Pharmacodynamics of drugs

Pharmacodynamics of drugs

Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their mechanism of action. It is the response of the organism to the action of a drug in the absence of a disease. Pharmacodynamics is ‘what the drug does to the body’.

Principles of drug action

Drugs do not impart new functions (they only alters pre-existing features in body)– except gene therapies.

Basic types of drug actions are listed here-

1. Stimulation – enhancement of existing level of action
   • Eg. adrenaline on heart, pilocarpine on salivary gland
2. Depression – selective diminution of activity of specialized cells
   • Eg. barbiturates on CNS, Acetylcholine on heart
3. Irritation – a nonselective, often noxious stimuli. Mild irritation on some cells (skin, connective tissue) stimulate some functions for a beneficial effect.
   • Eg. Bitters, topical counterirritants but severe irritation inflammation, necrosis, damage
4. Replacement – of natural substances eg.. hormonal therapy, deficiencies
5. Cytotoxicity – eg.  Antibacterials, antivirals, anticancer agents

Mechanisms of drug action

1. Physical action– physical property of the drug causes the main action
   • Eg. mass of the drug- bulk laxatives
   • Adsorption- charcoal
   • Osmosis- mannitol
   • Radioactivity– ¹³¹I – for hyperthyroidism
   • Radioopacity– as contrast media (barum)
2. Chemical action– chemical property of the drug responsible for action
   1. Antacids- AlOH_2 ­
   2. acidifiers- NH₄Cl
   3. alkalinizers- NaHCO₃
   4. oxidizers- KmnO₄, H₂O₂
   5. chelating agents– Ca Na EDTA, BAL, Pencillamine

Enzyme mediated drug action

Enzymes are ubiquitous biological catalysts – main targets of drug actions Drugs either increase or decrease enzyme mediated reactions Stimulation is done by endogenous sub. (cofactors) vitamins and minerals.

Rate of reaction increases

1. Enzyme induction – microsomal induction by drugs – increased synthesis of proteins
2. Enzyme inhibition – a most common mode of drug action
3. Non specific – metal salts, acids, alkalis inhibit nonspecifically
4. Specific – particular enzyme affected – either competitive or noncompetitive
5. Competitive – competition with normal substrate

Equilibrating type

Increasing the concentration of normal substrate reverses drug action. Example- sulfonamides and PABA for folate synthetase neostigmine and Ach for cholinesterase.

Non-equilibrating type

React with the same site as that of substrate but form strong covalent bonds or have very high affinity than the normal substrate eg.. organophosphates form covalent bond with cholineesterase methotrexate – 50,000 times more affinity for the enzyme DHFR than DHF Acid.

Non-competitive – reacts with some other site and not on the catalytic site but alters the enzyme loss of catalytic property eg.. aspirin – Cyclooxygenase disulfiram – aldehyde dehydrogenase digoxin – Na⁺ K⁺ ATPase.

Receptor mediated drug action

Receptor mediated drug action is the most important type of drug action. Receptor is a binding site within biological tissues for either endogenous or exogenous(!!!) substances. Macromolecules situated on the surface of the cell or inside the cell. Regulate critical functions like enzyme activity, permeability, structural features, etc.

Evidence of Receptor mediated drug action

1. Many drugs show structural specificity minor substitution alters the effect.
2. Stereospecificity of drugs d-propranolol less active than l-isomer, l-noradrenaline – more potent than d- noradrenaline
3. antagonism between substances of closely related structures some chemical identity Langley (1878) proposed the term receptive substance
4. This idea developed by Clark (1920) – propounded the Receptor occupation theory D + R DR E (effect)
5. The postulates of the theory are:
   • Intensity of response α fraction of receptors occupied; maximal response when all receptors are occupied ‘all or none’ action of drug on each receptor – each receptor is either fully activated or not at alldrug and receptor have structurally ‘lock and key’ arrangement.

Terms related to drug-receptor binding

Agonists

Agonists are agents that mimic the effects of the endogenous regulatory compound. Agonists may be defined as drugs that possess affinity for a particular kind of a receptor and has the ability to cause a change in the receptor that gives rise to an observable effect. Their value in clinical practice often rests on their greater capacity to resist degeneration and thus acts for a longer duration than the natural substances they mimic. For this reason, bronchodilatation produced by salbutamol lasts longer than that induced by adrenaline.

The properties exhibited by agonists include affinity, intrinsic activity, maximal efficacy, potency, selectivity and specificity.

Affinity of a ligand (drug or endogenous substance) is a measure of its capacity to bind to the receptor. Affinity may vary greatly among agonists as well as antagonists. Intrinsic activity is a measure of the ability of the agonist-receptor complex to initiate the observed biological response. A full agonist has an intrinsic activity of 1.

Maximal efficacy reflects the upper limit of the dose-response relationship without toxic effects being evident. Agonists differ from each other in this regard.

Potency refers to the range of concentrations over which an agonist produces increasing responses. Highly potent drugs produce their effects at lower concentrations; this may impart an advantage to their clinical use, provided the increase in potency is not accompanied by an increase in toxicity.

Agonists in their occupation of receptors exhibit selectivity and specificity. Few agonists are so specific that they interact only with a single subtype of receptor. However, several agonists do show evidences of selectivity for certain subpopulation of receptors.

Full agonists

Full agonists are agonists that produce a maximal response by occupying all or a fraction of receptors.

Partial agonists

Partial agonists are drugs that act both as agonists and antagonists. These drugs in addition to blocking access of the natural agonist to the receptor are capable of a low degree of activation. These agents produce less than a maximal response even when they occupy all of the receptors.

Inverse agonists Some substances produce effects that are specifically opposite to those of agonists and are called as inverse agonists.

Antagonists

Antagonists are agents that are themselves devoid of any intrinsic activity but cause the effects by inhibition of the action of an agonist. Drugs that have no activating effect whatsoever on the receptor are termed as pure antagonists.

They are sufficiently similar to the natural agonist to be ‘recognized’ by the receptor and to occupy without activating it, thereby preventing the natural agonist from exerting its effect.

Down regulation

When tissues are continuously exposed to an agonist, the number of receptors decreases and this may lead to a reduction in the number of receptors. This may be a reason for tachyphylaxis.

Up regulation

Prolonged contact with an antagonist leads to formation of new receptors and this phenomenon is known as up regulation.

Spare receptors

This term refers to the production of a maximal tissue response when only a fraction of the total number of receptors is occupied.

EC₅₀

The concentration of an agonist that produces half maximal effect is known as EC₅₀.

IC₅₀

The concentration of an antagonist that produces half maximal inhibition is known as IC₅₀.