Mechanism of Drug Action

MECHANISM OF DRUG ACTION

Only a handful of drugs act by virtue of their simple physical or chemical property; examples are:

§  Bulk laxatives (ispaghula)—physical mass

§  Dimethicone, petroleum jelly—physical form, opacity

§  Paraamino benzoic acid—absorption of UV rays

§  Activated charcoal—adsorptive property

§  Mannitol, mag. sulfate—osmotic activity

§  131I and other radioisotopes—radioactivity

§  Antacids—neutralization of gastric HCl

§  Pot. permanganate—oxidizing property

§  Chelating agents (EDTA, dimercaprol)—chelation of heavy metals.

§  Cholestyramine—sequestration of cholesterol in the gut

§  Mesna—Scavenging of vasicotoxic reactive metabolites of cyclophosphamide

Majority of drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. Such mechanism confers selectivity of action to the drug. Functional proteins that are targets of drug action can be grouped into four major categories, viz. enzymes, ion channels, transporters and receptors (See Fig. 4.1). However, a few drugs do act on other proteins (e.g. colchicine, vinca alkaloids, taxanes bind to the structural protein tubulin) or on nucleic acids (alkylating agents).

I. ENZYMES

Almost all biological reactions are carried out under catalytic influence of enzymes; hence, enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated reactions. However, in physiological systems enzyme activities are often optimally set. Thus, stimulation of enzymes by drugs, that are truly foreign substances, is unusual. Enzyme stimulation is relevant to some natural metabolites only, e.g. pyridoxine acts as a cofactor and increases decarboxylase activity. Several enzymes are stimulated through receptors and second messengers, e.g. adrenaline stimulates hepatic glycogen phosphorylase through β receptors and cyclic AMP. Stimulation of an enzyme increases its affinity for the substrate so that rate constant (kM) of the reaction is lowered (Fig. 4.2).

Apparent increase in enzyme activity can also occur by enzyme induction, i.e. synthesis of more enzyme protein. This cannot be called stimulation because the kM does not change. Many drugs induce microsomal enzymes.

Inhibition of enzymes is a common mode of drug action.

A.   Nonspecific inhibition

Many chemicals and drugs are capable of denaturing proteins. They alter the tertiary structure of any enzyme with which they come in contact and thus inhibit it. Heavy metal salts, strong acids and alkalies, alcohol, formaldehyde, phenol inhibit enzymes nonspecifically. Such inhibitors are too damaging to be used systemically.

B.    Specific inhibition

Many drugs inhibit a particular enzyme without affecting others. Such inhibition is either competitive or noncompetitive.

i)  Competitive (equilibrium type) The drug being structurally similar competes with the normal substrate for the catalytic binding site of the enzyme so that the product is not formed or a nonfunctional product is formed (Fig. 4.1A), and a new equilibrium is achieved in the presence of the drug. Such inhibitors increase the kM but the Vmax remains unchanged (Fig. 4.2), i.e. higher concentration of the substrate is required to achieve ½ maximal reaction velocity, but if substrate concentration is sufficiently increased, it can displace the inhibitor and the same maximal reaction velocity can be attained.

§  Physostigmine and neostigmine compete with acetylcholine for cholinesterase.

§  Sulfonamides compete with PABA for bacterial folate synthetase.

§  Moclobemide competes with catecholamines for monoamine oxidaseA (MAOA).

§  Captopril competes with angiotensin 1 for angiotensin converting enzyme (ACE).

§  Finasteride competes with testosterone for 5αreductase

§  Letrozole competes with androstenedione and testosterone for the aromatase enzyme.

§  Allopurinol competes with hypoxanthine for xanthine oxidase; is itself oxidized to alloxanthine (a non competitive inhibitor).

§  Carbidopa and methyldopa compete with levodopa for dopa decarboxylase.

A nonequilibrium type of enzyme inhibition can also occur with drugs which react with the same catalytic site of the enzyme but either form strong covalent bonds or have such high affinity for the enzyme that the normal substrate is not able to displace the inhibitor, e.g.

§ Organophosphates react covalently with the esteretic site of the enzyme cholinesterase.

§ Methotrexate has 50,000 times higher affinity for dihydrofolate reductase than the normal substrate DHFA.

In these situations, kM is increased and Vmax is reduced.

ii)  Noncompetitive The inhibitor reacts with an adjacent site and not with the catalytic site, but alters the enzyme in such a way that it loses its catalytic property. Thus, kM is unchanged but Vmax is reduced. Examples are given in the box.

N

Acetazolamide     — Carbonic anhydrase

Aspirin, indomethacin — Cyclooxygenase

Disulfiram           — Aldehyde dehydrogenase

Omeprazole         — H+ K+ ATPase

Digoxin               — Na+ K+ ATPase

Theophylline       — Phosphodiesterase

Propylthiouracil   — Peroxidase in thyroid

Lovastatin           — HMGCoA reductase

Sildenafil             — Phosphodiesterase5

II. ION CHANNELS

Proteins which act as ion selective channels participate in transmembrane signaling and regulate intracellular ionic composition. This makes them a common target of drug action (Fig. 4.1B). Drugs can affect ion channels either through specific receptors (ligand gated ion channels, Gprotein operated ion channels, see Fig. 4.4 and p. 48), or by directly binding to the channel and affecting ion movement through it, e.g. local anaesthetics which physically obstruct voltage sensitive Na+ channels (See Ch 26). In addition, certain drugs modulate opening and closing of the channels, e.g.:

§  Quinidine blocks myocardial Na+ channels.

§  Dofetilide and amiodarone block myocardial delayed rectifier K+ channel.

§  Nifedipine blocks Ltype of voltage sensitive Ca2+ channel.

§  Nicorandil opens ATPsensitive K+ channels.

§  Sulfonylurea hypoglycaemics inhibit pancreatic ATPsensitive K+ channels.

§  Amiloride inhibits renal epithelial Na+ channels.

§  Phenytoin modulates (prolongs the inactivated state of) voltage sensitive neuronal Na+ channel.

§  Ethosuximide inhibits Ttype of Ca2+ channels in thalamic neurones

III. TRANSPORTERS

Several substrates are translocated across membranes by binding to specific transporters (carriers) which either facilitate diffusion in the direction of the concentration gradient or pump the metabolite/ion against the concentration gradient using metabolic energy (see p. 13–15; Fig. 2.5). Many drugs produce their action by directly interacting with the solute carrier (SLC) class of transporter proteins to inhibit the ongoing physiological transport of the metabolite/ion (Fig. 4.1C). Examples are:

§  Desipramine and cocaine block neuronal reuptake of noradrenaline by interacting with norepinephrine transporter (NET).

§  Fluoxetine (and other SSRIs) inhibit neuronal reuptake of 5HT by interacting with serotonin transporter (SERT).

§  Amphetamines selectively block dopamine reuptake in brain neurons by dopamine transporter (DAT).

§  Reserpine blocks the granular reuptake of noradrenaline and 5HT by the vesicular amine transporter.

§  Hemicholinium blocks choline uptake into cholinergic neurones and depletes acetylcholine.

§  The anticonvulsant tiagabine acts by inhibiting reuptake of GABA into brain neurones by GABA transporter GAT 1.

§  Furosemide inhibits the Na+K+2Cl¯ cotransporter in the ascending limb of loop of Henle.

§  Hydrochlorothiazide inhibits the Na+Cl¯ symporter in the early distal tubule.

§  Probenecid inhibits active transport of organic acids (uric acid, penicillin) in renal tubules by interacting with organic anion transporter (OAT).

IV. RECEPTORS

The largest number of drugs do not bind directly to the effectors, viz. enzymes, channels, transporters, structural proteins, template biomolecules, etc. but act through specific regulatory macromolecules which control the above listed effectors. These regulatory macromolecules or the sites on them which bind and interact with the drug are called ‘receptors’.

Receptor:

It is defined as a macromolecule or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function.

Though, in a broad sense all types of target biomolecules, including the effectors (enzymes, channels, transporters, etc.) with which a drug can bind to produce its action have been denoted as ‘receptors’ by some authors, such designation tends to steal the specific meaning of this important term. If so applied, xanthine oxidase would be the ‘receptor’ for allopurinol, Ltype Ca2+ channel would be the ‘receptor’ for nifedipine, serotonin transporter (SERT) would be the ‘receptor’ for fluoxetine; a connotation not in consonence with the general understanding of the term. It is therefore better to reserve the term ‘receptor’ for purely regulatory macromolecules which combine with and mediate the action of signal molecules including drugs.

The following terms are used in describing drugreceptor interaction:

Agonist

An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule.

Inverse Agonist

An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist.

Antagonist

An agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have any effect of its own.

Partial agonist

An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist.

Ligand

(Latin: ligare—to bind) Any molecule which attaches selectively to particular receptors or sites. The term only indicates affinity or binding without regard to functional change: agonists and competitive antagonists are both ligands of the same receptor.

The overall scheme of drug action through receptors is depicted in Fig. 4.1D.