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PHARMACOLOGY

CHAPTER 1

GENERAL PHARMACOLOGY

Definitions:

Pharmacology:

Defined as the study of biochemical and physiologic aspects of drug effects, including

absorption, distribution, metabolism, elimination, toxicity, and specific mechanisms of drug

action.

Pharmacokinetics:

The way in which body handles the drug. Includes absorption, distribution, metabolism and

elimination of the drug.

Pharmacodynamics:

Effects of drug on the body. Includes drug receptor concept (mechanism of action of drug), and

dose response relationships (biochemical and physiological effects of drug).

Medical pharmacology:

Science of materials used to prevent, diagnose, and treat disease.

Toxicology:

Deals with undesirable effects of chemicals in biologic systems.

Pharmacy:

Deals with preparation, dispensing, and proper utilization of drugs.

Pharmacognosy:

Deals with biological, biochemical, and economic features of natural drugs and their

constituents.

Drug:

Any small molecule that, when introduced into the body, alters the body’s function by

interactions at the molecular level.

Prodrugs:

Compound that on administration into the body, must undergo chemical conversion by metabolic

processes before becoming an active pharmacological agent.

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Pharmacopoeia:

Book containing a list of products used in medicine.

Examples:

1. USP= United States Pharmacopoeia

2. BP= British Pharmacopoeia

Routes of drug administration of drugs:

A. Enteral (alimentary) routes:

1. Oral

2. Sublingual/Buccal

3. Rectal

B. Parenteral (extra-alimentary) routes:

1. Intravenous: drug introduced into a subcutaneous vein

2. Intramuscular: drug introduced into a muscle (e.g. deltoid or gluteus maximus)

3. Subcutaneous: drug injected below the skin

4. Intraperitoneal: drug introduced in the peritoneal cavity

5. Intra-arterial: drug introduced into an artery

6. Intra-thecal: drug introduced through theca of spinal cord into subarachnoid space

7. Transdermal: drug applied across dermis of skin

8. Topical: drug applied over skin or mucous membrane

9. Inhalational: drug introduced into the respiratory tract

10. Intracardiac: drug injected directly into heart

11. Intra-articular: drug injected into joint cavity

12. Bone marrow injection: drug injected into bone marrow (e.g. sternum in adult and

tibia in children)

Oral route:

Advantages:

1. Most convenient, most economical, most commonly used route

2. Can be used for local as well as systemic actions of drugs

3. Safest route

4. Convenient dosage forms that do not require sterile techniques

5. Delivery into circulation slow so that rapid, high blood conc. are avoided and untoward

effects are less

6. Largest surface area for absorption

7. Drugs that cause irritation on parenteral administration can be given

8. Larger dose can be given

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Disadvantages:

1. Rate of absorption variable

2. Irritation of mucosal surface can occur

3. Compliance of patient is ensured

4. First pass effect (i.e. extensive hepatic metabolism of drug before it reaches its site of action)

5. Cannot be used in comatose pts. or in pts. with emergency

6. Poorly lipid soluble drugs (e.g. Neostigmine) are not absorbed

7. Drugs destroyed by digestive enzymes (e.g. insulin, pituitary hormones) or by gastric acidity

(e.g. benzyl penicillin) cannot be given

8. Certain GIT pathologies interfere with absorption of drugs, e.g. gastritis, peptic ulcer,

vomiting, and diarrhea

9. Drugs that undergo enterohepatic circulation (e.g. epinephrine) are destroyed

10. Some drugs are not absorbed from GIT (e.g. streptomycin); thus given parenterally

Sublingual route:

Advantages:

1. Rapid absorption

2. Excess drug can be removed from mouth

3. First pass effect avoided

4. Can be used in emergency conditions, e.g. nitroglycerin in angina attack

Disadvantages:

1. Drugs that cause vasoconstriction of sublingual mucosa can’t be given

2. Large doses cannot be administered

3. Repeated administration damages oral mucosa

4. Irritation of oral mucosa can occur

Rectal route:

Advantages:

1. Used when oral administration is impractical, e.g. coma

2. Drugs irritant to stomach can’t be given

3. Can be used in uncooperative pts. and in children

4. Can be used in unconscious pts. or in vomiting

5. First pass effect partially avoided

Disadvantages:

1. Absorption is imperfect

2. Cannot be used frequently

3. Patient feels embarrassed and might not prefer administration at times

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Parenteral route:

Advantages:

1. Rapid response, thus can be used in emergency situations

2. Comatose or uncooperative pts.

3. Dose can be accurately delivered

4. First pass effect is avoided

5. Drugs irritant to GIT can be given

Disadvantages:

1. Rapid absorption leads to increased untoward effects

2. Sterile formulation and aseptic technique are required

3. Local irritation at the site of injection may occur

ABSORPTION OF DRUG

Passage of drug from site of administration into the blood stream

Mechanisms of drug absorption from GIT

1. Passive diffusion

2. Facilitated diffusion

3. Active transport

4. Endocytosis and exocytosis

Factors that modify drug absorption:

A. Factors related to the drug:

1. Lipid-water partition coefficient: directly proportional to absorption

2. Degree of ionization: inversely proportional to absorption

3. Chemical nature of molecules

4. Dosage form: solutions are better absorbed than suspensions

B. Factors related to the patient:

1. Route of administration: absorption is poor from intact skin, good from mucous

membrane, and complete from parenteral sites

2. Area and vascularity of absorbing surface: directly proportional to absorption

3. State of health of absorbing surface

4. Rate of general circulation: influences rate of transport of drug

5. Specific factors: e.g. “intrinsic factor” for absorption of vit. B12

Factors influencing absorption of a drug:

1. Effect of pH on drug absorption

a) Most drugs are either weak acids or weak bases.

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b) Acidic drugs (HA) release a proton (H+), causing a charged anion (A-) to form:

HA ↔ H+ + A-

c) Weak bases (BH+) can also release an H+. However, the protonated form of the basic

drug is usually charged, and the loss of a proton produces the uncharged base (B):

BH+ ↔ B + H+

d) Drugs pass readily through membranes if they are uncharged

e) Thus, for weak acids, the uncharged protonated HA can permeate through

membranes, and A- cannot.

f) For weak bases, the uncharged form, B, penetrates through cell membrane, but the

protonated BH+ does not.

2. Blood flow to absorption site

a) Because blood flow to intestines is greater than flow to stomach, absorption from

intestine is favoured over that from the stomach.

b) Shock severely reduces the blood flow to cutaneous tissues, thereby minimizing

absorption from SC administration.

3. Total surface area available for absorption

a) Intestines have a large surface area for absorption because of the surface rich brush

borders containing microvilli.

4. Contact time at the absorption surface

a) If a drug moves through the GIT very quickly, as in diarrhea, it is not well absorbed

b) Anything that delays the transport of the drug from the stomach to the intestine delays

the rate of absorption.

c) Parasympathetic input increases the rate of gastric emptying

d) Sympathetic input, prompted during exercise or stressful conditions, as well as

anticholinergics, delays gastric emptying.

e) Presence of food in the stomach both dilutes the drug and slows gastric emptying.

Therefore, a drug taken with a meal is generally absorbed slowly.

5. Expression of P-glycoprotein

a) Is a multi-drug transmembrane transporter protein responsible for transporting

various molecules, including drugs, across cell membranes.

b) Expressed throughout the body

c) Its functions include:

i. In the liver: transporting drugs into bile for elimination

ii. In kidneys: pumping drugs into urine for excretion

iii. In the placenta: transporting drugs back into the maternal blood, thereby

reducing fetal exposure to drugs

iv. In the intestines: transporting drugs into the intestinal lumen and reducing drug

absorption into the blood

v. In the brain capillaries: pumping drugs back into blood, limiting drug access to

the brain.

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d) In areas of high expression, P-glycoprotein reduces drug absorption

e) Also associated with multi-drug resistance.

Bioavailability:

The fraction (or percentage) of the administered dose of drug that reaches the systemic

circulation.

The route by which a drug is administered, as well as the chemical and physical properties of the

agent, affects its bioavailability.

Factors that influence bioavailability:

In contrast to IV administration of a drug which confers 100% bioavailability, oral

administration of a drug involves first pass metabolism. This biotransformation of the drug

determines the amount of agent reaching the circulation and at what rate.

1. First pass hepatic metabolism

a) When drug absorbed across GIT, it enters portal circulation before entering systemic

circulation

b) If drug is rapidly metabolized in the liver or gut wall during this initial passage,

amount of unchanged drug that reaches the systemic circulation is decreased

c) Drugs exhibiting high first pass metabolism should be given in sufficient quantities to

ensure that enough of the active drug reaches the target concentration

2. Solubility of the drug

a) Very hydrophilic molecules are poorly absorbed because of their inability to cross

lipid-rich cell membranes.

b) Drugs extremely hydrophobic are also poorly absorbed because they are totally

insoluble in body fluids, therefore, cannot gain access to the surface of cells

c) For a drug to be readily absorbed, it must be largely hydrophobic, yet have some

solubility in aqueous solutions. This is one reason why many drugs are either weak

acids or weak bases.

3. Chemical instability

a) Some drugs, like penicillin G, are unstable in the pH of gastric contents.

b) Other drugs, like insulin, are destroyed in the GIT by degradative enzymes.

4. Nature of drug formulation

a) Drug absorption may be altered by factors unrelated to the chemistry of the drug

b) Particle size, salt form, crystal polymorphism, enteric coatings, and presence of

excipients (such as binders and dispersing agents), can influence ease of dissolution,

therefore altering the rate of absorption.

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Binding of drugs to plasma proteins

1. Upon entering blood, some drugs bind nonspecifically and reversibly to plasma proteins, e.g.

albumin and globulin

2. An equilibrium is produced between the bound and free drug

3. Bound drug:

a) Cannot leave vascular space

b) Is not metabolized

c) Is not eliminated

d) Is inactive pharmacologically

e) Forms a storage depot from which small proportion of active drug is freed constantly

4. Free drug:

a) Exerts pharmacological effects

b) Is metabolized by liver microsomal enzymes

c) Is eliminated by kidneys

DISTRIBUTION OF DRUGS

Process by which drug reversibly leaves the bloodstream and enters the interstitium (extracellular

fluid) and then the cells of the tissues.

Delivery of the drug from the plasma to the interstitium depends mainly on:

Cardiac output

Regional blood flow

Capillary permeability

Tissue volume

Degree of binding of the drug to plasma and tissue proteins

Relative hydrophobicity of the drug

Volume of distribution:

Total Body Water

42 liters

Intracellular volume

28 liters

Extracellular volume

14 liters

Interstitial volume

10 liters

Plasma volume

4 liters

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Apparent volume of distribution

The apparent volume of distribution, Vd, can be thought of as the fluid volume that is

required to contain the entire drug in the body at the same concentration measured in the

plasma

Calculated by dividing the dose that ultimately gets into the systemic circulation by the

plasma concentration at time zero (C0):

𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 =𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦

𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑎𝑡 𝑡𝑖𝑚𝑒 𝑧𝑒𝑟𝑜

A drug rarely associates with only one of the water compartments of the body

Vast majority of the drug distributes into several compartments, avidly binding to cellular

components like lipids, proteins, and nucleic acids.

Effect of Vd on drug half-life

A large volume of distribution has an important effect on the half-life of a drug, because drug

elimination depends on the amount of drug delivered to the liver or kidney (or other organs

where metabolism occurs) per unit of time.

Delivery of drugs to organs of elimination depends not only on blood flow, but also on

fraction of drug in the plasma.

If Vd is large, most of the drug is present in the extraplasmic space and is unavailable to

excretory organs.

Any factor that increases Vd leads to increase in half-life and extends the duration of action

of the drug.

Drug clearance:

Ratio of rate of elimination of a drug to the concentration of the drug in the plasma or blood.

Drug eliminated with first order kinetics, clearance is a constant; i.e. ratio of rate of

elimination to plasma concentration is same regardless of plasma concentration

Drug eliminated with zero order kinetics, clearance is not a constant.

Half-life:

Time required for the amount of drug in the body or blood to fall by 50%.

For drugs eliminated by first order kinetics, this number is a constant regardless of the

concentration.

Loading dose:

Dose which is administered to quickly achieve the desired concentration of drug in the body.

Maintenance dose:

It is the dose which is administered to replenish the amount of drug which is eliminated in

intervals between two doses, so that a steady concentration of drug is maintained in the plasma.

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Therapeutic window:

It is safe range between the minimum therapeutic concentration and the minimum toxic

concentration of a drug.

Minimum effective concentration usually determines the desired trough levels of a drug

given intermittently.

Minimum toxic concentration determines the permissible peak plasma concentration.

METABOLISM OF DRUGS

Metabolism of a drug sometimes terminates its action, at other times it enhances it.

First pass effect / pre-systemic elimination

The elimination of drug that occurs after administration but before it enters the systemic

circulation (e.g. during passage through the gut wall, portal circulation, or liver for an orally

administered drug).

Drug metabolism occurs primarily in the liver.

A. Drug metabolism as a mechanism of termination of action of the drug

The actions of many drugs (e.g. sympathomimetics, phenothiazines) is terminated before

they are excreted by being metabolized to biologically inactive derivatives.

B. Drug metabolism as a mechanism of drug activation

Prodrugs (e.g. levodopa, minoxidil) are inactive as administered, metabolized in the body to

become active. Many drugs are active when administered and have active metabolites (e.g.

morphine, some benzodiazepines)

C. Drug elimination without metabolism

Some drugs (e.g. lithium, among others) are not modified by the body; they continue to act

until they are excreted.

Phase I reactions

Reactions that convert the parent drug to a more polar (water-soluble) or more reactive

product by unmasking or inserting a polar functional group such as —OH, —SH, or —NH2.

Include the following reactions:

Oxidation (by cytochrome P450 group of enzymes, also called mixed function

oxidases)

Reduction

Deamination

Hydrolysis

These enzymes found in high concentrations in the smooth endoplasmic reticulum of the

liver.

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Phase II reactions

Reactions that increase water solubility by conjugation of the drug molecule with a polar

moiety such as glucuronate, acetate, or sulfate.

Synthetic reactions that involve addition (conjugation) of subgroups to —OH, —SH, and

—NH2 functions on the drug molecule.

Reactions include:

Glucuronidation

Acetylation

Glutathione conjugation

Glycine conjugation

Sulfation

Methylation

Factors affecting biotransformation rate

Chemical properties of the drug: molecular weight and ionic charge

Route of administration: oral route causes first-pass effect

Genetic factors: e.g. acetylation of isoniazid is under genetic control

Diet: starvation depletes glycine and alters glycine conjugation

Dosage: toxic doses depletes enzymes

Age: liver cannot detoxify chloramphenicol in neonates

Gender: young males are prone to sedation from barbiturates than females are.

Diseases: liver disease decreases metabolism and kidney disease decreases excretion of drug.

ELIMINATION OF DRUGS

The phase of drug inactivation or removal from the body by metabolism or excretion.

Major organs for excretion of drug from body are:

Kidneys

Glomerular filtration

Active tubular secretion

Passive tubular reabsorption

Liver

Polar metabolites of drugs that are poorly absorbed from bile, are excreted

through bile.

Some drugs undergo enterohepatic circulation

GIT

When high conc. of drugs are present in blood, they are transferred from

blood into GIT lumen by passive diffusion, e.g. morphine

Lungs

Mainly gaseous anesthetics are excreted into expired air

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Minor routes

Tears

Sweat

Saliva

Breast milk

Drug clearance by kidney

A. Glomerular filtration

1. Free drug (not bound to albumin) flows through capillary slits into Bowman’s space

as part of the glomerular filtrate.

2. Lipid solubility and pH do not influence the passage of the drugs into the glomerular

filtrate

3. Varying the glomerular filtration rate and plasma binding of the drugs may affect this

process

B. Proximal tubular secretion

1. Secretion primarily occurs in the proximal tubules by two energy-requiring active

transport systems; one for anions (e.g. for deprotonated forms of weak acids) and one

for cations (e.g. for protonated forms of weak bases)

2. Each of these transport systems show low specificity and can transport many

compounds.

3. As a result, competition between drugs for these carriers can occur within each

transport system

4. Premature infants and neonates have an incompletely developed tubular secretory

mechanism, thus retaining certain drugs in the glomerular filtrate

C. Distal tubular reabsorption

1. As drug moves toward DCT, its conc. in the filtrate increases and exceeds that of the

perivascular space

2. If uncharged, the drug may diffuse out of the nephric lumen back into the systemic

circulation

3. Manipulating the pH of the urine to increase the ionized form of the drug in the lumen

may be done to minimize the amount of back-diffusion, and, hence, increase the

clearance of the drug

4. Weak acids better excreted in alkaline urine. Weak bases better excreted in acidic

urine. This process is called “ion trapping”.

5. For example, a patient presenting with phenobarbital (weak acid) overdose can be

given bicarbonate, which alkalinizes urine, keeps the drug ionized, thereby

decreasing its reabsorption.

6. If overdose is with a weak base, like amphetamine, acidification of urine with NH4Cl

leads to protonation of the drug (it becomes charged), leading to its excretion

enhancement

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First order elimination

Rate of elimination is proportional to the concentration (i.e. higher the concentration, greater

the amount of drug eliminated per unit time).

As a result, drug’s concentration in the plasma decreases exponentially with time

Most drugs in clinical use exhibit first order elimination.

Zero order elimination

Rate of elimination is constant regardless of concentration

As a result, the concentration of these drugs in plasma decrease in a linear fashion over time.