Mechanisms of drug action

pharmacodynamics  What the drug does to the body  This illustrates on the process of which drug alters the body environment, either by interfering with hormones, receptors, enzymes or other macromolecules

Mechanisms of drug action  Drugs acting on cell membranes  Drugs acting on metabolic processes within the cell  Drugs acting outside the cell

Drugs acting on cell membrane  Acting on receptors on cell membrane –agonists and antagonists  Interference with selective passage of ions across the cell membrane  Inhibition of membrane bound enzymes or pumps

Drugs acting on cell membrane receptors  What is a cell membrane receptor? A macromolacular complex that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment.

Receptor down regulation  When a receptor is continuously exposed to an agonist the number of receptors decrease  This is known as receptor down regulation  Ex- nitrates given for angina looses its effect with time

Receptor up regulation  Pronged contact with antagonist results in formation of new receptors  Ex-suddern withdrawal of B blockers lead to worsening of angina /arrythmi  Abrupt withdrawal of the drug lets circulatory NA and A having access to the up regulated receptor number

Antagonists Some drugs bind to cell surface receptors, but do not activate the receptors to trigger a response. When cell surface receptors bind the drug, the endogenous chemical cannot bind to the receptor and cannot trigger a response. The compound is said to “antagonize” or “block” the receptor and is referred to as a receptor antagonist.

example  β 1 receptors are a sub group of adrenoceptors. Endogenous adrenaline and nor adrenaline act on these receptors in heart and increase heart rate and cardiac contractility there by increasing the cardiac work load and the blood pressure.  Propranolol is a β receptor antagonist. It binds to β 1 receptors and block NA and adrenaline binding, there by lowering cardiac contractility and BP

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Cell Membrane Unbound Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Cellular Response

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Cell Membrane Displaced Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment Bound Antagonist of Receptor (Drug)

Agonists Some drugs bind to cell surface receptors, and activate the receptors to trigger a response. The compound is said to “agonize ” the receptor and is referred to as a receptor agonist.

Example  The bronchioles have B2 receptors. Adrenaline act on them to cause bronchiodilatation.  In asthma, the bronchioles constrict giving rise to breathing difficulty  The drug used,salbutamol is a B2 receptor agonist that bind B2 receptors and act on them to cause bronchodilatation

Partial agonists  Some drugs,which block the receptors and prevent natural ligands bind can also have a mild stimulating effect on the receptor as well.  So they have both agonist and antagonist actions

Receptor binding  Some drugs bind receptors with weak bonds.(hydrogen bonds,van der Waals bonds etc.)this type of binding would be rapidly reversible and can be displaced by increasing the endogenous substance concentration.  Some drugs bind receptors with strong bonds (covalent bonds)and then the binding would be irriversible

Receptor binding  Irreversible antagonism-The drug phenoxybenzamine is an alpha receptor blocker.  In a condition where there is a tumor of the adrenal gland which releases adrenaline(pheochomocytoma), this drug is given during surgery  The reason is that during surgery, high amounts of adrenaline is released to the circulation

 Adrenaline can bind to alpha receptors to increase the blood pressure  To prevent this a drug that can block the alpha receptors are used  However if a reversible alpha antagonist is used, it can get displaced by high adrenaline levels,and to avoid this an irreversible alpha receptor blocker is used

Physiological antagonism  Drugs might not always act on the same receptor which a physiological substance binds, in order to counteract its action,  Anaphylactic shock is a condition where due to an allergy, mast cells are activated and releases histamine which acts on histamine receptors to cause bronchoconstriction  The drug adrenaline is given as treatment and it acts via a different receptor,the beta 2 adrenoceptor to cause bronchodilatation.

Drugs acting on cell membrane  Acting on receptors on cell membrane –agonists and antagonists  Interference with selective passage of ions across the cell membrane  Inhibition of membrane bound enzymes or pumps

Interference with selective passage of ions across the cell membrane  Calcium channel blockers Calcium is needed for muscle contraction.CCB drugs act on the vascular smooth muscle and block the calcium transport, preventing contraction of vascular smooth muscle. This causes vasodilatation and lowering of blood pressure

Inhibition of membrane bound enzymes or pumps  Cardiac glycosides interfering with the Na+ K+ ATPase pump of the heart muscle which causes Na+ to accumulate within the myocardium.This Na+ is exchanges to Ca2+, so the calcium increases in myocardium increasing contractility of the heart muscle

Drugs acting on metabolic processes with in the cell  Enzyme inhibition  Inhibition of transport process that carry substances across cells  Incorporation of larger molecules  Altering other metabolic processes

Enzyme inhibition  Some important drugs act as enzyme inhibitors  Inhibition caused by drugs may be either reversible or irreversible.  Drug binds to the enzyme by weak bonds in reversible inhibition

Example for competitive enzyme inhibition  Angiotensin II is a very potent chemical that causes rise in BP. Angiotensin II is formed from angiotensin I by the enzyme angiotensin converting enzyme (ACE). ACE inhibitors are medications that slow (inhibit) the activity of the enzyme ACE, which decreases the production of angiotensin II. As a result, the blood vessels dilate, and blood pressure is reduced.

Inhibition of transport process that carry substances across cells  Blocking anion tansport of renal tubule by probenacid can be used to delay excretion of penicillin

Incorporation of larger molecules  Some Anticancer drugs mimic nucleotides and bind the nucleotide chains inhibiting DNA synthesis

Drugs acting outside the cell  Direct chemical interactions Ex- antacids- MgOH is an antacid. In patients with gastritis MgOH when given orally neutralizes the acids in the stomach, with out getting absorbed into cells  Osmosis Ex-magnisium sulphate is a laxative which is given to treat constipation. It is a molacule that is not absorbed into the GIT and remains in the gut.It holds water, so stools become bulky and constipation is relieved

Terminology….

 Affinity—tendency of a drug to combine with a receptor, to produce drug receptor complex and maintain it. There is always affinity constant for specific receptors.   Affinity may vary—it ↑ when the receptor is vacant and ↓ when the receptor is occupied.

Selectivity  Is the ability of the drug to produce the expected action,with out giving rise to unwanted side effects

potency  The amount of drug in relation to its effect Ex- if Xmg of drug A has more effect than the same weight of drug B, drug A is said to be more potent

Lethal dose  A lethal dose (LD) is an indication of the lethality of a given substance. Because resistance varies from one individual to another, the 'lethal dose' represents a dose (usually recorded as dose per kilogram of subject body weight) at which a given percentage of subjects will die.  Animal-based LD measurements are a commonly-used technique in drug research..  LD values for humans are generally estimated by results from testing on animals on human cell cultures

Toxic dose  the dosage that may be expected to cause a toxic effects in majority of the patients to whom it is given.

 ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves  TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect  LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects

The ‘therapeutic index’ Therapeutic dose Toxic dose Therapeutic index = Toxic dose Therapeutic dose

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