AGONIST
• Agonist is a chemical(drug) that binds to the receptor and activates the receptor to produce biological response.
OR
• Agonist is a drug that produce effects on endogenous compounds, when it interacts with it’s receptor.
=> Agonists are of following types:
(1) Full agonists
(2) Partial agonists
(3) Inverse agonists
(1) Full Agonists
• If a drug binds to a receptor and produce maximal biological response that mimics the response to endogenous ligand is called full agonist.
- All full agonists for a receptor population should produce the same Emax.
For Example : phenylephrine is a full agonist at alpha1-adrenoceptors, because it produce the same Emax as the endogenous ligand, norepinephrine. Upon binding with aplha1-adrenoceptors on vascular smooth muscle, both phenylephrine and norepinephrine stablize the receptor in its active state, thereby increasing the Gq activation. Activation of Gq increase intracellular Ca++ causing interaction of actin and myosin filaments, causing shortening of muscle cells.
(2) Partial Agonists
• These ligands partially increase the activity of receptor but do not produce maximal response like full agonists even when present in excess amount.
OR
• These ligands when binds with receptors, it slightly blocking the access of agonists and also slightly activating the receptor.
=>Partial agonists have intrinsic activities greater than zero but less than one1. These also have less efficacy than full agonists.
=> When number of receptors occupied by partial agonists increase, the number of receptors that can be occupied by full agonists decrease and therefore Emax would decrease untill it reaches the Emax of partial agonists.
For Example : Aripiprazol is an atypical antipsychotic, is a partial agonist at selected dopamine receptors.
(3) Inverse Agonists
• Inverse agonists inactivates such constitutively active receptors and therefore prevents its basic activity.
As a result inverse agonist produce an effect opposite to the full agonists.
=> some receptors shows spontaneous conversion from inactive R to active R* in the absence of agonists. Inverse agonist, unlike full agonists stablize the inactive R form and cause R* to convert to R. This decrease the number of activated receptors to below that observed in the absence of drug.
For Example : Beta Carbolines at Benzodiazepine receptors.
=> Inverse receptors have intrinsic activity less than zer0.
ANTAGONISTS
• A drug that binds to its receptor without activating it thereby blocking the attachments of agonists.
=> Antagonists binds to receptor with high affinity but posses zero intrinsic activity.
=> Antagonist has no biological function in the absence of agonist, but can decrease the effect of agonist when present.
=> Antagonism may occur either by blocking the drug’s ability to bind to the receptor or by blocking its activity to activate the receptor.
>Antagonist have following types :
(1) Pharmacological antagonist
(a) competitive/reversible antagonist
(b) non competitive/irreversible antagonist
(c) allosteric antagonist
(2) Physiologic antagonist
(3) Chemical antagonist
(1) Pharmacological antagonist
• In this antagonist binds to a receptor preventing an agonist from interacting with its receptors to produce an effect. DRUGS INTERACTING WITH SAME RECEPTOR.
(a) Competitive antagonist/ reversible antagonist :
• In this antagonist binds to the same site on the receptor as the agonist in reversible manner and maintain the receptor in its inactive state.
=> High antagonist concentration prevent agonist response completely.
=> Sufficiently high concentration of agonist can completely nullify the effect of antagonist.
For example : the antihypertensive drug terazosin compete with the endogenous ligand norepinephrine at alpha-1-adrenoceptor, thus decrease the vascular smooth muscle tone and reduce the blood pressure. Other examples are atropine at muscarinic receptors and Propranolol at beta receptors.
(b) Non-Competitive / Irreversible antagonists :
• Irreversible antagonists bind covalently to the active site of the receptor, thereby permanently reducing the number of receptor available to agonist.
=> In contrast to competitive antagonists, addition of more agonists does not overcome the effect of irreversible antagonists.
=> The fundamental difference between competitive and non competitive antagonists is that competitive antagonists reduce agonist potency(increase Ec 50) and non-competative antagonists reduce agonist activity( decrease Emax).
For Example : organophosphates at muscarinic receptors and phenoxybenzamine at alpha receptors.
(c) Allosteric antagonists :
• An allosteric antagonists binds to a site (allosteric site) other than agonist-binding site and prevents receptor activation by the agonists.
=> This type of antagonists also cause the downward shift of Emax of the agonist, with no change in Ec 50 value.
For Example : Picrotoxin , which binds to the inside of GABA-controlled chloride channel. When picrotoxin binds inside this channel, no Chlorine can pass through channel, even when GABA fully occupies the receptor.
(2) Physiological Antagonists :
• Antagonist act on separate receptor & brings about effects opposite to that of agonist. DRUG INTERACTING WITH DIFFERENT RECEPTORS.
For example : Excessive hypoglycemia caused by Insulin which is then opposed by giving Glucagon.
Another is Administration of sympatholytic ( Labetolol in hypertensive emergencies to counteract endogeno-sympatho-mimetics.
=> The effects produce by physiologic antagonists is less specific and difficult to control.
(3) Chemical antagonist :
• In this two drugs combine with each other to form inactive compound. It is also know as neutralisation. RECEPTORS ARE NOT INVOLVED.
For Example : Protamine is +ve charge while heparin is -ve charge and when they binds with each other and cause inactivation.