Sudan International University Pharmacology Lecture Notes (PDF)

‫بسم هللا الرحمن الرحيم‬ Sudan International University Faculty of Medicine Department of Pharmacology Qusay Osman Mohamed Abdalla B. Pharm., M. Pharm., Clinical Pharmacology qusaysiu22@gmail...

‫بسم هللا الرحمن الرحيم‬ Sudan International University Faculty of Medicine Department of Pharmacology Qusay Osman Mohamed Abdalla B. Pharm., M. Pharm., Clinical Pharmacology [email protected] 2023 3/20/2023 1  Lectures outlines: By the end of this lecture student should be able to know: 1) Parasympathetic nervous system. 2) Para-sympathomimetics (direct acting). 3) Indirect acing parasympathomimetics; classes, members, clinical uses, side effects. 4) Toxicity of cholinomimetics. 5) Parasympatholytics; members, clinical uses, side effects and toxicities. 3/20/2023 2  Parasympathetic Nervous system Rest and digest system. The main NT: Acetylcholine. Receptors: cholinergic receptors mainly muscarinic receptors. 3/20/2023 3  Parasympathomimetics 3/20/2023 4 3/20/2023 5  Parasympathomimetics: They mimic the actions of acetylcholine (parasympathetic), they devided into: (A) Direct-acting cholinomimetics: Direct-acting cholinomimetic agents bind to and activate muscarinic or nicotinic receptors directly. (B) Indirect-acting: Indirect-acting produce their primary effects by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid, By inhibiting acetylcholinesterase, the indirect-acting drugs increase the endogenous acetylcholine concentration in synaptic clefts and neuroeffector junctions. The excess acetylcholine, in turn, stimulates cholinoceptors to evoke increased responses 3/20/2023 6 (A)The direct-acting cholinomimetic drugs are further divided into: 1. Esters of choline (including acetylcholine, Methacholine, carbachol and bethanechol). 2. Alkaloids (such as muscarine and nicotine). 3/20/2023 7 Effects of muscarinic agonists: 3/20/2023 8 1- Effects on the eye (M3): a. It causes contraction of the smooth muscle of the iris sphincter (resulting in miosis). b. contraction of the ciliary muscle (resulting in accommodation). c. It facilitate aqueous humor outflow into the canal of Schlemm, which drains the anterior chamber. 3/20/2023 9 2- Cardiovascular system (M2): a. Cardiac slowing and a decrease in cardiac output. (Parasympathetic innervation of the ventricles is much less extensive than that of the atria; activation of ventricular muscarinic receptors causes much less physiologic effect than that seen in atria). b. Generalized vasodilatation also occurs (a nitric oxide- mediated effect). These two effects combine to produce a sharp fall in arterial 3/20/2023 pressure. 10 3- Respiratory system (M3): a. Muscarinic stimulants contract the smooth muscle of the bronchial tree. b. Increase bronchial secretion. (The combined effect of bronchial secretion and constriction can interfere with breathing). 4- Gastrointestinal tract (M1, M3): Administration of muscarinic agonists increases the secretory and motor activity of the gut. a. The salivary and gastric glands are strongly stimulated. b. Peristaltic activity is increased throughout the gut. c. Most sphincters are relaxed. 3/20/2023 11 5- Genitourinary tract (M3): In bladder they cause contraction of Detrusor muscle and relaxation of the trigon and sphincter smooth muscles. The human uterus is not notably sensitive to muscarinic agonists. 6- Secretory glands: Muscarinic agonists stimulate secretion of sweat, lacrimal, and nasopharyngeal glands. 3/20/2023 12 7- Central nervous system: Muscarinic agonists that are able to penetrate the blood- brain barrier produce marked central effects, due to activation mainly of M1-receptors in the brain. These include:  Tremor, hypothermia and increased locomotor activity, as well as improved cognition. (M1-selective agonists are being developed for possible use in treating dementia). 3/20/2023 13 Conclusion: 3/20/2023 14 Clinical uses of muscarinic agonist: 1. Treatment of glaucoma: The main use of muscarinic agonists is in treating glaucoma, by local instillation in the form of eye drops. Pilocarpine is the most effective as, being a tertiary amine; it can cross the conjunctival membrane. 2. Bethanechol is occasionally used to assist bladder emptying or to stimulate gastrointestinal motility. (It acts mainly on M3-receptors and has little effect on the heart). 3/20/2023 15 N.B: Ach. Has no therapeutic dose, why? 1- Hydrolyzed rapidly. 2- Irregular absorption. 3- Multiplicity of action (non selective). But may given in cataract surgery (Michol 10 mg/l) 3/20/2023 16  Unwanted effects:  Ophthalmology: cornea opacity  Systemic:  Headache, Bradycardia, Cardiac failure, Hypotension, Arrhythmias.  Flush, sweating.  Nausea, vomiting, salivation, abdominal spasm.  Bladder tension. 3/20/2023 17  (B) The indirect-acting cholinomimetic drugs: The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule by the action of acetyl-cholinesterase. Drugs can enhance cholinergic transmission by inhibiting cholinesterase enzyme. There are two distinct types of cholinesterases, namely Acetyl- cholinesterase (AChE) and Butyryl-cholinesterase (BChE): 3/20/2023 18 a- Acetylcholinesterase (True cholinesterase): Distribution: synaptic cleft at cholinergic synapses, cholinergic nerve terminals and erythrocyte. Substrate specificity: AChE is quite specific for acetylcholine and closely related esters such as methacholine. 3/20/2023 19 b- Butyrylcholinesterase (pseudocholinesterase): Distribution: has a widespread distribution, being found in tissues such as liver, skin, brain and gastrointestinal smooth muscle, as well as in soluble form in the plasma. Substrate specificity: it has a broader substrate specificity than AChE. It hydrolyses Butyrylcholine more rapidly than acetylcholine, as well as other esters such as procaine, and Suxamethonium. 3/20/2023 20  Cholinesterase Inhibitors Reversible Irreversible Medium acting Organophosphorus Short-acting Edrophonium Tertiary Ecothiophate Quaternary physostigmine ammonium cpd Pyridostigmine. Rivastigmine Neostigmine 3/20/2023 21 Cholinesterase Inhibitors (indirect-acting cholinomimetics): Anticholinesterase drugs fall into two main groups: A) Reversible anticholinesterase: 1- Short-acting anticholinesterases: Example: Edrophonium: (a quaternary ammonium group). It is used mainly for diagnostic purposes to diagnose myasthenia gravis; since the improvement of muscle strength by an anticholinesterase is characteristic of myasthenia gravis. 3/20/2023 22 2-Medium-duration of action anticholinesterases: Examples: (a) Quaternary ammonium compounds: Neostigmine, Rivastigmine Pyridostigmine and Ambenonium. (b) Tertiary amine: physostigmine (lipid soluble). is well absorbed from all sites and can be used topically on the eye and It is distributed into the central nervous system. 3/20/2023 23 b) Irreversible anticholinesterases: They are organic derivatives of phosphoric acid (organophosphates).  Eg, Soman, Sarin, parathion and ecothiopate. Most of these organophosphorus compounds were developed as war gases and pesticides as well as for clinical use (echothiophate). 3/20/2023 24 Effects of anticholinesterase drugs: 1- Effects on autonomic cholinergic synapses:  These mainly reflect enhancement of acetylcholine activity at parasympathetic postganglionic synapses (i.e. increased secretions from salivary, lacrimal, bronchial and gastrointestinal glands, increased peristaltic activity, bronchoconstriction, bradycardia and hypotension, pupillary constriction, fixation of accommodation for near vision, fall in intraocular pressure). Large doses can stimulate, and later block, autonomic ganglia, producing complex autonomic effects. [depolarization block]. Anti-cholinesterase poisoning (e.g. from contact with insecticides or war gases) causes severe bradycardia, hypotension and difficulty in breathing. Combined with a depolarizing neuromuscular block, and central effects, the result may be fatal. 3/20/2023 25 2- Effects on the CNS: Tertiary compounds (e.g. physostigmine) and the non-polar organophosphates penetrate the blood-brain barrier freely and affect the brain. The result is an initial excitation, which results in convulsions, followed by depression, which causes unconsciousness and respiratory failure. N.B: These central effects result mainly from the activation of muscarinic receptors and are antagonized by atropine. 3/20/2023 26 3- Eye, respiratory tract, gastrointestinal tract, urinary tract: Similar to the effects of the direct-acting cholinomimetics. 4- Cardiovascular system: The net cardiovascular effects of moderate doses of cholinesterase inhibitors consist of modest bradycardia, a fall in cardiac output, and no change or a modest fall in blood pressure. Large (toxic) doses of these drugs cause more marked bradycardia (rarely tachycardia) and hypotension. 3/20/2023 27 6- Neurotoxicity of organophosphates: Many organo-phosphates can cause a severe type of peripheral nerve demyelination, leading to slowly developing weakness and sensory loss. 3/20/2023 28  Clinical uses of anticholinesterase drugs: 1. Edrophonium (a short-acting drug) is given intravenously as a test for myasthenia gravis. 2. Neostigmine (2-4 hour duration) or Pyridostigmine (3-6 hour duration) is used to treat myasthenia gravis. 3. Ecothiopate eye drops are used to treat glaucoma. 4. To reverse the action of non-depolarizing neuromuscular- blocking drugs at the end of an operation. 5. Physostigmine used as antidote for muscarinic antagonist overdose. 3/20/2023 29 Conclusion: 3/20/2023 30 Toxicity of cholinomimetics: A. Direct-acting Muscarinic Stimulants: Drugs such as pilocarpine and the choline esters cause predictable signs of muscarinic excess when given in overdose. These effects include: Diarrhea, Urinary Urgency, Miosis, Bronchial Constriction, Bradycardia, Emesis (Nausea, Vomiting), Lacrimation, Salivation, Sweating and cutaneous vasodilation. ttt: The effects are all blocked competitively by atropine and its congeners. 3/20/2023 31  B) Indirect acting toxicity : The major source of cholinesterase inhibitors intoxications is pesticide use in agriculture and in the home. Acute intoxication must be recognized and treated promptly in patients with heavy exposure. The dominant initial signs are those of muscarinic excess: Miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system involvement and depolarizing neuromuscular blockade. 3/20/2023 32 Treatment: (1) Maintenance of vital signs: respiration in particular may be impaired. (2) Decontamination to prevent further absorption: this may require removal of all clothing and washing of the skin in cases of exposure to dusts and sprays. (3) Atropine parenterally in large doses, given as often as required to control signs of muscarinic excess. (4) Therapy may also includes treatment with pralidoxime. 3/20/2023 33  Cholinoceptor- Blocking Drugs 3/20/2023 34  Cholinocepter blockers Non Selective M1- selective Ganglia NMJ 3/20/2023 35 Cholinoceptor-Blocking Drugs: Cholinoceptor antagonists are divided into muscarinic and nicotinic subgroups. Ganglion-blockers and neuromuscular junction blockers comprise the anti- nicotinic drugs. The Muscarinic Receptor-blocking Drugs: Muscarinic antagonists (antimuscarinic) are sometimes called parasympatholytic. All of them are competitive antagonists. The two naturally occurring compounds, atropine and hyoscine, are alkaloids found in solanaceous plants. 3/20/2023 36 1-Atropine (hyoscyamine): Prototype. Found in the plant Atropa belladonna, or deadly nightshade, and in Datura stramonium ( thorn apple). 2-Hyoscine (Scopolamine): Occurs in Hyoscyamus niger, or henbane. These are tertiary ammonium compounds that are sufficiently lipid soluble to be readily absorbed from the gut or conjunctival sac and importantly, to penetrate the blood-brain barrier. 3/20/2023 37 3-Ipratropium, quaternary ammonium compound, is used by inhalation as a bronchodilator. 4-Cyclopentolate and Tropicamide are tertiary amines developed for ophthalmic use and administered as eye drops. 5-Pirenzepine: is a relatively selective M1- receptor antagonist. 6-Oxybutynin, Tolterodine and Darifenacin are new drugs developed for treating urinary incontinence. Though lacking receptor selectivity, they appear to act preferentially on the bladder to inhibit micturition. All produce unwanted effects typical of muscrinic antagonists. 3/20/2023 38 Mechanism of action: Atropine causes reversible competitive blockade of cholinomimetic actions at muscarinic receptors, ie, blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist. Atropine does not distinguish between the M1, M2, and M3 subgroups of muscarinic receptors (ie, non selective). 3/20/2023 39 Effects of muscarinic antagonists: 1- Inhibition of secretions: Salivary, lacrimal, bronchial and sweat glands are inhibited by very low doses of atropine, producing an uncomfortably dry mouth and skin. Gastric secretion is only slightly reduced. Muco-ciliary clearance in the bronchi is inhibited; as a result residual secretions tend to accumulate in the lungs. Ipratropium lacks this effect. 2- Effects on heart rate: Atropine causes tachycardia through block of cardiac muscarinic receptors. At very low doses, atropine causes a paradoxical bradycardia, which results from a central action, increasing vagal activity. 3/20/2023 40 3- Effects on the eye: The pupil is dilated (mydriasis) by atropine administration and becomes unresponsive to light. Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia); as a result, near vision is impaired. Intraocular pressure may rise; though this is unimportant in normal individuals, it can be dangerous in patients suffering from narrow-angle glaucoma. 4- Effects on the gastrointestinal tract: Gastrointestinal motility is inhibited by atropine. Pirenzepine, owing to its selectivity for M1-receptors, inhibits gastric acid secretion in doses that do not affect other systems. 3/20/2023 41 5- Effects on other smooth muscle: Bronchial, biliary and urinary tract smooth muscle are all relaxed by atropine. Atropine and similar drugs commonly precipitate urinary retention in elderly men with prostatic enlargement. 3/20/2023 42 6- Effects on the CNS: Atropine produces mainly excitatory effects on the CNS. At low doses, this causes mild restlessness; higher doses cause agitation and disorientation. These central effects are the result of blocking muscarinic receptors in the brain, and they are opposed by anticholinesterase drugs such as physostigmine, which is an effective antidote to atropine poisoning. Hyoscine in low doses causes marked sedation but has similar atropine effects in toxic concentrations. Hyoscine also has a useful antiemetic effect and is used in treating motion sickness. 3/20/2023 43 Muscarinic antagonists also affect the extrapyramidal system, reducing the involuntary movement and rigidity of patients with Parkinson's disease and counteracting the extrapyramidal side- effects of many antipsychotic drugs (dopamine antagonists). 3/20/2023 44 Clinical uses of muscarinic antagonists: 1- Cardiovascular: Treatment of sinus bradycardia (e.g. after myocardial infarction)- Atropine. 2- Ophthalmic: To dilate the pupil (diagnosis): e.g. Tropicamide eye drops or Cyclopentolate eye drops (longer acting). 3- Neurological: 1. Prevention of motion sickness: e.g. Hyoscine (orally or transdermally). 2. Parkinsonism, especially to counteract movement disorders caused by antipsychotic drugs: e.g. Benzhexol, Benztropine. 3/20/2023 45 4- Respiratory system: Asthma: Ipratopium by inhalation. 5- Anaesthetic premedication: To dry secretions: e.g. Atropine, Hyoscine. 3/20/2023 46 6- Gastrointestinal: 1. To facilitate endoscopy and gastrointestinal radiology by relaxing gastrointestinal smooth muscle (antispasmodic action), e.g. Hyoscine. 2. As an antispasmodic in irritable bowel syndrome or colonic diverticular disease, e.g. Dicycloverine (Dicyclomine). 3. To treat peptic ulcer disease by suppressing gastric acid secretion, e.g. Pirenzepine (M1-selective antagonist). 3/20/2023 47 7- Urinary disorders: A. Atropine and other anti-muscarinic drugs have been used to provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders. B. Oxybutynin, (selective for M3 receptors) is used to relieve bladder spasm after urologic surgery, eg, prostatectomy. It is also valuable in reducing involuntary voiding in patients with neurologic disease (incontinence). 3/20/2023 48 C. Imipramine (a tricyclic antidepressant drug) with strong anti-muscarinic actions, has long been used to reduce incontinence in elderly patients. It is moderately effective but causes significant central nervous system toxicity. D. Anti-muscarinic agents have also been used in urolithiasis to relieve the painful ureteral smooth muscle spasm caused by passage of the stone. 3/20/2023 49 8- Hyperhidrosis (excessive sweating) is sometimes reduced by anti-muscarinic agents. 9- Cholinergic poisoning: Antimuscarinic therapy Cholinesterase regenerator compounds: e.g (oxime agents include pralidoxime (PAM), diacetylmonoxime (DAM)) 3/20/2023 50 Adverse effects: At higher concentrations, atropine causes block of all parasympathetic functions. Dry mouth, mydriasis, blurred vision, tachycardia, hot and flushed skin, agitation, delirium and confusion. Body temperature is frequently elevated. These effects are memorialized in the adage, "dry as a bone, blind as a bat, red as a beet, mad as a hater." 3/20/2023 51 Contraindications: 1- Glaucoma, especially angle-closure glaucoma. 2- In elderly men, with a history of prostatic hyperplasia. 3-Nonselective anti-muscarinic agents should never be used to treat acid- peptic disease. 3/20/2023 52  Any Qs? 3/20/2023 53 3/20/2023 54