PARASYMPATHOMIMETICS. Indirec t

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1 PARASYMPATHOMIMETICS - These are drugs that stimulate the muscarinic receptors. - Classification: A. Direct Parasympathomimetics: They stimulate the Muscarinic Receptors directly: 1. Choline Esters: a. A.Ch. b. Methacholine. c. Carbachol. d. Bethanechol. 2. Cholinomimetic Alkaloids: a. Pilocarpine. b. Muscarine. Indirec t B. Indirect Parasympathomimetic (Anti-Cholinesterases); They Cholinesterase enzymes Accumulation of Endogenous A.Ch. 1. Reversible Anti-Cholinesterases: a. Quaternary Alcohols (Rapidly acting): Edrophonium b. Carbamate Derivatives (Slowly acting) 1. Physostigmine. 2. Neostigmine. 3. Neostigmine Substitues e.g. Pyridostigmine. 2. Irreversible Anti-Cholinesterases (Organophosphorus Compounds): They produce Non-competitive irreversible inhibition of C.E. e.g. a. Insecticides: Parathion & Malathion. b. War gases: Sarin, Tabun & Soman. c. Anti-Bilharzial: Metrifonate d. Anti-Glaucoma: - Echothiophate (Eye drops). - Isoflurophate (DFP): (Eye Ointment) N.B.: Parasympathomimetics that pass BBB are contraindicated in Parkinsonism Acetyl-choline - Natural Direct Parasympathomimetic Choline ester. - It is the chemical transmitter at: 1. All Post-ganglionic para-sympathetic 2. post-ganglion sympathetic to sweat glands 3. All Autonomic ganglia 4. Adrenal medulla 5. Neuromuscular junction 6. C.N.S.: Cortex & Spinal Cord. Ch.E enz + M.R Direct 67

2 Cholinergic transmission: 1-Synthesis of A.Ch: Choline Acetate + Co A + ATP Acetyl Co A Triethylcholine Vesamicol CAT - -. Ch.E Hemicholinium - Choline Acetic a. 1. Active Uptake of Choline occurs by cholinergic varicosity. N.B. Hemicholinium: Inhibits Neuronal Uptake of Choline 2. In mitochondria of cholinergic varicosity: Acetate + Co. A + A.T.P. Acetyl Co. A + A.D.P. 3. In cytoplasm of cholinergic Varicosity: Choline + Acetyl Co.A CholineAcetylTrarsferase(CAT) Cytoplasm A.Ch. + Co.A N.B. Triethylcholine: Inhibits utilization of choline by C.A.T. 2- Stotage: In specific Granules (Vesicles) inhibited by Vesamical (Experimental drug) 3- Release: by Exocytosis. N.B. Release is blocked by: Mg ++, Botulinium toxins & Procaine. 4- Fate: Metabolism by Acetyl-Cholinesterase enzyme. (NO Uptake). Pharmacokinetics of A.Ch: 1. Not Absorbed Orally: Quaternary Ammonium Compound N + Ionized. 2. Not pass B.B.B. 3. Fate: Hydrolyzed by Cholinesterase enzymes. NO Uptake. - Anionic CE Estratic Cationic Estratic + Types of Cholinesterase Enzymes: 1- Acetyl Choline estrase (True) 2- Butyryl Choline estrase (Pseudo) 68

3 Types of Cholinesterase Enzymes: Acetyl (true) Ch.E. Butyryl (pseudo) Ch.E. 1. Sites: All Cholinergic Sites, RBCs Liver & Plasma 2. Regeneration Time: 2-3 Months 2-3 Weeks 3. Substrates: 1- Endogenous A.Ch. 2- Methacholine 1- Exogenous A.Ch. 2- Butyryl Ch. 3- Succinyl Ch. 4- Procaine 5- Propanidid. 6- Mivacurium Mechanism of action of A.Ch: A.Ch. Stimulates directly both Muscarinic & Nicotinic Receptors. A. Muscarinic Receptors: 1. They are Membrane-bound G-linked receptors 2. They are classified into 5 types TYPE SITE MECHANISM BLOCKER M 1 Ganglia, Gastric Parietal Cells, Pre-Synaptic & C.N.S G q Phospholipase CI.P3 & D.A.G Pirenzepine Telenzepine Dicyclomine. (Dicycloverine) M 2 M 3 Myocardium, Smooth Muscles, Pre-synaptic & C.N.S Exocrine gl., Endothelium,Smooth m. & CNS - G i ca.m.p - K + Efflux As M 1 (G q ) Atropine Gallamine Atropine Tolterodine Oxybutinin Darifenacin Solifenacin Atropine. M 4 CNS locomotion As M 2 (G i ) Atropine. M 5 CNS As M 3 (G q ) Atropine. B) Nicotinic Receptors: There are 2 types of Nicotinic Receptors (N n & N m ): Site: Mechanism: Blocker N n -C.N.S., -Ganglia -Adrenal Medulla Opening of ion Channel Depolarization. Ganglion Blockers e.g. Nicotine L.D. N m Motor end plate of N-M junction. As N n N-M Blockers e.g. Curare. 69

4 Actions of A.Ch.: A)Muscarinic actions of A.Ch. 1-Eye: a. Miosis (Constrictor Pupillae Muscle) Wide Angle of Filtration. b. Spasm or Ciliary Muscle Open Canal Of Schlemm Accommodation for NEAR vision c. I.O.P. d. Lacrymation e. Conjunctival V.D 2. C.V.S: a. Heart: - ve Chronotropic & -ve Dromotropic. C.O. - Atrial conductivity b. Bl V.: VD (Through of non-innervated muscarinic receptors on endothelium(m 3 ) Endothelium Derived Relaxing Factor (EDRF) = Nitric Oxide cg.m.p. V.D.) c. Bl. Pr: Hypotension 3. Respiration: a. Bronchospasm. b. Bronchial Secretions. 4. G.I.T.: a. Secretion: Profuse & Watery. b. Contract the wall & Relax sphincters. 5. Urinary Bladder: Contract the wall & Relax the sphincter 6. Uterus: Contract Non-pregnant uterus. 7. Exocrine Glands: Stimulate all secretions e.g. Sweating. B) Nicotinic Actions of A.Ch.: Twitches + Hypertension 1- Autonomic Ganglia & Adrenal Medulla (N n ): - A.Ch. L.D. after Atropine Hypertension (A.Ch. Reversal): *Abolished either by Ganglion Blocker or Labetalol. *Reversed by Alpha-Blockers. SD LD M only M+N n SD M Atrop. SD N n LD 2- Motor End Plate Sk.m. Twitches ( N m ) Uses: not used clinically because: -not absorbed orally. - non-specific. - Short Duration. Synthetic Choline esters 1. They are Quaternary ammonium compounds but Effective Orally 2. Never injected I.V. or I.M. Toxicity, ttt by Atropine. 3. Contraindicated in: a. Thyrotoxicosis (Atrial Fibrillation). b. Angina Pectoris (Hypotension Coronary Flow). c. Bronchial Asthma (Bronchospasm & Secretion). d. Peptic Ulcer (Gastric Acid Secretions). 70

5 1. Kinetic: a- Oral absorption & Administration Not I.V. A. Ch. Methacholine Carbachol Bethanechol Partial Oral& S.C. Complete Oral, S.C. Eye drops. Complete Oral, S.C. Eye drops. b- Metabolism Both true & True Only Pseudo Not Not 2. Dynamic a- Muscarinic b- Nicotinic No 3. Specificity Not specific C.V.S. Eye, G.I.T., & U.B. Uses of Choline Esters : A. Methacholine: Oral, S.C. 1. Treatment of Paroxysmal Atrial Tachycardia (P.A.T.). 2. Treatment of Peripheral Vascular Disease (P.V.D.). 3. Diagnosis of Paroxysmal Pheochromocytona. 4. Provocative test for bronchial asthma. B- Carbachol & Bethanechol : Oral, S.C. & Eye Drops. 1- Eye drops in Glaucoma. (Miosis + I.O.P + Twitches with carbachol.) 2- Non-Obstructive e.g. Post-operative Paralytic Ileus. 3- Non-Obstructive e.g. Post-operative Retention of Urine. Cholinomimetic alkaloids Pilocarpine: Methach. Natural Alkaloid, of Plant Origin.,Tertiary amine Kinetics: 1- Given Orally. & Passes the B.B.B. (Avoid in Parkinsonism) 2- Not affected by Ch.E 2- Excreted in urine. Actions: 1- Direct Muscarinic Agonist: Specific on Eye, Secretions& smooth m. 2- Very Weak nicotinic. Uses: 1. Hair lotion to promote growth of Hair. 2. Miotic Eye Drops (Miosis + NO Twitches + IOP + Lacrymation). a. Treatment of Glaucoma. b. To Counteract Mydriatics. e.g after Fundus examination. c. Alternatively with mydriatics to cut recent adhesions between iris & lens. 3. Sialagogue to treat dry mouth (Xerostomia). 4. Diaphoretic: as non-specific treatment of fever. 71 Normal. Paroxysmal Pheochromo

6 Anti-CHOLINESTERASES Drugs that Cholinesterases Accumulation of Endogenous A.Ch They are either reversible or irreversible A- Reversible Anti-choline esterases 1. Quaternary Alcohols: (Rapidly acting) Edrophonium. Synthetic, Quaternary, Alcohol Anionic Estratic * Kinetic: 1. Given IV (Immediate Onset & Short Duration Edrophonium 5 minutes ) 2. Attaches mainly to the anionic site But Not substrate for the enzyme (Not Hydrolysed by the enzyme). 3. Excreted in Urine Unchanged. *Actions: 1. Rapidly Reversible Anti-Ch.E. muscarinic & nicotinic actions 3. Sk.m. stimulant, more specific than Neostigmine. 4. Ganglion stimulant. * Uses: I.V. a. Diagnosis of Myasthenia gravis. b. Differentiation between myasthenic & cholinergic crises Myasthenic crisis - Due to ineffective or insufficient treatment a.ch severe weakness - Edrophonium more weakness Cholinergic crisis - Due to excessive of choline estrase a.ch maintained depolarization & exhaustion - Edrophonium muscle improvement c. Curare poisoning (Edrophonium has to be repeated if used alone) d. Paroxysmal Atrial Tachycardia (PAT) Carbamate Derivatives: (Slowly acting) (Physostigmine, Neostigmine& Neostigmine substitute) a. Attach at both sites of the Enzyme. b. They are Substrate for the Enzyme. (Hydrolysed slower than A.Ch.) Anionic Estratic Stigmines 72

7 PHYSOSTIGMINE* (Eserine) NEOSTIGMINE (Prostigmine) 1. Nature: Natural from Physostima plant. Tertiary amine Synthetic Quaternary ammonium 2. Kinetics: 1. Well absorbed Orally 1. Irregular Oral absorption 2.Passes B.B.B. 2. Not pass B.B.B. 3. Rapid Metabolism by Ch.E. 3. Slow Metabolism by Ch.E 3. Dynamics: 1. Reversible Anti-Ch.E. A.Ch. like (Muscarinic & Nicotinic actions). 1. Reversible Anti Ch.E. A.Ch. like (Muscarinic & Nicotinic actions). 2. C.N.S. Stimulation 2. Direct Sk.m. Stimulant. 4. Uses: 1. Miotic eye Drops ½ - 1% 1. Myasthenia gravis: As Pilocarpine but with Diagnosis & treatment. twitches 2. I.V. in Atropine poisoning 2. Curare poisoning. 3. Alzheimer Disease 3. Paralytic Ileus.. 4. Retention of Urine. 5.P.A.T. 5. Toxicity 1. Exaggerated A.Ch.Like Actions. 2. Convulsions. 1. Exaggerated A.Ch. Like Actions 2. No Convulsions. Management 1. Atropine 1. Atropine 2. Anti-Convulsants. 2. No need for anti-convulsants *Neostigmine substitute: 1- Anti-Glaucoma: Demecarium eye drops 2- Anti-Myasthenia Gravis: Ambenonium & Pyridostigmine Like Neostigmine but. More specific on Sk.m. & Longer Duration 3- Anti- Retention of Urine & Anti- Paralytic Ileus: Benzpyrinium 4- Anti-Alzeheimer: - Tacrine: (hepatotoxic) - Donepezil: (not hepatotoxic) - Rivastigmine: (More selective on CNS) - Galantamine: (Anti-Ch.E & brain nicotinic receptors) Alzheimer disease: - It is the commonest cause of dementia in elders over 65 years - Cause: - Hyperactivity of glutaminergic neurons apoptosis - Marked loss of cholinergic innervation of cerebral cortex - Treatment: - Glutamate activity: Memantine (Block NMDA receptors of glutamate) - Ach activity: by choline estrase inhibitors (See above) - NB.: Ginkgo can be used to ttt dementia of Alzheimer disease * Physostigmine: obtained from African plant (Physostima), which has been long used both as a weapon & as an ordeal poison 73

8 Myasthenia Gravis A) Etiology: - Autoimmune disease due to antibody formation against N m -receptors of motor end plate impairing the responsiveness of the N-M junction muscle weakness B) Diagnosis: 1. IV Edrophonium: used for diagnosis & differentiate between Cholinergic & Myasthenic crises. 2. IM Neostigmine 0.5 mg + Atropine 0.5 mg. 3. Antibody titer. C) Treatment: 1. Neostigmine. Also Pyridostigmine & Ambenonium. Atropine may be added to block the unwanted muscarinic actions 2. Ephedrine & Caffeine are adjuvant to Neostigmine. 3. Immuno-suppressants: Steroids & Antimetabolites e.g. Azathioprine. 4. Thymectomy ( as the thymus gland may play an important role in the genesis of antibodies) 5. Plasmaphoresis (to purify plasma from antibodies) Drugs Contraindicated in Myasthenia Gravis: 1. Skeletal m. relaxants as curare & drugs having curare like effect 2. Antimicrobials: Aminoglycosides 3. Antiarrhythmics: Quinidine, Lidocaine 4. β-blockers e.g. Propranolol. 5. Lithium (presynaptic transmittion or postsynaptic receptors) 74

9 B- Irreversible Anti - Cholinesteraes: [Organophosphorus Compounds.] a. Attach to & phosphorylate the Estratic site. At first reversible then irreversible (Aging of Enzyme). b. The body has to Re-synthesize New enzymes. About 3 weeks for the Pseudo & 3 months for the True. c. Long duration of Action. *Include: 1. Insecticides: Parathion & Malathion. 2. War (Nerve) gases: Sarin, Tabun & Soman. 3. Anti-Bilharzial: Metrifonate 4. Anti-Glaucoma: - Echothiophate (Eye drops) - Isoflurophate (DFP): (Eye ointment) 75 Autonomic Nervous System *Pharmacokinetics: Highly lipid soluble & Absorbed from ALL sites even the skin except Echothiophte *Pharmacodynamics: Irreversible Non-Competitive Block Accumulation of Endogenous A.Ch. Muscarinic & Nicotinic Actions. *Toxicity: (Oragnophosporus Poisoning): Anionic OPC Estratic -Causes: 1. Inhalation of spray or dusts of insetieides 2. Contamination of skin or food -Manifestations: A) Muscarinic: - Miosis - Bronchospasm - Colic. - Lacrymation - Sweating - Salivation. - bronchial secretions Vomiting - Diarrhea - Urination - Bradycardia & Hypotension. B) Nicotinic: Sk.m. twitches followed by Paralysis C) C. N. S.: Excitation, Convulsions followed by Coma. - Cause of Death: Respiratory Failure (Central & Peripheral). -Treatment of Acute Toxicity: 1. Endotracheal Intubation & Artificial Respiration. 2. Decontamination: a. Remove contaminated Clothes & wash Skin by NaHCO 3. b. Stomach wash by NaHCO 3 if ingested. *3. ATROPINE:* - It is a life saving blocking peripheral Muscarinic & Central manifestations. - I.V. 2 mg / 10 minutes till Mydriasis, Dry mouth or Tachycardia. 4. Oximes (Cholinesterase Reactivators): Pralidoxime (PAM): Not passes BBB Di-Acetyl-Monoxime (D.A.M): Passes BBB. a. Useful only in early cases of poisoning as adjuvant to Atropine. b. They react with phosphorus Harmless Compounds = Chelation c. Reactivates recently inhibited enzymes before Aging. 5. Anti-Convulsants: as Diazepam

10 CHOLINOCEPTOR ANTAGONISTS 1. Muscarinic Antagonists = Parasympatholytics. 2- Nicotinic Antagonists = Ganglion Blockers & N-M Blockers Parasympatholytics [Antimuscarinic] Drugs that compete with A.Ch. for the Muscsarinic Receptors A) Natural: B) Synthetic Substitutes 1. Atropine 1. Mydriatics 2. Hyoscine (Scopolamine) 2. Antisecretory & Antispasmodics *They are of plant origin present in 3. For urinary incontinence - Atropa belladonna * - Datura Stramonium 4. Anti - Asthmatics. - Hyoscyamus niger 5. Anti-Parkinsonians. Atropine Natural Parasympatholytic, tertiary amine alkaloid Kinetics: 1. Absorbed from all sites but limited from Intact Skin. 2. Distributed all over the body & Passes B.B.B. 3. Metabolised in Liver. 4. Excreted in urine & Acidification of urine Its Excretion. N.B: Rabbits have atropinase enzyme. (Species Tolerance) Autonomic Nervous System Pharmacodynamics: - Local - Parasympatholytic - CNS A) Local Actions: a. Eye: 1. Onset: 60 minutes. Duration : 7-12 Days. 2. Paralysis of Constrictor Pupillae Muscle (C.P.M.) Passive Mydriasis: Loss of Light Reflex. Narrow Angle of Filtration. 3. Paralysis of Ciliary muscle Cycloplegia: Loss of accommodation for Near vision. Close canal of Schlemm. 4. Intra-Ocular Pressure (I.O.P.) (Contraindicated in Glaucoma) 5.Lacrymation. b- Skin & mucous membrane: Local analgesic action. * Atropa belladonna: Atropa, from a legendary Atropos, and belladonna (Italian: beautiful woman) as it dilates the pupil making the woman attractive 76

11 B) Parasympatholytic Actions: blocks all types of Muscarinic receptors. 1. C.V.S.: a. Heart (M 2 ): 1. Tachycardia: Initial bradycardia may occur due to initial block of Presynaptic M 1 receptors Release of A.Ch., or due to of C.I.C. 2. Atrial conductivity. 3. A-V conduction (+ve Dromotropic effect). b. Blood Vessels: 1. Theraputic Dose NO effect (NO Parasympathetic Tone). 2. Large dose especially in Children Atropine Flush. c. Blood Pressure: 1. Small Therapeutic Dose NO effect. 2. Reverse Hypotension of A.Ch. & Carbachol (M & N n ). 3. Abolishes Hypotension of Bethanechol (M Only). 2. Respiratory System: Bronchodilatation. & Dry Secretions (Avoid in Bronchial Asthma). N.B: Ipratropium & Oxytropium: Atropine substitute Bronchodilatation without dryness of secretions. Used by inhalation in Bronchial asthma 3. G.I.T.: a. Salivary secretion Dry mouth (Xerostomia). b.hcl secretion. c. Relax the wall & spasm the sphincters Constipation. 4. Urinary Tract: Relaxes the wall & spasm of the sphincter Retention of Urine 5. Skin: Sweating (Anhydrosis) leading to dry, red & hot skin. 6. ALL Exocrine secretions: except Milk, Bile & Urine C) C. N. S. Actions: 1. C.N.S. Stimulation.: Restlessness, Excitation, Hallucination, Mania &convulsions 2. Medulla: - R.C. (Analeptic), C.I.C. (Vagal Center) - Vomiting Center. 3. Basal Ganglia : Anti-Parkinsonian 77 (Brenner & Stevens 2006)

12 Uses of Atropine: Orally and Parenterally. 1. Antidote for Parasympathomimetic poisoning e.g. Organophosphorus 2. Preanaesthetic Medication: a. R.C. to counteract the depressant effect of Anaesthesia & Morphine b. Salivary & Bronchial secretions to prevent Aspiration c. To protect the heart from Vagal tone induced by Halothane d. Vomiting center 4. CNS: Parkinsonism 5. Skin: Hyperhydrosis (excessive sweating) 6. Eye: Mydriatic in Iridocyclitis, Uveitis & Corneal Ulcer. 7. CVS: - Vagotonia & Vaso-Vagal Attacks (Carotid Sinus Syndrome). - Heart Block - Excessive bradycardia 8. Respiration: Bronchial Asthma but Ipratropium & Oxytropium are better. 9. GIT: - Vomiting & Motion Sickness - Peptic Ulcer. - Intestinal & Biliary colic. - Diarrhoea 10. Urinary: - Renal colic - Nocturnal Enuresis & Incontinence Side Effects & Toxicity of Atropine: 1. Allergic manifestations 2. CNS manifistations: Hallucination, Mania & Convulsions followed by Coma. 3. Parasympatholytic manifestations: 1. Dry, Red & Hot Skin Atropine Flush. 2. Dry mouth 3. Blurring of Vision & Acute Glaucoma. 4. Tachycardia. 5. Distention, Constipation. & Retention of Urine. Treatment of Atropine Poisoning: 1. I.V. Physostigmine to correct Central & Peripheral Manifestations. 2. Symptomatic treatment: - for Convulsions Diazepam. - for Coma Artificial Respiration. - for Oral Poisoning Stomach Wash. -for fever Cold fomentations. Contraindications of Atropine: The main contraindications are: 1- Glaucoma 2- Senile hypertrophy of prostate 78

13 Hyoscine (Scopolamine) Natural, parasympatholytic, tertiary amine, alkaloid. Dynamics As Atropine but: 1. No Local Analgesic effect 2. Parasympatholytic effects are Stronger on Eye & Secretions and weaker on Heart & G.I.T 3. C.N.S.: a. Depressant: Sedation, Hypnosis & amnesia b. Euphoria. Uses: as atropine especially in: 1. Preanesthetic medication: Better than Atropine (Sedation, depression & amnesia) & preferred than atropine in cardiac & thyrotoxic patients ( less effect on heart) 2. Prophylaxis of Motion sickness 3. Labrynthitis & Meniere s disease NB.: It produces excitation & delirium if used alone in presence of pain Mydriatic Atropine substitute Atropine 1% Homatropine 1-2% Cyclopentolate & Tropicamde 0.5-1% Eucatropine 2-5% 1. Onset 60 Minutes 60 Minutes 30 Minutes Minutes 2. Duration 7-10 Days 24 Hours 6 Hours 3-4 Hours 3.Cycloplegia NO 5. Uses Iritis & Corneal Ulcer Fundus Examination N.B: They are contraindicated in Glaucoma Antisecretory & Antispasmodic Atropine Substitute: 1. Atropine Methyl Nitrate 2. Hyoscine Butyl Bromide (Buscopan) 3. Oxphenonium 4. Propantheline Uses: 1- Peptic Ulcer. 2- Colics: Intestinal, Biliary & Renal. N.B.: Pirenzepine, Telenzepine & Dicyclomine: Selective M 1 BlockerGastric acidityuseful in Peptic Ulcer. 79

14 Atropine substitutes used for Overactive bladder Autonomic Nervous System 1- Emepronium: Derivative of Propantheline. 2- Oxybutynin more selective for M 3 receptor 3- Tolterodine, Darifenacin & Solifenacin: as Oxybutinin Uses: 1- Urinary incontinence 2- Enuresis 3- Bladder spasm after urological surgery Ipratropium (Atrovent) 2- Oxytropium 3- Tiotropium Anti-Asthmatic Atropine substitute 1- Quaternary ammonium compound. 2- Bronchodilatation without dryness of bronchial secretion. 3- Inhalation in Prophylaxis of Bronchial Asthma Antiparkinsonian atropine substitute Trihexphenidyl (Benzhexol), Benztropine & Carmiphen (central antitussive) N.B.: Drugs having Atropine like effect: 1. Atropine substitutes 2. Antihistaminics (1 st generation) 3. Antipsychotic (eg.: chlorpromazine) 4. Antiarrhythmics (Disopyramide & Quinidine) 5. Antidepressants (Tricyclic antidepressants [strong] & MAO.I [weak]) 6. Meperidine 7. Gallamine 80

15 DRUGS AFFECTING GANGLION 81 Autonomic Nervous System 1. Ganglion stimulants They N n receptors (in both sympathetic and parasympathetic ganglion), so the effect will depend on the predominating tone. S.D depolarization followed by repolarization L.D depolarization followed by maintained depolarizationdepolarizing block They include: Nicotine and lobeline in small doses. Nicotine Mechanism of action: 1. ganglion in small dose and block in large dose. 3. catecholamine release from chromaffin tissue. 4. chemoreceptors in carotid and aortic bodies. 4. C.N.S. Actions: - C.V.S: Tachycardia, C.O., B.P., V.C. of all vessels except, coronary and skeletal (which are dilated). -Blood : Fatty acid concentration and platelet aggregation. - G.I.T. : Gut motility. - CNS: C.T.Z., ADH release, indirect R.C. & direct C.N.S.. N.B: Tolerance occurs on repeated use and cross-tolerance with lobeline. Acute toxicity: - Nausea, vomiting, diarrhea, - Hypertension then hypotension, - Miosis then mydriasis, - Convulsions, and respiratory then. Treated by: stomach wash with K-permanganate and artificial respiration. *Effect of chronic tobacco smoking: 1. GIT:Salivation and inhibition of hunger pains. 2. CVS:Extrasystole, atherosclerosis, angina pectoris and Buerger's disease. 3. Respiratory:Cancer lung and larynx - Nasopharyngeal and bronchial irritation 4. Eye:Spasm of retinal vessels, so acuity of vision (tobacco amblyopia). 5. Pregnancy:High incidence of abortion and neonatal mortality. Interactions: Tobacco smoking is enzyme inducer so decreases the effect of itself, caffeine, theophylline, and pentazocine. Contraindications: - Peripheral vascular disease - Angina pectoris - Hypertension - Arrhythmias - Respiratory diseases - Peptic ulcer. Lobeline Used as a respiratory stimulant (reflex) in neonatal asphyxia, it is given intraumbilical.

16 Classifications: 2- Ganglion blockers: Autonomic Nervous System a. Depolarizing blockers: They are ganglion stimulants in large dose, they produce initial stimulation then block (partial agonist). b. Non-depolarizing (competitive) blockers: 1. Quaternary amines: Tetraethylammonium (TEA), Hexamethonium, Pentamethonium, Pentolinium, and Chlorisondamine[Ecolid] 2. Tertiary amine (Pempidine). 3. Secondary amine (Mecamylamine) 4. Trimethaphan (Arfonad): Action: Normally the parasympathetic is predominating allover the body except on B.V., so ganglion blockers will produce effects as atropine + postural hypotension + impotence. Uses: Obsolete except Trimethaphan N.B:Trimethaphan: Short acting, given by IV infusion Actions: - Ganglion blocker - Histamine releaser - Direct vasodilator Uses: - Hypertensive emergency - To induce controlled hypotension in surgery 82