Biosynthesis ,Catabolism ,Classification and MOA of Adrenergic Agents

About Adrenergic receptors , Biosynthesis and Catabolism, various classification of Adrenergic

1. Aderigenic Agents Pramod Kumar

2. voluntary Non-voluntary fight-or-flight maintain normal body function and conserve energy

3. ADRENERGIC NEUROTRANSMITTERS: NE, E, and DA are chemically catecholamines (CAs), Contain Acatechol nucleus (ortho- dihydroxybenzene ) Ethylamine group

4. Metabolism MAOs oxidatively deaminate CAs

5. SAR OF ADRENERGIC/SYMPATHOMIMETIC AGENTS

6. These two hydroxyl groups are what enable the catechol ring to be effective at the beta and alpha catecholamine receptors. The parent structure with the features in common for many of the adrenergic drugs is beta-phenylethylamine. The absence of hydroxyl groups permits phenylethylamine to penetrate the blood brain barrier. In general, a primary or secondary aliphatic amine separated by two carbons from a substituted benzene ring is minimally required for high agonist activity in this class. Agents in this class have a hydroxyl group on C1 of the side chain, β to the amine, as in epinephrine and norepinephrine This hydroxyl-substituted carbon must be in the (R) absolute configuration for maximal direct activity . The nature of the other substituents determines receptor selectivity and duration of action.

7. R1 substitution in the amino nitrogen R1 is increased in size from hydrogen in norepinephrine to methyl in epinephrine to isopropyl in isoproterenol, activity at α-receptors decreases, and that activity at β-receptors increases. the smaller the group, the more alpha effect there is. The activity at both α- and β-receptors is maximal when R1is methyl as in epinephrine, but α-agonist activity is dramatically decreased when R1is larger than methyl and is negligible when R1 is isopropyl, as in isoproterenol Increase of the alkyl substituent on the amine group increases the molecules preference for beta receptors instead of alpha. The bigger the alkyl substituent, the more beta effect there is. The N-substituent can also provide selectivity for differentβ-receptors, with a t-butyl group affording selectivity for β2-receptors ( eg;colterol ), whereas isoproterenol is a nonselective β-agonist.

8. R2, Substitution α to the Basic Nitrogen, Carbon-2 Small alkyl groups, methyl or ethyl, can be present on the carbon adjacent to the amino nitrogen, carbon-2, Such substitution slows metabolism by MAO, and thus increases half life. An ethyl group in this position diminishes α-activity far more than β-activity Substitution on this carbon also introduces another asymmetric center into these molecules producing pairs of diastereomers, which can have significantly different biologic and chemical properties .

9. R3, Substitution on the Aromatic Ring Having no groups like phenylethylamine results in good CNS penetration. The natural 3′,4′-dihydroxy–substituted benzene ring in norepinephrine provides excellent receptor activity for both α- and β-sites. 3′,5′-Dihydroxy compounds are not good substrates for COMT but provide selectivity for β2-receptors .Positions 3 and 5 = beta -2 selectivity in compounds with large amino substituents. 3′-hydroxymethyl and 4′-hydroxy substitution pattern enhance oral activity and provide selective β2-activity the 3′-amino or 3′-formylamino, which are also resistant to COMT At least one of the groups must be capable of forming hydrogen bonds, and if there is only one, it should be at the 4′ position to retain β-activity. When the phenyl ring has no phenolic substituents (i.e., R3 = H), these phenylethanolamines can have both direct and indirect activity. Direct activity (i.e., agonist) is the stimulation of an adrenoceptor by the drug itself; indirect activity is the result of displacement of norepinephrine from its storage granules or reuptake inhibition, resulting in nonselective stimulation of the adrenoceptors

10. CLASSIFICATION  OF SYMPATHOMIMETIC DRUGS

11. Direct Acting Sympathomimetic

12. ADRENERGIC RECEPTOR AGONIST These are those drugs and Agents which directly bind with adrenergic Receptors(Both α and β) and gives its Pharmacological action. The action produced are of rapid onset and of short duration. Nor-epinephrine : It is a natural catecholamine phenethylamine derivative. Properties: It is a white or brownish-White, crystalline powder, slightly soluble in ethanol and soluble in water. MOA: Potent at α- receptor.(Less potent adrenalins).  Also effect on β1- receptor but no effect on β2- receptor. Uses :  Strong Vasoconstriction properties. So it is used in local anaesthetic solutions for dental use.  Reduced the absorption and to localize the effects of local anastetics .  Intravenous infusion for the treatment of hypotension.  Its principle use is to support blood in various acute hypotensive states, especially in myocardial shock

13. Epinephrine-  Adrenaline is  a catecholamine and belongs to the family of biogenic amines. Mechanism of action:  It directly bind with α1 and β1 and β2 receptor.(Potent for all)  It given by oral route in the form of pro-drug (Pivalic acid) to prevent first pass metabolism. Uses :  It is used as a sympathomimetic, broncholytic , and anti-asthmatic.  It is used to prevent bleeding during surgery or in case of inner organ bleeding. Because adrenaline leads to constriction of blood vessel.  It is administered in combination with local anesthetic  It is used in the treatment of heart block or circulatory collapse and open-angle glaucoma.  It is usually the drug of choice in acute allergic disorders and histamine reactions.  In emergency treatment of anaphylaxis and anaphylactic shock in the cardio pulmonary disease

14. Phenylephrine*- . Mechanism of action : Bind at α1 receptor. No action on β receptor 

15. α 2  - ADRENERGIC RECEPTOR AGONIST Clonidine and methyl dopa

16. β1 - ADRENERGIC RECEPTOR AGONIST Dobutamine Dobutamine is a synthetic direct acting catecholamine with relatively selective β1 receptor agonistic action.  Dobutamine resembles dopamine structurally, but does not cause release noradrenaline. Pharmacological effects: Intravenous infusion of dobutamine increase cardiac contractility and cardiac output, without significant change in heart rate, peripheral resistance and blood pressure. Increased myocardial contractility may increase oxygen demand and coronary blood flow. Overall, dobutamine is a more effective positive inotropic than dopamine, but it does not dilate the renal vascular bed. Clinical use :Primarily used as an inotropic agent in severe congestive heart failure Dobutamine

17. β 2  - ADRENERGIC RECEPTOR AGONIST In general, β 2  receptor agonists relax smooth muscles of bronchi and uterus and blood vessels of skeletal muscles. At high doses, however, may exhibit β 1  action on heart. Tachycardia is common after systemic administration which is due to the agonistic action of β 1  receptors. Long term use of β 2  receptor agonists, may result in their down regulation with subsequent decreased pharmacological response. Important selective β 2 - adrenoceptor stimulant include clenbuterol, terbutaline, isoxuprine , salbutamol (albuterol) and orciprenaline ( metaproterenol). Salbutamol has highest ratio of β 2 : β 1 action ( about 10 times) These are primarily used as bronchodilators and as uterine relaxants to delay premature labour .

18. Noncatechol amines

19. Pharmacological actions Pharmacological actions are similar to epinephrine as they act on both of the adrenergic receptors. Various actions mediated by alpha receptors are Vasoconstriction leading to rise in blood pressure &Nasal decongestion Similarly action on beta receptors produce Increase in rate and force of contraction of heart,Increase in cardiac output,Bronchodilatation,Increased renin release,Increase in blood glucose levels Apart from these, ephedrine can enter into the CNS and produce euphoria. This can result in drug addiction leading to its abuse. That's why ephedrine use is somewhat limited to nasal decongestion. Side effects No need to say that they produce side effects attributed to sympathetic activation. Rise in blood pressure,Tachycardia,Palpitations,Anxiety,Tremor,Headache,Tension,Insomnia,Euphoria , I ndications Currently ephedrine is very little used while pseudoephedrine is used as nasal decongestant in few of cough syrups.  

20. Indirect acting

21. Amphetamine

22. Mixed acting adrenergic agonists

23. Ephedrine and pseudoephedrine belong to this category. Ephedrine is a natural alkaloid obtained from ephedra species like ephedra sinica and ephedra officialis . Ephedrine and pseudoephedrine differ only in stereochemistry. They act on both alpha and beta adrenergic receptors producing both direct and indirect actions. These drugs can directly bind to the adrenergic receptors and produce cellular effect just like epinephrine. Again these drugs can’t be metabolised by COMT hence bind for longer period They also show indirect action by entering into the presynaptic nerve terminals by uptake 1 process. Within the nerve terminal they displace the norepinephrine from storage vesicles increasing its leak into synaptic cleft. Increased norepinephrine levels then act on postsynaptic receptors and produce cellular effects.

24. ANTIADRENERGIC DRUGS / ADRENERGIC ANTAGONISTS These are drugs that interfere with the functions of the sympathetic nervous system either by blocking the adrenergic receptors or by interfering the synthesis, storage or release of nor adrenaline in sympathetic nerve terminals. Accordingly these drugs are divided into two groups: Adrenergic receptor antagonists Adrenergic neuron blocking drugs

25. Adrenergic receptor antagonists Adrenergic neuron blocking drugs Act on post junctional or pre junctional Receptors Act on adrenergic neuron membrane (pre junctional) Act by   blocking adrenoceptors  (alpha and beta)  Act by inhibiting synthesis, storage or release of nor adrenaline Effects of exogenous  adrenergic drugs  is blocked Not blocked

26. ADRENERGIC RECEPTOR ANTAGONISTS These drugs interact with adrenergic receptors (α and / or β) on effector cells (post junctional) or on adrenergic neurons ( pre junctional) and prevent their access to either endogenous  catecholamines  or exogenous  adrenergic drugs , except phenoxybenzamine, almost all these drugs act as competitive antagonists. These are further divided into three groups, based on the type of receptors they antagonize: α receptor antagonists  (selective and non selective) β receptor antagonists (selective and non selective) α and β receptor antagonist

27. a small vascular tumour of the adrenal medulla, causing irregular secretion of adrenalin and noradrenaline leading to attacks of raised blood pressure, palpitations, and headache

28. Pharmacological effects: Most important effects are seen on cardiovascular system and uterine smooth muscle. Cardiovascular system: Initially cause direct peripheral vasoconstriction and pressor response that may persist for longer duration. Larger doses may cause blockade of α- receptors and can reverse the pressor response of adrenaline to depressor action. Still larger doses cause intense and persistant peripheral vasoconstriction leading to stasis of blood, thrombosis and obliterative endoarterities causing gangrene and sloughing of extremities ( ergotism). Other effects: Initially stimulate the central nervous system followed by depression. Stimulates the chemoreceptor trigger zone and produce vomition . It also stimulates gastrointestinal tract and uterine smooth muscles. Clinical uses: Ergometrine is primarily used for contraction of the uterus post-partum. Other drugs: Although neuroleptic drugs like chlorpromazine and haloperidol produce significant α- receptor blockade effect , these are not clinically used for α – receptor blockade  because of their many other pharmacological actions.

29. Methysergide is a  semisynthetic ergot alkaloid ergometrine derivative , introduced in pharmacotherapy for migraine prophylaxis as a specific serotonin (5HT) receptor antagonist Methysergide

30. β - ADRENERGIC RECEPTOR ANTAGONIST Depending on the selectivity for β-receptor blockade, these are grouped as follows: Non selective β-adrenergic receptor antagonists  (beta 1 and 2). Eg : Propranolol, Nadolol, Pindolol, Timolol, Sotalol. Selective β- adrenergic receptor antagonists Selective β1- adrenergic receptor antagonists . Eg : Metoprolol, Atenolol, and Esmolol Selective β2-adrenergic receptor antagonist. Eg : Butoxamine .

31. NON SELECTIVE β - ADRENERGIC RECEPTOR ANTAGONIST Propranolol It interacts with both β 1  and β 2  receptors and blocks them competitively. It has powerful local anesthetic effect also. Cardiovascular effects Blockade of β 1  –receptors produces decrease in heart rate, force of contraction and cardiac output. These are more evident during stress or exercise. Cardiac work and oxygen demand are reduced. The AV conduction time is slowed, ectopic pacemaker activity is reduced and automaticity is suppressed. Propranolol blocks cardiac stimulant action of adrenergic agonistic drugs, but not that of digitalis, Ca ++  or methylxanthines. Clinically used as an anti arrhythmic drug.

32. SELECTIVE β - ADRENERGIC RECEPTOR ANTAGONIST Selective β 1  – receptor antagonists Metoprolol is the prototype of cardioselective β 1 - receptor blockers. Its potency to block β 1 - receptors equals that of propranolol, but about 50-100 times higher dose is required to block β 2 -receptors. Clinical uses :  It is used in arrhythmias, systemic hypertension, ventricular hypertrophy. Atenolol Unlike propranolol and metoprolol, atenolol has very low lipid solubility, so it penetrates the brain only to a very limited extent. Esmolol It is an ultra short acting β 1 -rceptor blocker. It is given IV when β 1 - receptor blockade is required for short duration. It is very useful for the investigation and immediate therapy of tachycardia.

33. Labetolol Labetolol at lower doses blocks only β receptors but at higher doses blocks both α and β receptors. Though it non selectively blocks β 1  and β 2  receptors, its α- receptor blockade is limited to only α 1 -receptors. Labetolol produces fall in blood pressure without producing peripheral vasoconstriction. Used for treating hypertension. It is also an important experimental tool. α AND β - ADRENERGIC RECEPTOR ANTAGONIST