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4. Antimuscarinic drugs and Ganglionic

antimuscarinic and ganglionics
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List antimuscarinic Drugs
tertiary amines - atropine, scopolamine, homatropine, tolterodine, trihexyphenidyl. Quaternary ammonium compounds - glycopyrrolate, Ipratropium
Muscarinic drugs mechanism of action
competitively block muscarinic receptors. Atropine and scopolamine block all M receptors. Other antimuscarinic drugs are selective. Tertiary antimuscarinics don't block Nn. Quarernary block muscarinic but also Nn.
Effects of antimuscarinic mnemonic
mad as hatter, blind as bat, red as beat, dry as bone, bloated as toad, hot as hell.
Antimuscarinics on CNS intermediate dose
mild vagal stimulation. Fatigue, sedation, drowsiness, depression of vestibular, reduction in parkinsonian tremor and rigidity
Antimuscarinic on CNS high dose
amnesia, malaise, restlessness, irritability, disorientation, halluciations, delirium. Coma.
Antimuscarinics on heart low dose
decrease in heart rates (due to blockade of M2 presynaptic autoreceptors and to central vagal stimulation.
Antimuscarinics on heart intermediate dose
tachycardia. Many types of reflex vagal cardiac slowing can be abolished. Atria - increase in automaticity and contractility. AV node - increase in conduction and automaticity, decrease in refractoriness. Ventricles - minimal direct effect.
Antimuscarinics on Cardiovascular vessels therapeutic dose
negligible effects (but vasodilation and hypotension caused by choline esters are antagonized)
Antimuscarinics on CV vessels after high dose
dilation of cutaneous blood vessels (unknown mechanism) in children can cause atropine flush.
Antimuscarinics on GI
decreased gastric secretion, decreased tone, contractions, peristaltic activity. Relaxation of LES, gallbladder, bile ducts
Antimuscarinics on Genitourinary system
relaxation of pelves, calyces, ureters. Decreases peristalsis, relaxation of detrusor muscle (increased capacity)
Antimuscarinics on respiratory system
bronchial relaxation, decreased secretions, decreased mucociliary clearance (except ipratropium)
Antimuscarinics on eyes
relaxation of sphincter of iris (mydriasis), relaxation of ciliary muscle (cycloplegia, accommodation is lost) hinders outflow of aqueous humor thru schlemm's canal. When atropine is given locally, these effects last for 3 days. Decreased lacrimal gland secretion
Antimuscarinics on skin
decreased sweat. Raises body temperature. Infants and children are prone to atropine fever.
Antimuscarinic absorption
oral biovaliability = atropine = 70%, scopolamine = 30%, ipratropium >1%
Antimuscarinic distribution
tertiary amines all tissues, quaternary derivatives don't enter cns
Atropine excretion
60% excreted by kidney
Atropine and scopolamine half life
3 hours
Glycopyrrolate halflife
10 hours
Antimuscarinic toxicity
skin rashes, urticarial, fever. Therapeutic index >100 adults, but a dose of 5mg can be lethal to children. Serious atropine poisoning appears in 30 minutes, lasts for 2-7 days. Death due to respiratory failure may follow coma and collapse.
Diagnosis of antimuscarinic poisoning
IM injection of physostigmine. If signs of muscarinic activation do not occur, poisoning with antimuscarinic drug is almost always certain.
Antimuscarinic treatment
maintenance of vital signs, alleviation of convulsion with diazepam, temp control with icebag and alcohol sponges.
Poisoning by antimuscarinics
mydriasis, blurring of vision, dryness conjunctiva, difficulty speaking, dyspnea, respiratory depression, dry hot red skin, dryness of mouth, difficulty swallonging, no bowel sounds, difficulty in micturition, tachycardia, arrhythmias, fatigue, ataxia, restlessness, delirium, hallucinations, coma
Contraindications of antimuscarinics
glaucoma, prostatic hypertrophy, urinary tract obstruction, GI tract obstruction, adynamic ileus, gastric ulcer, infectious diareah, UC, chron's disease, tachyarrhythmias, coronary artery disease, hyperthyroidism, children, elderly
Therapeutic uses of antimuscarinics
funduscopic exam (mydriasis), measurements of refractive errors, iritis, chroiditis. IBS diahrea, renal colic, enuresis, urinary incontinence (to reduce frequency), preoperative lung surgery to reduce secretions, bronchial asthma and copd (ipratropium), cardio resuscitation (when vagal hyperactivity is the cause of cardiac arrest), sinus or nodal bradycardia, AV block due to increased vagal tone. CNS - prevention of motion sickness (scopolamine), parkinsons (triexyphenidyl). To counteract parasympathomimetic effects of neostigmine in myasthenic patients. Poisoning by AchE inhibitors or mushrooms containing muscarine.
Atropine
visceral hypermotility and spasms, excessive salivation, cardio disorders, cholinesterase inhibitor overdose, ophthalmology, preanesthetic medication
Scopolamine
motion sickness, ophthalmology, preanesthetic medication
Homatropine
ophthalmology
Tolterodine
neurogenic bladder, urinary urge incontinence
Trihexyphenidyl
parkinsons
Glycopyrrolate
vvisceral hypermotility and spasms, cardiovascular disorders, preanesthetic medication
Ipratropium
bronchospastic disorders
Ganglionic stimulating drugs
nicotine, tetramethylammonium (carbachol, cholinesterase inhibitors, succinylcholine less used)
Ganglionic blocking drugs
hexamethonium, mecamylamine (glycopyrrolate, ipratropium, tubocurarine less used)
Nicotine pharm
natural alkaloid. Basic amine 8.5 pka. Mechanism of action - low doses activate nicotinic receptors at autonomic ganglia, nm junction, presynaptic nerve terminals, adrenal medulla, cns. Large doses - depolarization blockade (prolonged depolarization of post junctional membrane hinders neuronal transmission.
Nicotine pharm effects cns
stimulation of renshaw cels (interneurons in ventral horn of spinal), stimulation of RF (low doses), depression of RF (high doses). Reflex stimulation of emetic (vomit), direct stimulation of chemoreceptor trigger zone, stimulation of ADH secretion.
Nicotine effects CV
increased CO and HR. constriction of skin and splancnic. Dilation of muscular vessels. Increased BP. After toxic doses- CV collapse.
Nicotine effects GI
anorexia, nausea, vomiting, stimulation of peristalsis. Toxic doses - paralytic ileus.
Nicotine effects
Respiratory - stimulation of respiration, bronchoconstriction and increased secretions. Toxic - apnea due to central depression and block of diaphragm and intercostals.
Nicotine effects urinary
decreases diuresis (due to ADH release). Contraction of detrusor, relaxation of trigone and internal sphincter of urethra
Nicotine general effects
stimulation of sweat glands, miosis (activation of nn receptors of ciliary ganglion), rate of metabolism of many drugs increases, loss of body weight, increased hand tremors, paralysis of skeletal muscles with toxic doses
Nicotine tolerance and dependence
nausea vomiting, dizziness, headache, dysphoria and effects to peripheral ganglionic stimulation undergo tachyphylaxis. Rapid tolerance is lost overnight.
Nicotine bioavailability
oral 30%, smoking 90%, transdermal 89-90%. Distributed in all tissues (smoked reaches brain faster than IV). Most biotransformed by liver, kidney, lung. Half life = 2 hours
Nicotine poisoning
salivation, nausea, vomiting, abdominal pain, loss of urine and feces, cold sweat, tachypnea, tachycardia, disturbed hearing and vision, headache, dizziness, confusion, marked weakness. Then symptoms progress to faintness, falling of BP, weak irregular rapid pulse, difficulty breathing, tremors, convulsions. Death in a few minutes from respiratory failure
Ganglionic blocker on heart effect
tachycardia (M2)
Ganglionic blocker arterioles
vasodilation, orthostatic hypotension
Ganglionic blocker veins
vasodilation, venous pooling, decreased cardiac output
Ganglionic blocker iris
mydriasis
Ganglionic blocker ciliary muscle
cycloplegia
Ganglionic blocker GI tract
decreased motility and tone, constipation
Ganglionic blocker urinary bladder
urine retention
Ganglionic blocker exocrine glands
reduced secretion
Ganglionic blocker sweat glands
reduced secretion (anhydriosis)
Ganglionic blocker sex organs
impaired erection, impaired ejaculation
Mechanism of action of ganglionic blockers
competitive blockade of Nn receptors in autonomic ganglia, adrenal medulla, presynaptic nerve terminals, CNS (mecamylamine)
Only ganglionic blocker available
mecamylamine
Ganglionic blockers CV
moderate HR increase, decreased CO (b/c of peripheral venous pooling decreases preload), marked decrease in venous tone and peripheral resistance (hypotension in upright position), skin blood flow is decreased, spanchnic and renal blood flow are decreased.
Pharmacokinetics of ganglionic blocker s
hexamethonoium is quaternary ammonium, mecamyalamine is secondary amine (active by oral and enters CNS)
Therapeutic uses of ganglionic blockers
mecamylamine treats neurological disseases, ie tourettes. Also may be used for nicotine and cocaine dependence.