ADRENERGIC TRANSMISSION AUTONOMIC PHARMACOLOGY BY DR UMAR SHARIF ABDULSALLAM

Adrenergic transmission

1. ADRENERGIC TRANSMISSION AUTONOMIC PHARMACOLOGY DR. UMAR SHARIF ABDUSSALAM MBBS, MSc , PhD Department of Clinical Pharmacology and Therapeutics Faculty of Basic Clinical Sciences Bayero University, Kano

2. OUTLINE Learning objectives Introduction to the course Synthesis, Storage, Release and Metabolism of Noradrenaline Neuronal and Extraneural uptake of Noradrenaline Drugs affecting storage, release and metabolism of Noradrenaline Adrenoceptors Pharmacological actions of Noradrenaline

3. LEARNING OBJECTIVES After completing this lecture, students should be able to: Describe the synthesis, storage, release and metabolism of Noradrenaline Appreciate the molecular mechanisms of adrenoceptors activation Appreciate the role of neuromodulators on adrenergic transmission Understand the pharmacological actions of catecholamines

4. INTRODUCTION The sympathetic nervous system is an important regulator of virtually all organ systems The autonomic nervous system is crucial for the maintenance of blood pressure even under relatively minor situations of stress ( e.g. the gravitational stress of standing ) The ultimate effects of sympathetic stimulation are mediated by release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites

5. INTRODUCTION Also, in response to a variety of stimuli such as stress, the adrenal medulla releases epinephrine, which is transported in the blood to target tissues Sympathetic nerves release norepinephrine while adrenaline is secreted into the bloodstream by adrenal medulla Epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter

6. INTRODUCTION ANS has 2 neurons in the efferent pathway 1 st neuron has its cell body in gray matter of brain or spinal cord. Preganglionic neuron. 2 nd neuron synapses with 1 st neuron within an autonomic ganglion. Postganglionic neuron . Preganglionic autonomic fibers originate in midbrain, hindbrain, and upper thoracic to 4 th sacral levels of the spinal cord Presynaptic neuron is myelinated and postsynaptic neuron is unmyelinated Autonomic nerves release neurotransmitter(s) that may be stimulatory or inhibitory

7. INTRODUCTION

8. CONTROL OF ANS Sensory input transmitted to brain centers that integrate information Can modify activity of preganglionic autonomic neurons Medulla: Directly controls activity of autonomic system Location of centers for control of cardiovascular, pulmonary, urinary, reproductive and digestive systems Hypothalamus: Regulates medulla Cerebral cortex and limbic system: Responsible for visceral responses that are characteristic of emotional states

9. NEUROTRANSMITTER Neurotransmitters are chemical messengers produced by the nervous systems of higher organisms in order to relay a nerve impulse from one cell to another cell The two cells may be nerve cells, also called neurons, or one of the cells may be a different type, such as a muscle or gland cell Neurotransmitters are formed in a presynaptic neuron and stored in small membrane-bound sacks, called vesicles , inside this neuron

10. NEUROTRANSMITTER Criteria: Found and made presynaptically Mechanism for inactivation Stimulating neuron releases it Receptors found postsynaptically Has a specific agonist which mimics its biological effect Has a specific antagonist which inhibits its biological effect

11. NEUROTRANSMITTER The primary neurotransmitter of both sympathetic and parasympathetic preganglionic neurons is A cetylcholine The primary transmitter of sympathetic postganglionic fibers is usually noradrenaline (NA), but at least some sympathetic postganglionic fibers to sweat glands are cholinergic ( acetylcholine) Dopamine is a neurotransmitter in the central nervous system and probably also in some neurons in the superior cervical ganglion and the kidney Noradrenaline, adrenaline and dopamine are sometimes collectively referred to as Catecholamines

12. Synthesis, Storage, Release & Metabolism of Norepinephrine

13. Synthesis, Storage, Release & Metabolism of Norepinephrine Tyrosine in the bloodstream is taken up into nerves and converted into catecholamine by the following enzymes : Tyrosine hydroxylase (Tyrosine to DOPA) is the rate limiting step in NA synthesis and is located in the cytoplasm . Catecholamines act as feedback inhibitors of this enzyme . A clinically useful inhibitor of this enzyme is Metyrosine Dopa decarboxylase (DOPA to Dopamine ) is found in the cytoplasm of many non-neural as well as neural tissues Dopamine-ß-hydroxylase (Dopamine to Noradrenaline ) is a copper-containing enzyme located primarily within the membrane of amine storage granules

14. Phenylethanolamine-N- methyltransferase (Noradrenaline to Adrenaline ) is restricted to the adrenal medulla and the brain with trace amounts in other locations Strongly inhibited by adrenaline (negative feedback mechanism) Glucocorticoid increases enzyme activity Local synaptic concentrations of catecholamines modulate their own release by interacting with presynaptic α 2 – receptors to reduce release of additional noradrenaline and presynaptic β 2 – receptors to increase release of noradrenaline Synthesis, Storage, Release & Metabolism of Norepinephrine

15. Synthesis, Storage, Release & Metabolism of Norepinephrine Released catecholamines may: be retaken up into the neuron (noradrenaline transporter or uptake I), is an energy requiring, saturable membrane transport system, that can be blocked by tricyclic antidepressants, amphetamine and cocaine be taken up by the extraneuronal tissue (uptake II), or be metabolized . Termination of action of released catecholamine varies with organ site: Heavily innervated tissues with narrow synaptic clefts like the heart depend on the noradrenaline transporter (90%) Less dense innervated tissues with wide synaptic clefts such as aorta rely more on enzymatic inactivation

16. METABOLISM OF CATECHOLAMINES The catecholamines may be metabolized by one of two enzymes : Monoamine oxidase is located in the outer membrane of mitochondria as well as extraneuronally, It occurs in two forms (A and B ) It converts catecholamines to their corresponding aldehydes Inhibitors include Pargyline , Tranylcypromine, and Selegiline Catechol-o-methyltransferase (COMT) is found especially in the liver and kidney

17. ADRENERGIC RECEPTORS The adrenergic receptors are divided into two subtypes based on their affinity for different agonists and antagonists alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors). Alpha receptors have also been subdivided into Alpha 1 (3 subtypes): alpha 1A , alpha 1B and alpha 1C Alpha 2 (3 subtypes): alpha 2A , alpha 2B and alpha 2C Beta receptors have been further subdivided into Beta 1, beta 2 , beta 3 receptors

18. Mechanism of Adrenergic Receptors Activation

19. Mechanism of Adrenergic Receptors Activation

20. RECEPTORS DISTRIBUTION & PHARMACOLOGICAL ACTIONS OF CATECHOLAMINES Alpha 1 Adrenergic receptor Location: Most vascular smooth muscle (Contraction) Pupillary dilator muscle (Contraction, Mydriasis and decreased aqueous secretion) Pilomotor smooth muscle (Erects hair) Prostate gland (Contraction), Male sex organ (Ejaculation) Glands (Secretion), Liver (Glycogenolysis) Heart (Increase force of contraction, Arrhythmia)

21. RECEPTORS DISTRIBUTION & PHARMACOLOGICAL ACTIONS OF CATECHOLAMINES Alpha 2 Adrenergic receptor Location: Prejunctional on nerve endings ( inhibits transmitter release ) Post junctional in the brain ( Decrease sympathetic outflow ) Pancreatic β cells ( Decrease insulin release ) Platelets ( aggregation ) Certain blood vessels ( vasodilation ) Fat cells ( Inhibits lipolysis )

22. RECEPTORS DISTRIBUTION & PHARMACOLOGICAL ACTIONS OF CATECHOLAMINES Beta 1 Adrenergic receptor Location: Heart ( Increases rate and force of contraction ) JGA in the kidneys ( Increases renin secretion )

23. RECEPTORS DISTRIBUTION & PHARMACOLOGICAL ACTIONS OF CATECHOLAMINES Beta 2 Adrenergic receptor Location: Respiratory, uterine and vascular smooth muscle ( Promotes smooth muscle relaxation ) Skeletal muscle ( Glycogenolysis, increases K + uptake ) Liver: ( activates glycolysis) GIT:( intestinal relaxation ) Eye: ( slight relaxation of iris, Enhanced aqueous secretion ) Urinary tract: ( relaxation of detrusor muscle )

24. RECEPTORS DISTRIBUTION & PHARMACOLOGICAL ACTIONS OF CATECHOLAMINES Beta 3 Adrenergic receptor Location: urinary bladder ( Relaxes detrusor muscle ) Adipose tissue ( Activates lipolysis ) D 1 Dopamine receptor: smooth muscle ( Dilates renal blood vessels ) D 2 Dopamine receptor: Nerve endings ( Modulates transmitter release )

25. RELATIVE RECEPTOR AFFINITIES Alpha agonist Effects on receptor Phenylephrine, Methoxamine α1 > α2 >>>>> β Clonidine, Methylnorepinephrine α2 > α1 >>>>> β Mixed Alpha And Beta Agonists Norepinephrine α1 = α2; β1 >> β2 Epinephrine α1 = α2; β1 = β2 Beta Agonists Dobutamine β1 > β2 >>>> α Isoproterenol β1 = β2 >>>> α Albuterol, Terbutaline, Metaproterenol , Ritodrine β2 >> β1 >>>> α Dopamine Agonists Dopamine D1 = D2 >> β >> α Fenoldopam D1 >> D2

26. ADRENERGIC DRUGS AUTONOMIC PHARMACOLOGY DR. UMAR SHARIF ABDUSSALAM MBBS; M.Sc.; PhD

27. OUTLINE Learning objectives Introduction to the course Classification of adrenergic drugs Pharmacological actions of prototypes Clinical applications of adrenergic drugs

28. LEARNING OBJECTIVES After completing this lecture, students should be able to: Classify adrenergic drugs Appreciate the pharmacological actions of adrenergic drugs Appreciate the clinical applications of adrenergic drugs

29. INTRODUCTION Adrenergic drugs are drugs with actions similar to that of adrenaline or sympathetic stimulation Drugs that mimic the actions of adrenaline or noradrenaline are called sympathomimetic drugs. Adrenergic drugs are classified based on their mechanism of action

30. CLASSIFICATION OF ADRENERGIC DRUGS Adrenergic drugs are classified into: Direct agonists: they act directly as agonists and activate α and/or β adrenoceptors Adrenaline Noradrenaline Isoprenaline Phenylephrine Methoxamine Salbutamol Xylometazoline

31. CLASSIFICATION OF ADRENERGIC DRUGS (B) Indirect agonists: these are drugs which enhance the actions of endogenous catecholamines by: (i) Inducing the release of catecholamines by displacing them from the nerve endings ( e.g. Tyramine ) (ii) Decreasing the clearance of catecholamines by inhibiting their neuronal uptake (e.g. Cocaine ), TCA, e.g. Imipramine (iii) Preventing the enzymatic metabolism of noradrenaline (e.g. MAOIs- P argyline and COMTIs- E ntacapone )

32. CLASSIFICATION OF ADRENERGIC DRUGS (C) Mixed acting agonists : these are drugs that have both direct and indirect modes of actions e.g. E phedrine, Mephentermine

33. CLASSIFICATION OF ADRENERGIC DRUGS

34. CLASSIFICATION OF ADRENERGIC DRUGS The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for receptor subtypes and relative expression of these receptors in the target tissues The pharmacologic effects of indirect agonists are greater under conditions of increased sympathetic activity and noradrenaline storage and release

35. ADRENERGIC DRUGS ADRENALINE is an agonist at α 1 , α 2 , β 1 , β 2 and β 3 adrenergic receptors It is a very potent vasoconstrictor and cardiac stimulant It induces vasoconstriction in many vascular beds ( α -receptors) and vasodilatation in skeletal muscles ( β -receptors) Adrenaline increases systolic BP and decreases diastolic BP

36. ADRENERGIC DRUGS Noradrenaline is an agonist at both α 1 and α 2 receptors It also activates β 1 receptors with similar potency like adrenaline, but has little or no effect on β 2 receptors Consequently, Noradrenaline increases peripheral resistance and both systolic and diastolic BP

37. Direct- Acting α Agonist Oxymetazoline is a direct- acting α agonist used as a topical decongestant because of its ability to promote constriction of the vessels in the nasal mucosa and conjunctiva Overdose of Oxymetazoline may cause hypotension due to central Clonidine-like effect Other direct- acting α agonist used as a topical decongestant is Xylometazoline hydrochloride

38. α 1 -Selective Direct Acting Agonists Phenylephrine is an α 1 -selective direct acting agonist It has longer duration of action and is used as a decongestant Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine Midodrine is used primarily in the treatment of orthostatic hypotension caused by impaired autonomic nervous system function

39. α 2 -SELECTIVE DIRECT ACTING AGONISTS α 2 -selective agonists decrease BP through their actions in the CNS that reduce sympathetic tone These drugs are used in the treatment of HTN. e.g. Clonidine, Methyldopa, Guanfacine The major side effect of α 2 -selective agents is sedation

40. DIRECT- ACTING β AGONIST Isoproterenol is a very potent β 1 and 2 receptor agonist and has little or no effect on α receptors It has positive inotropic and chronotropic actions It is a potent vasodilator

41. β SELECTIVE AGONISTS The separation of β 1 and β 2 effects is sufficient to reduce adverse effects in many clinical situations β 1 -selective agents increase cardiac output with less reflex tachycardia than Isoproterenol, because they are less effective in activating vasodilator β 2 receptors

42. β SELECTIVE AGONISTS Dobutamine is a β 1 -selective agent and has a positive inotropic action more than chronotropic action It is used in the treatment of cardiogenic shock β 2 - selective agonists ( e.g Salbutamol, Salmetrol ) are used mainly in the treatment of: Bronchial Asthma COPD P remature labour

43. INDIRECT ACTING SYMPATHOMIMETICS (IAS) IAS can have one of two different mechanisms of action: (1) they may enter the sympathetic nerve ending and displaced stored catecholamine transmitter. Such drugs are called Amphetamine-like or displacers (2) they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter

44. INDIRECT ACTING SYMPATHOMIMETICS (IAS) Amphetamine is an important drug due to its use and misuse as a CNS stimulant Amphetamine crosses BBB and produces marked stimulant effect on mood and alertness and a depressant effect on appetite Amphetamine actions are mediated through the release of Norepinephrine and, to some extent, dopamine

45. INDIRECT ACTING SYMPATHOMIMETICS (IAS) Methylphenidate is an Amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of Amphetamine. Methylphenidate may be more effective in children with attention deficit hyperactivity disorder (ADHD)

46. INDIRECT ACTING SYMPATHOMIMETICS (IAS) TYRAMINE is a normal byproduct of tyrosine metabolism in the body It is an indirect sympathomimetic, inducing the release of catecholamines from noradrenergic neurones Tyramine can be produced in high concentration in protein-rich foods by decarboxylation of tyrosine during fermentation Patients treated with MAO inhibitors taking tyramine-containing food may have marked increased in BP. “Cheese reaction”

47. CATECHOLAMINE REUPTAKE INHIBITORS Many inhibitors of the amine transporters for norepinephrine, dopamine and serotonin are used in treating some medical conditions Many antidepressants can inhibit norepinephrine and serotonin reuptake to a different degree Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions are produced by potentiation of norepinephrine levels in noradrenergic synapses It is used in the treatment of attention deficit disorder

48. INDIRECT ACTING SYMPATHOMIMETICS (IAS) Cocaine is a local anaesthetic agent with peripheral sympathomimetic actions that result from inhibition of reuptake at noradrenergic synapses It freely enters CNS and produces an Amphetamine-like psychological effect that is shorter lasting and more intense than Amphetamine The major actions of Cocaine in the CNS is to inhibit dopamine reuptake into neurones in the “pleasure centers of the brain”

49. MIXED ACTING AGENTS Ephedrine occurs in various plants and has been used in china for over 2000 years. It was introduced into clinical use in 1924 as the first orally active sympathomimetic drug Ephedrine was used previously in the treatment of Asthma Psudoephedrine is an ephedrine enantiomer and is used as a component of many decongestant mixtures

50. CLINICAL APPLICATIONS OF ADRENERGIC DRUGS 1. Cardiogenic shock e.g. Dobutamine, Dopamine, Adrenaline 2. Chronic orthostatic hypotension e.g. Midodrine 3. Nasal decongestion e.g. Phenylephrine, Ephedrine, Pseudoephedrine Xylometazoline 4. Anaphylaxis e.g. Adrenaline 5. Narcolepsy e.g . Modafinil

51. CLINICAL APPLICATIONS OF ADRENERGIC DRUGS 6. ADHD e.g. Methylphenidate 7. Asthma and COPD e.g. Salbutamol, Salmeterol 8. Hypertension e.g. Clonidine 9. Mydriasis e.g. Phenylephrine 10. Skeletal muscle relaxation e.g. Tizanidine

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