Cholinergic drugs Flashcards
What are the direct-acting cholinomimetics?
ACh
Bethanechol
Carbachol
Cevimeline
Methacholine
Pilocarpine
Varenicline (Chantix)
What are the common cholinesterase inhibitors?
Ambenonium
Donepezil
Echothiphate
Edrophonium
Galantamine
Neostigmine
Pyridostigmine
Rivastigmine
Tacrine
What is the common cholinesterase regenerator?
Pralidoxime
What antimuscarinic drugs are used for motion sickness?
Scopolamine
What antimuscarinic drugs are used for tx of GI disorders?
Atropine
Dicyclomine
Glycopyrrolate
Hyoscyamine
What antimuscarinic drugs are used for tx of respiratory disorders (asthma and COPD)?
Ipratropium
Tiotropium
What antimuscarinic drugs are used for tx of urinary disorders?
Darifenacin
Feoterodine
Oxybutynin
Solifenacin
Tolterodine
Trospium
What antimuscarinic drugs are used for tx of cholinergic poisoning?
Atropine (+ pralidoxime)
What antimuscarinic drugs are used for tx of movement disorders?
Benztropine
Biperiden
Orphenadrine
Procyclidine
Trihexyphenidyl
What is the common ganglion blocker?
Mecamylamine
What is the overarching MOA of cholinergic agonists?
They mimic the actions of ACh on mAChR OR nAChR
What is specific about choline esters (ACh, bethanechol, carbachol) that results in poor absorption and distribution in the CNS?
These drugs have a charged quarternary ammonium group
All choline esters (ACh, bethanechol, carbachol) are hydrolyzed by cholinesterasem but at varying rates resulting in _____.
Varying durations of action
What is specific about cholinoreceptor alkaloid agents (muscarine, nicotine, pilocarpine) that allow for them to be well absorbed at most sites of administration?
They are uncharged tertiary amines (except for muscarine, which is a quarternary amine)
Effects of direct-acting cholinergic agonists on skeletal muscle
only nAChR are present on skeletal m.
Agents that activate nAChR will produe muscle contraction
Effects of direct-acting cholinergic agonists on the eye
Contraction of the iris sphincter and ciliary m. leading to drainage of the anterior chamber
Effects of direct-acting cholinergic agonists on the heart
Reduction in PVR and changes in HR through M2 mAChR
Usually results in decrease in BP and increase in HR with minimally effective doses of ACh agonist
Large doses of ACh agonist leads to bradycardia, decreased AV node conduction velocity and HoTN
Effects of direct-acting cholinergic agonists on GI/GU tracts
Increase in glandular sections, primarily salivary and gastric glands
What type of mAChR is required for direct activation of smooth m. contraction in GI/GU tracts?
M3
What type of mAChR is required to reduce relaxation caused by adrenergic effects in GI/GU tracts?
M2
What type of mAChR is involved in increased cognitive function and seizure activity?
Excitatory
What type of mAChR plays a role in tremors, hypothermia and analgesia?
inhibitory
What are the effects of nicotine on the CV system?
Sympathomimetic (HTN, alternating tachycardia and bradycardia)
What are the major clinical uses of direct-acting cholinomimetics?
Glaucoma
Accommodative esotropia
Post-operative atony
Neurogenic bladder
What direct acting cholinomimetic is the most widely used choline ester for GI/GU disorders?
Bethanechol
What direct-acting cholinomimetics are used to increase salivary secretions (typically in patients with Sjogrens disease)?
Pilocarpine
Cevimeline
What drug is used when a suspected direct-acting cholinomimetic toxicity is suspected?
Atropine
What are the contraindications to using mAChR agonists that are distributed systemically?
Patients with asthma, hyperthyroidism, coronary insufficiency, or acid-peptic disease
What are symptoms corresponding to acute nicotine toxicity?
Convulsions –> coma and respiratory arrest
Respiratory paralysis
HTN
Cardiac arrhythmias
What are symptoms corresponding to chronic nicotine toxicity?
Increased risk of vascular disease
Sudden coronary death
Ulcers
Clinical use of ACh
Used during ocular surgery to induce miosis (pupillary constriction)
Clinical use of Methacholine
Used to diagnose bronchial airway hyperreactivity
Clinical use of Bethanechol
It is a selective mAChR agonist that can be used to tx patients with urinary retention and heart burn
Clinical use of Carbachol
Used to tx glaucoma
Used to produce miosis during ocular surgery
Clinical use of Cevimeline
Tx xerostomia
Clinical use of Pilocarpine
Tx xerostomia
Induce miosis during ophthalmic procedures
Topical tx for glaucoma
Clinical use of Varenicline
Smoking cessation
What are the three subgroups of AChE inhibitors?
Alcohols
Carbamic acid esters (carbamates)
Organophosphates
The group of alcohol AChE inhibitors function by binding to AChE nonconvalently and thus reversibly. Give an example of a drug in this class.
Edrophonium
What drugs are considerd to be carbamates?
Neostigmine
Pyridostigmine
Physostigmine
Carbaryl
What specific features of organophosphates allow them to induce CNS toxicity?
They are charge-neutral and highly lipid soluble, thus they can cross the BBB
What type of bonding to organophosphates have with AChE?
Covalent and irreversible
Describe the pharmacokinetics of quaternary and charged AChE inhibitors
insoluble in lipids
absorption is poor
No CNS distribution
duration of effect is dtermined by the stability of the inhibitor-enzyme complex
Describe the pharmacokinetics of tertiary and uncharged AChE inhibitors
Well absorbed from all sites
CNS distribution
More toxic
Duration of action of alcohol AChE inhibitors
2-10 minutes
Duration of action of carbamate AChE inhibitors
30 min to 6 hours
Duration of action of organophosphate AChE inhibitors
Hundreds of hours (very slow!!!)
What are the effects of AChE inhibitors on the CNS?
At high concentrations: convulsions
What are the effects of AChE inhibitors on the eye, respiratory tract, GI tract, urinary tract?
- *Eye:** contraction of ciliary m. and iris sphincter
- *GI/GU tract:** increased glandular secretions
What are the effects of AChE inhibitors on the CV system?
Decreased cardiac output
Bradycardia
Increased BP
What are the effects of AChE inhibitors on the NMJ?
Increased strength of contraction
Fasciculations
What are common clinical uses of AChE inhibitors?
Reversal of pharmacologic paralysis
Glaucoma
Dementia
Antidote
What are the signs and symptoms of acute AChE inhibitor toxicity?
Miosis
Salivation
Sweating
Bronchial constriction
Vomiting and diarrhea
How can you diagnose an acute AChE inhibitor toxicity?
Measure AChE activity in erythrocytes and plasma
What drug is used as prophylaxis against AChE inhibitor poisoning?
Pyridostigmine
What are the most clinically useful cholinergic antagonists?
mAChR antagonists
What is the prototype antimuscarinic compound?
Atropine
What tissues are most sensitive to atropine?
Salivary glands
Bronchial glands
Sweat glands
Effects of mAChR-blocking drugs on CNS
Slow, long-lasting sedative effect on the brain
Effects of mAChR-blocking drugs on the eye
Mydriasis
Cycloplegia and loss of accommodation
Reduced lacrimal secretions
Effects of mAChR-blocking drugs on the CV system
can cause tachycardia
Effects of mAChR-blocking drugs on respiratory tract
Bronchodilation and reduced secretions
Effects of mAChR-blocking drugs on GI tract
Reduced salivary secretions
Prolonged gastric emptying
Lengthened intestinal transit time
Effects of mAChR-blocking drugs on GU tract
Relaxes smooth m. and subsequently slows voiding (i.e. useful in tx of urinary incontinence)
No significant effect on the uterus
What clinical conditions are cholinergic antagonists (mAChR-blocking drugs) used for?
Parkinson disease
Motion sickness
Prevent synechia in uveitis and iritis
Asthma and COPD
Travelers diarrhea
Urinary urgency
Overdoses of mAChR antagonists should be treated with what drug type?
Cholinesterase inhibitor (physostigmine) and seizure control (with diazepam)
Contraindications of muscarinic antagonists such as atropine
Moderate to high doses in children can cause death 2/2 hyperthermic effects
Contraindicated in patients with glaucoma and acid-peptic disease
Use with caution in men with prostatic hyperplasia
