العوضي Pharmacology Lecture Notes PDF

5 Complete ANS 7 Prof. Dr. Mohammed El-Awady  Parasympatholytic A- Muscarinic-antagonists a) Natural Atropine and hyoscine They are...

5 Complete ANS 7 Prof. Dr. Mohammed El-Awady  Parasympatholytic A- Muscarinic-antagonists a) Natural Atropine and hyoscine They are long-acting and non-selective blockers (antagonists) at all M receptors 1. selective on UT and GIT 2. selective M1 3. selective on 4. centrally-acting 5. mydriatics- 6. For Overreactive antagonists respiratory tract cycloplegics Bladder Propantheline Pirenzepine ipratropium Benztropine Homatropine Oxybutynin Glycopyrrolate (short-acting) trihexphenidine (duration 1 day), Tolterodine b) Synthetic Homatropine tiotropium Cyclopentolate Darifenacin Hyoscine-N-butyl (long-acting) (duration 6-12 h) (Selective M3 bromide (Buscopan) Tropicamide antagonist). antispasmodic HCl inhaled as 3◦-amm compds can pass BBB (duration 2-6 h). secretion bronchodilators ttt of parkinsonism (in which dopamine is  leaving cholinergic Atropine has very ttt of in asthma but system predominates in long duration peptic ulcer mainly in COPD extrapyramidal system). (about 7 days) Pharmacological actions of M-antagonists On CVS 2- ON GIT 3- ON UT 4- On eye 5- respiratory tract (RT) initial bradycardia due to (M1&M3)👉 M3 passive mydriasis (by blocking M3 relaxation of M3 secretions and bronchodilation. stimulation of vagus nerve secretions (HCl, relaxation of circular muscle only radial muscle is active) and loss 6. Exocrine glands then tachycardia ( HR) saliva, pancreatic, urinary bladder of light reflex. M3 all exocrine secretions due to M2 blocking. gastric)& motility leading to urine Cycloplegia (loss of accommodation to the near 7- CNS  Conductivity of heart  HCl (M1) retention. vision due to paralysis of ciliary muscle).  Antiemetic little effect on blood vessels  motility (M3). IOP by paralysis of ciliary muscle block canal of  anti motion sickness (M3) schlemm decrease aqueous humor drainage.  antiparkinsonism. Dr.Islam Elshinawy  Pharmacology 1  Uses of M-antagonists 1- Treatment of peptic ulcer Pirenzipine 2- Antispasmodic atropine, propantheline 3- Antiparkinsonian benztropine 4- Treatment of bronchial asthma Ipratropium, tiotropium 5- Mydriatics /Cycloplegics Tropicamide, cyclopentolate 6- Treatment of organophosphorus poisoning Atropine 7- Treatment of nocturnal enuresis Oxybutynin, Tolterodine and Darifenacin 8- Pre-anaesthetic medication (atropine) to prevent vagal attack (block M2), prevent asphyxia through  bronchial secretions and saliva in addition to central stimulation of respiratory centre. 9- Antiemetic and for treatment of motion sickness. Hyoscine Adverse effects of M-antagonists ‫زغلوله الناشفه حبست جوزها ابوسريع‬ Dry blurred precipitation constipation urinary retention in high doses cause excitability, tremors, mouth vision of glaucoma (not used in prostatic enlargement) hyperthermia and tachycardia Atropine It is antimuscarinic (anticholinergic) drug Frequently used in patients with cardiac arrest, heart block or bradycardia characters When heart rate (H.R) falls to 40 beats/min or less, the emergency medical team will use atropine to H.R. by blocking muscarinic receptors in myocardium  Cardiac arrest in patients with significant bradycardia  First-degree heart block (AV block). Indications  During intubations as preanesthetic medications (When attempts at intubation lead to vagal nerve (a parasympathetic nerve) stimulation resulting in symptomatic bradycardia  Atropine should be given via rapid IV push at doses ranging from 0.5 to 1.0 mg every 3 to 5 minutes until the desired heart rate is achieved. N.B  Atropine products are unstable when exposed to light for long periods. They should be protected from light during storage Serious ADRs Less severe ADRs ADRs Worsening of MI, myocardial ischemia (anginal attacks). Dry mouth Blurred Constipation Urinary Mydriasis Atropine flush in Ventricular fibrillation vision retention children Ventricular tachycardia. CNS excitations: Nervousness, insomnia, mental confusion and even convulsion Palpitations Worsening of angle-closure glaucoma (due to mydriasis). Dr.Islam Elshinawy  Pharmacology 2  II- Nicotinic-antagonists: A- Ganglionic blockers Characters  Drugs which block or inactivate Nn receptors in all autonomic ganglia leading to inhibition of the release of ACh, NE, and Epi. Classification 1- Competitive ganglionic blockers 2- Depolarizing ganglionic blockers MOA ▲ They competitively block N1. ▲ In small dose they stimulate ganglia ▲ but in large dose they cause maintained depolarization leading to blocking or inactivating of the N1 in ganglia. Ex Hexamethonium, trimethaphan, mecamylamine Nicotine and dopamine They suppress both sympathetic and parasympathetic NS and the net effect depends on the predominant tone (which of the 2 systems is more active). 1- Heart 2- Eye 3- GIT & UT Actions  Tachycardia (by blocking parasympathetic NS)  Mydriasis & cycloplegia (by   motility leading to constipation and urine   contractility and orthostatic hypotension (by blocking blocking parasympathetic NS) retention (by blocking parasympathetic NS) sympathetic NS) Uses  Little used now, only trimethaphan (short duration) is used as IV infusion to control hypertension. They were used as antihypertensives. N.B  Nicotine in cigarettes causes tachycardia, increase HCl (precipitate ulcer), increase GIT & UT motility, increased bronchial secretions and cough. In ‫من الكتاب لم‬ addition, cigarettes contain compounds that can cause cancer and atherosclerosis. ‫تشرح‬  Nicotine in large dose acts as ganglionic blocker and CNS stimulant (symptoms as above in addition to muscle twiches and even convulsions). Skeletal muscle relaxants Central  Acting on cerebral cortex and/or spinal cord: Barbiturates- Benzodiazepines- Baclofen- mephenesine 1- NMBs 2- Direct skeletal muscle relaxant 3- Other Motor-end-plate blockers  Competitive Dantrolene  Botulinum toxin:  ACh release. Peripheral NMBs   Ca2+ release from endoplasmic reticulum.  β-bungarotoxin, Mg2+ and aminoglycosides: ACh release  Depolarizing  Used to reduce spasticity in hemiplegia and cerebral palsy. and block NM NMBs  Drug of choice for malignant hyperthermia  Local anaesthetics: block nerve action potential propagation Dr.Islam Elshinawy  Pharmacology 3  B- Neuromuscular blockers (NMBs) def  They block neuromuscular junction (motor-end plate) leading to relaxation of skeletal muscles  (eye muscles, face, neck, hands, feet, limbs, and finally respiratory muscles). Recovery is in the opposite direction A- Competitive NMBs B- Depolarizing (non-competitive) NMBs ▲ They block N2 receptors at motor-end plate  opening ▲ They initially produce stimulation of N2 receptors persistent opening of of sodium channels no depolarization relaxation. sodium channels sodium channels stay in the open state which cannot respond Classification to any stimuli (inactivated) muscle paralysis. Long acting Intermediate Short acting Ex. Suxamethonium (succinylcholine) and decamethonium. Pancuronium, Vecuronium, Mivacurium Atracurium NB. D-tubocurarine, gallamine not used now. Pharmacokinetics  Most NMBs are quaternary compounds – not absorbed orally and Do not cross blood brain barrier or placenta, thus administered IV.  Succinylcholine is metabolized by pseudocholinesterase (If genetically deficient, prolonged apnea).  Atracurium is inactivated in plasma by spontaneous non-enzymatic degradation (Hoffman elimination). Uses of NMBs 1- Surgical operations 2- Electroshock theapy and certain types of 3- Endoscopy and endotrachial intubation (pre-anaesthetic medications). convulsions Adverse effects 1- Histamine release leading to hypotension and allergic reactions. 2- Atropine-like effects. 3- Malignant hyperthermia (succinylcholine) Comparison of NMBs Competitive NMBs Depolarizing NMBs Initial stimulation (fasciculations) Absent Present Type of paralysis Flaccid Spastic Effect of neostigmine Antagonism Enhance block Effect of d-tubocurarine Enhance block Decrease block Effect of myasthenia gravis Enhance block Decrease block Antidote Neostigmine + atropine None- plasma transfusion + artificial respiration END of ANS Dr.Islam Elshinawy  Pharmacology 4