drug is excreted unchanged in

the urine. • The most common dose-related side effects are

gastrointestinal complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough).


Benzodiazepines• Clonazepam and clorazepate have been approved for

the long-term treatment of certain types of seizures.• Diazepam and lorazepam have well-defined roles in the

management of status epilepticus.• The antiseizure actions of the benzodiazepines, as well

as other effects that occur at non-sedating doses, result in large part from their ability to enhance GABA-mediated synaptic inhibition.

• Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children.


Barbiturates

• Most barbiturates have antiseizure properties. However, only some of these agents, such as Phenobarbital, exert maximal antiseizure action at doses below those required for hypnosis, which determines their clinical utility as antiseizure agents.

• Phenobarbital is an effective agent for generalized tonic-clonic and partial seizures. Its efficacy, low toxicity, and low cost make it important for these types of epilepsy.

• Its sedative effects and its tendency to disturb behavior in children have reduced its use as a primary agent


Newer anti-seizure drugs• Gabapentin: GABA agonist. • Tiagabine: inhibits the GABA transporter, GAT-1. • Vigabatrin:irreversible inhibitor GABA-transaminase• Lamotrigine: inactivation of Na+ channels; inhibition

glutamate relaese.• Topiramate: inactivation of Na+ channel; activation

K+ current, enhancing GABA; inhibits glutamate activity.


Status epilepticus …• Status epilepticus is a neurological emergency. Mortality

for adults approximates 20%. • Critical to the management is a clear plan, prompt

treatment with effective drugs in adequate doses, and attention to hypoventilation and hypotension.

• Four IV treatments: diazepam followed by phenytoin; lorazepam; Phenobarbital; and phenytoin alone .

• Success rates ranged from 44% to 65%, but lorazepam alone was significantly better than phenytoin alone.

• No significant differences with respect to recurrences or adverse reactions.

•


Anti-Seizure Therapy and Pregnancy

• Infants of epileptic mothers are at 2x risk of major congenital malformations (heart defects, neural tube defects) than offspring of non-epileptic mothers (4-8% vs. 2- 4%).

• The failure rate of oral contraceptives is in women receiving antiseizure drugs is high compared to non-epileptic women (3.1/100 years vs. 0.7/100 years).

• Phenytoin, carbamazepine, valproate, and phenobarbital all have been associated with teratogenic effects.

• Newer antiseizure drugs have teratogenic effects in animals but whether such effects occur in humans is yet uncertain.


Anesthetics & Central Muscle Relaxants


Anesthetics• Surgery is generally painful, it must thus be preceded by

the administration of anesthetics. Anesthetics block the perception of pain.

• Anesthetic agents are categorized in to general and local.

• Given and monitored by doctors (anesthesiologists), nurse and anesthesia practitioners (anesthetists).

• The practice of anesthesia also includes controlling breathing and monitoring body's vital functions.

• In modern practice, different drugs (anesthetics, analgesics, muscle relaxants, amnesiatic, anxiolytics, etc.) are used to achieve balanced anesthesia.

• Stages of anesthesia: analgesia, excitement, surgical anesthesia and medullary depression.


General anesthetics• Drugs that induce general anesthesia, a global but

reversible depression of CNS function resulting in the loss of response to and perception of all external stimuli.

• They also suppress normal homeostatic reflexes. Besides, they have low therapeutic indices.

• Classified as inhaled and injectable. Inhaled: Nitrous oxide, halothane, enflurane Injectable: ketamine ,propofol ,thiopental • Generally act by enhancing GABA activity. • Adverse effects: Myocardial depression, Malignant

hyperthermia(MH)• MH: uncontrolled increase in skeletal muscle oxidative

metabolism, overwhelms capacity to supply oxygen, eventually leading to circulatory collapse.


Adjunctive agents It is mandatory to use combinations of anesthetics,

analgesics, muscle relaxants, and other drugs to come up with balanced anesthesia.

Balanced anesthesia allows us to minimize patient risk and maximize patient comfort and safety.

Adjunctive agents include:• Sedative-hypnotics ( calming and amnesiatic )• Opioids (analgesics)• Neuromuscular blocking agents (muscle relaxants)• Anticholinergic (antispasmodic & antisecretory)


Local Anesthetics• Bind reversibly to a specific receptor site within the pore

of the Na+ channels in nerves and block ion movement through this pore.

• In clinical practice, a vasoconstrictor, usually epinephrine, is often added to local anesthetics.

• Classified in to two as ester type (procine, tetracaine) and amide type ( lidocaine, bupivacaine).

• Hypersensitivity occurs more frequently with ester type. Amides produces faster, more intense, longer lasting, and more extensive anesthesia than does an equal concentration of esters.

• The side effects of amides include drowsiness, tinnitus, dizziness, and twitching.


Centrally acting muscle relaxants Include Diazepam, Baclofen and Dantrolene Used to treat spasm and spasticity. Common causes are

epilepsy, trauma, stroke etc. Baclofen is a GABAB agonist that suppresses

hyperactive reflexes Dantrolene depresses excitation-contraction

coupling in skeletal muscle by binding to the ryanodine receptor, and thus decreasing intracellular calcium concentration. It is the only specific and effective treatment for malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia.


Analgesics1.Opioid analgesics2.NSAIDS3. Others


Pain Unpleasant physical or emotional experience, associated

with actual or potential tissue damage. Intact neural pathways (nociceptive pain) or damage to

neural structures(neuropathic pain). Endogenous Opioids:enkephalin, dynorphins, endorphins Exogenous Opioids: obtained from the juice of the opium

poppy, Papaver somniferum. Opioid receptors: , and k. Analgesics: Opioid analgesics ,NSAIDs Opioids are classified as:Agonist: Morphine, Codeine, Methadone, Fentanyl,

Meperidine Antagonist: Naloxone, Naltrexone


Opium Poppy-Papaver somniferum


1. Morphine• Continuous dull pain is relieved more effectively than

sharp intermittent pain.• Depress the cough reflex at least in part by a direct effect

on a cough center in the medulla. • Provoke histamine release which causes hypotension.• Erratic oral availability; thus given parentrally. • The half-life is about 2 hours; eliminated by GF, primarily

as morphine-3-glucuronide.• Adverse effects: Nausea, Vomiting, constipation,

hypotension, sedation, respiratory depression, miosis, tolerance, dependence.

• Therapeutic use: Relief of pain ,Diarrhea, Cough

•


Others 2. Tramadol: A synthetic codeine analog that is a weak( 1/6000 that of morphine) -

opioid receptor agonist. • Part of its analgesic effect is produced by inhibition of uptake of norepinephrine

and serotonin. • Used in the treatment of mild-to-moderate pain.• Can cause seizures. 3. Naloxone: Reverses all of the effects of morphine. Onset 3-5 min; duration is 30-45

minutes. Naltrexone is used orally and has long duration of activity (24hrs)4. Dextromorphan: relatively devoid of analgesic action. It is effective antitussive drug. 5. Loperamide, Diphenoxylate: Peripheral opioid agonists


Non-Steroidal Anti-inflammatory Drugs(NSAIDS)• Inflammatory mediators (e.g. prostaglandins, serotonin,

Leukotriens etc.) released from non-neuronal cells during tissue injury increase the sensitivity of nociceptors and potentiate pain perception.

• The principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production through inhibition of cyclo-oxygenases ( COX-1 and COX-2).

• Classified into TWO categories:1.Non-selective COX inhibitors: Aspirin, Paracetamol

Ibuprofen, indomethacin, Diclofenac, Dipyrone2.Selective COX-2 inhibitors: celecoxib, rofecoxib.


NSAIDs…• Effective only against low to moderate pain• Generally are well absorbed orally.• Distributed widely throughout the body and readily

penetrate arthritic joints, yielding adequate synovial fluid concentrations (i.e., ibuprofen, indomethacin).

• Most NSAIDs achieve sufficient concentrations in the CNS to have a central analgesic effect.

• Hepatic biotransformation and renal excretion are the principal route of elimination.


Aspirin(Acetylsalicylic Acid)• Mechanism: Irreversibly inhibits both COX-1 and COX-2• Reduces the risk of serious vascular events in high-risk

patients (e.g. Myocardial infarction) by 20-25%. • Rapidly and completely absorbed from the GIT, with peak

concentrations occurring within 1-4 hrs.• Extensively protein-bound (95% to 99%).• Anti-inflammatory, analgesic, antipyretic and anti-platelet• Adverse effects: Hypersensitivity ,CV risks, GIT, Salicylism

(ringing in the ears, nausea, and vomiting), Respiratory failure, Reye’s syndrome (when used in viral illnesses).

• Reye's syndrome: Potentially fatal disease that has numerous detrimental effects to brain and liver, as well as causing hypoglycemia. The classic features are a rash, vomiting, and liver damage.


Paracetamol(Acetaminophen)• Chronic use of >2 g/day is associated with

hepatotoxicity. Kidney damage has been reported.• Rash and other allergic reactions occur occasionally. • Acetaminophen, at therapeutic doses, is oxidized only to

a small fraction to form traces of the highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI).

• Glucuronic acid (60%), sulfuric acid ( 35%), cysteine ( 3%). CYP induction (heavy alcohol consumption) or GSH depletion(fasting or malnutrition) increase the susceptibility to hepatic injury.

• Antidote: N- acetylcysteine-both repletes GSH stores and may conjugate directly with NAPQI by serving as a GSH substitute.


Acetaminophen metabolism


Pharmacology of GIT


Peptic Ulcer Disease • Erosion of the mucous membrane that lines the upper

digestive tract (gastric ulcer, duodenal ulcer). • Imbalance between mucosal defense factors

(somatostatin, bicarbonate, mucus, prostaglandin) and injurious factors (gastrin, HCl and pepsin) due to mainly of Helicobacter pylori (80%),non-steroidal anti-inflammatory drugs (NSAIDs), ethanol, cigarette & stress.

• H. pylori is a spiral-shaped, pH-sensitive, gram-negative, microaerophilic bacterium that resides between the mucus layer and surface epithelial cells in the stomach, or any location where gastric-type epithelium is found.

• H. pylori produces large amounts of urease, which hydrolyzes urea in the gastric juice and converts it to ammonia and carbon dioxide.


Physiology of acid secretion• ACh, histamine, and gastrin all increase acid secretion

through their specific receptors (M3, H2, and CCK2 receptors, respectively) on parietal cells.

• In parietal cells, the cAMP and the Ca2+-dependent pathways activate H+,K+-ATPase, which exchanges H+ and K+ ions across the parietal cell membrane.

• Drugs: 1. Antisecretory: proton-pump inhibitors(PPIs), histamine

receptor blockers(H2-blockers)2. Mucosal protective: Misoprostol, Sucralfate, Bismuth3. Antacids4. Antibacterials


PPIs

• Includes omeprazole, esomeprazole, lansoprazole• Mechanism: irreversibly inactivate H+/K+ATPase. Acid

secretion resumes only after new pump molecules are synthesized(24-48hrs).

• Diminish the daily production of acid by 80% to 95%. • All PPIs have equivalent efficacy at comparable doses.• Plasma half-life -0.5-2 hrs. • Adverse effects : Nausea, Diarrhea, abdominal pain,

constipation, flatulence. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported.

• Use: PUD, Gastro-esophageal reflux disease(GERD), Zollinger-Ellison syndrome (ZES)


H2 Receptor Antagonist• Includes cimetidine, ranitidine, famotidine• Mechanism: Inhibit acid production by reversibly

competing with H2 receptors on the parietal cells. • Suppress 24-hr gastric acid secretion by about 70%,

predominantly inhibit basal acid secretion. • Long-term use of cimetidine at high doses can cause

galactorrhea in women and gynecomastia, reduced sperm count, and impotence in men.

• Adverse effects: Diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation.

• Cimetidine inhibits cytochrome enzymes .• Use: PUD, GERD.


Mucosal Protectives• Misoprostol: analog of prostaglandin E1

• The usual recommended dose is 200 g four times a day. A single dose inhibits acid production within 30 minutes.

• Can cause diarrhea and abdominal pain. It is contraindicated during pregnancy.

• FDA approved to prevent NSAID-induced mucosal injury. • Sucralfate: at pH <4, it undergoes extensive cross-linking

to produce a viscous, sticky polymer that adheres to epithelial cells and ulcer craters for up to 6 hours.

• Should be taken on empty stomach 1 hour before meals.• The most common side effect is constipation.• Bismuth subsalicylate: bind to the base of the ulcer,

promote mucin and bicarbonate production, and have significant antibacterial effects.


Antacids

• Magnesium and Aluminum salts e.g. Mg(OH)2, Al(OH)3

• Combinations of Mg2+ (rapidly acting, diarrhea) and Al3+ (slowly acting, constipation) hydroxides provide a relatively balanced and sustained neutralizing capacity.

• Antacids are given orally 1-3 hrs after meals and at bedtime. Cleared from the empty stomach in 30 min.

• With renal insufficiency, Al3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy.

• By altering pH and through chelation, antacids may affect the absorption of a number of drugs (e.g. ketoconazole, allopurinol). Such problems can be avoided by taking antacids 2 hrs before or after ingestion of other drugs.


Antibacterials • Includes amoxicillin, tetracycline, clarithromycin, and

metronidazole. Single-antibiotic regimens are ineffective. • Eradicating H.pylori infection is a current standard care. • Triple therapy : Omeprazole 2X/d + Clarithromycin 500

mg plus metronidazole 500 mg/Amoxicillin 1g 2X/d (tetracycline 500 mg can be substituted for amoxicillin or metronidazole)

• Quadruple therapy: Omeprazole 2X/d + Metronidazole 500 mg 3X/d plus Bismuth Subsalicylate 525 mg + Tetracycline 500 mg 4X/d OR Famotidine 2X/d plus Bismuth subsalicylate 525 mg + Metronidazole 250 mg + Tetracycline 500 mg 4X/d.

• 10-14 days regimen is better.


Antiflatulent• "Gas" is a common but relatively vague GI complaint,

used in reference not only to flatulence and eructation, but also bloating or fullness.

• Simethicone: a mixture of siloxane polymers stabilized with silicon dioxide.

• It is an inert, nontoxic insoluble liquid. Because of its ability to collapse bubbles by forming a thin layer on their surface, it is an effective antifoaming agent.

• Available either by itself or in combination with other OTC medications including antacids and digestants.


Laxatives• water accounts for 70-85% of total stool weight. • Net stool fluid content reflects a balance between

luminal ingestion and secretion of water and electrolytes and absorption along the length of the GIT.

• About 8-9L of fluid enter the Small intestine daily. The colon extracts most of the remaining fluid, leaving about 100 ml of fecal water daily.

• With decreased motility and excess fluid removal, feces can become inspissated and impacted, leading to constipation. On the other hand, when the capacity of the colon to absorb fluid is exceeded, diarrhea will occur.

• Constipation is treated by laxatives/purgatives, whereas diarrhea is treated with antidiarrheal agents.


Laxatives

• Classified in as bulk-forming, stimulant, osmotic, and

surfactant based on their actions.

• Bulk-forming: Bran, methylcellulose

• Stimulant: Bisacodyl, cascara, Castor Oil

• Osmotic: MgSO4, Lactulose, Polyethylene Glycol

• Surfactant: Docusate sodium,Mineral oil.


Diarrhea• Diarrhea (Greek and Latin: dia, through, and rheein, to

flow or run); “Too rapid evacuation of too fluid stools.“• Diarrhea can be caused by increased osmotic load within

the intestine; excessive secretion of electrolytes and water into the intestinal lumen; exudation of protein and fluid from the mucosa; and altered intestinal motility resulting in rapid transit.

• In severe cases, dehydration and electrolyte imbalances are the principal risk, particularly in infants, children, and frail elderly patients.

• Oral rehydration therapy is a cornerstone for patients with acute illnesses resulting in significant diarrhea.


Antidiarrheal agents

Nonspecific antidiarrheal agents: provide symptomatic

relief in mild cases of acute diarrhea.

• Opioids: diphenoxylate and loperamide.

• Clays such as kaolin and attapulgite bind water avidly

and also may bind enterotoxins.

• Bile Acid Sequestrants: Cholestyramine, colestipol;

effectively bind bile acids and some bacterial toxins.

Specific Antidiarrheal agents: infectious diarrhea

• Antimicrobials183Tusday ,May12,2015 Designed by YAYA

Emesis • The act of emesis and the sensation of nausea generally

are viewed as protective reflexes that serve to rid the stomach and intestine of toxic substances and prevent their further ingestion.

• Coordinated by a central emesis center adjacent to both the chemoreceptor trigger zone (CTZ) and the solitary tract nucleus (STN) of the vagus nerve.

• The CTZ has high concentrations of receptors for serotonin (5-HT3), dopamine (D2), and opioids, while the STN is rich in receptors for enkephalin, histamine, and ACh, and also contains 5-HT3 receptors.

• Antiemetics generally are classified according to the predominant receptor on which they are proposed to act.


Emetics Drugs that induce vomiting/emesis

Can be centrally acting (working on the CRTZ) or

peripherally acting (working on receptors locally)

Centrally acting

• Apomorphine

• Xylazine

Peripherally acting

• Ipecac syrup185Tusday ,May12,2015 Designed by YAYA

Antiemetic1. 5-HT3-Antagonists: Ondansetron,granisetron. • Long acting and thus administered just once a day.• Most effective in chemotherapy and radiation-induced

nausea and vomiting and hyperemesis of pregnancy; to a lesser degree, postoperative nausea.

• Very well tolerated. Most common adverse effects are constipation or diarrhea, headache.

2.Dopamine antagonists:chlorperazine, chlorpromazine, Metoclopramide.

3.H1-receptor antagonists: Cyclizine, Promethazine, and Diphenhydramine..

4.Anticholinergics: hyoscine.


Pharmacology of Inflammatory Disorders

Asthma

• A chronic inflammatory disorder of the airways

characterized by recurrent episodes of wheezing,

breathlessness, chest tightness, and coughing.

• The inflammation also causes an associated increase in

the existing bronchial hyperresponsiveness (BHR).

Anti-inflammatory: glucocorticoids, chromones)

Bronchodilators:β2-agonist,Methylxanthines, m3-

blocker

• The pharmacotherapy of asthma centers on controlling

the disease with drugs that inhibit airway inflammation

Bronchodilators

• Bronchodilator drugs relax constricted airway smooth muscle in vitro and cause immediate reversal of airway obstruction in asthma in vivo.

• They also prevent bronchoconstriction (and thereby provide bronchoprotection).

• Three main classes of bronchodilator are in current clinical use:

• 2 Adrenergic agonists • Methylxanthines• Anticholinergic agents

Β2- receptor agonists • Classified as short- or long-acting. Short-acting agonists

(e.g. Salbutamol, onset:1-5 min; duration 2-6 hrs ) are used only for symptomatic relief of asthma, whereas long-acting agonists (Salmeterol ; duration 12 hours) are used prophylactically in the treatment of the disease.

• The anti-asthmatic action is linked to the direct relaxation of airway smooth muscle and consequent bronchodilation.

• Short-acting agonists are prescribed on an as-needed basis

• Adding a long-acting β2 adrenergic agonist to the inhaled steroid regimen is more effective than doubling the steroid dose.

Anticholinergics: Ipratropium • Competitive antagonists of ACh binding to muscarinic

cholinergic receptors. The effects of Ach include bronchoconstriction and tracheobronchial secretion.

• Less effective as bronchodilators than 2 agonists and offer less efficient protection against bronchial challenges.

• They should be considered when there are problems with theophylline or when inhaled 2 agonists cause a troublesome tremor in elderly patients.

• Combined treatment with ipratropium and β2 agonists results in slightly greater and more prolonged bronchodilation than with either agent alone in baseline asthma.

Methylxanthine: Theophylline • Among the least expensive drugs used to treat asthma. • The solubility of the methylxanthines is low and is much

enhanced by the formation of complexes (theophylline + ethylenediamine= aminophylline).

• Theophylline is a nonselective PDE inhibitor and adenosine receptor antagonists.

• Therapeutic range : 5-15 mg/L.• t1/2: 3.5 hours in young children, 8-9 hrs in adults. • Adverse effects: headache, nausea, and vomiting,

abdominal discomfort, and restlessness. There may also be increased acid secretion and diuresis. At high concentrations, cardiac arrhythmias. At very high concentrations, seizures may occur.

Glucocorticoids• Asthmatic subjects who require inhaled β2 adrenergic

agonists four or more times weekly are viewed as candidates for inhaled glucocorticoids.

• The adrenal cortex secretes cortisol (hydrocortisone). • Systemic: prednisone, prednisolone, dexamethasone. • Topical: beclomethasone, triamcinolone, fluticasone.• Inhaled corticosteroids are recommended as first-line

therapy for all patients with persistent asthma.• Intravenous steroids are indicated in acute asthma.• Mechanism: inhibitory effects on many inflammatory

and structural cells that are activated in asthma• Adverse effects: Cough, Candidiasis ,fluid retention,

weight gain, osteoporosis, hypertension, peptic ulceration, diabetes.

Cromones• Cromolyn (cromoglycate) and nedocromil • Inhibiting mediator release from bronchial mast cells;

reversing increased functional activation in leukocytes. • Prevent asthmatic attacks in individuals with mild to

moderate bronchial asthma. • Nedocromil generally is more effective than cromolyn in

animal models and human beings.• The addition of cromolyn to inhaled glucocorticoid

therapy yields no additional benefit in moderately severe asthma.

• Nedocromil may allow a reduction of steroids in patients receiving high doses of inhaled steroids.

Histamine• Named after the Greek word for tissue, histos. The

predominant storage site for histamine in most tissues is mast cell.

• Plays a role in the immediate allergic response(H1) and is an important regulator of gastric acid secretion(H2).

• The concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial tree mucosa, and intestinal mucosa.

• Activation of H1 receptors in hypothalamus, increases wakefulness and inhibits appetite.

• H1 receptors mediate vasodilation that is relatively rapid in onset and short-lived. By contrast, activation of H2 receptors causes vasodilation that develops more slowly and is more sustained.

First Generation H1-receptor antagonists• Dimenhydrinate, diphenhydramine, Chlorphenramine,

promethazine• Reversible inhibitors of H1 and Muscarnic receptors. • During immediate hypersensitivity reactions, edema

formation and itch are effectively suppressed. Other effects, such as hypotension, are less well antagonized. Bronchoconstriction is reduced little, if at all.

• Counter motion sickness.• Adverse effects: Sedation. Central excitation is a striking

feature of overdose, which commonly results in convulsions, particularly in infants.

• Use: seasonal rhinitis and conjunctivitis, Acute urticaria, Motion Sickness.

Second-generation H1 antagonists • Cetirizine, Loratadine , ketotifen• Do not cross the BBB appreciably in therapeutic doses. • Because of the sedation that occurs, the first-generation

antihistamines cannot be tolerated or used safely by many patients unless given only at bedtime.

• Even then, patients may experience an antihistamine "hangover" in the morning, resulting in sedation with or without psychomotor impairment .

• Thus, nonsedating antihistamines allowed the general use of these agents.

• Use: Chronic urticaria

Antihypertensive Medications

198

Hypertension (HTN)

• Hypertension is defined conventionally as a sustained increase in blood pressure ≥140/90 mm Hg.

• BP= CO x PVR• At every level of diastolic pressure, risks are greater with

higher levels of systolic blood pressure.• Elevated arterial pressure causes pathological changes in

the vasculature and hypertrophy of the left ventricle. • Concomitant cigarette smoking, diabetes, or elevated

low-density lipoprotein are risk factors that increases cardiovascular morbidity and mortality.

• HTN can be classified as Primary (essential/idiopathic) where the cause is unknown; or secondary where it happens as a result of known underlying causes.

199

Stages of Hypertension

Terminology Systolic Pressure (mm Hg)

Diastolic Pressure (mm Hg)

Normal < 120 < 80

Pre-hypertension 120-139 80-89

Hypertension stage 1 140-159 90-99

Hypertension stage 2 ≥ 160 ≥ 100

Hypertensive crisis ≥ 180 ≥ 120

Hypertensive emergency ≥ 180 ≥ 120

200

Hypertensive emergency• A hypertensive emergency (formerly called "malignant

hypertension") is severe hypertension (high blood pressure) with acute impairment of one or more organ systems (especially CNS, CVS and/or the renal system)

that can result in irreversible organ damage. • The BP should be substantially lowered over a period of

minutes to hours with an antihypertensive agent.• Hypertensive emergency pathophysiology includes:Abrupt increase in systemic vascular resistance, likely

related to humoral vasoconstrictorsEndothelial injuryFibrinoid necrosis of the arteriolesDeposition of platelets and fibrinBreakdown of normal autoregulatory function

201

Antihypertensive agents

α-blockers (prazosin,phentolamine) Centrally acting α-agonists (clonidine)) Mixed(α/β)-blockers (carvedilol) β-blockers (metoprolol, propranolol) Adrenergic neuron blocker (reserpine)

Diuretics Angiotensin Converting Enzyme(ACE) Inhibitors Angiotensin Receptor Blockers (ARBs) Calcium Channel Blockers(CCB) Direct Vasodilators

ANS Pharmacology

202

1. Alpha-blockers• Examples: Prazosin (selective 1), phentolamine and

phenoxybenzamine (non-selective). • Causes vasodilation which causes a reflex increase in

heart rate; however the vasodilation persists during long-term therapy.

• A major precaution is the first-dose phenomenon, in which symptomatic orthostatic hypotension occurs within 90 minutes of the initial dose.

• Retention of salt and water occurs in many patients during continued administration, and this attenuates the postural hypotension.

• Used primarily in conjunction with diuretics and other antihypertensive agents.

• Added benefit in patients with benign prostatic hyperplasia. 203

2. β-blockers…• Examples: Propranolol, Metoprolol, Atenolol• Provide effective therapy for all grades of hypertension. • Do not usually cause retention of salt and water.• Combination of a β-blocker, a diuretic, and a vasodilator

is effective for patients who require a third drug. • highly preferred drugs for hypertensive patients with

conditions such as MI, ischemic heart disease, or CHF. • NSAIDs can blunt the effect β-blockers probably through

inhibition of prostacyclin synthesis and Na+ retention..

• Adverse effects: Bradycardia, bronchoconstriction• Drug-interaction : Calcium channel blockers, Epinephrine• Contraindication: DM (glycogenolysis, blunt the

perception of symptoms such as tremor, tachycardia, and nervousness) ,Heart failure and Asthma . 204

3. Mixed blockers

• Examples: Labetalol and Carvedilol• Because of its capacity to block α1 adrenergic receptors,

labetalol given IV can reduce pressure sufficiently rapidly to be useful for the treatment of hypertensive emergencies.

• Carvedilol has been approved for the treatment of hypertension and symptomatic heart failure. It reduces mortality in patients with systolic dysfunction and heart failure when used as an adjunct to therapy with diuretics and ACE inhibitors.

205

4. Centrally acting α2-agonists• Methyldopa, an analog of DOPA, is metabolized by DOPA

decarboxylase to -methyldopamine, which then is converted to -methylnorepinephrine.

• -Methylnorepinephrine is stored in the secretory vesicles of adrenergic neurons, substituting for NE itself. Consequently, -methylnorepinephrine is released instead of norepinephrine. It acts in the CNS to inhibit adrenergic neuronal outflow probably through activation of presynaptic 2 receptors.

• Preferred for treatment of hypertension during pregnancy.

• Adverse effects: Sedation, dryness of mouth, diminished libido, parkinsonian signs, hyperprolactinemia, Hepatotoxicity, hemolytic anemia.

206

4. Centrally acting α2-agonists…• Clonidine stimulates the α 2 adrenergic receptors in the

CNS resulting in a reduction in sympathetic outflow .• Sudden discontinuation may cause a withdrawal

syndrome consisting of headache, apprehension, tremors, abdominal pain, sweating, and tachycardia.

• Has been used in hypertensive patients for the diagnosis of pheochromocytoma.

• Adverse effects: Sedation and xerostomia

207

5. Reserpine• Alkaloid extracted from the root of Rauwolfia serpentina• Binds tightly for prolonged period to adrenergic storage

vesicles and inhibits the vesicular catecholamine transporter(VMAT2).

• The nerve endings lose their capacity to concentrate and store NE and dopamine; thus they leak into the cytoplasm, where they are metabolized.

• Salt and water retention commonly results in "pseudotolerance.“

• Adverse effects: Sedation and inability to concentrate or perform complex tasks are the most common adverse effects. More serious is the occasional psychotic depression that can lead to suicide.

208

6.Diuretics• Diuretics are drugs that increase the rate of urine flow

and sodium excretion and are used to adjust the volume and/or composition of body fluids in a variety of clinical situations, including hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis.

• They may also modify renal handling of other cations (e.g., K+, H+, Ca2+, and Mg2+), anions (e.g., Cl-, HCO3 -, and H2PO4 -), and uric acid. In addition, diuretics may alter renal hemodynamic indirectly.

• Used alone or with other antihypertensive drugs to minimize the retention of salt and water.

• Classified as: Thiazide , Loop, K-sparing,osmotic and carbonic anhydrase inhibitors.

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Thiazide and Thiazide-like diuretics• Example:hydrochlorothiazide, metolazone• Mechanism :Inhibit the Na+-Cl- symporter.• More effective than are the loop diuretics in patients

who have normal renal function. This differential effect is most likely related to the short duration of action of loop diuretics (e.g. 1.5 hrs for furosemide).

• The effectiveness of thiazides is progressively diminished when the GFR falls below 30 ml/min. One exception is metolazone.

• Used in edema, hypertension, CHF• Adverse effects: hypokalemia, hyponatremia, and

hyperuricemia.

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Loop /High-ceiling Diuretics• Example: Furosemide• Mechanism: Na+-K+-2Cl- symporter in the thick

ascending limb of the loop of Henle.• Also inhibit Ca2+ and Mg2+ reabsorption. May cause

direct vascular effects which may be mediated by PGs. • Can cause "postdiuretic Na+ retention" which can be

overcome by restricting dietary Na+ intake or by more frequent administration of the loop diuretic.

• Used in edema, chronic CHF , hypertension• Adverse effects: Hyponatremia, hypokalemia,

hyperuricemia, ototoxicity.

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K+-sparing Diuretics• Classified in to two as Na+ channel

blockers(e.g.Triamterene and amiloride) and Aldosterone antagonist ( Spironolactone and eplerenone).

• blocks epithelial Na+ channels in the late distal tubule and collecting duct.

• Spironolactone and eplerenone competitively inhibit the binding of aldosterone to mineralocorticoid receptor.

• Spironolactone has also some affinity toward progesterone and androgen receptors resulting in adverse effects.

• Use: edema, hypertension, CHF and hyperaldosteronism.• Adverse effects: hyperkalemia, erectile dysfunction,

gynecomastia.

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7. Renin-Angiotensin System Inhibitors

Renin inhibitors

213

ACE inhibitors• Examples: captopril, enalapril, lisinopril, fosinopril.• Principal pharmacological and clinical effects apparently

arise from suppression of synthesis of angiotensin II.• Increase bradykinin levels and bradykinin stimulates

prostaglandin biosynthesis.• All ACE inhibitors have similar therapeutic indications,

adverse-effect profiles, and contraindications. • With the notable exceptions of fosinopril (which display

balanced elimination by the liver and kidneys), impaired renal function significantly diminishes the plasma clearance of most ACE inhibitors.

• Use: Hypertension, heart failure ,myocardial infarction• Adverse effects: hypotension, dry cough, hyperkalemia, angioedema ,teratogenic, Renal failure

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Ang II Receptor Antagonists (ARBs) • Examples: Losartan, Valsartan, candesartan• Bind to the AT1 receptor with high affinity .• Bioavailability (<50%) and protein binding (>90%). • Used in treatment of hypertension, heart failure and

diabetic nephropathy. • Adverse effects: Hypotension, hyperkalemia,

teratogenic, Renal failure . Renin Inhibitors• Aliskiren is the first orally-effective direct renin inhibitor

approved by the FDA in 2007.• Adverse effects: hyperkalemia, less angioedema,

teratogenic .• Use:hypertension

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8. Calcium Channel Blockers (CCBs)

• Examples: Dihydropyridines (Nifedipine, Amlodipine, Felodipine), Non-dihydropyridine (Verapamil, Diltiazem)

• CCBs lower BP by relaxing arteriolar smooth muscle and decreasing peripheral vascular resistance.

• Dihydropyridines act on blood vessels,whereas the non-dihydropyridines act on both blood vessels and heart.

• Used in treatment hypertension, angina, arrhythmia• Adverse effects: Headache, flushing, dizziness,

peripheral edema, reflex tachycardia, constipation (usually with verapamil), cause or aggravate gastroesophageal reflux.

• Drug- interaction: Verapamil or diltiazem with β receptor antagonists can cause cardiac inhibition.

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10. Direct Vasodilators A. Hydralazine: Arterial vasodilator• Causes direct relaxation of arteriolar smooth muscle. • well absorbed orally, bioavailability is low (16-35%), and

has half-life of 1 hr.• Adverse effects: headache, dizziness, nausea, flushing,

hypotension, reflex tachycardia.• Use: Hypertension(+preeclampsia) and CHF-with

sympatholytics and diuretics

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10. Direct Vasodilators…B. Minixodil: Arterial vasodilator by opening K+ channels.• Well absorbed orally with t1/2 of 3-4 hrs. • Use: severe hypertension(with diuretic and β-blocker). • Adverse effects: Retention of salt and water, reflex

tachycardia and hirsutism.C. Sodium nitroprusside :Arterial and venous vasodialtor• Acts by releasing nitric oxide leading to vasodilation. • Must be given by continuous IV infusion. • Used in hypertensive emergencies,CHF• Adverse effects: hypotension and Possible cyanide

poisoning (less commonly).

218

Drugs for Heart Failure

219

Heart failure• A clinical syndrome characterized by reduction in CO.

Symptoms: fatigue, shortness of breath, and congestion.• Cardiac output: the volume of blood pumped by the

heart per unit of time. It is the product of heart rate and stroke volume. Stroke volume is about 70 ml.

• It is accompanied by compensatory neurohormonal responses, including activation of the sympathetic nervous and renin–angiotensin–aldosterone axis.

• Pharmacologic therapies largely improve cardiac hemodynamics and function through preload reduction, afterload reduction, and enhancement of inotropy (i.e., myocardial contractility).

220

Pathophysiologic mechanisms of heart failure and major sites of drug action

221

Pharmacological Treatment of HF1.Diuretics- Furosemide, hydrochlorthiaze, sprinolactone2.Vasodilators- hydralazine, isosorbide dinitrate3.ACE-inhibitors and ARBs4.β-receptor blockers- metoprolol, carvedilol5.Positive Inotropic drugs

5.1 Cardiac glycosides-digoxin5.2 β-receptor agonists-dopamine, dobutamine5.3 Phosphodiesterase Inhibitors-amrinone, milrinone

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Diuretics• Diuretics remain central in the pharmacologic

management of congestive symptoms in patients with CHF. They reduce extracellular fluid volume and ventricular filling pressure (or "preload").

• Furosemide typically is started at a dose of 40 mg once or twice daily, and the dosage is increased until an adequate diuresis is achieved. Monotherapy with thiazide diuretics has a limited role in CHF.

• Loop and thiazide diuretics are not associated with a reduction in CHF mortality.

• Sprinolactone had a significant (~30%) reduction in mortality and CHF-related hospitalizations.

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β-receptor antagonists• Mechanism: attenuation or prevention of the β-receptor-

mediated adverse effects of catecholamines on the myocardium.

• For mild-to- moderate CHF• Should not be used in patients with new-onset.• Should be initiated at very low doses and increased

slowly.

ACE-inhibitors and AT1 Receptor Antagonists • Treatment of HF of any severity.• AT1 receptor antagonists provide an alternative to ACE

inhibitors in the treatment of HF and provide comparable mortality benefits.

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Positive Inotropic Drugs

225

1. Digoxin• A positive inotropic effect on the failing myocardium • Mechanism: Inhibition of Na+/K+-ATPase increased

intracellular Na activate Na-Ca exchange• It has also cholinergic effects on SA node and atria.• Extracellular K+ decreases the affinity of Na+/K+-ATPase

for digoxin. • t1/2 is 36-48 hrs. Serum levels at 0.5-1 ng/mL.• Adverse effects: Sinus bradycardia/arrythmia• Treatment of digitalis toxicity: atropine, KCl, Digoxin

Immune Fab (antidigoxin).• Use: CHF, Arrhythmia

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2. β-Adrenergic agonists• Dopamine and dobutamine are the positive inotropic

agents most often used for the short-term support of the circulation in advanced HF.

• The pharmacological effects of dopamine are dose dependent. At intermediate infusion rates (2-5mg/kg/min), dopamine directly stimulates β receptors.

• Dobutamine infusions are typically initiated at 2 to 3 mg/kg per minute.

• The major side effects are excessive tachycardia and arrhythmias, which may require a reduction in dosage.

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3. Phosphodiesterase Inhibitors• Mechanism: inhibition of cAMP-phosphodiesterase type

3 (PDE-3) enzyme, thus reducing the degradation of cAMP.

• “ino-dilators” effect - these drugs cause positive inotropism and vasodilation in blood vessels.

• Approved for short-term support of the circulation in advanced heart failure.

• The t1/2 of inamrinone and milrinone are 2-3 hrs and 0.5-1 hr, respectively.

• Thrombocytopenia occurs in 10% of patients receiving inamrinone but is rare with milrinone.

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Antianginal Drugs

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Angina Pectoris• Angina is caused due to an imbalance in the myocardial

oxygen supply-demand relationship(increased oxygen demand or reduced supply).

• Symptoms: a heavy, pressing substernal discomfort, often radiating to the left shoulder, flexor aspect of the left arm, jaw, or epigastrium.

• Classified as stable, variant and unstable angina• Typical /Stable /exertional angina: due to fixed

atherosclerotic narrowing of an epicardial coronary artery, on which exertion or emotional stress superimposes an increase in myocardial O2 demand.

• Drugs that reduce myocardial O2 demand are used (-blockers, Ca-channel blockers, organic nitrates).

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Angina pectoris…

• Variant/Prinzmetal angina: due to coronary vasospasm that episodically reduces coronary flow.

• Drugs that increase oxygen supply are used (Ca-channel blockers, organic nitrates).

• Unstable angina: due to rupture of atherosclerotic plaque, with consequent platelet aggregation/thrombosis, or vasospasm. Complete occlusion may lead to myocardial infarction.

• Treatment involves decreasing demand or increase supply based on underlying causes (-blockers, Ca-channel blockers, organic nitrates, antiplatelet (aspirin) and antithrombic (heparin) agents , lipid lowering agents , ACE-inhibitors).

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Organic Nitrates• Includes Glyceryl Trinitrate(nitroglycerin) ,Isosorbide

mononitrate, Isosorbide dinitrate. • Mechanism: release nitric oxide(NO) that increases level

of cGMP. cGMP in turn causes dilation blood vessels.• Nitroglycerin achieves peak concentrations in 4 min

sublingually with half-life of 1-3 min.• Sublingual organic nitrates should be taken at the time

of an anginal attack or in anticipation of exercise or stress.

• Adverse effects: Headache ,dizziness, weakness, hypotension, reflex tachycardia, tolerance.

• Use: CHF, Angina, Acute myocardial infarction

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Antiarrhythmic drugs

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Electrophysiology• Transmembrane current through voltage-gated ion

channels is the primary determinant of cardiac action potential morphology and duration.

• In response to changes in membrane potential, ion channels undergo conformational changes allowing for, or preventing, the flow of ions through the conducting pore along their electrochemical gradient.

• Cardiac action potential involves different phases.• Phase 0 (maximum upstroke) :surge of inward Na+

current• Phase 1 ("notch" ) : transient outward K+ current • Phase 2 ( plateau ): inward Ca2+ and outward K+ currents• Phase 3 (repolarization): outward K+ currents• Phase 4 (resting): K+ out

236

Action potential in cardiac muscle cells

237

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

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Arrhythmia (dysrhythmia)• Abnormal electrical activity in the heart. The primary

tool for diagnosis of arrhythmias is the ECG.• The heart beat may be too fast (>100 beat) or too

slow(<60 beats/min), and may be regular or irregular.• Can occur if the electrical signals that control the

heartbeat are delayed or blocked. • Also can occur if another part of the heart starts to

produce electrical signals. • Cause: strong emotional stress, cardiovascular disorder,

thyroid gland dysfunction, congenital.

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Types• Premature atrial and ventricular contractions: skipped

heartbeat. In some people, it can be related to stress, too much caffeine or nicotine, or too much exercise.

• Atrial flutter: a condition marked by rapid, but regular heartbeat. It often converts to atrial fibrillation.

• Atrial fibrillation: a condition marked by rapid, but irregular heartbeat.

• Sinus node dysfunction: a slow heart rhythm due to an abnormal sinus node. It is treated with pacemaker

• Paroxysmal supraventricular tachycardia: a rapid heart rate, usually with a regular rhythm, originating from above the ventricles.

• Ventricular fibrillation: an erratic, disorganized firing of impulses from the ventricles. The ventricles quiver and are unable to contract or pump blood to the body. 240

Antiarrhythmic drugs• Two goals: termination of an ongoing arrhythmia or

prevention of an arrhythmia.• Anti-arrhythmic drugs almost invariably have multiple

effects in patients, and their effects on arrhythmias can be complex.

• A drug can modulate additional targets in addition to its primary mode of action. At the same time, a single arrhythmia may result from multiple underlying mechanisms (e.g., torsades de pointes can result either from increased Na+ channel late currents or decreased inward rectifier currents).

• Thus, anti-arrhythmic therapy should be tailored to target the most relevant underlying arrhythmia mechanism.

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Vaughan-Williams Classification(1992)

Class I : Na-Channel blockers• IA: Procainamide, Quinidine (Intermediate ,3 seconds)• IB: Lidocaine, Phenytoin (Rapid ,0.1 seconds)• IC: Flecainide, Propafenone (Slow, 11 seconds)

Class II : β-blockers (Propranolol, metoprolol) Class III : K-Channel blocker (Amiodarone, Bretylium) Class IV: Ca-Channel Blocker(Verapamil) Class V: cholinergics (digoxin, adenosine)

242

Lipid Lowering Drugs

Statins Niacin Fibrates Bile acid sequestrants Cholesterol absorption inhibitors

243

244

Hyperlipidemia Elevated levels of triglycerides or cholesterol. Lipoproteins are macromolecular assemblies that

contain lipids and proteins. Lipoproteins: chylomicrons, VLDL, IDL, LDL and HDL. Chylomicrons: carry triglycerides (fat) from

the intestines to the liver, to skeletal muscle, and to adipose tissue.

LDL: carry cholesterol from the liver to cells of the body. LDLs are sometimes referred to as the "bad cholesterol" lipoprotein.

HDL: collect cholesterol from the body's tissues, and bring it back to the liver. HDLs are sometimes referred to as the "good cholesterol" lipoprotein.

Lipid Profile

Total Cholesterol < 200 mg/dl

LDL-Cholesterol < 100 mg/dl

HDL-Cholesterol ≥ 60 mg/dl

Triglycerides < 150 mg/dl

245

246

HMG-Co A reductase inhibitors (statins) Example: Lovastatin, atorvastatin, simvastatin Reduces cholesterol synthesis through inhibition 3-

hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which converts Acetyl CoA to Cholesterol.

Most effective and best-tolerated agents.• After an oral dose, peak in 1 to 4 hours. The half-lives

are in the range of 4- 20hours. • Metabolized by the liver and eliminated in the feces. • Adverse effects: GI

disturbance ,Hepatoxicity ,Myopathy• The safety of statins during pregnancy has not been

established.

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Niacin• Niacin reduces formation of triglycerols by blocking the

breakdown of fats in adipose tissue. This decreases formation of LDL

• Most effective drug available clinically for raising HDL.• Triple therapy (niacin + statin + bile-acid sequestrant)

can decrease LDL cholesterol by 70% or more. • Adverse effects: Hepatotoxicity, flushing, pruritus,

hyperpigmentation. • Niacin, at doses used in humans, has been associated

with birth defects in experimental animals and should not be taken by pregnant women.

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Fibrates• Example: Gemfibrozil and Fenofibrate • Reduce triglycerides and LDL. • Absorbed rapidly and efficiently (>90%) with a meal. • Half-life;1.1 hours (gemfibrozil), 20 hours (fenofibrate). • 60% to 90% excreted in urine as glucuronide conjugates.• Adverse effects: Fatigue, headache, abdominal pain,

Cholelithiasis, hepatotoxicity, myopathy.• Drug Interaction: Gemfibrozil displaces warfarin from

plasma albumin• Contraindication: children or pregnant women.

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Bile-acid sequestrants • Example: Colestipol, cholestyramine• They are highly positively charged resins which bind

negatively charged bile acids. • Because of their large size, the resins are not absorbed,

and the bound bile acids are excreted in the stool. Since over 95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases. As a result, hepatic cholesterol content declines.

• Adverse effects: Constipation, Bloating, indigestion

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Cholesterol Absorption Inhibitors : Ezetimibe Acts on cells of the brush border of the SI Blocks absorption of dietary cholesterol as well as

cholesterol secreted in the bile. Indicated as an adjunct to diet modification for primary

hypercholesteremia. Other than rare allergic reactions, specific adverse

effects have not been observed in patients taking ezetimibe

The safety of ezetimibe during pregnancy has not been established.

Pharmacology of Antimicrobial agents

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Host-Pathogen-Drug Interaction

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Pathogenic activities

Immune system

Principles of antimicrobial therapy• An important revolution in human understanding of

nature was the germ theory of disease based on the work of Louis Pasteur and Robert Koch, which linked specific microorganisms to specific diseases.

• Microorganisms of medical importance: bacteria, viruses, fungi, protozoans and helminthes

• The microbial proteins targeted by the antibiotic are essential components of biochemical reactions in the microbes, and interference with these physiological pathways kills the microorganisms.

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History Paul Ehrlich(1910): fundamental difference between the

2 types of cells. He found arsphenamine for syphilis. Alexander Fleming (1928): Penicillium, a bacteria-killing

substance from mold. A decade later, penicillin was developed as a systemic

therapeutic agent by the concerted research of a group of investigators at Oxford University headed by Florey, Chain, and Abraham.

Gerard Domagk(1930s):discovered PRONTOSIL against streptoccocal species.

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Goals of Antimicrobial Therapy

• Empirical/ initial therapy: either combination therapy or, preferably, treatment with a single broad-spectrum agent may be employed.

• Definitive therapy: Once a pathogen has been isolated and susceptibilities results are available, therapy should be streamlined to a narrow targeted antibiotic.

• Prophylactic therapy: used to protect healthy persons from acquisition of or invasion by specific microorganisms to which they are exposed.

255

Features of antibacterials• Modes of actions can be bacteriostatic or bactericidal. • The outcome of combining antibiotics could be additive,

synergism, potentiation or antagonism. Antimicrobial agents were viewed as miracle cures when

first introduced into clinical practice. However, it became evident rather soon after the discovery of penicillin that resistance developed quickly, terminating the miracle.

Two major factors are associated with emergence of antibiotic resistance: evolution and clinical/ environmental practices.

Transfer of resistance determinants from a donor cell, often of another bacterial species, by transduction(bacteriophage), transformation(uptake), or conjugation(bacterial sex). 256

Classification of Antibacterials

1. Cell wall synthesis inhibitors : Penicillins, Cephalosporins, Carbapenems, Monobactams, Vancomycin

2. Protein synthesis inhibitors :Aminoglycosides, Chloramphenicol, Tetracyclines, Erythromycin, Clindamycin, Linezolid,

3. Nucleic Acid synthesis inhibitors : Rifamycins, Quinolones

4. Antifolates: Trimethoprim, Sulfonamides 5. Agents affecting cell membrane : Polymyxin B

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Porin pores are important for drugs to cross the outer membrane of gram negative

bacteria.

Bacterial Cell Wall

258

Penicillins

Mode of action: bactericidal Active against many gram(+) and some gram(-) bacteria. Natural penicillin has a very narrow spectrum. Chemically modifying penicillin broadens the spectrum. t1/2: 20-50 min. About 30% is metabolized to penicilloic

acid. Does not cross BBB; 79% to 85% is excreted in the urine as unchanged drug.

Probenecid may potentiate penicillin's effects. Hypersensitivity reactions occur in 0.7% to 8% of cases.

10% of allergic reactions are life threatening. Other adverse effects include N,V,D, abdominal pain

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1. Natural Penicillins Benzylpenicillin (penicillin G), Phenoxymethylpenicillin

(penicillin V= gastric acid resistant) Destruction by gastric acidity (I.V / I.M) Destruction by β-lactamase Short duration of action (6 hrs) Longer acting natural penicillin: procaine penicillin,

benzathine penicillin

2. Antistaphylococci penicillin• Narrow spectrum Penicillinase-resistant penicillin• Active only against -lactamase producing staphylococci• Include Methicillin, Cloxacillin,oxacillin

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3. Aminopenicillins Broader antibacterial spectrum that have additional

activity against gram (-) bacteria. Produced by increasing hydrophilic character that

enables them to enter gram (-) via porins. Amoxicillin, ampicillin, bacampicillin Amoxicillin has better oral absorption and acid

resistance than ampicillin. Destroyed by β-lactamase Active against gram positive cocci and gram negative

cocci and gram negative bacilli except pseudomonas

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4. Extended spectrum penicillins Anti-pseudomonas P. Aeruginosa is a bacterium with particular porins

resistant to aminopenicilins. These Penicillins are similar to aminopenicillins but

are effective against P. aeruginosa as well and should be used ONLY for it.

Carbenicillin, mezlocillin ,ticarcillin, piperacillin Acid sensitive, Destroyed by β-lactamase

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-lactamases inhibitors

The second way to overcome -lactamase producing staphylococci is to combine penicillin with -lactamase inhibitors.

-lactamase inhibitors⁻ Ampicillin + sulbactam = Unasyn⁻ Amoxicillin + clavulanic acid = Augmentin⁻ Ticarcillin + clavulanic acid = Timentin⁻ Piperacillin + tazobactam = Zosyn Active against -lactamase producing bacteria and others penicillin Sensitive species

-lactam 263

Cephalosporins Broader spectrum alternatives to penicillins. Obtained from Cephalosporium acremonium Mode of action: bactericidal Three generations(1st, 2nd and 3rd ): As we go from 1st to

3rd :- gram negative activity, BBB penetration and -lactamases resistance increases

Half-life 30-90 min; ceftriaxone 4-7 hr Do not penetrate cells or the CNS, except for 3rd G. Mostly excreted unchanged by the kidney Probenecid slows their elimination. Adverse effects : Hypersensitivity reactions,

Nephrotoxicity (cephradine only)

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1st G Cephalexin , cephradine Penicillin sensitive streptococci, methicillin susceptible staphylococci

2nd G cefaclor, cefuroxime E.coli, Klebsiella, Proteus, Haemophilus influenzae, Bacteroides fragilis

3rd G Cefotaxime,ceftriaxone Enterobacteriaceae, Pseudomonas aeruginosa, Neisseria gonorrhoeae.

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Cephalosporin generation/activity

Carbapenems: from Streptomyces cattleya; Broader spectrum;not absorbed orally Imipenem is degraded by renal dipeptidase enzyme;

thus should be adminstered by dipeptidase inhibitor cilastatin. Meropenem is resistant to dipeptidase .

It is very resistant to hydrolysis by most -lactamases. Adverse effect: N and V. Seizure is also reported. Aztreonam: from Chromobacterium violaceum. Resistant to many of the -lactamases that are

elaborated by most gram-negative bacteria. Has activity only against gram-negative bacteria Well tolerated; Good alternative to an aminoglycoside.

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Vancomycin Glycopeptide produced by Streptococcus orientalis. Important in the management of known or suspected

penicillin-resistant pneumococcal infections, particlularly methicillin-resistant staphylococci.

Essentially all species of gram-negative bacilli and mycobacteria are resistant to vancomycin.

Poorly absorbed orally, 90% excreted by GF. Adverse effects: hypersensitivity, CVS toxicity, ototoxicity,

nephrotoxicity.

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Proteins Synthesis inhibitors

• Tetracycline• Chloramphenicol• Erythromycin• Aminoglycosides• Others: Clindamaycin, Linezolid

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Tetracyclines Oxytetracycline: obtained from Streptomyces rimosus Others: tetracycline, doxycyline;democycline Broad spectrum bacteriostatic; activity against aerobic

and anaerobic gram-positive, gram-negative bacteria; chlamydiae; mycoplasmas; rickettsiae; spirochetes.

Mechanism of Action: inhibit bacterial protein synthesis by binding to the 30 S subunit.

Half lives range from 6-18hrs. Accumulate in liver, spleen, bone marrow, bone, dentine, and enamel.

Eliminated by kidney(except doxycycline: fecal route) Adverse effects: GIT irritation, Photosensitivity, Hepatic

toxicity, Kidney toxicity (except doxcycline), deformity of teeth and bone development; Fanconi syndromes (expired tetracyclines only).

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Erythromycins Erythromycins: isolated from Streptomyces erythraeus Bacteriostatic; binds to the 50S subunit.Diffuse well into

body fluids, except CSF. Excretion is mainly in bile. Active against aerobic and anaerobic gram-positive cocci,

except for many S.aureus strains, Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydophila pneumoniae, Treponema pallidum, Borrelia burgdorferi.

Clarithromycin and azithromycin are semi-synthetic modifications :improved acid stability and tissue penetration; enhanced activity against gram negative , mycobacteria.

SE:GI disturbances, QT-interval prolongation, Transient auditory impairment

Drug interaction: erythromycin is enzyme inhibitor. 270

Chloramphenicol Isolated from cultures of Streptomyces venezuelae. Bacteriostatic; binds to the 50S subunit. Broad spectrum: Aerobic and anaerobic Gram(+) and

gram(-) negative cocci and bacilli; Rickettsia, Mycoplasma, Chlamydia.

Given orally and IV. Distributed widely in body fluids, including CSF, and is

excreted in urine; Hepatic metabolism. Adverse effects: Bone marrow depression, Nausea,

vomiting, and diarrhea, Gray baby syndrome (characterized by abdominal distension, grey color skin, vomiting, depressed respiration and circulatory collapse, death.

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Aminoglycosides From Streptomyces(“mycin”);micromonospora ( “micin”). Tobramycin,gentamicin,amikacin,streptomycin Mechanism: bind to the 30S ribosome; bactericidal Serious gram-negative bacillary infections. Usually used with β-lactam for severe infection suspected

to be due to a gram-negative bacillus. Highly polar cations; thus very poorly absorbed from GIT.

Excreted almost entirely by GF. Amikacin: broad spectrum(also active against gram-

positive bacteria such as Staphylococci). Neomycin, is highly nephrotoxic in human beings and

should not be administered systemically. Adverse effect:nephrotoxicity;ototoxicity

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Nucleic Acid Synthesis Inhibitors

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Quinolones Mechanism: inhibit topoisomerase II/DNA gyrase (gram

negative) and topoisomerase IV (gram positive), enzymes essential for bacterial DNA replication.

The first quinolone, nalidixic acid, was isolated as a by-product of the synthesis of chloroquine. It did not achieve systemic antibacterial levels and were useful only for treatment of lower urinary tract infections.

Fluorinated derivatives have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.

Norfloxacin,Ciprofloxacin, levofloxacin, ofloxacin: possess excellent gram-negative activity and moderate to good activity against gram-positive bacteria.

Also active against methicillin-resistant S. aureus.274

Quinolones… Gemifloxacin, moxifloxacin: improved activity against

gram-positive organisms. Moxifloxacin also has good activity against anaerobic bacteria.

Fluoroquinolones also are active against mycoplasmas, chlamydiae, Legionella and some mycobacteria.

The serum t1/2 is 3-5 hours for norfloxacin and ciprofloxacin. Cleared predominantly by the kidney.

Adverse effects: mild nausea, vomiting, and/or abdominal discomfort; Achilles tendon rupture or tendinitis. Ciprofloxacin is the most common cause of C. difficile colitis.

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Rifamycins Rifampicin, Rifabutin Mechanism: inhibits DNA-dependent RNA polymerase ,

preventing transcription to RNA. Active against Mycobacterium infections, methicillin-

resistant S.aureus, Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.

Well absorbed, widely distributed in body(including CSF).

Urine, sweat, tears, and contact lenses may take on an orange color because of rifampicin administration, this effect is harmless. Rifampicin is enzyme inducer.

Rifabutin is a less potent enzyme inducer and also more effective than rifampicin.

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Folic acid

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Structural analogs of para-aminobenzoic acid (PABA) Sulfamethoxazole, Sulfadoxine, silver sulfadiazine Mechanism: inhibitors of dihydropteroate synthase, the

bacterial enzyme responsible for the incorporation of PABA into dihydropteroic acid, the immediate precursor of folic acid.

Bacteriostatic against both gram-positive and gram-negative bacteria.

Trimethoprim and pyrimethamine are not chemically related to sulfonamides; but mode of action is complementary to sulfonamides.

They are competitive inhibitor of dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate.

Sulfonamides

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Sulfonamides…• Silver sulfadiazine is the agents of choice for the

prevention of burn infection• The combination of pyrimethamine and sulfadiazine is

the treatment of choice for toxoplasmosis.• Absorbed rapidly from the GIT, peak plasma levels are

achieved in 2-6 hrs. Distributed throughout all tissues of the body. The largest fraction is excreted in the urine.

Adverse effects Hypersensitivity reactions/ Stevens-Johnson syndrome Crystalluria: Fluid intake should be sufficient to ensure a

daily urine volume of at least 1200 mL Bone marrow depression and hemolytic anemia (G6PD

deficiency);kernicterus;anorexia, nausea, and vomiting.279

p-aminobenzoic acid + Pteridine

Dihydropteroic acid

Dihydrofolic acid

Tetrahydrofolic acid

Dihydropteroatesynthase

Dihydrofolate synthetase

Dihydrofolate reductase

Trimethoprim

Sulfonamides

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Co-trimoxazole: Trimethoprim + Sulfamethoxazole• Synergistic effect (bactericidal).• Trimethoprim is absorbed more rapidly than

sulfamethoxazole.• Available as a fixed combination consisting of a 1:5 ratio

(80 mg TMP plus 400 mg SMX or a double-strength tablet of 160 mg TMP plus 800 mg SMX).

• Urinary tract infection ,Pneumocystis jiroveci, shigellosis, Salmonella typhi , Acute diarrhea owing to sensitive strains of enteropathogenic E. coli , acute otitis media in children and acute maxillary sinusitis.

• Nausea, Vomiting, Glossitis, stomatitis,hypersensitivity reactions ,Permanent impairment of renal function may follow in patients with renal disease.

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Tuberculosis Caused by Mycobacterium tuberculosis Barriers:• Rich mycolic acids (extraordinary shield)• Abundance of efflux pumps• Propensity to hide inside the patient's cells

First-Line Agents Isoniazid Ethambutol Pyrazinamide Rifampicin Streptomycin

Second-Line Agents

•Amikacin

•Aminosalicylic acid

•Capreomycin

•Clofazimine

•Cycloserine

•Ethionamide

•Levofloxacin

•Rifabutin

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Antimycobacterial

Tusday ,May12,2015 Designed by YAYA 283

Isoniazid (Isonicotinic acid hydrazide), INH A prodrug that is converted to active metabolite by

mycobacterial catalase-peroxidase. MZM: Inhibit synthesis of mycolic acids; bactericidal Well absorbed, widely distributed in body, including CSF;

can also penetrate into macrophages and caseous foci. Metabolized in the liver by acetylation (fast, slow

acetylators) ; excreted by kidney. Adverse effects: Peripheral neuritis, Hepatotoxicity The prophylactic administration of pyridoxine prevents

peripheral neuritis, as well as most other nervous system disorders in practically all instances.

"slow" acetylators have enhanced adverse effects compared to “fast” acetylators.

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Ethambutol Mechanism: cell wall synthesis inhibition; bacteriostatic Oral bioavailability is ~80%. Decline in ethambutol is biexponential( t1/2 : 3 & 9 hrs )

due to redistribution of drug. Alcohol dehydrogenase oxidizes ethambutol to an

aldehyde(20%). However, 80% of the drug is not metabolized at all and is renally excreted

Adverse effects: optic neuritis, resulting in decreased visual acuity and loss of ability to differentiate red from green. The incidence of this reaction is proportional to the dose of ethambutol. The other is rash.

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Pyrazinamide • A prodrug converted to the active pyrazinoic acid .• Mechanism: inhibit mycolic acid synthesis; bactericidal• Well absorbed orally ,metabolized in liver ,excreted

mainly through kidney. Widely distributed in body tissues, including inflamed meninges.

• Adverse effects: Liver damage is the most serious and common adverse reactions. It also inhibits excretion of urate, resulting in hyperuricemia in nearly all patients, and may cause acute episodes of gout.

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Leprosy• Caused by Mycobacterium leprae• Dapsone: a structural analog of PABA and a competitive

inhibitor of dihydropteroate synthase;Bacteriostatic.• Well absorbed orally, widely distributed with half-life 1-2

days. Excreted into bile and reabsorbed in the intestine. Approximately 70-80% of a dose of dapsone is excreted in the urine.

• Adverse effects: Hemolysis in patients with G6PD deficiency, Methemoglobinemia and hypersensitivity.

• Clofazimine: Mechanism remains to be established. It has also anti-inflammatory effects. Absorption from the gut is variable. Given orally ; t1/2 of 2 months.

• Adverse effects: abdominal pain, D,N,V and body secretion discoloration.

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Fungal infections Fungal infections (mycoses) can be both superficial and

systemic. Systemic infections (Candidiasis, Cryptococcal

meningitis, Aspergillosis, Blastomycosis). Superficial infections (Oral and vulvovaginal

candidiasis,Tinea pedis, Tinea corporis, ringworm, etc.) Drugs• Polyene antifungals: Amphotericin B, nystatin• Antimetabolites: 5-Fluorocytosine • Azoles:

Imidazoles: Ketoconazole, miconazole, Clotrimazole Trizoles: Itraconazole, Fluconazole

• Griseofulvin

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Amphotericin-B and Nystatin• Mechanism: bind to ergosterol allowing leakage of a

variety of small molecules.• Amphotericn B: Choice for most systemic fungal

infections. GI absorption of amphotericin B is negligible. Little amphotericin B penetrates into CSF, vitreous humor, or normal amniotic fluid.

• Adverse effects: nephrotoxicity; hypokalemia• Nystatin: not absorbed from the GI tract, skin, or vagina.

It is useful only for candidiasis and is supplied in preparations intended for cutaneous, vaginal, or oral administration.

• Infections of the nails and hyperkeratinized or crusted skin lesions do not respond.

• Adverse effects : bitter taste; occasional nausea.289

Azoles• Mechanism: inhibit ergosterol synthesis.• Triazoles are metabolized more slowly and have less

effect on human sterol synthesis than the imidazoles. • Ketoconazole: Broad-spectrum antifungal agent, given

orally, and requires acidity for dissolution. Inhibits steroid and testosterone synthesis at high dose, resulting in gynecomastia in some male patients.

• Fluconazole: Fungicidal; does not require low gastric pH for absorption.. CSF concentration is 70% that of plasma. Does not inhibit steroidogenesis.

• Important for fungal meningitis.

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Others• Flucytosine: Converted to 5 fluorouracil a potent

antimetabolite . It may depress the bone marrow and lead to leukopenia and thrombocytopenia.

• Griseofulvin: inhibits microtubule function and thereby disrupts assembly of the mitotic spindle ; fungistatic

• The drug is tightly bound to, and persists in, keratin, providing prolonged resistance to fungal invasion. For this reason, the new growth of hair or nails is the first to become free of disease.

• Can be given with fatty foods to increase absorption• Adverse effect: headache, GIT disorders

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Pharmacology of antimalarial drugs Malaria is a vector borne parasitic disease caused by the

genus Plasmodium Four species of the genus Plasmodium cause nearly all

malarial infections in humans • P. falciparum, P. malariae (Non-relapsing)• P. vivax , P. ovale (Relapsing)

A female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal initiates infection.

Symptoms: Fever, Lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches, mild anemia

Complications: cerebral malaria, "respiratory distress“, Severe anemia, Hypoglycemia etc

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Malaria Life Cycle Mosquito infected with the malaria parasite bites

human, passing cells called sporozoites into the human’s bloodstream.

Sporozoites travel to the liver. Each sporozoite undergoes asexual reproduction, in which its nucleus splits to form two new cells, called merozoites.

Merozoites enter the bloodstream and infect red blood cells.

In red blood cells, merozoites grow and divide to produce more merozoites, eventually causing the red blood cells to rupture. Some of the newly released merozoites go on to infect other red blood cells.

Some merozoites develop into sex cells known as male and female gametocytes.

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Exo-erythrocytic (hepatic) cycle

Hypnozoites

Sporozoites

Mosquito Salivary Gland

Malaria Life Cycle

Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

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Anti-malarial Drugs• Antimalarial drugs act at different stages of the

plasmodium life cycle– Class I:Sporozoites– Class II: Liver stages(Primary, hypnozoites)– Class III: RBC stages(Asexual, Gametocytes)

• Chemical classification:– Quinolines: chloroquine,amodiaquine,primaquine– Biguanides:Proguanil– Quinoline methanol:Mefloquine– Phenanthrene: Halofantrine– Cinchona alkaloids: Quinine– qing hao sesquiterpenes: Artimesinins

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Artemisia annua

Artimesinins• Derived from the weed qing hao (Artemisia annua)• Artemether(oil-soluble);artesunate(water-soluble)• Potent and fast-acting against the asexual erythrocytic

stages of P. vivax and P. falciparum with no clinical evidence of resistance. Have gametocytocidal activity.

• Mechanism: Heme catalyzes cleavage of the drug with subsequent generation of free radical.

• Absorption after oral dosing typically is 30% or less. • Should not be used for prophylaxis because of their

short half-life.• No systematic changes were attributable to treatment in

patients older than 5 years of age.• SE: reversible changes in reticulocyte and neutrophil

counts and in transaminase levels;Allergic reaction.297

Lumefantrine• Appears to be effective and well tolerated.• The fixed-dose combination of artemether-lumefantrine,

called co-artem, contains 20mg of artemether and 120mg of lumefantrine.

• Artemether has a rapid onset of action and is rapidly eliminated from the plasma (t1/2:2-3hrs). Lumefantrine is cleared more slowly (t1/2 4.5 days).

• Co-artem also reduces gametocyte carriage and thus should have an impact on malaria transmission.

• Adverse effects: headache anorexia, dizziness, asthenia, arthralgia, myalgia.

298

Chloroquine• Highly effective for treatment and prophylaxis of P.

vivax, P. ovale, and P. malariae.• Mechanism: concentrates in the food vacuoles of

plasmodia and disrupts heme sequestration.• Well absorbed from GIT and rapidly from IM/SC sites.

Distributes relatively slowly. Metabolised by liver. The terminal half-life ranges from 30 to 60 days.

• Adverse effects : hypotension, arrhythmias, Confusion, convulsions, and coma

• Drug interaction: inhibits of CYP2D6.

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Quinine• Obtained from the bark of cinchona tree.• A mainstay for treatment of P. vivax and chloroquine-

and multidrug-resistant P. falciparum malaria.• Because of its toxicity and short half-life, quinine

generally is not used for prophylaxis.• Readily absorbed when given orally or intramuscularly.• Peak plasma level is reached within 3 to 8 hours ; half-

life of about 11 hours. Metabolized extensively, especially by hepatic CYP3A4,

resulting in active metabolite 3-hydroxyquinine. Adverse effects: Cinchonism (tinnitus, visual

disturbances, headache), hypoglycemia, hypotension abdominal pain,Rashes ,milder hemolysis in people with G6PD deficiency

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Primaquine• In contrast with other antimalarials, primaquine acts on

tissue stages (exoerythrocytic) of plasmodia in the liver to prevent and cure relapsing malaria.

• The drug will not treat ongoing attacks of malaria, even though it displays some activity against the erythrocytic stages. Also exert a marked gametocidal effect against all four species of plasmodia

• Therapeutic or higher doses of primaquine may cause acute hemolysis and hemolytic anemia in humans with G6PD deficiency

• Others: Atovaquone, Amodiaquine, Proguanil, Mefloquine, Doxycycline, Clindamycin

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Antimalarial during Pregnancy • Lack of sufficient formal safety data (antifolates,

atovaquone-proguanil, and artemether-lumefantrine)• Known potential risks for the fetus (tetracycline,

doxycycline, primaquine, and mefloquine). • The recommended treatment of uncomplicated malaria

during pregnancy relies on chloroquine in areas with chloroquine-sensitive parasites, and quinine, alone (in P. vivax infections) or in combination with clindamycin (in P. falciparum infections), in areas with chloroquine-resistant parasites.

• Pregnant patients with P. vivax or P. ovale infections should be kept under chloroquine chemoprophylaxis until delivery.

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Amoebiasis• Caused by E. histolytica. Humans are the only known

hosts for these protozoa, which are transmitted almost exclusively by the fecal-oral route.

• Ingested E. histolytica cysts survive acid gastric contents and transform into trophozoites that reside in the large intestine. Many individuals remain asymptomatic but excrete the infectious cyst form.

• In other individuals, the trophozoits invade the colonic mucosa and develop colitis and bloody diarrhea (amebic dysentery).

• In a smaller proportion of patients, trophozoites invade through the colonic mucosa, reach the portal circulation, and travel to the liver, and develop an amebic liver abscess. 303

Pharmacology of Amoebiasis• The cornerstone of therapy for amebiasis is the

nitroimidazoles (metronidazole, tinidazole). Luminal amoebicides: paromomycin , Iodoquinol,

Diloxanide furoate Tissue amoebicides:Chloroquine, Metronidazole,

Tinidazole, Dehydroemetine Chloroquine: directly toxic to trophozoite; highly

concentrated within the liver. Not effective against luminal amebiasis because of its rapid absorption.

Dehydroemetine: Derived from ipecac. It is used to treat both intestinal and extraintestinal amebiasis.

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Nitroimidazoles• Metronidazole: a prodrug that requires reductive

activation. Electron transfer forms a highly reactive nitro radical anion that kills susceptible organisms.

• Absorbed completely; half-life of about 8 hours.• Clinically effective in trichomoniasis, amebiasis, and

giardiasis, as well as in a variety of infections caused by obligate anaerobic bacteria, including Bacteroides, Clostridium, Helicobacter etc.

• Tinidazole: effective for the treatment of amebiasis, giardiasis, and trichomoniasis. Its longer half-life (>12 h) offers potential cure with a single dose.

• Adverse effects: headache, N, dry mouth, and a metallic taste. Metronidazole can cause disulfiram-like effect.

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Giardiasis• Caused by the flagellated protozoan Giardia lamblia• Infection results from ingestion of the cyst form of the

parasite from fecally contaminated water or food.• One of three syndromes: an asymptomatic carrier state,

acute self-limited diarrhea, or chronic diarrhea. • Most adults with symptomatic infection will develop an

acute self-limited illness with watery, foul-smelling stools, abdominal distension, and flatus.

• Drugs: Metronidazole, Tinidazole

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Diabetes mellitus (DM) Characterized by hyperglycemia; altered metabolism of

lipids, carbohydrates, and proteins; and an increased risk of complications from vascular disease.

Type 1: auto-immune destruction of the pancreatic beta cells which produce insulin (probably genetic plus some environmental trigger)

Type 2: insulin resistance is the primary cause and is related to sedentary lifestyles, heredity, ethnicity, obesity, advancing age, or use of certain medications

The major sources of the morbidity of diabetes are the chronic complications. • Acute: Ketoacidosis and hyperosmolar, infections• Chronic: Retinopathy, Nephropathy, Neuropathy, MI,

Stroke307

Treatment Approach

Type 1 – The pancreas no longer makes insulin: insulin– Source: Human insulin, Bovine,porcine

Type 2– Pancreas not making enough insulin to control blood

glucose: insulin or insulin secretagogues– Tissues not responding to insulin or not taking in

glucose as before: biguanide or TZD– Overproduction of glucose (e.g. hepatic): biguanide ACE inhibitors and aspirin to prevent complications

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Insulin• The mainstay for treatment of virtually all type 1 and

many type 2 diabetes patients.• Actions include the stimulation of intracellular use and

storage of glucose, amino acids, and fatty acids, whereas it inhibits catabolic processes such as the breakdown of glycogen, fat, and protein.

• Preparations: regular/soluble(e.g. Insulin lispro), Intermediate-acting insulins (e.g.neutral protamine Hagedorn), long acting(e.g Insulin glargine ).

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Sulfonylureas Tolbutamide, chlorpropamide, glyburide, glipizide Stimulate insulin release by binding to a specific site on

the cell KATP channel complex and inhibiting its activity. Effectively absorbed from the GIT. Food and

hyperglycemia can reduce absorption of sulfonylureas. Although their half-lives are short (3 to 5 hours), their

hypoglycemic effects are evident for 12 to 24 hours, and they often can be administered once daily.

Metabolized by the liver, and excreted in the urine. • Side effects: hypoglycemia, weight gain, Less frequent

side effects include N,V, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions.

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Short-Acting Insulin Secretagogues• Nateglinide and repaglinide stimulate insulin secretion

from the β cells of the pancreas.• Require the presence of glucose to stimulate insulin

secretion.• Rapidly absorbed (~0.5 to 1 hour) and have a short half-

life (1 to 1.5 hours).• In monotherapy, both significantly reduce postprandial

glucose excursions and reduce HbA1c levels.• Can be used to provide increased insulin secretion

during meals, when it is needed, in patients close to glycemic goals.

• Can be used in patients with renal insufficiency• Side effects: Hypoglycemia, Weight gain

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Biguanides Metformin: increases the activity of the AMP-dependent

protein kinase(AMPK). The net result of these actions is increased glycogen

storage in skeletal muscle, lower rates of hepatic glucose production, increased insulin sensitivity, and lower blood glucose levels. Half-life is about 2 hours

Metformin is currently the most commonly used oral agent to treat type 2 diabetes and is generally accepted as the first-line treatment for this condition. It is effective as monotherapy and in combination with nearly every other therapy.

Contraindication: renal impairment and hepatic disease. Adverse effects: Diarrhea, nausea, lactic acidosis.

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Thiazolidinediones: Rosiglitazone, pioglitazone Activate peroxisome proliferator activated receptor- (PPAR). Insulin sensitizers and increase insulin-mediated glucose

uptake by 30-50% in patients with type 2 diabetes SEs: edema, CHF, hepatotoxicity, weight gain, fractures,

macular edema.

-Glucosidase Inhibitors: Acarbose,miglitol Reduce intestinal absorption of starch, dextrin, and

disaccharides by inhibiting the action of -glucosidase in the intestinal brush border.

Do not result in hypoglycemia. Adverse effects: flatulence, hepatotoxicity

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Introduction• Thyroid hormone is essential for normal development,

especially of CNS. In the adult, It maintains metabolic homeostasis and influences the function of virtually all organ systems. The thyroid gland contains large stores of thyroid hormone in the form of thyroglobulin.

• The principal hormones are the iodothyronines : thyroxine (T4) and 3,5,3'-triiodothyronine (T3).

• The thyroidal secretion is predominantly the prohormone thyroxine, which is converted in the liver and other tissues to the active form, triiodothyronine.

• Serum concentrations of thyroid hormones are precisely regulated by the thyrotropin (TSH), in a classic negative-feedback system. 314

Thyroid Release• Iodine is necessary for the production of T3 and T4. A

deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as goitre.

• The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. The ratio of T4 to T3 released into the blood is roughly 20 to 1.

• T4is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a).

• All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.

315

Thyroid Disorders• Thyroid nodules and goiter, thyroid enlargement, can be

either benign or malignant processes. In most of these patients, circulating thyroid hormone levels are normal.

• Overt hyperthyroidism and hypothyroidism, thyroid hormone excess or deficiency, are usually associated with dramatic clinical manifestations.

• Treatment of the hypothyroid patient consists of thyroid hormone replacement. Treatment options for the hyperthyroid patient include anti-thyroid drugs to decrease hormone synthesis and secretion, destruction of the gland by the administration of radioactive iodine, or surgical removal.

• In most patients, disorders of thyroid function can be either cured or have their diseases controlled.

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Biosynthesis of Thyroid Hormones• Uptake of iodide ion (I–) by the gland• Oxidation of iodide and the iodination of tyrosyl groups of

thyroglobulin• Coupling of iodotyrosine residues by ether linkage to

generate the iodothyronines• Resorption of the thyroglobulin colloid from the lumen

into the cell• Proteolysis of thyroglobulin and the release of T4 and T3

into blood• Recycling of iodine within thyroid cell via de-iodination of

mono- and diiodotyrosines and reuse of the I–

• Conversion of T4 to T3 in peripheral tissues/thyroid

317

Biosynthesis…• Iodine ingested reaches the circulation in the form of

iodide ion (I–). The thyroid efficiently and actively transports the ion via a specific membrane-bound protein, the sodium-iodide symporter (NIS)

• The iodide transport is inhibited by ions such as thiocyanate and perchlorate. TSH stimulates NIS gene expression.

• Decreased stores of thyroid iodine enhance iodide uptake, and the administration of iodide can reverse this situation.

• The oxidation of iodide to its active form is accomplished by thyroid peroxidase,resulting in the formation of monoiodotyrosyl and diiodotyrosyl residues in thyroglobulin just prior to its extracellular storage.

318

Biosynthesis• The coupling of two diiodotyrosyl residues form thyroxine

or of monoiodotyrosyl and diiodotyrosyl residues form triiodothyronine. These reactions apparently are catalyzed by the same thyroid peroxidase.

• The normal daily production of thyroxine is estimated to range between 80 and 100 g; that of triiodothyronine is between 30 and 40 g. Although triiodothyronine is secreted by the thyroid, metabolism of thyroxine by 5', or outer ring, deiodination in the peripheral tissues accounts for 80% of circulating triiodothyronine.

• Thyroxine is eliminated slowly from the body, with a t1/2 of 6-8 days. In hyperthyroidism, the t1/2 is shortened to 3-4 days, whereas in hypothyroidism it may be 9-10 days.

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Biosynthesis…• The deiodinases (D1, D2) convert T4 to T3. D1 is

expressed primarily in the liver and kidney, and also in the thyroid and pituitary. It is upregulated in hyperthyroidism and downregulated in hypothyroidism.

• A clinically important feature of D1 is its inhibition by the anti-thyroid drug propylthiouracil.

• D2 is expressed primarily in the CNS and brown adipose tissue, also in the thyroid. Elevated levels are found in hypothyroidism and suppressed levels are found in hyperthyroidism.

• D3 is found at highest levels in the CNS and placenta, and it also is expressed in skin and uterus.

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Major Clinical Effects of Thyroid Hormones• Growth and Development: e.g Cretinism is a condition of

severely stunted physical and mental growth due to congenital hypothyroidism.

• Thermogenic Effects• CVS: Hyperthyroidism-tachycardia, increased stroke

volume, cardiac hypertrophy, decreased peripheral resistance,increased pulse pressure,atrial fibrillation. Hypothyroid patients have bradycardia, increased peripheral vascular resistance, decreased pulse pressure, and elevation of mean arterial pressure.

• Metabolic Effects: e.g Thyroid hormone stimulates the expression of hepatic LDL receptors and the metabolism of cholesterol to bile acids; hypercholesterolemia is a characteristic feature of hypothyroidism.

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Hypothyroidism• Known as myxedema when severe, is the most

common disorder of thyroid function. Worldwide, hypothyroidism resulting from iodine deficiency remains an all-too-common problem.

• Symptoms: fatigue, lethargy, cold intolerance, mental slowness, depression, dry skin, constipation, mild weight gain, fluid retention, muscle aches and stiffness, irregular menses, and infertility.

• Signs: goiter, bradycardia, delayed relaxation phase of the deep tendon reflexes, cool and dry skin, hypertension, nonpitting edema, and facial puffiness.

• Deficiency of thyroid hormone during the first few months of life causes feeding problems, failure to thrive, constipation, and sleepiness.

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Hypothyroidism: Diagnosis• Elevated TSH serum concentration• Low Free and/or total T4 and T3 serum concentrations • Anti-thyroidperoxidase antibodies and anti-thyroglobulin

antibodies are likely to be elevated in autoimmune thyroiditis.

• As the disease progresses T3 concentrations will often be maintained in the normal range in spite of a low T4.

• The goals of therapy are to restore normal thyroid hormone concentrations in tissue, provide symptomatic relief, prevent neurologic deficits in newborns and children, and reverse the biochemical abnormalities of hypothyroidism.

• The recommended daily adult iodide (I–) intake is 150 mcg (200 mcg during pregnancy). 323

Hyperthyroidim:Thyrotoxicosis• Thyroid crisis (storm),is a sudden worsening of

hyperthyroidism symptoms that may occur with infection or stress.

• The typical clinical manifestations of thyrotoxicosis include nervousness, anxiety, palpitations, emotional lability, easy fatigability, menstrual disturbances, and heat intolerance. A cardinal symptom is loss of weight concurrent with an increased appetite.

• A variety of physical signs can be elicited including warm, smooth, moist skin, exophthalmos, pretibial myxedema, and unusually fine hair. Separation of the end of the fingernails from the nail beds (onycholysis) may be noted.

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Thyrotoxicosis…• Ocular signs that result from thyrotoxicosis include

retraction of the eyelids and lagging of the upper lid behind the globe when the patient looks downward.

• Physical signs of a hyperdynamic circulatory state are common and include tachycardia at rest,a widened pulse pressure, and a systolic ejection murmur.

• Gynecomastia is sometimes noted in men. • Neuromuscular examination often reveals a fine tremor

of the protruded tongue and outstretched hands. • Deep tendon reflexes are generally hyperactive.

Thyromegaly is usually present.

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Thyrotoxicosis: Diagnosis• Low TSH serum concentration. Elevated free and total

T3 and T4 serum concentrations, particularly in more severe disease.

• Elevated radioactive iodine uptake (RAIU) by the thyroid gland when hormone is being overproduced; suppressed RAIU in thyrotoxicosis caused by thyroid inflammation (thyroiditis)

• Thyroid stimulating antibodies• Thyroglobulin• Thyrotropin receptor antibodies• Thyroid biopsy• Thyroperoxidase antibodies

326

Treatment• Three common treatment modalities are used in the

management of hyperthyroidism: surgery, antithyroid medications, and RAI.

• The overall therapeutic objectives are to eliminate the excess thyroid hormone and minimize the symptoms and long-term consequences of hyperthyroidism.

• Therapy must be individualized based on the type and severity of hyperthyroidism, patient age and gender, existence of nonthyroidal conditions, and response to previous therapy.

327

Thyroid Preparations• May be synthetic (levothyroxine, liothyronine, liotrix) or of

animal origin (desiccated thyroid).• Synthetic levothyroxine is the preparation of choice

because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration.

• In addition, T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones.

• Although liothyronine (T3) is 3-4X more potent than levothyroxine, it is not recommended for routine replacement therapy because of its shorter half-life (24 hours); its higher cost; and the greater difficulty of monitoring its adequacy of replacement by conventional laboratory tests. 328

Thyroid…• Because of its greater hormone activity and consequent

greater risk of cardiotoxicity, T3 should be avoided in patients with cardiac disease. It is best used for short-term suppression of TSH.

• Desiccated thyroid’s disadvantages of protein antigenicity, product instability, variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of low cost.

• Significant amounts of T3 found in some thyroid extracts and liotrix may produce significant elevations in T3 levels and toxicity.

• Equivalent doses are 100 mg of desiccated thyroid, 100 mcg of levothyroxine, and 37.5 mcg of liothyronine.

329

Thyroid…• The shelf life of synthetic hormone preparations is about

2 years, particularly if they are stored in dark bottles to minimize spontaneous deiodination. The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry.

• Absorption of thyroxine occurs in the stomach and small intestine and is incomplete. Absorption is slightly increased when the hormone is taken on an empty stomach. In situations where patients cannot take oral medications or where intestinal absorption is in question, levothyroxine may be given intravenously once a day at a dose 80% of the patient's daily oral requirement.

• The serum T4 peaks 2-4 hours after oral ingestion.330

Thyroid…• Liothyronine sodium (L-T3): absorption is nearly 100%

with peak serum levels 2-4 hours following oral ingestion. Liothyronine may be used occasionally when a more rapid onset of action is desired such as in the rare presentation of myxedema coma or if rapid termination of action is desired such as when preparing a thyroid cancer patient for 131I therapy.

• A mixture of thyroxine and triiodothyronine 4:1 by weight is marketed as liotrix. Desiccated thyroid preparations, with a similar T4:T3 ratio, also are available. A 60-mg (1 grain) desiccated thyroid tablet is approximately equivalent in activity to 80 g of thyroxine.

331

Antithyroid Agents• The antithyroid compounds used clinically include the

thioamides, iodides, and radioactive iodine.• Thioamides: carbimazole, methimazole and

propylthiouracil are major drugs for treatment of thyrotoxicosis. Methimazole is about ten times more potent than propylthiouracil.

• Mechanism:The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. Propylthiouracil inhibit the peripheral deiodination of T4 and T3.

• The onset of these agents is slow, often requiring 3–4 weeks before stores of T4 are depleted.

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Thioamides• Propylthiouracil is rapidly absorbed, reaching peak serum

levels after 1 hr;half-life: 1.5 hrs. Most of an ingested dose is excreted by the kidney as the inactive glucuronide within 24 hrs. Methimazole is completely absorbed but at variable rates;half-life:6 hrs. 65–70% of a dose is recovered in the urine in 48 hrs.

• Because of the risk of fetal hypothyroidism, both thioamides are classified as pregnancy category D. Propylthiouracil is preferable in pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily. Both thioamides are considered safe for the nursing infant.

• Methimazole is the drug of choice for Graves' disease; and is less toxic than propylthiouracil.

333

Thioamides…• Most reactions occur early, especially nausea and

gastrointestinal distress. An altered sense of taste or smell may occur with methimazole. The most common adverse effect is a maculopapular pruritic rash (4–6%), at times accompanied by systemic signs such as fever.

• Hepatitis (more common with propylthiouracil) and cholestatic jaundice (more common with methimazole) can be fatal; although asymptomatic elevations in transaminase levels also occur.

• The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm3), an infrequent but potentially fatal adverse reaction. The cross-sensitivity between propylthiouracil and methimazole is about 50%.

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Iodides• In pharmacologic doses (> 6 mg/d), the major action of

iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis.

• Improvement in thyrotoxic symptoms occurs rapidly—within 2–7 days—hence the value of iodide therapy in thyroid storm. In addition, iodides decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs valuable as preoperative preparation for surgery.

• The maximal effect is attained after 10-15 days of continuous therapy when the signs and symptoms of hyperthyroidism may have greatly improved.

• Unfortunately, iodide therapy usually does not completely control the manifestations of hyperthyroidism

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Radioactive Iodine• The radioactive isotopes 123I and 131I are used for the

diagnosis and treatment of thyroid disease. • The short-lived radionuclide of iodine, 123I, is primarily a -

emitter with a t1/2 of only 13 hours and is used in diagnostic studies to measure 24-hour iodine uptake and for thyroid imaging.

• In contrast, 131I has a t1/2 of 8 days and emits both rays and particles. More than 99% of its radiation is expended within 56 days. It is used therapeutically for thyroid destruction of an overactive or enlarged thyroid and in thyroid cancer for thyroid ablation and treatment of metastatic disease.

• Sodium iodide 131I is available as a solution or in capsules containing essentially carrier-free 131I suitable for oral administration. 336

Ethiopan Pharmacology 2015

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Transcript of Ethiopan Pharmacology 2015