Drugs act on ANS cholinergic agonists and antagonists

1. Drugs act on ANS cholinergic agonists and antagonists Dr. Hashem Mansour

2. OVERVIEW • Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of neuron involved in their mechanism of action. • The cholinergic drugs, which are activated by acetylcholine (ACh). • The adrenergic drugs act stimulated by norepinephrine or epinephrine.

4. Division of peripheral N. S

6. Neurotransmission at cholinergic neurons • Neurotransmission in cholinergic neurons involves six sequential steps: • 1) synthesis • 2) storage • 3) release • 4) binding of ACh to a receptor • 5) degradation of the neurotransmitter in the synaptic cleft • 6) recycling of choline and acetate.

7. Neurotransmission

8. CHOLINERGIC RECEPTORS • Two families of cholinoceptors, designated muscarinic and nicotinic receptors. • Distinguished from each other on the basis of their different affinities for agents that mimic the action of ACh (cholinomimetic agents).

9. Muscarinic • These receptors are selectively stimulated by muscarine and selectively blocked by atropine. • They are located primarily in heart, blood vessels, eye, smooth muscles and glands of gastrointestinal, respiratory and urinary tracts, sweat glands, and in the CNS.

10. Subtypes of muscarinic receptor • The muscarinic divided into 5 subtypes M1, M2, M3, M4 and M5. • M1: located in cortex, hippocampus and corpus striatum. • It plays a major role in mediating gastric secretion and relaxation of lower esophageal sphincter caused by vagal stimulation. • M2: Cardiac muscarinic receptors mediate vagal bradycardia. • M3: Visceral smooth muscle contraction and glandular secretions and vasodilatation.

11. Nicotinic • These receptors are selectively activated by nicotine and blocked by tubocurarine it is two subtypes NM and NN are recognized. • NM: These are present at skeletal muscle endplate They mediate skeletal muscle contraction. • NN: These are present on ganglionic cells, adrenal medullary cells, in spinal cord and certain areas of brain.

12. CHOLINERGIC DRUGS(Cholinomimetic, Parasympathomimetic) • These are drugs which produce actions similar to that of ACh, either by directly or indirectly. • CHOLINERGIC AGONISTS (direct acting) • Choline esters Alkaloids • Acetylcholine Muscarine • MethacholinePilocarpine • CarbacholArecoline • Bethanechol

13. ACTIONS of ACh • 1. Heart: Negative ionotropic and chronotropic effects • 2. Blood vessels: All blood vessels are dilated, thus, fall in BP and flushing. • 3. Smooth muscle: Tone and peristalsis in the gastrointestinal tract is increased and sphincters relax → abdominal cramps and evacuation of bowel. • Peristalsis in ureter is increased, the detrusor muscle contracts while the sphincter relaxes → voiding of bladder. • Bronchial muscles constrict → dyspnoea.

14. ACTIONS of ACh • 4. Glands Secretion from all parasympathetically innervated glands is increased—sweating, salivation, lacrimation. • 5. Eye Contraction of circular muscle of iris → miosis. • Contraction of ciliary muscle → reduction in intraocular tension.

15. CHOLINOMIMETIC ( direct acting) • Pilocarpine: exhibits muscarinic activity and used primarily in ophthalmology. • 1. Actions: similar to ACh. • 2. Therapeutic use: itis the drug of choice for both open -angle and angle-closure glaucoma. • Treatment xerostomia and Sjogren syndrome

16. Pilocarpine effect

17. Pilocarpine • Adverse effects: blurred vision, night blindness, and brow ache. • Poisoning characterized by exaggeration of various parasympathetic effects. • Parenteral atropine, is administered to counteract the toxicity of pilocarpine.

18. INDIRECT-ACTING CHOLINERGIC AGONISTS:ANTICHOLINESTERASE AGENTS • Inhibitors of AChE thus indirectly provide a cholinergic action by preventing the degradation of ACh. • This results in an accumulation of ACh in the synaptic Space. • Therefore, these drugs can provoke a response similar to Ach.

19. ANTICHOLINESTERASES (ACHEI) • Anticholinesterases (anti-ChEs) are agents which inhibit AChE. • Reversible • Carbamates • Physostigmine • Neostigmine • Pyridostigmine • Irreversible • Dyflos, Echothiophate , Malathion*

20. ACHEI effect

21. ACHEI (organophosphates) • 1.Physostigmine stimulates the muscarinic and nicotinic receptors. • 2. Therapeutic uses: Treatment of intestinal and bladder motility atony. • Treatment of overdoses of a atropine. • 3. Adverse effects: CNS may lead to convulsions at high doses. • Paralysis of skeletal muscle.

22. Physiostigmen side effects

23. TOXICOLOGY OF ANTICHOLINESTERASE AGENTS • Irreversible AChE inhibitors are commonly used as agricultural insecticides • Toxicity with these agents is manifested as nicotinic and muscarinic signs and symptoms (cholinergic crisis).

24. Treatment of ACHEI toxicity • Pralidoxime: (2-PAM) can reactivate inhibited AChE. • Athigher doses, may cause side effects similar to other AChE inhibitors. • B. Other treatments • Atropine to prevent muscarinic side effects of these agents. • Diazepamis also administered to reduce the persistent convulsion caused by these agents.

25. ANTICHOLINERGIC DRUGS (Muscarinic receptor antagonists, Parasympatholytic) • Anticholinergic drugs are those which block actions of ACh on ANS and in the CNS.

26. ANTICHOLINERGIC DRUGS • Atropine, scoplamine, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide, Trihexyphenidyl.

27. PHARMACOLOGICALACTIONS(Atropine) • 1. CNS Atropine has an overall CNS stimulant action. • Atropine stimulates many medullary centres—vagal, respiratory, vasomotor. • It suppresses tremor and rigidity of parkinsonism.

28. Atropineffcts • CVS: Heart tachycardia. • Eye: mydriasis, results in photophobia. • Smooth muscles All visceral smooth muscles are relaxed. constipation may occure. • Atropine causes broncho-dilatation • Glands Atropine markedly decreases sweat, salivary, tracheobronchial and lacrimal secretion. • Body temperature Rise in body temperature occurs at higher doses. Children are highly susceptible to atropine fever.

29. Therapeutic uses of anticholinergic agents • Ophthalmic: Topical atropine exerts both mydriatic • Cardiovascular: Treat bradycardia of varying etiologies. • Antisecretory: Sometimes used in the upper and lower respiratory tracts prior to surgery. • Antidote for cholinergic agonists: Treatment of organophosphate poisoning,

30. Therapeutic uses of anticholinergic agents • Parkinsonism: trihexiphenidyl hydrochloride. • Motion sickness: Hyoscine is highly effective. • Asthma: Ipratropium bromide.

31. Adverse effect of atropine

32. REHABILITATION FOCUS • Cholinomimetics may enhance or inhibit rehabilitation program. • Scheduling treatment Program will enhance functional or cognitive activities. • In patients with spastic bladder and incontinence, the therapist may reduce inadvertent voiding by scheduling treatment periods.

33. CLINICAL RELEVANCE FOR REHABILITATION • Adverse Drug Reactions • Shortness of breath and altered heart rate may both occur with muscarinic agonists. • Nicotine may increase blood pressure and possibly resulting cardiac arrhythmias. • Muscarinic agonists can decrease visual acuity by preventing pupillary dilation in response to decreased light. • Antimuscarinics can cause sedation and decrease cognitive function.

34. Effects Interfering with Rehabilitation • Bronchoconstriction may decrease patients' ability to participate in aerobic activities. • Hyperthermia, increased blood pressure and heart rate can also decrease patient participation in aerobic activities . • Sedation and decreased cognitive function can decrease patients' understanding of instructions for home treatment programs. • Changes in light levels in the room in conjunction with sedation may increase the chance of falls.

35. Possible Therapy Solutions • To avoid dyspnea and cardiac dysfunction, aerobic treatment prescriptions should be designed to allow the patient more time to achieve their aerobic goal. • If sedation or decreased cognitive function is a problem, consider therapy at the end of a dosage period when the drug's plasma levels will be at their lowest.