Cholinergic Agonists Flashcards
Bethanechol
Class: Synthetic cholinergic muscarinic receptor agonist
MOA: Direct agonist at muscarinic receptors, especially those of the detrusor muscle of the bladder (but not highly specific); stimulation enhances the tone of that muscle, encouraging bladder wall contraction and urination; Quaternary ammonium structure prevents CNS action; not degraded by AChE, which prolongs half-life and occupancy at receptor;
Indications: used to treat urinary retention associated with neurogenic bladder; also used in past to treat ileus of GI tract (not terribly helpful!)
PK: older drug, not well absorbed; F not known; effects last about 1 hour
ADRs, contraindications: avoid in patients with asthma, bladder outlet obstruction, bradycardia, CAD, GI obstruction, parkinsonism; ADRs include abd pain, diarrhea, flushing, HA, lacrimation, salivation, N, V, wheezing
Other facts: Not used much today, but of historical interest, and also illustrates clinical problems with such non-specific muscarinic receptor agonists
Dose: Oral tablets need to be taken every few hours
Nicotine (NicoDerm™, Nicorette™, Nicotrol™)
Drug class: Direct-acting nicotinic cholinergic receptor agonist (primarily at NN receptors)
MOA: potent ganglionic and CNS stimulant; in small doses, stimulates all ganglionic transmission; in larger doses, can actually block ganglionic transmission (think of succinylcholine); CNS stimulation and convulsions may occur at higher doses
Indications: Treatment to aid smoking cessation, and for the relief of nicotine withdrawal symptoms
PK: different kinetics for transdermal systems, chewing gum, lozenges
ADRs, contraindications: avoid in patients with angina, post-MI, arrhythmias; can cause tachycardia, N,V, salivation, insomnia, chest pain, atrial fibrillation
Other info: Patients usually advised to stop smoking completely upon initiation
Dose: Often start with new transdermal patch every day (21 mg/24 hours), along with gum 2-4 mg per square as needed for urge to smoke; counseling program also helpful
Pilocarpine HCl
Class: Alkaloid derived from plant (1875), with particular affinity for sweat glands and eye receptors, approved by FDA in 19745, as antiglaucoma agent; also used for xerostomia
MOA: Stimulates muscarinic receptors of the sphincter muscles in the iris, producing miosis; also, produces vasodilation of conjunctival vessels of the outflow tract and contraction of ciliary muscles, resulting in deepening of the anterior chamber; both actions help to lower ocular pressure through enhanced clearance of aqueous humor in anterior chamber of eye
Indications: emergency treatment of acute narrow-angle glaucoma; chronic management of open-angle glaucoma; to counteract effect of mydriatic eyedrops
PK: reduction in eye pressure reaches maximum in 75 min; is eventually absorbed from tears, nose, stomach; metabolic pathway not clear; when taken by mouth, half-life around 1 h
ADRs, contraindications: do not use in acute iritis, inflammatory disease of anterior chamber, or asthma; can cause blurred vision, N,V, salivation, , excessive sweating
Other facts: Oral formulation (Salagen™) given to treat xerostomia from salivary gland hypofunction, usually caused by radiotherapy to head and neck cancers
Dose: Instill 1-2 drops into affected eye (various concentrations) q4-12 h
Succinylcholine (Anectine™)
Drug class: Neuromuscular blocking agent, of the depolarizing type (only member of this class); approved by the FDA in 1952
MOA: binds to NM receptors (specifically) and causes inward Na current and depolarization of the muscle cell; this leads to influx of calcium and contraction, visible as muscle fasciculations; tight binding to receptor prevents Ach from binding to receptor; drug itself is not cleaved by AChE; eventually the cell extrudes calcium, and the fasciculations and contraction ceases, leading to a flaccid paralysis (remember, Ach can’t access the nicotinic receptor, it is blocked
Indications: to produce muscle paralysis quickly and briefly, as needed for emergency intubations, or for brief procedures such as ECT
PK: when given iv 90% of drug is eventually metabolized pseudocholinesterase, but not by the actual synaptic AChE; complete relaxation is produced within 30-60 sec, and lasts 2-10 minutes, with gradual recovery of muscle strength and ability to contract
Contraindications, ADRs: previous malignant hyperthermia, or prolonged paralysis (due to deficiency in pseudocholinesterase); avoid in patients with burns, trauma, or renal disease (prolonged half-life of succinylmonocholine); ADR’s include apnea, bradycardia, cardiac arrest, asystole, bronchospasm, malignant hyperthermia, salivation, hypotension
Other info: quickest onset of all muscle relaxants (makes intubation easier, more quickly); known to release histamine in some patients; reserved now for use in emergencies that require “crash intubation”
Dose and route: for iv route in adults, 1.0-1.5 mg/kg, up to 150 mg total dose
Varenicline (Chantix™)
Drug class: Very selective and potent competitive partial agonist of α4-β2 nicotinic (NN) receptors, for smoking cessation; approved by FDA in 2006
MOA: By binding to nicotinic (NN) receptors in the brain, increases mesolimbic dopamine, preventing drop in dopamine levels and craving the next cigarette Indications: to help with smoking cessation programs, in conjunction with counseling
PK: well absorbed po; Tmax 4 h, t1/2 = 24 h; excreted primarily in urine as unchanged drug
Contraindications, ADRs: use cautiously in patients with severe renal impairment; Contraindicated in pregnancy/lactation. May produce abnormal dreams, anxiety, depression, irritability, insomnia, diarrhea, N, V, Causes drowsiness, caution operating machinery
Other info: Reports of suicidal thoughts and aggressive and erratic behavior → patients and caregivers should be instructed about the importance of monitoring for neuropsychiatric symptoms, and to communicate immediately with the prescriber the emergence of agitation, depression, unusual changes in behavior, or suicidality. Psychiatric patients – use extreme caution.
Dose and route: 1 mg po BID for healthy adults, 0.5 mg po BID fo patients with renal impairment CrCl < 50 ml/min; begin treatment 1 week before stop date
Edrophonium chloride (Tensilon™
Used as diagnostic aid in patients with possible myastenia
Give 2 mg IV push, watch for 30 sec (may increase dose)
If you see sudden significant increase in muscle strength of involved muscle, that is a positive test
Can also be used to distinguish myasthenic crisis from cholinergic crisis
Duration just 5-10 min
Ammonium (NH4+) group, so does not enter CNS
Bethanicol (Urecholine™)
Class: Synthetic cholinergic muscarinic receptor agonist
MOA: Direct agonist at muscarinic receptors, especially those of the detrusor muscle of the bladder (but not highly specific); stimulation enhances the tone of that muscle, encouraging bladder wall contraction and urination; Quaternary ammonium structure prevents CNS action; not degraded by AChE, which prolongs half-life and occupancy at receptor;
Indications: used to treat urinary retention associated with neurogenic bladder; also used in past to treat ileus of GI tract (not terribly helpful!)
PK: older drug, not well absorbed; F not known; effects last about 1 hour
ADRs, contraindications: avoid in patients with asthma, bladder outlet obstruction, bradycardia, CAD, GI obstruction, parkinsonism; ADRs include abd pain, diarrhea, flushing, HA, lacrimation, salivation, N, V, wheezing
Other facts: Not used much today, but of historical interest, and also illustrates clinical problems with such non-specific muscarinic receptor agonists
Dose: Oral tablets need to be taken every few hours
Neostigmine bromide (Prostigmin™)
Drug class: reversible acetylcholinesterase inhibitor; approved by FDA in
MOA: blocks hydrolysis of Ach by AChEsterase, resulting in accumulation of ACh at cholinergic synapses, which leads to increased stimulation of cholinergic receptors (both muscarinic and nicotinic); has charged ammonium group, so does not enter CNS
Indications: ongoing treatment of myasthenia gravis; to help reverse nondepolarizing neuromuscular blocker (like vecuronium, NOT like succinylcholine); to treat postoperative abdominal distention and bladder atony
PK: F about 1-2% (see large difference between IV and po doses noted below);iv dose produces effects in 4-8 min; po dose produces effects in 1 h; duration 2-4 h;
Contraindications, ADRs: contraindicated in patients hypersensitive to cholinergics, peritonitis, or mechanical obstruction of the intestine or urinary tract; ADRs include AV block, bradycardia, syncope, cardiac arrest, hypotension, abdominal cramps, diarrhea, excessive salivation, urinary urgency; increasing muscle weakness in myasthenia patients could be due to too much drug, or too little drug!!!
Other info: patients often quit due to N,V, diarrhea, urinary and fecal accidents (note muscarinic symptoms of excess)
Dose and route: for myasthenia, typical dose is aobut 150 mg po per 24 hours, usually divided qid; for antidote for nondeploarizing neuromuscular blockers, 0.5-2 mg slow IV push; may repeat up to 5 mg total dose; give atropine 0.6-1.2 mg IV prior to antidote dose if patient is bradycardic
Donepezil (Aricept™)
Drug class: acetylcholinesterase inhibitor; drug for improvement for symptoms of Alzheimers disease; approved by FDA in
MOA: able to enter the CNS, where it binds (reversibly) to the active site of the enzyme AChE, inhibits the enzyme, thereby increasing the concentration of Ach at CNS cholinergic receptors, temporarily improves cognitive function in many patients; doesn’t alter course of underlying destructive process; indicated for mild to severe AD Indications: mild to severe dementia of the Alzheimers type
PK: F about 100%; extensively metabolized by 2D6, 3A4, followed by glucuronidation
Contraindications, ADRs: contraindicated in patients with sick sinus syndrome, CV disease, asthma; ADRs include abnormal dreams, depression, seizures, blurred vision, N,V, frequent urination; overdose can lead to muscarinic crisis, and even death from weakness of respiratory muscles
Other info: patients often quit due to N,V, diarrhea, urinary and fecal accidents (note muscarinic symptoms of excess)
Dose and route: 5 to 10 mg po at hs
Echothiophate (Phospholine™)
Note: this is an irreversible inhibitor of AChE
The phosphate group of the drug binds covalently and irreversible to the serine group at the ative site of AChE
The drug is very slowly cleaved by by AChE, and its effects can last for 1 week or more
Given as topical drops to lower ocular pressure in patients with glaucoma
Physostigmine salicylate (Antilirium™)
Rarely used to reverse a severe or life-threatening anticholinergic overdose (such as caused by a TCA or an anticholinergic drug)
0-5-2 mg IV slowly over 2 min
