UNIT II: DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM

UNIT II: DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM:
ADRENERGIC NEUROTRANSMITTER
BIOSYNTHESIS OF CATECHOLAMINE
SYMPATHOMIMETIC DRUGS

1. Drugs acting on Autonomic Nervous System Presented by …. Prof. Sonali R. Pawar

2. CONTENT: Adrenergic Neurotransmission: Biosynthesis and Catabolism of catecholamine. Adrenergic Receptor (alpha and beta) and their distribution The  nervous system  is the part of an animal's body that coordinates its behavior and transmits signals between different body areas . In vertebrates it consists of two main parts, called the central  nervous system  (CNS) and the peripheral  nervous system  (PNS). The CNS contains the brain and spinal cord.

3. Adrenergic nervous system is a group of organs and nerves in which adrenaline and/or noradrenaline are released as neurotransmitters. Adrenergic nerve release neurotransmitters: noradrenaline, adrenaline, dopamine and produce their effect. Drugs that produce similar effects to those produced by sympathetic nervous system thus they are also called sympathomimetic drugs. It may refer to something which is susceptible to epinephrine or similar to substances, such as biological receptor especially adrenergic receptor. A great number of drugs available which can affect adrenergic receptors e.g. dopamine, noradrenaline, adrenaline, isoprenaline etc. Adrenergic Neurotransmission:

4. Autonomic Drugs Drugs that produce their primary therapeutic effect by Mimicking (copy) or altering the functions of the ANS.

5. Functions of the Sympathetic Nervous System: Is normally active, even at rest; however, it assumes a dominant role when the body becomes stressed (trauma, fear, hypoglycemia cold or exercise). Fight or Flight – Protective mechanisms designed to help person cope with the stress or get away from it. For example, if you sense danger: Your heart rate increase, BP rises, eyes dilates, blood sugar rises, bronchioles expand, and blood flow shift from skin to skeletal muscles. Functions of the Parasympathetic Nervous System: Rest and digest: maintains essential body functions; digestive process and elimination of wastes. Save energy. Dilation of blood vessels in skin. Decrease heart rate (bradycardia). Increase secretion of digestive enzymes. Constriction of smooth muscle of bronchi. Increase in sweat glands. Contraction of smooth muscles of urinary bladder.

6. Drugs affecting the ANS: are divided into two groups according to the type of neuron. The cholinergic drugs act on receptors activated by acetyl choline. The adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine.

7. An  adrenergic  nerve fibre is a neuron for which the  neurotransmitter  is either adrenaline (epinephrine), noradrenaline or dopamine. These   neurotransmitters  are released at a location known as the synapse, which is a junction point between the axon of one nerve cell and the dendrite of another .

8. Adrenergic receptors are membrane bound G-protein coupled receptors which function primarily by increasing or decreasing the intracellular production of second messengers cAMP or IP3/DAG. In some cases the activated G-protein itself operates K+ or Ca2+ channels, or increases prostaglandin production. Ahlquist (1948), on the basis of two distinct rank order of potencies of adrenergic agonists classified adrenergic receptors into two types α and β. This classification was confirmed later by the discovery of selective α and β adrenergic antagonists.

9. What are adrenergic drugs? Adrenergic drugs are medications that stimulate certain nerves in your body. They do this either by mimicking the action of the chemical messengers epinephrine and nor epinephrine or by stimulating their release. These drugs are used in many life-threatening conditions, including cardiac arrest, shock, asthma attack, or allergic reaction. Catecholamines The neurotransmitters of adrenergic system noradrenaline(norepinephrine) and a d re n a l in e ( e p i nep h r i n e ) be l ongs t o a c l ass catecholamines. They called catecholamines because they have an alkylamine chain linked to catechol ring.

10. Function of Catecholamine: Catecholamine's help the  body  respond to stress or fright and prepare the  body  for "fight-or-flight" reactions. The   adrenal glands  make large amounts of catecholamine as a reaction to stress . The main catechol amines are epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine . The enzymatic processes involved in the formation of catecholamines have been characterized . The component enzymes in the pathway have been purified to homogeneity, which has allowed for detailed analysis of their kinetics, substrate specificity and cofactor requirements and for the development of inhibitors CATECHOLAMINES

11. DOPAMINERGIC SYNAPSE AND DOPAMINE METABOLISM

12. Biosynthesis of catecholamines The biosynthesis of NE and adrenaline starts from the amino acid l-tyrosine. Adrenergic Neurotransmitters Biosynthesis of noradrenaline and adrenaline

13. All  catecholamine's are synthesized from the amino acid l-tyrosine according to the following sequence: tyrosine → dopa ( dihydroxyphenylalanine ) → dopamine → norepinephrine (noradrenaline) → epinephrine (adrenaline). Monoamine Oxidase (MAO). Catechol O Methyl Transferase (COMT) Tyrosine hydroxylase is the rate-limiting enzyme for the biosynthesis of catecholamines DOPA decarboxylase catalyzes the removal of the carboxyl group from DOPA to form dopamine For neurons that synthesize epinephrine or norepinephrine, dopamine β-hydroxylase is the next step in the biosynthetic pathway In cells that synthesize epinephrine, the final step in the pathway is catalyzed by the enzyme phenylethanolamine   N - methyltransferase

14. NORMAL VALUES OF CATECHOLAMINE AND METABOLITES

15. SAR of Sympathomimetic Agents

16. SAR of alpha and beta receptor agonist

17. SAR of alpha and beta receptor agonist

18. Separation of Aromatic Ring and Amino Group T he greatest adrenergic activity occurs when two carbonatoms separate the aromatic ring from the amino group Substitution on theAmino Nitrogen Determines - or -Receptor Selectivity

19. Substitution on either carbon-1 or carbon-2 yields optical isomers. (1R,2S) isomers seem correct configuration for direct-acting activity. The more potent enantiomer has the (1R) configuration. This enantiomer is typically several 100-fold more potent than the enantiomer with the (1S) configuration R2, Substitution on the -Carbon(Carbon-2). Methyl or ethyl substitution on the a-carbon of the ethylamine side chain reduces direct agonist activity at both α- andβ-receptors. a-Substitution also significantly affects receptor selectivity. a-methylnorepinephrine , it is the erythro (1R,2S) isomer that possesses significant activity at α2-receptors.

20. Substitution on the AromaticRing because the resorcinol ring is not a substrate for COMT , B-agonists that contain this ring structure tend to have better absorption characteristicsand a longer DOAthan their catechol-containing counterparts. replacement of the meta-OH of the catechol structure witha hydroxymethyl group gives agents are selective beta-2 agonist. Modification of the catechol ring can also bring about selectivity at α- receptors as it appears that the catechol moiety is more important for α2- activity than forα1-activity.

21. Adrenergic Receptors (Alpha and Beta) and their Distribution

22. Adrenergic Receptors (Alpha and Beta) and their Distribution The effects of catecholamines in the central and peripheral nervous systems appear to be mediated through interactions with 2 major classes of receptor : α- adrenoceptors and β- adrenoceptors .

23. Subtypes of both α- and β- adrenoceptors exist In the periphery, α 1 -receptors are located postsynaptically , mediating the excitatory effects of catecholamines at α-receptors. α 2 -Adrenoceptors, on the other hand, are autoreceptors involved in the regulation of noradrenaline (norepinephrine) release. In the central nervous system, both α 1 - and α 2 -receptors exist on postsynaptic cells; there are also 2 principal subtypes of β- adrenoceptors . β 1 -Receptors have a high affinity for both noradrenaline and adrenaline (epinephrine) and are found in the heart, brain, and adipose tissue. β 2 -Receptors have a low affinity for noradrenaline and are involved in mediation of relaxation of vascular and other smooth muscles and in many of the metabolic effects of catecholamines.

24. Sympathomimetic agents and Classification of adrenergic agonist/ drugs

25. Sympathomimetic Agents Adrenergic Agonist A drug that mimics the effects of stimulating postganglionic adrenergic sympathetic nerves. Included in this class are  drugs  that directly stimulate adrenergic receptors and  drugs  that act indirectly by provoking the release of adrenergic transmitters . Adrenergic Drugs Adrenergic Agonist Sympathomimetic Agents

26. Sympathomimetics  are drugs that mimic the stimulation of the sympathetic nervous system. They are classified as directly  acting  (act directly on α or β receptors), indirectly  acting  (act by providing more norepinephrine to act on α or β receptors), or mixed  acting  (act by both mechanisms ). The adrenergic receptors are G-protine couple receptors . The knowledge of binding site is based on the mutagensis studies and molecular modelling. From these studies it has been proposed that the three of the trans membrane helices (TM3, TM5, TM6) are involved in the binding site, These studies also indicate the importance of an aspartic acid residue (Asp- 113), a phenylalanine residue(phe-290) and two serine residue(ser-207, ser- 204). Modelling studies indicates that these groups can bind to adrenaline or noradrenaline Sympathomimetic Agents Adrenergic Agonist

27. The Adrenergic Binding Site

28. Classification of adrenergic drugs

29. General pharmacology of adrenergic antagonist

30. Classification of adrenergic drugs A . According to mode of action: 1) Directly acting – adrenaline, noradrenaline, dopamine, isoprenaline . Indirectly acting – amphetamine, methamphetamine, By both mechanism – ephedrine, metaraminol . B . According to receptor selectivity: α1 agonist – methoxamine, phenylepeneprine . α2 agonist – clonidine, α- methyl noradrenaline. Both α1-α2 agonist - adrenaline, noradrenaline. β1 agonist – prenalterol , dobutamine . β2 agonist – salbutamol, terbutaline. Both β1–β2 agonist – adrenaline, isoproterenol. Both α - β agonist – adrenaline, ephedrine. C . According to chemical nature: Catecholamines – adrenaline, noradrenaline, dopamine, isoprenaline . Noncatecholamines – ephedrine, amphetamine, metaraminol . D . According to therapeutic effect: i . Vasoconstrictor – adrenaline, noradrenaline, ephedrine, metaraminol . Vasodilator – dopamine, isoprenaline . Bronchodilator – salbutamol, terbutaline. CNS stimulant – amphetamine, methamphetamine. Cardiac stimulant – adrenaline, isoprenaline , prenalterol . Nasal decongestant – ephedrine, oxymethazoline . Uterine relaxants – Nylidrine , salbutamol .

31. Indication of Adrenergic drugs: Heart block. Treatment of asthma e.g. salbutamol. Hypertension, cardiogenic shock. Used for prolongation of local anesthetic action by vasoconstriction e.g. adrenaline. To control local bleeding e.g. adrenaline. As nasal decongestant e.g. oxymethaoline. Inhibition of uterine contraction e.g. nylidrine. Increase heart rate, increase force of contraction of heart, increase tissue perfusion. α agonist causes vasoconstriction β agonist causes vasodilation β2 agonist causes bronchial dilation Inhibit noradrenaline release. This is called auto inhibitory feedback mechanism noradrenaline release. Pharmacological action of Adrenergic drugs:

32. Sympathomimetic Agents

33. Clas s ifi c ation O f Di r e c t Acti n g Alpha A d r energic Agonist MOA: Adrenergic alpha-agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α₁ and α₂. Alpha 2 receptors are associated with sympatholytic properties. α Adrenergic agonists have the opposite function of alpha blockers . alpha-1 adrenergic receptor agonist Phenylephrine Methoxamine Midodrine Metaraminol alpha-2 adrenergic receptor agonist Clonidine Xylazine Guanfacine Guanabenz A p raclo n i d i n e Lofexidine SELECTIVE AGONIST

34. Classification of direct acting beta adrenergic agonist MOA: β adrenergic receptors are coupled to a stimulatory G protein of adenylyl cyclase. This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes, inactivate myosin light-chain kinase and activate myosin light-chain phosphatase. In addition, β 2 agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells. The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation.

35. Beta-1 receptor agonist Dobutamine Denopamine Xamoterol Prenalterol Dobutamine Denopamine Xamoterol p r enal t e r o l

36. Clenbuterol Isoe t ar i n e Salbutamol T e rb u t al i n e Colterol Orciprinaline Beta-2 receptor agonist Terbutaline Salbutamol Salmetrol Isoetarine C l en b uter o l Orciprinaline Colterol m e t ap r otere n ol NEWER DRUGS

37. Non selective adrenergic agonist MOA: They can stimulate either of the receptor i.e alpha as well as beta or both. Drugs Available Adrenaline Norepinephrine Isoprenaline Dopamine Ad r e n al i ne Norepinephrine Isoprenaline Do p amine

38. Mixed acting agonist Mixed - acting adrenergic agonists are compounds that cause activation of adrenergic receptors by both direct binding as well as release of endogenously-stored norepinephrine from presynaptic terminal. Ephedrine pseudoephedrine Ephedrine Pseudoephedrine

39. Indirect acting adrenergic agonist Indirect-acting adrenergic agonists are compounds that cause activation of adrenergic receptors by mechanisms other than their direct binding. MOA for indirect acting Indirectly acting adrenergic agonists affect the uptake and storage mechanisms involved in adrenergic signalling. Two uptake mechanisms exist for terminating the action of adrenergic catecholamines - uptake 1 and uptake 2 . Uptake 1 occurs at the presynaptic nerve terminal to remove the neurotransmitter from the synapse. Uptake 2 occurs at postsynaptic and peripheral cells to prevent the neurotransmitter from diffusing laterally .

40. There is also enzymatic degradation of the catecholamines by two main enzymes - monoamine oxidase and catechol-o-methyl transferase . Respectively, these enzymes oxidise monoamines (including catecholamines) and methylate the hydroxal groups of the phenyl moiety of catecholamines. These enzymes can be targeted pharmacologically. Inhibitors of these enzymes act as indirect agonists of adrenergic receptors as they prolong the action of catecholamines at the receptors. Indirect acting adrenergic agonist

41. co c a i n Sel e gi l ine enta c apone a m p h e t a m ine t y ramine The indirect acting adrenergic drugs may be classified as. Releasing agents- amphetamines, Uptake inhibitors- cocain MAO inhibitors- selegiline COMT inhibitors- entacapone

42. The drugs studied below are: Nor- epinephrine Epinephrine Phenylephrine Dopamine Methyldopa Clonidine Dobutamine Isoproterenol Terbutaline Salbutamol Bitolterol Naphazoline Oxymetazoline Xylomethazoline