PHARMACODYNAMICS

PHARMACODYNAMICS

• Pharmacodynamics (Gr. Pharmacon: drug; dynamis: power): In short, it covers all the aspects relating to ‘what the drug does to the body’. It is the study of drugs—their mechanism of action, pharmacological actions and adverse effects.

Types of Drug Action

1. Stimulation: e.g. adrenaline stimulates the heart resulting in an increase in heart rate and force of contraction.

2. Depression: e.g. general anaesthetics depress the central nervous system.

3. Irritation- e.g. methyl salicylate. 4. Replacement - e.g. insulin in diabetes

mellitus, thyroxine in hypothyroidism.5. Cytotoxic - e.g. antibiotics/ anticancer drugs.

Mechanism of Drug Action• Nonreceptor-mediated Mechanisms1. By physical action:a. Osmosis - e.g. 20% mannitol in cerebral

oedema b. Adsorption: Activated charcoal adsorbs

toxins.c. Demulcent: Cough syrup by coating the

inflamed mucosa.

Mechanism of Drug Action

2. By chemical action:a. Neutralize acid – eg : Antacids are weak

bases; hence they in the stomach in peptic ulcer.

b.Chelating agents - desferrioxamine in iron poisoning.

Mechanism of Drug Action3. Through enzymes

– Some drugs act either by activating or inhibiting the enzyme activity.

4. Through ion channels– Some drugs directly bind to ion channels and alter the flow of ions, e.g.

local anaesthetics block sodium channels in neuronal membrane to produce local anaesthesia.

5. Through antibody production– Vaccines produce their effect by stimulating the formation of

antibodies

6. Transporters– Selective serotonin reuptake inhibitors (SSRIs) _ bind to 5-HT

transporter _ block 5-HT reuptake into neurons _ antidepressant effect.

7. Others– Anticancer drugs like produce their effect by binding to nucleic acids.

Mechanism of Drug ActionReceptor-mediated MechanismsReceptors are macro-molecules present either

on the cell surface, cytoplasm or in the nucleus which the drug binds with it and interacts to produce cellular changes.

• Affinity: The ability of the drug to get bound to the receptor.• Intrinsic activity: The ability of the drug to produce

pharmacological action after combining with the receptor.• Agonist: A drug that is capable of producing pharmacological

action after binding to the receptor.• Antagonist: has high affinity Without intrinsic activity. It produces receptor blockade.

• Partial agonist: A drug that binds to the receptor but produces an effect less than that of an agonist. – Partial agonist has affinity + less intrinsic activity.

• Inverse agonist: It has full affinity towards the receptor but produces effect opposite to that of an agonist. – For example, benzodiazepines produce antianxiety and

anticonvulsant effects by interacting with its receptors; but b-carbolines act as inverse agonist at benzodiazepine receptor, and produce anxiety and convulsions.

RECEPTOR TYPES

Regulation of Receptors

Dose–Response Relationship

• The pharmacological effect of a drug depends on its concentration at the site of action which is determined by the dose of the drug administered.

• By increasing drug dose there will be an increase in response.

Efficacy Vs. Potency

• Efficacy is the response that can be produced by a drug.

• Potency is the amount of drug required to produce an effect.

Therapeutic Index

TI = LD50 / ED50

LD50 ( Lethal Dose): It is the dose of a drug that is lethal for 50% of the population.

ED50 ( Effective Dose ): It is the dose of the drug that produces desired effect in 50% of the population.

Combined Effects of Drugs

• A combination of two or more drugs can result in an increase or a decrease in response.

Increased response:1. Additive effect :

Effect of drugs A + B = Effect of drug A + Effect of drug B

2. Potentiation (supra-additive):Effect of drugs A + B > Effect of drug A + Effect of drug B

3. Synergism:When two drugs are given simultaneously, and the action of one drug is increased by the other.

Combined Effects of DrugsDecreased response (drug antagonism):1. Physical antagonism: e.g. activated charcoal adsorbs toxic

substances in poisoning.2. Chemical antagonism: e.g. chelating agents complex metals.3. Physiological (functional) antagonism: e.g. insulin and glucagon

on blood sugar.4. Receptor antagonism: The antagonist binds to the same receptor

as the agonist and inhibits its effects. It can be competitive or noncompetitive.a. Competitive antagonism: both agonist and the antagonist bind reversibly to the same site on the receptor. Can be overcome (reversible) by increasing the concentration of agonist.b. Noncompetitive antagonism: The antagonist binds to a different site on the receptor and prevents the agonist from interacting with the receptor.

ADVERSE DRUG REACTIONS

Adverse Effect

• Adverse effect is defined as any undesirable or unwanted effect due to drug administration.

Unpredictable reactions (Type B): – These are nondose-related unpredictable reactions to

a drug. – They are not related to the pharmacological actions

of the drug.1. Idiosyncrasy– It is usually a genetically determined abnormal

reaction to drugs.

Adverse Effect2. Drug AllergyIt is an abnormal response

(local or systemic) to a drug/foreign antigen mediated by the immune system.

• Type I hypersensitivity (immediate type, anaphylactic shock): It is a rapidly occurring reaction; anaphylactic shock.

Adverse Effect• Type I is a medical emergency and should be treated promptly with:1. Inj. adrenaline (1:1000) 0.3–0.5 mL intramuscularly.2. Inj. hydrocortisone 100–200 mg intravenously.3. Inj. pheniramine 45 mg intramuscularly/intravenously.4. Intravenous fluids.

• Type II hypersensitivity (cytotoxic reaction): The antibodies (IgG and IgM) react with cell-bound antigen and cause activation of complement, which destroys the cells.• Examples are blood transfusion reactions,

haemolytic anaemias produced by cephalosporins, etc.

Adverse Effect• Type III hypersensitivity (immune complex–mediated): In this

type of reaction, antibodies involved are mainly IgG.

AG:AB complexes are formed Fix complement Deposition of complexes on vascular endothelium Destructive inflammatory response.– For example, serum sickness (fever, urticaria, joint pain) with penicillins; acute

interstitial nephritis with (NSAIDs).

• Type IV hypersensitivity (cell-mediated or delayed hypersensitivity): • It is mediated by sensitized T-lymphocytes. Re-exposure to the antigen leads to a

local inflammatory response. • The manifestations usually occur 1–2 days after exposure to the sensitizing

antigen, e.g. contact dermatitis due to local anaesthetic creams, topical antibiotics.

Adverse EffectPredictable reactions (Type A): – These are predictable reactions to a drug related to its pharmacological

actions.• Side Effects– These are the unwanted pharmacological effects of a drug that are seen

with therapeutic doses, e.g. atropine used in the treatment of heart block also produces dryness of mouth, blurring of vision, urinary retention, etc., which are the side effects.

• Secondary Effects– The primary action of a drug may result in other effects, e.g.

immunosuppression by corticosteroids can lead to development of opportunistic infections, e.g. oral candidiasis.

• Toxic Effects– These are the effects of a drug that are either due to overdosage or chronic

use, e.g. bleeding due to chronic use/overdosage of anticoagulants.

Adverse Effect• Drug Dependence

1. Psychological dependence: There is an intense desire to continue taking the drug as the patients feel that their well-being depends upon the drug.

2. Physical dependence: Repeated drug use produces physiological changes in the body that makes continuous presence of the drug in the body necessary to maintain normal function.• The withdrawal signs and symptoms are generally opposite to the

effects produced by the drug.

• Iatrogenic Diseases• It is physician-induced disease (‘Iatros’ is a Greek word, means

‘physician’) due to drug therapy, e.g. acute gastritis and peptic ulcer due to NSIDs.

Adverse Effect

• Teratogenicity– Certain drugs when given during pregnancy may

cross the placenta and cause various dangerous effects in the fetus

• Carcinogenicity and Mutagenicity• Photosensitivity Reactions• Hepatotoxicity• Nephrotoxicity• Ototoxicity• Ocular Toxicity