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Home , Choline, Triethylcholine

Autonomic Nervous System

PARASYMPATHOMIMETICS

- These are that stimulate the muscarinic receptors. - Classification:

A.ch A.ch M.R A. Direct Parasympathomimetics: – – –

They stimulate the Muscarinic + Receptors directly: Ch.E enz 1. Esters: Indirec – a. A.Ch. b. . t c. . d. . Direct 2. Cholinomimetic : a. . b. . ------B. Indirect Parasympathomimetic (Anti-);

They § ¢ Accumulation of Endogenous A.Ch.

1. Reversible Anti-Cholinesterases: a. Quaternary Alcohols (Rapidly acting): b. Derivatives (Slowly acting) 1. . 2. . 3. Neostigmine Substitues e.g. .

2. Irreversible Anti-Cholinesterases (Organophosphorus Compounds): They produce Non-competitive irreversible inhibition of C.E. e.g. a. Insecticides: & . b. War gases: , & . c. Anti-Bilharzial: d. Anti-Glaucoma: - (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. 6. C.N.S.: Cortex & Spinal Cord .

67 Autonomic Nervous System

Cholinergic transmission: 1-Synthesis of A.Ch:

Acetate + Co A + ATP Choline Acetyl Co A

CAT - A.ch A.ch A.ch. - Ch.E

Acetic a. Hemicholinium - Choline

1. Active Uptake of Choline occurs by 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) A.Ch. + Co.A Cytoplasm N.B. Triethylcholine: Inhibits utilization of choline by C.A.T. 2- Stotage: In specific Granules (Vesicles) ¢ inhibited by Vesamical (Experimental ) 3- Release: by . N.B. Release is blocked by: Mg++, Botulinium toxins & Procaine. 4- Fate: by Acetyl-Cholinesterase . (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 Estratic - CE

Cationic Estratic + A.ch

Types of Cholinesterase Enzymes: 1- Acetyl Choline estrase (True) 2- Butyryl Choline estrase (Pseudo)

68 Autonomic Nervous System

Types of Cholinesterase Enzymes:

Acetyl (true) Ch.E. Butyryl (pseudo) Ch.E. 1. Sites: All Cholinergic Sites, RBCs & Plasma 2. Regeneration Time: 2-3 Months 2-3 Weeks 3. Substrates: 1- Endogenous A.Ch. 1- Exogenous A.Ch. 2- Methacholine 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 M1 Ganglia, Gastric Parietal Gq ¢£ Cells, Pre-Synaptic & C.N.S C¢£I.P3 & D.A.G Dicyclomine. () M2 Myocardium, Smooth - Gi ¢§ cA.M.P Gallamine + Muscles, Pre-synaptic & - £ K Efflux Atropine C.N.S M3 Exocrine gl., Endothelium As M1 (Gq ) ,Smooth m. & Oxybutinin CNS Atropine. M4 CNS ¢£locomotion As M2 (Gi ) Atropine. M5 CNS As M3 (Gq ) Atropine.

B) Nicotinic Receptors: There are 2 types of Nicotinic Receptors (Nn & Nm):

Nn Nm Site: -C.N.S., Motor end plate of -Ganglia N-M junction. -Adrenal Medulla Mechanism: Opening of As Nn Channel ¢ Depolarization. Blocker Ganglion Blockers N-M Blockers e.g. L.D. e.g. .

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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: - Chronotropic & -ve Dromotropic. ¢§C.O. - £ Atrial conductivity b. Bl V.: VD (Through £of non-innervated muscarinic receptors on endothelium(M3) ¢ Endothelium Derived Relaxing Factor (EDRF) = Nitric Oxide ¢ £ cG.M.P. ¢ V.D.) c. Bl. Pr: 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 (Nn): - A.Ch. L.D. after Atropine ¢ Hypertension (A.Ch. Reversal): *Abolished either by Ganglion Blocker or Labetalol. *Reversed by Alpha-Blockers. M Nn SD M only

A.ch LD M+Nn A.ch A.ch A.ch Atrop. SD SD LD

2-£ Motor End Plate ¢ Sk.m. Twitches ( Nm)

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 Autonomic Nervous System

A. Ch. Methacholine Carbachol Bethanechol 1. Kinetic: a- Oral absorption Not Partial Complete Complete & Administration I.V. Oral& S.C. Oral, S.C. Oral, S.C. Eye drops. Eye drops.

b- Metabolism Both true & True Only Not Not Pseudo 2. Dynamic a- Muscarinic +++ +++ +++ +++ b- Nicotinic +++ + +++ No 3. Specificity Not specific C.V.S. Eye, G.I.T., & U.B.

Uses of Choline Esters : Normal. A. Methacholine: Oral, S.C. 1. Treatment of Paroxysmal Atrial Tachycardia (P.A.T.). 2. Treatment of Peripheral Vascular Disease (P.V.D.). M ethach 3. Diagnosis of Paroxysmal Pheochromocytona. . 4. Provocative test for bronchial asthma. Paroxysmal Pheochromo 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:

Natural , 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 : Specific on Eye, Secretions& smooth m. 2- Very Weak nicotinic. Uses: 1. Hair lotion to promote growth of Hair. 2. Miotic Eye Drops (Miosis + Twitches § IOP + £ NO + 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 Autonomic Nervous System

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, 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 . b. Differentiation between myasthenic & cholinergic crises

Myasthenic crisis Cholinergic crisis - Due to ineffective or insufficient - Due to excessive § of choline estrase treatment ¢§ a.ch ¢ severe ¢£ a.ch ¢ maintained depolarization weakness & exhaustion - Edrophonium ¢ more weakness - Edrophonium ¢ muscle improvement

c. Curare poisoning (Edrophonium has to be repeated if used alone) d. Paroxysmal Atrial Tachycardia (PAT) ------

2. Carbamate Derivatives: (Slowly acting) (Physostigmine, Neostigmine& Neostigmine substitute)

a. Attach at both sites of the Enzyme. b. They are Substrate for the Enzyme. Anionic Estratic (Hydrolysed slower than A.Ch.)

Stigmines

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PHYSOSTIGMINE* NEOSTIGMINE (Eserine) (Prostigmine) 1. Nature: Natural from Physostima plant. Synthetic Tertiary amine 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. 1. Reversible Anti Ch.E. A.Ch. like (Muscarinic & A.Ch. like (Muscarinic & Nicotinic actions). 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 1. Exaggerated A.Ch. Like Actions. Actions 2. Convulsions. 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: - : (hepatotoxic) - : (not hepatotoxic) - : (More selective on CNS) - : (Anti-Ch.E & £ brain nicotinic receptors) ------Alzheimer disease: - It is the commonest cause of in elders over 65 years - Cause: - Hyperactivity of glutaminergic ¢ apoptosis - Marked loss of cholinergic innervation of cerebral cortex - Treatment: - § Glutamate activity: (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 Autonomic Nervous System

Myasthenia Gravis

A) Etiology: - Autoimmune disease due to antibody formation against Nm-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 & 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: , Lidocaine 4. β-Blockers e.g. Propranolol. 5. Lithium (§presynaptic transmittion or § postsynaptic A.ch receptors)

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B- Irreversible Anti - Cholinesteraes: [Organophosphorus Compounds.]

a. Attach to & phosphorylate the Estratic site. Anionic Estratic 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. OPC

*Include: 1. Insecticides: Parathion & Malathion. 2. War () gases: Sarin, Tabun & Soman. 3. Anti-Bilharzial: Metrifonate 4. Anti-Glaucoma: - Echothiophate (Eye drops) - Isoflurophate (DFP): (Eye ointment)

*Pharmacokinetics: Highly 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):

-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 - - 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 NaHCO3. b. Stomach wash by NaHCO3 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): ¢ (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 ¢ Harmless Compounds = Chelation c. Reactivates recently inhibited enzymes before Aging. 5. Anti-Convulsants: as Diazepam

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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 () 2. Antisecretory & Antispasmodics *They are of plant origin present in 3. For urinary incontinence - * - Stramonium 4. Anti - Asthmatics. - Hyoscyamus niger 5 . A n t i - 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)

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 Autonomic Nervous System

B) Parasympatholytic Actions: blocks all types of Muscarinic receptors. 1. C.V.S.: a. Heart (M2): 1. Tachycardia: Initial bradycardia may occur due to initial block of Presynaptic M1 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 & Nn). 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 , & 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

(Brenner & Stevens 2006) 77 Autonomic Nervous System

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 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

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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 & Eucatropine 1% 1-2% Tropicamde 0.5-1% 2-5% 1. Onset 60 Minutes 60 Minutes 30 Minutes 20-30 Minutes 2. Duration 7-10 Days 24 Hours 6 Hours 3-4 Hours 3.Cycloplegia ++++ +++ ++ NO 5. Uses Iritis & Corneal Fundus Examination Ulcer 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 M1 Blocker¢§Gastric acidity¢Useful in Peptic Ulcer.

79 Autonomic Nervous System

Atropine substitutes used for Overactive bladder

1- Emepronium: Derivative of Propantheline. 2- ¢ more selective for M3 3- Tolterodine, Darifenacin & Solifenacin: as Oxybutinin Uses: 1- Urinary incontinence 2- Enuresis 3- Bladder spasm after urological surgery ------

Anti-Asthmatic Atropine substitute

1- Ipratropium (Atrovent) 2- Oxytropium 3- Tiotropium

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 (1st generation) 3. Antipsychotic (eg.: ) 4. Antiarrhythmics (Disopyramide & Quinidine) 5. Antidepressants (Tricyclic antidepressants [strong] & MAO.I [weak]) 6. Meperidine 7. Gallamine

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DRUGS AFFECTING GANGLION

1. Ganglion stimulants • They £ Nn 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 depolarization¢depolarizing block • They include: Nicotine and 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 :£ 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: - , 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 smoking: 1. GIT:Salivation and inhibition of hunger pains. 2. CVS:Extrasystole, , angina pectoris and Buerger's disease. 3. Respiratory: lung and larynx - Nasopharyngeal and bronchial irritation 4. Eye:Spasm of retinal vessels, so § acuity of vision (tobacco amblyopia). 5. :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.

81 Autonomic Nervous System

2- Ganglion blockers: Classifications:

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: (TEA), , Pentamethonium, , and [Ecolid] 2. Tertiary amine (). 3. Secondary amine () 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

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