REVIEW OF BASIC PHARMACOLOGY. Describe the different branches of pharmacology Discuss the...

Dennis S. Flores, MD

REVIEW OF BASIC PHARMACOLOGY

OBJECTIVES

Describe the different branches of pharmacology

Discuss the important concepts and mechanisms of Pharmacodynamics Pharmacokinetics

Exercise on pediatric drug dosing

PHARMACOLOGY

Is the science that deals with the mechanism of action, uses, adverse effects, and fate of drugs in animals and humans

It provides the basis for the understanding of body function and the subsequent treatment of disease

BRANCHES OF PHARMACOLOGY PHARMACODYNAMICS

The study of what the drug does to the body

PHARMACOKINETICS The study of what the body does to the

drug Absorption, Distribution, Metabolism,

Excretion PHARMACOTHERAPEUTICS

The study of drugs in the treatment and prevention of disease

Pharmacodynamics + Pharmacokinetics

BRANCHES OF PHARMACOLOGY CLINICAL PHARMACOLOGY

The study of the clinical pharmacological evaluation of drugs in human use

Concepts and principles underlying approach to rational therapeutics

PHARMACOGENETICS The study of genetic variation in

response to drug efffects

BRANCHES OF PHARMACOLOGY PHARMACOVIGILANCE

All scientific and data gathering activities that relate to detection, assessment, understanding, and prevention of adverse events

PHARMACOECONOMICS The study of economic use and management of

disease Cost effectivity of drugs

TOXICOLOGY The study of adverse effects of drugs

PHARMACODYNAMICS

The action of a drug on the body Includes receptor interactions, dose-

response phenomena, and mechanisms of therapeutic and toxic action

PHARMACODYNAMICS

A drug will exert its activity through interactions at one or more molecular targets The macromolecular species that control

the functions of cells May be surface-bound proteins like

receptors and ion channels Species internal to cells, such as

enzymes or nucleic acids

PHARMACODYNAMICS

Other sites of drug binding: Proteins (in patient or microbes) Genome (cyclophosphamide) Microtubules (vincristine)

PHARMACODYNAMICSMECHANISMS AND SPECIFICITY OF DRUG BINDING

Majority occurs through non-covalent interactions

These govern The folding of proteins and DNA The association of membranes Molecular recognition ▪ Interaction between an enzyme and its

substrate or the binding of an antibody

PHARMACODYNAMICSMECHANISMS AND SPECIFICITY OF DRUG BINDING

They are generally weak and operate only over short distances

So for an effect to occur, you need: Large numbers of interactions for

stability High degree of complementarity

PHARMACODYNAMICSEFFECTS OF BINDING

CONFORMATION EFFECTS Binding also locks a mobile, flexible molecule into a

restricted conformation CONFIGURATION EFFECTS

Differences in configuration (e.g. stereochemistry) can lead to startling differences in the biological effect

E.g. the L-enantiomer of penicillamine is highly toxic and only the S-enantiomer of indomethacin acts as an anti-inflammatory agent

Wrong configuration either no reaction or a toxic effect

PHARMACODYNAMICSNON-RECEPTOR MEDIATED INTERACTIONS

Acid base reaction Outcome does not need a receptor, just a simple

acid-base equilibrium Ex. antacid

Counterfeit incorporation mechanism A form of poisoning Utilized in cancer chemotherapy Mechanism: feed the patient/cell with false

nucleotides to cheat the cancer cells Colligative mechanism

This elicits effect by means of numbers Ex. Acetylcysteine, Mannitol

PHARMACODYNAMICSDRUG RECEPTOR

A macromolecular component of a cell with which a drug interacts to produce a response

Usually a protein which requires translation to have an effect

AGONISTA drug that triggers the same events in the receptor as the native ligandANTAGONISTA drug that stops the binding of the native agent without eliciting a response

PHARMACODYNAMICSRECEPTOR TYPES

TYPE 1: ionotropic receptors (ligand-gated channels)

TYPE 2: metabotropic receptors (G-protein coupled)

TYPE 3: tyrosine kinase-linked receptors Ex. Insulin and growth factor receptors

TYPE 4: steroid receptors

PHARMACODYNAMICSENZYMES

Proteins that catalyze the reactions required for cellular function

Control a number of metabolic processes

PHARMACODYNAMICSENZYMES

INHIBITORS Molecules that restrict the action of enzyme on

its substrate REVERSIBLE (competitive or non-competitive)▪ A very common mode of action of many drugs▪ E.g. in the patient (ACE inhibitors)in microbes (sulfas, penicillins)in cancer cells (5-FU, 6-MP)

IRREVERSIBLE▪ Enzyme inhibitors might be seen to allow very fine

control of cellular processes ▪ E.g. 6-methylpurines death of CA cells

PHARMACODYNAMICSNUCLEIC ACIDS

Potentially the most exciting and valuable of the available drug targets

May be used in gene therapy BUT designing compounds that can

distinguish target nucleic acid sequences is not yet achievable

PHARMACODYNAMICSNUCLEIC ACIDS

ACTION: generally inhibit the processes of DNA manipulation required for protein synthesis and cell division

Suitable as drugs for applications where cell death is the goal of therapy – such as treatment of cancer

PHARMACODYNAMICSDRUG-RECEPTOR INTERACTION

DOSE-RESPONSE RELATIONSHIP Most important concept in

pharmacodynamics “Dose of a drug translates to an

effective response”

PHARMACODYNAMICSDRUG-RECEPTOR

CONCEPT OF A RECEPTOR For most drugs, the site of action is at a

specific macromolecule, termed as RECEPTOR Not all drug actions and effects are mediated

through receptors. An average of 10% of them is not

For most drugs, the magnitude of pharmacological response increases as the drug concentration (dose) increases at the site

PHARMACODYNAMICSTHEORY AND ASSUMPTIONS OF DRUG-RECEPTOR INTERACTIONS

Combination or binding of drug to receptor leads to response

Response to a drug is graded or dose-dependent

Drug-receptor interaction follows simple mass-action relationships. Only one drug molecule occupies each receptor site and binding is reversible

PHARMACODYNAMICSTHEORY AND ASSUMPTIONS OF DRUG-RECEPTOR INTERACTIONS

For a given drug, the magnitude of response is directly proportional to the number of receptor sites occupied by drug molecules (occupancy assumption)

The number of drug molecules is assumed to be much greater than the number of receptor sites

PHARMACODYNAMICSSIGNIFICANCE OF KD (DISSOCIATION CONSTANT)

Represents the drug concentration at which half maximal binding occurs

The smaller the KD, the greater the affinity the drug has for the receptor

The smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding

PHARMACODYNAMICSOTHER TERMS

SAFETY No drug is 100% safe

QUALITY Tests bioavailability How much of the drug will enter the

system VARIABILITY

Changes from patient to patient, drug to drug, and time to time

LOG DOSE RESPONSE CURVE

EFFICACY Maximal ceiling effect Drug effect irrespective of the dose

POTENCY Does not refer to the strength of the drug Drug effect with respect to the dose Location of the drug response curve along the

horizontal axis The nearer the dose to the y axis, the greater

the potency The farther the dose, the lesser potency

Log dose response curve

Log dose response curvecomparison of drugs

PHARMACODYNAMICSAGONISTS

AGONIST DURGS Drugs that interact with and activate

receptors Possess both affinity and efficacy

2 TYPES FULL – an agonist with maximal efficacy PARTIAL – an agonist with less than

maximal efficacy

PHARMACODYNAMICSAGONISTS

PARTIAL AGONISTS A partial agonist is one that produces

less of a response when all receptors are occupied than does a full agonist

Can compete with and can displace a full agonist for binding sites the maximal effect of the full agonist will be less

PHARMACODYNAMICSANTAGONISTS

COMPETITIVE

Reversible Maximal effect of the

agonist drug will not be affected, but larger concentrations of the agonist drug will be required to achieve maximal effect

Dose-effect curve is shifted to the right

NON COMPETITIVE Irreversible Antagonist will prevent the

agonist from producing a maximal effect, at any agonist concentration

Maximal effect of the agonist drug will be decreased, and this cannot be overcome by increasing the concentration of the agonist drug

Dose-effect curve flattened out

PHARMACOKINETICS

Action of the body to the drug COMPONENT PROCESSES ABSORPTION

The transfer of a drug from its site of administration to the blood stream

DISTRIBUTION The process by which drug reversibly

leaves the blood stream and enters the interstitium and/or other tissues

PHARMACOKINETICS

COMPONENT PROCESSES METABOLISM

Process by which drug structure is altered for removal from the body

Liver is the major site of drug metabolism

EXCRETION Usually through feces, urine, or bile

PHARMACOKINETICSABSORPTION

PASSIVE DIFFUSION Aqueous or Lipid diffusion Most common

ACTIVE TRANSPORT Important for some drugs, particularly

larger molecules


AQUEOUS DIFFUSION Within large aqueous compartments (e.g.

interstitial space, cytosol) Driving force: drug concentration

gradient (described by Fick’s Law) …. Molecules will tend to move from a higher concentration to a lower concentration

Plasma protein bound drugs cannot permeate through aqueous pores


LIPID DIFFUSION Most important barrier for drug

permeation due to many lipid barriers separating body compartments

Lipid-soluble drugs readily move across biological membranes

Ionization state of the drug is an important factor: charged drugs diffuse through lipid environments with difficulty


SPECIAL CARRIERS Peptides, amino acids, glucose Active transport, facilitated diffusion Saturable (unlike passive diffusion)

because of limited number of carrier sites


ENDOCYTOSIS/EXOCYTOSIS Entry into cells by very large substances E.g. iron, vit B12


PHYSICAL FACTORS INFLUENCING ABSORPTION Blood flow to the absorption site

Blood flow to intestine > blood flow to stomach Absorption from the intestine is favored

Total surface area available for absorption Intestines: rich in microvilli, surface area about

1000-fold that of the stomach Absorption from the intestine is favored

Contact time at the absorption surface E.g. Diarrhea – drug moves through the GI tract

very quickly, thus it is not well absorbed

PHARMACOKINETICSBIOAVAILABILITY

The fraction of administered drug that reaches the systemic circulation

Example 100 mg of a drug administered orally If 70 mg of this drug is absorbed

unchanged, bioavailability is 70%


HOW TO TEST FOR BIOAVAILABILITY Get plasma levels of a drug after a particular

route of administration (e.g. oral administration)

Compare the plasma levels obtained with plasma levels achieved by IV injection

By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC)

AUC – reflects the extent of absorption of the drug


FACTORS THAT INFLUENCE BIOAVAILABILITY First pass hepatic metabolism Solubility of the drug

Very hydrophilic drugs cannot cross cell membrane lipid component, thus, may not be well absorbed

Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body fluids, thus, cannot gain access to the surface of cells

FOR GOOD ABSORPTION: The drug must be largely hydrophobic yet have some solubility in aqueous solutions


FACTORS THAT INFLUENCE BIOAVAILABILITY

Chemical instability Ex. Penicillin G – unstable in the pH of

gastric contents Nature of the drug formulation

Unrelated to drug chemistry Ex. Enteric coatings


ROUTES OF ADMINISTRATION Enteral

Oral Sublingual

Parenteral IV, IM, SC


ORAL ADMINISTRATION Simplest, most convenient, most economical Disadvantages

Emesis (drug irritation of GI mucosa) Digestive enzymes/gastric acidity destroy the

drug▪ Enteric coating of the drug protects it from the acidic

environment Unreliable or inconsistent absorption due to food

or other drug effects Metabolism of drug by GI flora


ORAL ADMINISTRATION First-Pass Effect

Drugs absorbed from the GI tract passes through the portal venous system LIVER and systemic circulation

IMPORTANCE: Extensive hepatic metabolism/extraction results in minimal drug delivery to the systemic circulation


ORAL ADMINISTRATION First-Pass Effect

Therefore, drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target organ

Example: nitroglcerin▪ NOT given orally because 90% of the drug is

cleared during a single passage through the liver


SUBLINGUAL ADMINISTRATION Allows drug to diffuse into the capillary

network, and, therefore, to enter the systemic circulation directly

ADVANTAGES▪ Rapid absorption▪ Convenience of administration▪ Low incidence of infection▪ Avoidance of harsh GI environment▪ Avoidance of first-pass metabolism


PARENTERAL ADMINISTRATION Intravenous (IV)

Permits rapid effect and maximal degree of control over the circulating levels of the drug

May inadvertently introduce bacteria through contamination at the site of injection

Intramuscular (IM) Requires absorption Drug diffuses out of the muscle precipitates at

the site of infection dissolves slowly, providing a sustained dose over an extended period of time


PARENTERAL ADMINISTRATION Subcutaneous (SC)

Like IM administration, requires absorption

Slower than IV route but minimizes risks associated with intravascular injection


OTHER ROUTES: Inhalation Intranasal Intrathecal/Intraventricular Topical Transdermal Rectal


INHALATION Rapid delivery of a drug across the large

surface area of the mucous membranes of the respiratory tract and pulmonary epithelium, producing an effect as rapid as with IV injection

For patients with respiratory complaints Drug is delivered directly to the site of

action and systemic side effects are minimized


INTRANASAL Directly into the nose Ex. Nasal decongestants, Desmopressin

for DI


TOPICAL Used when a local effect of a drug is

desired Ex. Antifungal creams, cyclopentolate

eye drops (to dilate pupils)


TRANSDERMAL ADMINISTRATION Advantages: Sustained therapeutic plasma levels Avoids continuous infusion technique

difficulties Low side effect incidence (smaller

doses) Good patient compliance Examples of drugs: Fentanyl, Clonidine


RECTAL ADMINISTRATION Rectal mucosal irritation is possible Unpredictable pharmacological responses REASON: Proximal rectum administration

Absorption into superior hemorrhoidal veins then enters the portal venous system then to the liver (possible first pass hepatic effect) and finally into the systemic circulation

Low rectal administration Drug enters systemic circulation without passing

through the liver


AVOIDING FIRST-PASS EFFECT Sublingual Transdermal Suppositories in the lower rectum Inhalation (however, there is first-

pass pulmonary loss)

PHARMACOKINETICSDISTRIBUTION

Is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues

DETERMINANTS: Blood flow Capillary permeability Degree of binding of the drug to plasma and

tissue proteins Relative hydrophobicity of the drug


Volume of distribution (Vd) is the ratio between the amount of drug in the body (dose given) and the concentration of the drug measured in blood or plasma

FACTORS INFLUENCING (Vd) Drug pka Extent of drug-plasma protein binding Lipid solubility Gender, age, disease, body composition


IMPORTANCE OF Vd If Vd is large, most of the drug is in the

extraplasmic space and is unavailable to the excretory organs half life of the drug is increased extended duration of action of the drug

NOTE: an exceptionally large Vd indicates significant sequestration of the drug in some organ or compartment

PHARMACOKINETICSMETABOLISM

BIOTRANSFORMATION REACTIONS more polar, hydrophilic, biologically inactive molecules that are more readily excreted

Comes in 2 phases Principal organ: liver Other organs: lungs, skin, kidney,

and GI tract

PHARMACOKINETICSEXCRETION

Clearance is important for ensuring appropriate long term drug dosing for steady state drug concentration

It is additive: a function of elimination by all participating organs such as liver or kidney

KIDNEYS – most important organs for elimination of unchanged drug/drug metabolites


Water soluble compounds exhibit more efficient renal excretion compared to lipid soluble compounds

FACTORS AFFECTING RENAL CLEARANCE Renal disease Rates of filtration depend on▪ Volume filtered in the glomerulus▪ Unbound drug concentration in plasma (plasma

protein bound drugs are not filtered)


FACTORS AFFECTING RENAL CLEARANCE Drug secretion rates Changes in plasma protein concentration Blood flow Number of functional nephrons


KIDNEY Nearly all drugs filtered at the glomerulus Most drugs in a lipid soluble form will be

reabsorbed by passive diffusion To increase excretion: change the urinary

pH to favor the charged form of the drug Weak acids are excreted faster in alkaline pH Weak bases are excreted faster in acidic pH

PEDIATRIC DRUG DOSING

All drugs administered to the pediatric age group should be meticulously computed

Based on the WEIGHT


Example .. A child is brought to the emergency room with high-grade fever for the past 2 days. There were no other accompanying symptoms. An impression of Acute Viral Infection was given.

As in all viral infections, treatment is supportive

An antipyretic was prescribed


Paracetamol dose: 10-15 mg/kg/dose Paracetamol stock dose for children:

100 mg/ml drops, 120 mg/5 ml susp, 250 mg/5 ml susp

If the child weighs 10 kg10 kg x 10-15 mg/kg = 100-150 mg using a stock dose of 100 mg/mlyou should prescribe 1-1.5 ml per dose


If on history taking, you extracted the information that a drug was given, how do you determine if the dose given was adequate or not?


If the child weighs 20 kg, and was given Paracetamol 250 mg/5 ml 3 ml every 4 hours, was the dose given adequate?

250 mg/5 ml 3 ml = 150 mg/dose Normal therapeutic dose (10-15

mg/kg/dose) == child (wt 20 kg) should receive 200-300 mg/dose

Therefore, dose given was inadequate


QUIZ

PEDIATRIC DRUG DOSINGEXERCISE

CASE A child weighing 15 kg with

pneumonia1. Give a prescription for Amoxicillin2. Give a prescription for Coamoxyclav3. Give a prescription for Cefuroxime4. Give a prescription for

Clarithromycin5. Give a prescription for Paracetamol

Thank you

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