Parasympathetics and Pharmacolytics PDF

▪ The parasympathetic nervous system is often described as the "Feed and Breed" or "Rest and Digest" portion of the autonomic nervous system (ANS). ▪ The parasympathetic division of ANS maintains essential body functions, such as digestive processes and elimination of wastes, and i...

▪ The parasympathetic nervous system is often described as the "Feed and Breed" or "Rest and Digest" portion of the autonomic nervous system (ANS). ▪ The parasympathetic division of ANS maintains essential body functions, such as digestive processes and elimination of wastes, and is required for life. It usually acts to oppose or balance the actions of the sympathetic division. Parasympathomimetics ✓ The parasympathomimetics are also called the cholinomimetic drugs and they stimulate mainly the muscarinic receptors. 34 Classification: Direct acting and Indirect acting A - Direct parasympathomimetics: 1- Choline Esters : ▪ Natural : Acetylcholine ▪ Synthetic: Methacholine, carbachol, Bethanechol. 2- Natural Alkaloids :.Pilocarpine B- Indirect Parasympathomimetics (Anti-Cholinesterases): They ↓ cholinesterase enzymes → accumulation of endogenous Ach. 1- Reversible Anti-Cholinesterases: Edrophonium (rapidly acting) Neostigmine, physostigmine & pyridostigmine (slowly acting). 2- Irreversible Anti-Cholinesterases: They produce non-competitive irreversible inhibition of cholinesterase. Insecticides: parathion & malathion. War gases: soman & tabun Anti-Bilharzial : metrifonate. Anti-Glaucoma: echothiophate. Acetylcholine Acetylcholine is the postganglionic neurotransmitter in the parasympathetic nervous system. It is also the preganglionic neurotransmitter for both the sympathetic and parasympathetic nervous system. It is also important at non-autonomic sites, for example, Ach is the neurotransmitter by which motor nerves stimulate skeletal muscle, and also the neurotransmitter at many sites in the brain and spinal cord. Cholinergic transmission: Synthesis, release and degradation 35 -Active uptake of choline occurs by cholinergic varicosity. -In mitochondria of cholinergic varicosity: Acetate + CoA + ATP Acetyle CoA + ADP -In cytoplasm of cholinergic varicosity: Acetyle CoA + Choline CAT (choline acetyl transferase) Acetylcholine + CoA Storage: In specific granules and inhibited by vesamical. Release: by Exocytosis. It is blocked by Mg++ , botulinium toxins and procaine. Binding to the receptor: Acetylcholine released from the synaptic vesicles diffuses across the synaptic space. 36  Degradation of acetylcholine: The signal at the postjunctional effector site is rapidly terminated by acetylcholinesterase. Recycling of choline: Choline may be recaptured by a sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron, where it is acetylated into acetylcholine that is stored until released by a subsequent action potential. Pharmacokinetics: 1-Not absorbed orally: quaternary ammonium compound→ ionized. 2- Not pass B.B.B. 3- Fate: hydrolyzed by cholinesterase enzymes. No reuptake. N.B: Types of cholinesterase enzymes: 1-Acetyl choline esterase (True). 2-Butyrul choline esterase (Pseudo). Pharmacological actions: A- Muscarinic actions: 1-Eye: miosis, fix the accommodation for near vision,↑ lacrymation & ↓IOP. 3- C.V.S: - Heart : ↓ HR and SAN-conduction -Blood Vessels: Vasodiltation through the stimulation of muscrinic receptors in the endothelial cells (M3) of the vasculature→ release of nitric oxide (NO) → ↑ cGMP → V.D. despite of lack of cholinergic enervation in the BV. -Blood pressure: Hypotension. 37 3-GIT (↑motility, tone, and relax the sphinctors) 4-Urinary Tract (↑motility, tone, and realxs the sphinctors) 5-Bronchi (↑tone & secretion) 6-Exocrine Glands (profuse and watery secretions e.g. sweating) 7-Uterus: contract non pregnant uterus. B- Nicotinic actions: Twitches + Hypertension 1- Autonomic ganglia and adrenal medulla (Nn): Ach large dose (LD) after atropine → hypertension (Ach reversal): 2- Motor end plate→ skeletal muscle twitches (Nm). Uses: Not used clinically?? Synthetic Choline Esters: (e.g. carbacol, bethanehcole,…) 1- They are effective orally, never injected I.V or I.M and their toxicity treated by atropine. 2- Contraindicated in: a) Thyrotoxicosis (Atrial Fibrillation). b) Angina pectoris (Hypotension→↓ coronary flow). c) Bronchial asthma (Bronchospasm & ↑ secretions). d) Peptic ulcer (↑ Gastric acid secretions). 38  Methacholine Bethanechol Carbachol 1-Kinetic: a-Oral Oral &S.C. Oral, S.C. Oral, S.C. absorption Eye drops Eye drops &administration b-Metabolism Not Not True only 2-Dynamic: a-Muscarinic +++ +++ +++ b-Nicotinic + No +++ 3-Specificity C.V.S., R.S. GIT and Eye, GIT U.B. and U.B. 4-uses 1. Treatment of Post- Glaucoma paroxysmal operative Post- atrial paralytic operative tachycardia, ileus. paralytic Diagnose ileus. bronchial Urinary Urinary retention hyperreactivity retention 2. (bronchial challenge test) 39 Natural alkaloids (e.g. Pilocarpine) Pharmacokinitics: 1- Given orally& pass the B.B.B. 2- Excreted unchanged in the urine. 3- Not hydrolyzed by cholinesterases. Pharmacological Actions: 1- Mainly direct muscrinic actions Prominent ↑ in the secretory activity of the sweat glands, salivary, digestive, lacrimal and bronchial secretions. Miosis, ↓ I.O.P. ↑contractility of bronchi, intestine and urinary bladder 2- Very weak nicotinic action. Uses: 1- Hair lotion to promote hair growth. 2- Miotic eye drops → treat glucoma and counteract the medriatic effect ( iridocyclitis). 3-Xerostomia. Anticholinesterases Reversible Anticholinesterases They compete with Ach at its binding sites on the true- and pseudo-cholinesterase blocking its inactivation in a temporal way. The reversible anti-cholinesterases bind to the enzyme and hydrolyzed slowly than Ach. 40 Differences between physostigmine and neostigmine Physostigmine Neostigmine Kinetics ✓ It is Natural alkaloid ✓ Synthetic ✓ Tertiary amine ✓ Quaternary amine ✓ Cross B.B.B. (CNS and CVS ✓ Poorly absorbed from GIT toxicity {cholinergic syndrome}, ✓ Does not cross B.B.B. so its use is topical). Actions ✓ Muscarinic actions: eye (miosis, ✓ Mainly muscarinic on the contraction of the ciliary muscles GIT, urinary bladder and and ↓ I.O.P.). eyes. Skeletal muscles. ✓ Nicotinic action: twitches of eye lids. Uses ✓ Glaucoma ✓ Paralytic ileus ✓ Iridocyclitis ✓ Post-operative urine ✓ Poisoning of atropine and its retention. related drugs (i.v.) ✓ Antidote to competitive N- M-blockers ✓ Diagnosis and treatment of Myasthenia gravis. Side effects Exaggerated Ach like actions and No convulsions convulsions. It is treated with atropine Exaggerated Ach like actions and anticonvulsants. (mainly ocular as blurred vision). It is usually given along with a parasympatholytic drug such as atropine. 41 Edrophonium It has rapid onset and short duration of action Uses: Diagnosis of myasthenia Gravis Differentiate between Myasthenia Gravis and Cholinergic crisis. Antidote for Curare. Anticholinesterases used in Alzheimer disease  TACRINE→hepatotoxicity  DONEPEZIL, has an oral bioavailability of 100% and easily crosses the blood brain barrier.  Rivastigmine, can be administered orally or via a transdermal patch Irreversible Anticholinesterases The organophosphorus compounds are potent cholinesterase inhibitors because of the irreversable combination of the phosphate group with the esteratic head of the enzyme. Toxicity (Organophosphorus Poisoning): Causes: It is may be accidental or as a result of homicidal or suicidal intention. Manifestations: 1- Muscarinic as: Pin point pupil- ↑Secretions- Bronchospasm- vomiting and abdominal cramps- ↓B.P & H.R. 2- Nicotinic as: Ms weakness and paralysis of intercostal Ms and diaphragm. 3- CNS as: Restlessness- Confusion- Coma- Depression of VMC and R.C. Death may occur due to respiratory depression and secondary circulatory failure within minutes or reach to 24 h depending on: the agent type, duration of exposure, route….etc. 42 Treatment of organophosphorus poisoning: 1- Endotracheal intubation and artificial respiration. 2-Avoid further exposure, clean: skin- cloths- stomach wash, and care of vital systems. 3-Atropine: i.v. or i. m repeated every 5-10 min till atropine toxic signs appear as: mydriasis, dry mouth, tachycardia. It affects only the muscarinic, CNS but not nicotinic symptoms. 4-Cholinesterases (Oximes): e.g. Paralidoxime (PAM), Diacetylmonoxime (DAM). They combine with phosphorus group of the phosphorylated esteratic sites forming soluble complexes before the “ageing process” which is the formation of very stable complex resistant to the activator. 5-Anticonvulsants as diazepam 43  Parasympathetic antagonists (Parasympatholytics, or Anticholinergic Drugs) They include: 1. Antimuscarinic drugs 2. Ganglionic blocking drugs 3. Neuromuscular blocking drugs ❖ Antimuscarinic :are drugs that predominantly block the muscarinic actions of Ach or other parathympathomimetics when given in therapeutic doses (no or little effects on the ganglionic or neuro-muscular actions). They are classified into two groups: a. Belladona alkaloids as Atropine and Scopolamine (hyosine). b. Synthetic atropine substitute (selective in their action: e.g.: mydriatic, antispasmodic,antiparkinsonian). BELLADONA ALKALOIDS 1- ATROPINE It is a prototype of this class. It antagonize the muscrinic effects of exogenous Ach (mainly) and choline esters on the heart, smooth muscles and exocrine glands. It is absorbed from all sites of administration (except skin), widely distributed with high level in CNS because it is a tertiary amine. Half-life = 2 – 4 hours, and excreted by kidneys. Pharmacological actions: 1. CNS: A- Therapeutic doses produce medullary vagal stimulation that resulted in bradycardia and increase depth of respiration, 44 B- Large doses produce non selective actions on the muscarinic and nicotinic functions, with very large and toxic doses restlessness and hallucination occurs and then depression and medullary paralysis leading to DEATH. 2. Peripheral effects (anti-muscarinic): A- CVS: a- Heart rate: initial bradycardia and then tachycardia b- ↑conduction in AVN and A V bundle. c- No effect on BP with therapeutic doses, but toxic doses produce cutaneous vasodiltation producing Atropine flush. B- GIT: ↓ tone and motility (antispasmodic), ↓ gastric secretions. C- Urinary tract: Relaxation of the detruser Ms & spasm of the sphincters lead to urine retention. It has anti-spasmodic effect in the ureters. D- Bronchi: broncho-diltation and ↓ secretions (Ipratropium bromide is better in ttt of bronchial asthma because of the dryness of the pharynx and bronchi with atropine that usually aggravate the attack). E- Secretions: ↓gastric, resp., lacrimal. (But no effect on pancreatic secretions, intestinal juice, and milk. ↓ Sweat glands secretions atropine fever (toxic doses). F- Eyes: Local or systemic (7 – 10 days) passive medriasis, loss of accomodation, ↑ I.O.P., loss of light reflex, and ↓ lacrimation sandy eyes with large doses. Uses: 1. Preanaesthetic medication: to overcome the vagal reflex but with new anaesthetic agents no irritation and no role of atropine to decrease the secretions. 2. Anti-spasmodic (renal, GIT, or biliary). 3. Treatment of heart block due to infarction, or digitalis toxicity and in case of syncope associated with hyper-reactive carotid sinus reflex. 45 4. Organophosphorus poisoning to control the SLUDGE syndrome (salivation, lacrimation, urination, diaphoresis, gastrointestinal motility, emesis). 5. Peptic ulcer, bronchial asthma, parkinsonism, and in nocturnal enuresis (synthetic preparations of atropine are preferred). 6. Eye: In fundus examination (synthetic preparations are preferred) and ttt of iridocyclitis in alternation with myotics. 7. Hyperhidrosis. Side Effects: Dryness of mouth, blurring of vision, tachycardia, acute glucoma, urine retention, constipation. Contraindications: It is contraindicated in: glucoma, old patients, and tachydysrrhythmais. ACUTE ATROPINE POIISOINING Symptoms: Dry mouth, blurring of vision because of the accommodation paralysis, tachycardia and ↓ sweating. Skin: Hot, dry, and flushed. CNS: 1st stimulatory effects, and then depressant action that may cause death due to respiratory failure. Treatment: General: Gastric lavage (in oral route), Ice bags, and artificial respiration. Specific: Physostigmine (1–2 mg slowly I.V.) – Diazepam (for excitation & convulsions) 2- SCOPOLAMINE (HYOSCINE) The differences between it and atropine are: 1. More CNS depressants (sedation, hypnosis, amnesia, and anti-motion sickness). 46 2. Stronger eye and exocrine, sweat gland actions. 3. Weaker GIT, cardiac, bronchial actions. USES: Preanesthetic medication, antispasmodic, antimotion sickness (antihistaminic is preffered ) and in ttt of Vertigo in Meniere’s disease. SYNTHETIC ATROPINE SUBSTITUTE EYE (mydriasis): a. Homatopine 2%:1-3 days, Cyclopentolate 0.5-1%: 24h, b. Tropicamide 0.5-1%: 1⁄2 - 6h. Eucatropine 2-5%: 3 -4h. Antisecretoty-antispasmodic: a. Propantheline: 15mg orally relives spasm for about 6 h. b. Oxyphenonium bromide (Antrenyl): 5 -10mg orally c. Hyoscine Butyl bromide (Buscopan): It is used in the GIT, biliary, and urinary colics orally or parenterally. d. Pirenzepine (Gastrozepine) & Telenzepine: selective M1 blocker, used in ttt of peptic ulcer. Antiparkinsonian: Benztropine (Cogentin), Procyclidine, Trihexyphenid (Artane), & Biperiden. Bronchial asthma: e.g Ipratropium bromide (Atrovent): It is broncho-selective, it is used by inhalation with no systemic effects. ↓Urinary bladder activity: e.g Emepronium & Tolterodine in cases of nocturnal enuresis and urinary incontinence. 47