Clinical Pharmacology

1. Clinical Pharmacology Autonomic pharmacology Jane M Johnston Ph.D.

2. Efferent (motor) nerves • Two systems • Autonomic nerves (unconscious) • Eg cardiac output, respiration, etc • Somatic nerves (voluntary)

3. ANS branches • cholinergic fibres - acetylcholine • adrenergic fibresnoradrenaline (norepinepherine NE)

4. Functions and origins of the ANS

5. Action of ANS drugs • Drugs to block ANS chemical transmission • Drugs to mimic ANS action • ANS drugs can modify a variety of effector tissues • Cardiac muscle • Blood pressure • Exocrine glands

6. Cholinergic transmission • Acetylcholine is at motor neuron and CNS nerve terminals • Synthesized from • Acetyl coA (mitochondria) • Choline (dietary) • Catalyzed by choline acetyl transferase (ChAT) • Release is dependent on Calcium (Ca2+) • Causes muscle contraction

7. Acetylcholine • Identified 1921 • Present at all NMJ and also CNS • Synthesized in the axon terminal • Diffuses across synaptic cleft • Two receptor subtypes • Nicotinic ACh receptors • Muscarinic ACh receptors

8. The discovery of vagusstoff E.Chudler 2001

9. Neuromuscular Junction 1999 Sinauer Associates Inc

10. Acetylcholine and NMJ

11. Characteristics of a neurotransmitter • Synthesized in (or transported to) presynaptic terminal • Stored in vesicles • Regulated release • Receptor located on postsynaptic membrane • Termination of action

12. Synaptic vesicles at the NMJ (EM) Heuser and Heuser

13. Synthesis and release of neurotransmitters Synaptic Transmission in: Basic Neurochemistry 6th Edition

14. Presynaptic events • Calcium influx releases synaptic vesicles from microtubules • Movement of synaptic vesicles to sites of action • Interaction of specific proteins • Vesicle docking • Membrane fusion • Calcium dependent exocytosis

15. Fusion proteins regulate neurotransmitter release • Vesicle proteins • Synaptobrevin • Presynaptic membrane proteins • Syntaxins • SNAP-25

16. The SNARE hypothesis SNARE (Soluble N’ethylmalemide sensitive fusion Attachment protein REceptor) A. Pestronk www.neuro.wustl.edu/neuromuscular 2003

17. Many presynaptic proteins regulate neurotransmitter release Synaptic Transmission in: Basic Neurochemistry 6th Edition

18. Vesicular transport of NT – drug implications • Toxins targeting neurotransmitter release • Spider venom (excess ACh release) • Botulinum (blocks ACh release) • Tetanus

19. Postsynaptic events • Boutons have multiple nerve terminals • Simultaneous release • Stimulation of contraction via AP • Acetylcholine degraded after action • ACETYLCHOLINESTERASE (AChE)

20. Motor neuron innervating skeletal muscle

21. Cholinergic receptors • Two classes for acetylcholine • Nicotinic and muscarinic • Nicotinic are ion channels Ionotrophic • Muscarinic are G-protein coupled Metabotrophic

22. Nicotinic AChR are sodium channels 1999 Sinauer Associates Inc

23. Ionotropic AChR • Consist of five polypeptide subunits • Receptors vary in: • subunit structure • agonist sensitivity • distribution • Mediate fast synaptic transmission

24. Muscarinic AChR activate G-proteins 1999 Sinauer Associates Inc

25. Metabotropic AChR • Five muscarinic AChR subtypes • G protein coupled • Slower synaptic transmission via intracellular signaling cascade

26. Mode of cholinergic drug action • Cholinomimetics • agonist • antagonist • Cholinesterase inhibitors • Clinical applications

27. Cholinomimetics Katzung, 2001

28. AChR agonists and antagonists • Nicotinic AChR agonists • Nicotine • Nicotinic AChR antagonists • Strychnine • Snake toxins • Bungarotoxin • Muscarinic AChR agonist • Muscarine • Muscarinic AChR antagonists • Atropine

29. Cholinesterase inhibitors • Inhibit breakdown of acetylcholine at the synapse • Act by • Binding to acetylcholine esterase (steric hinderance or hydrolysis) • Actions of acetylcholine persist at synapse • Pesticides and nerve gases

30. Clinical Implications • Myasthenia Gravis • Glaucoma • Cholinergic poisons • CNS – • Alzheimer’s Disease • Schizophrenia

31. Myasthenia gravis • Affects skeletal muscle at NMJ • Involves autoimmunity to nicotinic receptors • Extreme weakness, difficulty speaking, eating, breathing • Cholinesterase inhibitors for therapy

32. Adrenergic transmission • Catecholamines are the neuroTs • Complex synthesis • Secretion at nerve terminals and adrenal glands • Adrenal glands • Two adrenal glands • Consist of cortex (outer) medulla (inner) medulla secretes: • Epinephrine (adrenaline) • Norepinephrine

33. NE and E are released at nerve terminals and secreted by the adrenal medulla

34. Norepinephrine and epinephrine • Catecholamines • Synthesized from dopamine • Present in CNS and sympathetic nerves • Widely distributed, general behavioral arousal eg raise blood pressure etc • Stress increases release of norepinephrine

35. Synthesis of norepinephrine (NA)

36. Synthesis of epinephrine (adrenaline)

37. Adrenergic receptors • Four receptor subtypes • a1, a2, b1, b2 • G protein linked • Bind either norepinephrine or epinephrine

38. Sympathetomimetic drugs • Can act directly or indirectly • Direct binding to receptors • Epinepherine, dopamine (CNS and renal) • Indirectly • Drugs targeting synthesis and release of NE and NA egDBH inhibitors, reserpine - depletes stores • Drugs targeting reuptake at synapse eg cocaine, Tricyclic antidepressants

39. Importance of sympathetomimetic drugs • Cardiovascular system • Regulation of smooth muscle affects heart and blood pressure • beta blockers • Respiratory tract • Smooth muscle relaxation – bronchodilation • Isoproterenol, albuterol (asthma) • Metabolic effects • Liver effects, insulin secretion • CNS • Nervousness, emotional well-being, psychosis etc