Pharmacology

Lec 1

Introduction

• Pharmacology is the science of the drugs system. It includes the knowledge of history, source,

biochemical and physiological effect, mechanism of action and therapeutic uses of drug.

• Pharmacotherapeutics:- It is branch of medicine concerned with the cure of diseases or relief

of symptoms and includes drug treatment.

• Toxicology:- science of poisons. Poisons are substances that cause harmful, dangerous or shows

fatal symptoms in animals and human beings; many drugs in large dose acts as poisons.

• Pharmaco-epidermiology:- It is study of the effect of the drugs in large number of people in

community.

Pharmacokinetics & Pharmacodynamics

• Pharmacokinetics (ADME ) is the fate of drugs within the body. It involves:

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

• Pharmacodynamics: Involves the biochemical and physiologic effects of drugs on the body.

Absorption & Bioavailability

• Absorption is the movement of a drug from its site of administration into

the central compartment. For solid dosage forms, absorption first requires

dissolution of the tablet or capsule, thus liberating the drug.

• Bioavailability is the relative amount of the administered drug that reaches

the systemic circulation from which the drug has access to its site of action.

A drug given orally must be absorbed first from the GI tract.

Distribution of Drugs

Drug distribution is the process by which a drug reversibly leaves the

bloodstream and enters the extracellular fluid and tissues.

The lipid solubility, pH of compartment, extent of binding with plasma protein

and tissue proteins, cardiac output, regional blood flow, capillary permeability

are associated for distribution of the drug trough tissues. The drug is easily

distributed in highly perfused organs like liver, heart, kidney etc in large

quantities & in small quantities it is distributed in low perfused organs like

muscle, fat, peripheral organs etc.

Binding to Plasma Proteins

• Many drugs circulate in the bloodstream bound to plasma proteins. The

binding is usually reversible.

• Albumin is a major carrier for acidic drugs

• α1-acid glycoprotein binds to basic drugs.

• The fraction of total drug in plasma that is bound is determined by the drug

concentration, the affinity of binding sites for the drug, disease-related

factors (e.g., hypoalbuminemia).

Metabolism of Drugs

• Same like metabolism of carbohydrate, protein, lipids, the drug will metabolized by enzymes present in the body.

• The conversion of lipid soluble substances or drug in to water soluble compound by enzymatic reaction is called as bio-transformation. It involves alteration of drug molecule.

• Biotransformation, which almost always produces metabolites that are more polarthan the parent drug.

• The pathways of drug metabolism can divide in to:

• phase I

• phase II

Phase-I reactions

• It includes oxidative, reductive and hydrolytic reactions.

• It is asynthetic reaction because only small polar groups are introduced, not

the whole complex is synthesized.

• The polar group like –OH, -COOH & -SH are added, so the drug molecule

becomes solubilized and excreted.

The metabolism of drug leads to

• Inactivation of drug: The active drug is converted in to inactive metabolites & excreted.

• Active metabolites from equally active metabolites: The drug is converted in to similar active metabolites. Ex- conversion of codeine in to morphine, having similar activity.

• Active metabolites from inactive drug (prodrug): Some drugs given in the form of inactive form which are made active by metabolism. Eg- enalapril which activated in the form of enalaprilat, which is prodrug.

• Conversion in to toxic substances: Xenobiotics metabolizing enzymes are responsible for elimination of drug but may convert it in to toxic metabolites.

Enzymes catalyzing phase I

biotransformation

Cytochrome P-450 monooxygenase

(1) Induction

Induction can be caused by a wide variety of clinically useful drugs (drug–drug

interactions), such as quinidine, phenytoin, griseofulvin, phenobarbital, troglitazone,

omeprazole, rifampin, carbamazepine, and st. John’s wort, and by environmental

agents such as tobacco smoke.

(2) Inhibition can be caused by a number of commonly used drugs, including

cimetidine, fluconazole, fluoxetine, and erythromycin or environmental or dietary

agents (e.g., grapefruit juice), and is another major source of drug–drug interactions.

Phase-II reaction

• These reactions involve covalent attachment of small polar endogenous

molecule like glucuronic acid, sulphate, glycine etc. to form highly water

soluble substances. Thus, they are known as conjugation reaction.

• The formed products have more molecular size. So, termed as synthetic

reaction.

Excretion of Drugs

• Routes of excretion may include urine, feces, saliva, sweat, tears, milk (with possible transfer to neonates), and lungs (e.g., alcohols and anesthetics). Any route may be important for a given drug, but the kidney is the major site of excretion for most drugs.

• Alkalinization of the urine will result in a higher proportion of the ionized form of an acidic drug that will decrease its reabsorption and hence increase its elimination.

• In the presence of renal failure, the clearance of a drug may be reduced significantly, resulting in higher plasma levels. For those drugs with a narrow therapeutic index (TI), dose adjustment may be required.

Half-Life (t1/2)

• The t1/2 is the time it takes for the plasma concentration to be reduced by 50%.

• For a limited number of drugs, some effect of the drug is easily measured (e.g.,

blood pressure, blood glucose) and can be used to optimize dosage using a trial-and-

error approach.

• For many drugs, however, the effects are difficult to measure (or the drug is given

for prophylaxis), toxicity and lack of efficacy are both potential dangers, or the

therapeutic index is narrow.

• Thus, the therapeutic goal is to maintain steady-state drug levels within the

therapeutic window.

Maintenance dose & Loading dose

• Maintenance dose rate: is the dose of a drug required per unit of time to

maintain a desired steady-state level in the plasma to sustain a specific

therapeutic effect.

• Loading dose: A large loading dose may be needed initially when the

therapeutic concentration of a drug in the plasma must be achieved rapidly

(e.g., a life-threatening situation in which one cannot wait for five half-lives

for the drug to reach the desired steady-state level). In this situation one may

administer a loading dose.

Pharmacodynamics: Molecular

Mechanisms of Drug Action

• Pharmacodynamics: is the study of the biochemical, cellular, and physio-

logical effects of drugs on the body and their mechanisms of action.

• Affinity: binding of drug to a given receptor

• Potency: generation of a response in a biological system

• Receptor a macromolecule to which a drug binds to bring about a response.

• Agonist a drug that activates a receptor upon binding.

• Partial agonist: A drug that binds to a receptor but produces a smaller

effect at full dosage than a full agonist.

• Pharmacological antagonist : A drug that binds without activating its

receptor and, thus, prevents activation by an agonist.

• Competitive antagonist a pharmacological antagonist that binds reversibly

to a receptor so it can be overcome by increasing agonist concentration.

• Irreversible antagonist: A pharmacological antagonist that cannot be

overcome by increasing agonist concentration.

Drug Receptors

Drug receptors are biologic components on the surface of or within cells that

bind with drugs, resulting in molecular changes that produce a certain response.

1. Membrane receptors are coupled with a G protein, an ion channel, or an

enzyme. e. g. Growth factors, insulin receptor

2. Intracellular receptors; inside cells, Nuclear and cytosolic receptors

e. g. Steroid hormones, Thyroid hormones, Vitamin D, & Antimicrobials drugs.

Pharmacodynamically Altered Responses

1. Antagonism resulting from drug interactions. Physiologic (functional)

antagonism Examples: Naloxone, when blocking the effects of morphine,

Flumazenil, when blocking the effects of diazepam at a benzodiazepine

receptor

2. Tolerance: diminished response to the same dose of a drug over time a.

Example: Continuous exposure to b-adrenergic agonist (e.g., use of albuterol in

asthma) results in decreased responsiveness.

Continued

3. Supersensitivity or hyperactivity

Enhanced response to a drug may be due to an increase in the number of

receptors (up-regulation).

4. Potentiation

Enhancement of the effect of one drug by another which has no effect by

itself, when combined with a second drug. Examples: Physostigmine, an

acetylcholinesterase inhibitor (AChEI), potentiates the response to

acetylcholine (ACh), Clavulanic acid (a penicillinase inhibitor) potentiates the

response to amoxicillin in penicillinase producing bacteria.

Dependence

Dependence or Addiction: Individuals continue substance use despite significant substance-related problems.

Individuals use a drug repeatedly for personal satisfaction.

Adverse Effects: A new clinical response to a medicine which is noxious and unintended

Drug allergies (hypersensitivity)

Abnormal response resulting from previous sensitizing exposure activating immunologic mechanism when given offending or structurally related drug, Examples Penicillins, Sulfonamides

Dose–Response Relationships

Drug effects are produced by altering the normal functions of cells and tissues in the body via one of the four general mechanisms:

1. Interaction with receptors, naturally occurring target macromolecules that mediate the effects of endogenous physiologic substances such as neurotransmitters and hormones. e.g acetylcholine interacting with a nicotinic receptor.

2. Alteration of the activity of enzymes by activation or inhibition of the enzyme’s catalytic activity. e. g β-adrenoceptor, somatostatin

3. Antimetabolite action in which the drug, acting as a nonfunctional analog of a naturally occurring metabolite, interferes with normal metabolism. e.g., insulin

4. Nonspecific chemical or physical interactions such as those caused by antacids, osmotic agents, and chelators. e.g., cortisol