AUTONOMIC PHARMACOLOGY CONTINUE Professor Dr Ahmed Abu Raghif

AUTONOMIC PHARMACOLOGY (CONTINUE) Professor Dr Ahmed Abu Raghif Ph. D Pharmacology

q. Complex Organ Control: The Eye • The pupil is under reciprocal control by the SANS (via receptors on the pupillary dilator muscle) and the PANS (via muscarinic receptors on the pupillary constrictor). • The ciliary muscle, which controls accommodation, is under primary control of muscarinic receptors innervated by the PANS, with insignificant contributions from the SANS. • The ciliary epithelium, on the other hand, has important β receptors that have a permissive effect on aqueous humor secretion.

Sympathetic: Contraction of radial muscle produces dilation (mydriasis) Parasympathetic: Contraction of circular muscle produces constriction (miosis) 11/21/2020

Cholinomimetic drugs ﺩﻛﺘﻮﺭ ﺃﺤﻤﺪ ﺃﺒﻮ ﺭﻏﻴﻒ Ph. D Pharmacology

q. Cholinomimetic drugs are drugs that mimic acetylcholine by directly or indirectly activating the receptors with which acetylcholine interacts. q. The direct-acting agents combine with the cholinoceptor in the same way as acetylcholine. a-Choline esters (acetylcholine, methacholine, carbachol, and bethanechol) b-Alkaloids (muscarine, pilocarpine, nicotine, lobeline). These agents differ in their spectrum of action (amount of muscarinic versus nicotinic stimulation) and in their pharmacokinetics. Both factors influence their clinical use.

q. The indirect-acting cholinesterase inhibitors have many effects like those of the directacting agonists, but they act by inhibiting the enzyme that terminates the action of endogenous acetylcholine. Ø Short-acting anticholinesterases edrophonium Ø Medium-duration anticholinesterases neostigmine Physostigmine Pyridostigmine Ø Irreversible anticholinesterases Organophosphate : parathion, Echothiophate

• Organ effects of cholinomimetic drugs • Cardiovascular effects. These include cardiac slowing and a decrease in cardiac output. • The latter action is due mainly to a decreased force of contraction of the atria, because the ventricles have only a sparse parasympathetic innervation and a low sensitivity to muscarinic agonists. • Generalised vasodilatation also occurs (a nitric oxide -mediated effect), and these two effects combine to produce a sharp fall in arterial pressure

• Sinoatrial node Decrease in rate (negative chronotropy), but note important reflex response in intact subject • Atria Decrease in contractile force (negative inotropy); decrease in refractory period • Atrioventricular node Decrease in conduction velocity (negative dromotropy), increase in refractory period • Ventricles Small decrease in contractile force

• Effects on the eye • Contraction of the ciliary muscle in response to activation of muscarinic r pulls the ciliary body forwards and inwards, thus relaxing the tension on the suspensory ligament of the lens, allowing the lens to bulge more and reducing its focal length. This parasympathetic reflex is thus necessary to accommodate the eye for near vision. • The constrictor pupillae is important also in regulating the intraocular pressure. In acute glaucoma, drainage of aqueous humour becomes impeded when the pupil is dilated, because folding of the iris tissue occludes the drainage angle, causing the intraocular pressure to rise.

• Activation of the constrictor pupillae muscle by muscarinic agonists in these circumstances lowers the intraocular pressure, although in a normal individual it has little effect. • The increased tension in the ciliary muscle produced by these drugs may also play a part in improving drainage by realigning the connective tissue trabeculae through which the canal of Schlemm passes

Sympathetic: Contraction of radial muscle produces dilation (mydriasis) Parasympathetic: Contraction of circular muscle produces constriction (miosis

q A-CHOLINE ESTERS • Acetylcholine Ø Activates muscarinic (M) and nicotinic (N) receptors Ø Rapidly hydrolyzed by cholinesterase (Ch. E); duration of action 5– 30 s; poor lipid solubility • Bethanechol: Ø Activates muscarinic (M) receptors; increases IP 3 and DAG Ø Indications: Bladder and bowel atony, for example, after surgery or spinal cord injury , congenital megacolon post operative urine retention, post partum urinary retention

Ø Pharmacokinetics: Oral, IM activity, poor lipid solubility: does not enter CNS; not active in eye after topical application Duration: 0. 3– 2 h Ø adverse effects: All parasympathomimetic effects: cyclospasm, diarrhea, urinary urgency, plus vasodilation, reflex tachycardia, and sweating Carbachol Activates muscarinic (M) and nicotinic (N) receptots. Used locally in treatment of glucoma (pilocarpine is preferable) Methacholine Used to test bronchial hyper-reactivity

• B-ALKALOIDS • Pilocarpine : Ø It induce contraction of ciliary muscle and smooth muscle of the iris sphincter (miosis) – facilitate aqueous humor outflow, drainage of the anterior chamber(Activates muscarinic (M) receptors; increases IP 3 and DAG) Ø Indications: - Sjögren's syndrome (increases salivation); - Consider to be drug of choice in emergency treatment of glaucoma (causes miosis, cyclospasm)

ØPharmacokinetics of Pilocarpine : Oral, IM activity Good lipid solubility, duration of action 30 min to 2 h topical activity in eye Similar to bethanechol but may cause vasoconstriction via ganglionic effect • Nicotine: Ø Activat nicotinic(N)receptor Like pilocarpine; Ø duration of action 1– 6 h; high lipid solubility

THE INDIRECT-ACTING CHOLINESTERASE INHIBITORS have many effects like those of the direct-acting agonists, but they act by inhibiting the enzyme that terminates the action of endogenous acetylcholine. q Reversible anticholinesterases Short-acting anticholinesterases edrophonium ØThe action of edrophonium is similar to physeostigmine, except that it is more rapidly absorbed and has short duration of action (10 -20 min). ØUsed in diagnosis of myasthenia gravis(I. V injection lead to rapid increase in muscle strength)

• Neostigmine Ø Action: Inhibitor of cholinesterase; amplifier of endogenously released Ach plus small direct nicotinic agonist action Ø Reversal of NM block caused by tubocurarine, treatment of myasthenia(Myasthenia Gravis appears to be caused by the binding of anti-nicotinic receptor antibodies to the nicotinic cholinergic receptor) Ø It differ from physeostigmine in: v. More polar(does not inter CNS) but orally active v. Has greater effect on skeletal muscles Ø Duration: 2– 4 h Ø Adverse effect: Generalized cholinergic stimulation

• Physostigmine • Action: Inhibitor of cholinesterase; amplifier of endogenously released ACh • Indications: v. Reversal of severe atropine poisoning (IV); voccasionally used in acute glaucoma (topical) (induce miosis and spasm of accommodation) v. Used in intestinal atony (increases their motility) • Pharmacokinetics: Lipid soluble; can be used topically in the eye. Duration of action: 2– 4 h • Adverse effect: Generalized cholinergic stimulation plus CNS effects: seizures

q. Irreversible anticholinesterases • Organophosphates are long-acting drugs; they form an extremely stable phosphate complex with the enzyme. After initial hydrolysis, the phosphoric acid residue is released over periods of days to weeks. Recovery is due in part to synthesis of new enzyme • Effects • By inhibiting cholinesterase, these agents cause an increase in the concentration, half-life, and actions of acetylcholine in synapses where acetylcholine is released physiologically. .

• Therefore, the indirect agents have muscarinic or nicotinic effects depending on which organ system is under consideration • Cholinesterase inhibitors do not have significant actions at uninnervated sites where acetylcholine is not normally released (eg, vascular endothelial cells). • Parathion v Insecticide only v. Duration: days to weeks Highly lipid-soluble Highly v dangerous insecticide; causes all parasympathetic effects plus muscle paralysis and coma

• Malathion v. Insecticide and scabicide (topical) v. Duration: days v. Highly lipid-soluble but metabolized to inactive products in mammals and birds v. Much safer insecticide than parathion • Ecothiophate, • Therapeutic uses: An ophthalmic solution of the drug is used directly in the eye for the chronic treatment of open-angle glaucoma. • The effects may last for up to one week after a single administration. • Echothiophate is not a first-line agent in the treatment of glaucoma.

v. Donepezil: v Cholinesterase inhibition plus variable other poorly understood effects USED in Alzheimer's disease Lipid soluble, enter CNS Half-lives: 1. 5– 70 h S. E Nausea, vomiting Alzheimer’s Disease pathology – loss of cholinergic neurons and reduced synthesis of ACh • Anticholinesterases may improve cognitive function and memory in up to 40% of patients

• Toxicity by organophosphorus is due to A- muscarinic effects (bradycardia, bronchoconstriction, excessive sweating, salivation, lacrimation, miosis, nausea, vomiting, abdominal cramps, urinary incontinence). B- nicotinic effects (muscle twitches, neuromuscular blockade of diaphragm and intercostal muscles). C- CNS effects (restlessness, insomnia, tremors, confusion, convulsions, coma, death from respiratory failure).

• Management of organophosphorus Toxicity • After standard protection of vital signs • the antidote of first choice is the antimuscarinic agent atropine , but this drug has no effect on the nicotinic signs of toxicity. • Nicotinic toxicity is treated by regenerating active cholinesterase. Immediately after binding to cholinesterase, most organophosphate inhibitors can be removed from the enzyme by the use of regenerator compounds such as pralidoxime and this may reverse both nicotinic and muscarinic signs • If the enzyme-phosphate binding is allowed to persist, however, aging (a further chemical change) occurs and regenerator drugs can no longer remove the inhibitor.

Clinical uses of cholinergic drugs 1. Glaucoma: a. Short acting (1 -2 hrs): Pilocarpine, carbachol b. Long acting (100 hrs): Ecothiophate, isofluorophate 2. Myasthenia gravis: a. Treatment: Neostigmine (rapid & short acting, 2 hrs) Pyridostigmine (slow & long acting, 6 hrs) b. Diagnosis: Edrophonium (very short acting, 15 min) 3. Paralytic ileus & urine retention: Post anesthesia & post operative Neostigmine, bethanechol 26

4. Reversal of muscle relaxation after anesthesia: Neostigmine, edrophonium 5. Anti-cholinergic poisoning: Physostigmine (being tertiary amine, lipid soluble, crosses blood brain barrier), controls central & peripheral symptoms 6. Dry mouth in Sjogren syndrome: Pilocarpine 7. Alzheimer’s disease: Donepezil, torcine 8. Helminthiasis (Scistosoma haematobium) Metrifonate 27

Anticholinergic drugs ﺩﻛﺘﻮﺭ ﺃﺤﻤﺪ ﺃﺒﻮ ﺭﻏﻴﻒ M B Ch B , M Sc, Ph. D

q. Anticholinergic drugs: • These drugs prevent the action of acetylcholine at postganglionic parasympathetic endings. • Acetylcholine is released but its receptor site is completely blocked by anticholinergic drugs. • The cholinoceptor antagonists are grouped into subclasses on the basis of their spectrum of action (ie, whether they block muscarinic or nicotinic receptors).

• Muscarinic Antagonists • Muscarinic antagonists can be subdivided according to their selectivity for specific M receptors or their lack of such selectivity. • Atropine is the prototypical nonselective muscarinic blocker • only 2 receptor-selective M 1 antagonists have reached clinical trials (eg, pirenzepine, telenzepine). • tolterodine and darifenacin (M 3 -selective) are new drugs that act on the bladder to inhibit micturition, and are used for treating urinary incontinence

• The muscarinic blockers can also be subdivided on the basis of their primary clinical target organs (CNS, eye, bronchi, or gastrointestinal and genitourinary tracts). • Drugs used for their effects on the CNS or the eye must be sufficiently lipidsoluble

q. Antimuscarinic, nonselective • tertiary amine Atropine, Scopolamine, Benztropine, Homatropine, cyclopentolate, tropicamide • quaternary amine Ipratropium, Oxybutynin, glycopyrrolate q. Antimuscarinic, selective • Darifenacin, tolterodine (M 3) • Pirenzepine, telenzepine(M 1)

• Pharmacokinetics of Atropine • Atropine is the prototypical nonselective muscarinic blocker. • This alkaloid is found in Atropa belladonna and many other plants. Because it is a tertiary amine, atropine is relatively lipid-soluble and readily crosses membrane barriers. • The drug is well distributed into the CNS and other organs and is eliminated partially by metabolism in the liver and partially unchanged in the urine. • The elimination half-life is approximately 2 h, and the duration of action of normal doses is 4– 8 h except in the eye, where effects last for 72 h or longer.

• Pharmacokinetics of Other Muscarinic Blockers • In ophthalmology, topical activity (the ability to enter the eye after conjunctival administration) and duration of action are important in determining the usefulness of several antimuscarinic drugs. • Similar ability to cross lipid barriers is essential for the agents used in parkinsonism. • In contrast, the drugs used for their antisecretory or antispastic actions in the gut, bladder, and bronchi are often selected for minimum CNS activity; these drugs may incorporate quaternary amine groups to limit penetration through the blood-brain barrier.

• Effects of Muscarinic Antagonists • The peripheral actions of muscarinic blockers are mostly predictable and include the ocular, gastrointestinal, genitourinary, and secretory effects. • The CNS effects are less predictable. CNS effects seen at therapeutic concentrations include sedation, reduction of motion sickness, and, as previously noted, reduction of some of the signs of parkinsonism