Parasympathetic Drugs Flashcards
cholinomimetics are drugs that _____
mimic acetylcholine
direct acting cholinomimetics MOA
ACh receptor agonists
direct acting cholinomimetics MOA
cholinesterase inhibitors- inhibit the hydrolysis of endogenous ACh
all cholinergic agonists are metabolized by ____:
- at ____
- in the ____
- in the ____
cholinesterase;
receptor;
blood;
liver
ACh, Carbachol, Bethanechol (synthetic choline esters)
- not very lipid soluble (poorly absorbed)
- highly charged molecules
- differ in susceptibility to cholinesterase
- mainly excreted by the kidneys
susceptibility to cholinesterase:
acetylcholine
rapidly hydrolyzed; brief duration of action
susceptibility to cholinesterase:
carbachol and bethanechol
more resistant to cholinesterase; longer duration of action
Pilocarpine, Nicotine, Muscarine (cholinomimetic alkaloids)
- readily absorbed form most sites of administration
- nicotine absorbed across skin
- muscarine is toxic and crosses BBB
- all mainly excreted by the kidneys
muscarinic receptors are ____ receptors;
activation produces ____;
organ function is _____
G-protein;
a cascade of 2nd messengers;
directly altered
there are also muscarinic receptors on the _____ (both parasympathetic and sympathetic);
activation causes _____;
organ function is _____
presynaptic nerve terminal;
an inhibition of ACh and/or NE release (feedback inhibition);
indirectly altered
nicotinic receptors are ____ receptors;
activation causes _____;
prolonged agonist binding causes _____
ion channel;
conformational change allowing sodium and potassium ions to diffuse down their concentration gradients (produces depolarization of nerve cell or neuromuscular end plate membrane);
the post-ganglionic neuron to stop firing- prevents recovery (depolarizing blockade) and the receptor becomes desensitized to agonist
muscarinic effects:
eye
- contraction of iris sphincter (miosis)
- contraction of ciliary muscle (accommodation)
- above result in opening of TM and lowering IOP
muscarinic effects:
cardiovascular system
heart:
- decrease in HR
- hyperpolarization of SA and AV node
- decreases duration of action potential and decreases contractility of atrial and ventricular cells
blood vessels:
- vasodilation (decreases peripheral resistance)
- in presence of endothelial damage (atherosclerosis), will cause vasoconstriction
muscarinic effects:
respiratory system
- contraction of bronchial smooth muscle (bronchoconstriction)
- stimulation of bronchial glands (increase mucous secretion)
muscarinic effects:
GI tract
- increase smooth muscle motility
- relax most sphincters
- stimulate salivary and gastric glands to secrete
muscarinic effects:
genitourinary tract
-stimulate detrusor muscle and relax the trigone and sphincter muscles of bladder
(promote urination)
muscarinic effects:
miscellaneous glands
-stimulate secretion by sweat, lacrimal, and nasopharyngeal glands
nicotinic effects:
PNS
- activation of nicotinic receptors in autonomic ganglia
- sympatheticomimetic in cardiovascular system (increase HR and BP)
- parasympatheticomimetic in GI and urinary tracts (all previously noted responses and nausea, vomiting, diarrhea, and urination)
activation of nicotinic receptors often resembles _____
simultaneous discharge of both para and sympathetic system
nicotinic effects:
NMJ
-causes depolarization followed by depolarization blockade
most indirect-acting cholinomimetics are ____; chemistry determines _____
simple alcohols or esters of alcohols;
duration of action
indirect-acting cholinomimetics that are derivatives of phosphoric acid (organophosphates) have _____;
many _____;
some used as _____
longest duration of action;
different compounds;
nerve gas or insecticides
absorption of indirect-acting cholinomimetics
- variable absorption
- physostigmine is well absorbed from all sites and can be used topically in the eye
- organophosphates are absorbed from skin, lung, gut, and conjunctiva (dangerous to humans)
administration of indirect-acting cholinomimetics
any (including IV)
distribution and elimination of indirect-acting cholinomimetics
- variable
- organophosphates are distributed to CNS (CNS toxicity is common, exception is echothiophate)
indirect-acting cholinomimetics MOA
- increase concentration of endogenous ACh by inhibiting ACh-esterase
- chemistry determines interaction with the enzyme
short-acting indirect-acting cholinomimetics MOA
- edrophonium
- forms reversible bond with the enzyme
- not actually a substrate for ACh-esterase
intermediate-acting indirect-acting cholinomimetics MOA
- neostigmine, physostigmine, pyridostigmine
- resistant to part of enzyme action so takes longer
long-acting indirect-acting cholinomimetics MOA
- echothiophate, malathion, parathion, sarin
- forms phosphorylated enzyme complex that strengthens the bond with the drug
indirect-acting cholinomimetics effects:
CNS
- low concentrations: alerting response
- high concentrations: convulsions
indirect-acting cholinomimetics effects:
eye, respiratory tract, GI tract, urinary tract
similar to the direct-acting cholinomimetics
indirect-acting cholinomimetics effects:
cardiovascular system
- increased activity in both sympathetic and parasympathetic ganglia as well as at muscarinic receptors
- parasympathetic effects dominate due to direct muscarinic innervation (decreased HR and decreased cardiac output)
- minimal effect on vascular smooth muscle (not innervated) (allows vasoconstriction and increased BP as a result of activity in the sympathetic ganglia)
indirect-acting cholinomimetics effects:
neuromuscular junction
- therapeutic concentrations prolong and intensify the actions of acetylcholine
- increases strength of muscle contraction (esp. in patients with myasthenia gravis)
- high or prolonged concentrations will cause depolarizing neuromuscular blockade
clinical uses of cholinomimetics:
eye
- cause contraction of the ciliary body (increases aqueous outflow)
- older treatment of glaucoma
- pilocarpine, carbachol, echothiophate
clinical uses of cholinomimetics:
GI and urinary tract
- used to treat disorders that involve a decrease in smooth muscle activity without obstruction
- postoperative atony or urinary retention
- neurogenic bladder (secondary to spinal cord injury)
- bethanechol or neostigmine most common
- can be used to increase salivary secretion (Sjogren’s syndrome)
- pilocarpine, cevimeline
clinical uses of cholinomimetics:
neuromuscular junction
- treatment of myasthenia gravis
- cholinesterase inhibitors used in treatment
- edrophonium used more for diagnosis- pt displays an improvement in muscle strength after injection
- pyridostigmine is most common for long-term treatment
- neostigmine also used
- reverse neuromuscular blockade produced during surgical anesthesia
- neostigmine, edrophonium
clinical uses of cholinomimetics:
treatment of Alzheimer’s
- donepezil
- galantamine
- rivastigmine
adverse effects of direct-acting cholinomimetics
- nausea
- vomiting
- diarrhea
- urinary urgency
- salivation
- sweating
- flushing of the skin (vasodilation)
- bronchial constriction
adverse effects of cholinesterase inhibitors
- same as direct-acting
- also includes: muscle weakness, convulsions, respiratory failure
-the above often result from exposure to pesticides (organophosphates)
cholinergic blockers:
- interrupt _____
- prevent ACh from _____
parasympathetic nerve impulses;
stimulating cholinergic receptors
cholinoceptor antagonists:
- ganglion blockers _____
- muscarinic blockers can be further divided based on _____
have little clinical use;
affinity for certain receptor subtype (M1-M5)
many muscarinic antagonists are _____, but ____ have also been formulated
naturally occurring compounds (ex: atropine derived from nightshade plant); synthetic compounds (ex: tropicamide)
muscarinic antagonists:
absorption
most are well absorbed from the gut, conjunctiva, and across skin (some formulations)
muscarinic antagonists:
distribution and elimination
- most are widely distributed with CNS penetration
- eliminated via the kidney
muscarinic antagonists MOA
- block ACh action at muscarinic receptors
- moderately selective for various muscarinic receptor subtypes
- atropine is non-selective (useful in treating cholinomimetic toxicity)
muscarinic antagonist effects:
CNS
- atropine has minimal effects
- scopolamine has marked effects- drowsiness and amnesia at normal doses, reversal of vestibular disturbances (Tx of motion sickness/sea sickness)
muscarinic antagonist effects:
cardiovascular system
increased HR
muscarinic antagonist effects:
eye
- mydriasis (blockage of muscarinic activation of pupillary constrictor muscle allows unopposed sympathetic dilator activity)
- cycloplegia (weakens contraction of ciliary muscle)
- reduction in lacrimal secretion
muscarinic antagonist effects:
respiratory system
- bronchodilation
- decreased secretions in the lung
muscarinic antagonist effects:
GI tract
- decreased salivation
- decreased production of stomach acid (very large doses)
- decreased smooth muscle tone and propulsive movements
muscarinic antagonist effects:
urinary tract
-relax bladder smooth muscle
-slows voiding
(reduced urinary activity)
muscarinic antagonist effects:
sweat glands
- reduces sweating
- can produce fever in young patients
clinical uses of antimuscarinic drugs:
CNS disordesr
- Parkinson’s disease (mainly adjunctive)
- treatment of motion sickness
clinical uses of antimuscarinic drugs:
ocular disorders
- accurate refraction (usually homatropine or cyclopentolate)
- dilated fundus exam (usually tropicamide or cylcopentolate)
- treatment of uveitis (prevents synechia, usually homatropine or cyclopentolate)
atropine duration of effect
7-10 days
homatropine duration of effect
1-3 days
cyclopentolate duration of effect
1 day
tropicamide duration of effect
6 hours
clinical uses of antimuscarinic drugs:
respiratory disorders
- pre-anesthesia (prevent airway secretions and laryngospasm; usually atropine or scopolamine)
- COPD and asthma (causes bronchodilation; usually ipratropium or tiotropium via inhaler)
clinical uses of antimuscarinic drugs:
urinary disorders
-treatment of urinary urgency or bladder spasm (usually oxybutynin)
clinical uses of antimuscarinic drugs:
cardiovascular system
-treatment of bradycardia and some types of arrhythmias
clinical uses of antimuscarinic drugs:
cholinergic poisoning
- considered a medical emergency
- common in rural communities (insecticides)
- no effective method for directly blocking nicotinic effects
- antimuscarinic therapy- atropine preferred, usually multiple doses required
- cholinesterase regenerator compounds- pralidoxime; can “regenerate” phosphorylated enzyme, must be used rapidly
adverse effects of antimuscarinic drugs
- mydriasis (contraindicated in patients w/ glaucoma)
- cycloplegia
- dry mouth
- tachycardia
- flushed skin
- agitation
- delirium
- elevated body temperature
many antihistamines, antipsychotics, and antidepressants have _____ activity
muscarinic cholinoreceptor antagonist activity
cholinoreceptor agonists cause _____
SLUD
- salivation
- lacrimation
- urination
- diarrhea
cholinoreceptor antagonists have ____
the opposite effect of SLUD
- dry mouth
- dry eyes
- urinary retention
- constipation
