Pharm - Colinergic Agonists and Antagonists Flashcards
What are the 4 cholinergic agonists classified as choline esters?
Acetylcholine, carbachol, bethanechol, and methacholine
Describe the absorption, distribution, and metabolism of the choline esters.
All contain quaternary ammonium groups preventing absorption and distribution into the CNS. Hydrolyzation will occur in the GI tract leading to lower activity for oral administrations. All are metabolized at different rates by cholinesterase (acetylcholine > methacholine > carbachol > bethanechol)
Note: Methacholine and bethanechol do not have action at nicotinic receptors
What are the 3 cholinergic agonists classified as alkaloids?
Muscarine, nicotine, and pilocarpine
Describe the absorption, distribution, and metabolism of the cholinergic alkaloids.
All the alkaloids are uncharged tertiary amines, with the exception of muscarine (quaternary). All are readily available through most sites of administration (especially nicotine through skin).
Although it is quaternary, muscarine found in mushroom can be highly toxic when ingested because it is still able to enter the CNS.
All are readily excreted by the kidneys facilitated by acidifcation of the urine.
Note: Muscarine and Pilocarpine bind to mAChRs
What is the location and mechanism of action for the M1 receptor?
Nerves and IP3, DAG cascade
What is the location and mechanism of action for the M2 receptor?
Nerves, Cardiac, and smooth muscle
Inhibition of cAMP production and activation of K+ channels
What is the location and mechanism of action for the M3 receptor?
Glands, smooth muscle, and endothelium
IP3, DAG cascade
What is the location and mechanism of action for the M4 receptor?
CNS
Inhibition of cAMP production
What is the location and mechanism of action for the M5 receptor?
CNS
IP3, DAG production
What is the location and mechanism of action for the Nm receptor?
Skeletal muscle at the neuromuscular junction
Na+ and K+ depolarizing channels
What is the location and mechanism of action for the Nn receptor?
Postganglionic cell bodies, CNS, and dendrites
Na+ and K+ depolarizing channels
Describe the effects of direct-acting cholinergics on skeletal muscle.
These drugs must have affinity for nAChRs - carbachol, acetylcholine, and nicotine (which is preferential to nerves)
Contraction of skeletal muscle will be stimulated until a depolarizing blockade is reached and flaccid paralysis is assumed
Describe the effects of direct-acting cholinergics on the eye.
Causes constriction of the iris –> increased aqueous humor outflow from the anterior chamber
Describe the cardiovascular effects mediated by cholinergic agonists via M2 receptor
The M2 receptor is primarily responsible for controlling the speed of AV node conduction
Describe the cardiovascular effects mediated by cholinergic agonists via M3 receptor
Stimulation of the M3 receptor will result in systemic vasodilation by causing the production of cGMP.
cGMP –> EDRF –> NO –> smooth muscle relaxation
Note: At low doses decreased TPR is accompanied by homeostatic reflexive tachhycardia. At high doses TPR is accompanied by bradycardia
Describe the effects of direct-acting cholinergics on the GI/GU tracts
Increased glandular secretion tends to occur in the salivary and gastric glands.
M3 receptors cause direct contraction of smooth muscle, while M2 receptors cause reduction in cAMP formation, reducing relaxation
NO stimualtes sphincter relaxation
Describe the effects of direct-acting cholinergics on the brain
The brain is rich in mAChRs
Stimulatory mAChRs will result in increased cognitive function and inhibitory mAChRs result in tremors, hypothermia, and analgesia.
Describe the effects of direct-acting cholinergics on the spinal cord.
The spinal cord is rich in nAChRs
Effects of nicotine here are dose dependent. Moderate doses - alerting brain aciton. High doses - emesis, tremors, and activation of the respiratory center. Lethal doses - convulsions and fatal coma
Describe the effects of direct-acting cholinergics on the PNS
At autonomic ganglia nicotine seems to trigger both sympathetic and parasympathetic discharge.
In the CV system the response is hypertension with alternating tachycardia and bradycardia.
In the GI/GU system the response is parasympathomimetic,
What are three clinical uses of direct-acting cholinergic agonists?
Glaucoma, GI/GU disorders, and Accomodative esotropia
Describe how glaucaoma can be treated with direct-acting cholinergic agonists
Cholinergic agonists cause contraction of the ciliary body, increasing outflow of aqueous humor through canal of schlemm
Note: this drug has been replaced by topical beta-blockers and prostaglandin derivatives
Describe accomodative esotropia
Children born with farsightedness overcorrect and develop misalignment of eyes
Describe how direct-acting cholinergic agonists can treat GI/GU disorders
(3 Drugs)
Bethanechol can be used to treat paralysis in these two systems: congenital megacolon, post-operative ileus, esophageal refulx, and urinary retention
Note: obstruction should be ruled out
Pilocarpine and cevimeline increase salivary secretions and treat xerostomia
Describe the effects of muscarinic toxicity and how it is treated
SLUDGE symptoms or DUMBELS
Treat with atropine, muscarinic antagonist
What are the contraindications for administering muscarininc agonists?
Asthma, coronary insufficiency, acid-peptic disease, and hyperthyroidism
Describe the presentation of acute nicotine toxicity
Initially the patient will present with convulsions and muscle contractions. Convulsions will progress towards coma.
Muscle contractions progress towards depolarizing blockade and flaccid paralysis.
How do you treat acute nicotine poisoning?
Administer atropine and a parenteral anticonvulsant
Note: Neuromuscular blockade does not respond to pharmacological treatment
What is the clinical use of acetylcholine?
Normally prescribed to produce miosis for procedures.
Note: Not typically given systemically
What are the clinical uses of bethanechol?
Used to treat esophageal reflux and urinary retention
Note: purely a muscarinic agonist with little cardiovascular effects
What is the clinical use of cevimeline?
treatment of xerostomia in sjogren syndrome
What is the clinical use of pilocarpine?
A pure mAChR agonist for treatment of xerostomia in sjogren syndrome or cancer of head and neck or production of miosis
What is the clinical use, MOA, and adverse side effects of varenicline?
Clinical use - smoking cessation
MOA - partial agonist for nicotinic receptors in the brain
Adverse side effects - Nausea is most common but changes in behavior consisting of depression, aggression, and suicidal thinking have been noted
What are the subgroups of indirect-acting cholinergic agonists
Alcohols, carbamic acid esters, and organophosphates
Describe the pharmacokinetics of Quaternary AChE inhibitors and give examples (3).
These are charged compounds and will not pass into the CNS. Best administered parenterally. Duration of effect is proportional to the stability of the enzyme-inhibitor complex
Ex: neostigmine, pyridostigmine, and echothiophate
Describe the pharmacokinets of tertiary AChE inhibitors and give examples (4)
Well absorbed and distributed to the CNS.
Ex: physostigmine, donepezil, tacrine, and rivastigmine
Describe the pharmacokinetics of organophosphates
These are well absorbed through all sites and distribute everywhere
Describe the duration of action of carbamic acid ester drugs
The drugs will bind to AChE and inhibit action. They undergo a two-step hydrolysis similar to that of acetylcholine. The second step of the hydrolysis forms a covalent bond between substrate and enzyme which last 30 minutes to 6 hours
Describe the effects of AChE inhibitors on CNS, eye, and Cardiovascular systems
CNS - low doses cause diffuse activation on EEG; high doses cause convulsions
Eye - miosis leading to increased aqueous humor outflow
CV system - Stimulates sympathetic and parasympathetic outflow, but parasympathetic predominates.
Describe the effects of AChE inhibitors at the NMJ
Causes strengthening of contraction at therapeutic doses, but at higher doses progression towards flaccid paralysis
What are four therapeutic uses of AChE Inhibitors?
Dementia, visceral paralysis (paralytic ileus, etc.), glaucoma, and antidote to anticholinergic compounds (antihistamines, tricyclic antidepressants, and sleep aids)
Describe the 4 identified clinical uses of AChE Inhibitors
Dementia - tertiary ions will cross the BBB and increase action of remaining intact cholinergic neurons
Anticholinergic Compounds - Increase the concentration of ACh near receptors
Glaucoma - increase ACh to cause contraction of ciliary body
Reversal of visceral paralysis - post-operative ileus, congenital megacolon, and urinary retention all treated with quaternary ions
How do AChE inhibitors interact with non-depolarizing neuromuscular blocking agents? What is the one exception to this?
AChE inhibitors will diminished the duration of effect that these compounds have at the NMJ.
Mivacurium is metabolised by plasma AChE, so it’s effect will be prolonged
How will AChE interact with succinycholine
Prolong phase I of depolarizing neuromuscular block, but antagonize phase 2
How will AChE inhibitors interact with systemic corticosteroids?
Muscle weakness in myasthenia gravis patients will be increased
Describe the presentation of acute AChE inhibitor toxicity and how it can be treated
The initial presentation of toxicity includes all muscarinic (SLUDGE) symptoms, which vary based on route of administration. Oral = GI symptoms. Percutaneous = local sweating and muscular fasciculations.
CNS symptoms (convulsions and coma) will rapidly follow. Ultimately death is a result of respiratory failure.
Treatment should entail administration of atropine (muscarinic antagonist), pralidoxime (AChE regenerator at NMJ), and benzodiazepam (anticonvulsant)
Note: pralidoxime is only effetive against organophosphates
What is the half-life and distribution of atropine?
The half-life of atropine is 2 hours. Effects from this drug decrease rapidly except for in the eye.
Atropine is a tertiary amine and able to enter the eye and CNS. It does not distinguish between the subtypes of mAChRs
Describe the CNS effects of atropine
Atropine will cause a mild sedative effect. Note: Beneficial in the treatment of tremors related to Parkinsons
Describe the effects of scopolamine on the CNS
Scopolamine has a greater effect on the CNS than atropine including amnesia and drowsiness. Effective in the prevention of motion sickness
Describe how muscarinic antagonists effect the eye
Ciliary contraction will be prevented causing unopposed sympathetic dilator activity and loss of accomodation. Decrease in lactimal secretions.
Note: Useful in ophthalmologic procedures
Describe the effects of muscarinic antagonists on the cardiovascular and respiratory systems
Cardio - initially bradycardia will present, but as the dose increases tachycardia will occur due to blockade of vagal slowing
Respiratory - blockade of bronchoconstriction and bronchial secretions
Describe the effects of muscarinic antagonists on the GI tract
Salivary glands will decrease in secretions. Pancreatic, gastric, and intestinal secretions will be minimally affected. Prolonged gastric emptying and intestinal transit times
Describe the effects of muscarinic antagonists on genitourinary tract and sweat glands
Relaxation of the smooth muscle of the ureters and bladder slow voiding
Suppression of thermoregulatory sweating by inhibition of cholinergic SYMPATHETIC nerve fibers
Note: Children can develop atropine fever
What CNS disorders (3) can anticholinergics be used to treat and what are the effects?
Parkinsons - reduces tremors, but not as effective as dopaminergic therapy
Motion sickness - effectively limits vestibular disturbances
Anesthesia - blocks vagal reflexes elicited by surgical manipulation and blocks parasympathetic effects when administered with neostigmine in reversal of skeletal muscle relaxation
What ophthalmologic disorders can be treated with anticholinergics and what are the effects?
Prolonged mydriasis for procedures
Note: alpha agonists are preferred for short duration, also have less side effects
Prevention of synechia in cases of iritis and uveitis
What would be the respiratory uses of anticholinergics?
Pre-operative - limited the secretions of the respiratory system elicited by irritating anesthetics like ether
COPD/Asthma
Which antimuscarinics (2) would be used for the treatment of asthma/COPD? What are their half-times?
Ipratropium - half-life of 2 hours
Tiotropium - half-life of 120 hours
What are cardiovascular conditions which can be treated with anticholinergics?
Note: antimuscarinics are rarely used for cardiovascular disorders
Can be used to treat depressed nodal conduciton of the heart due to vagal reflexes secondary to myocardial infarction. Also used to treat hyperresponsive carotid sinus reflexes.
What GI disorders can anticholinergics be effective against?
Used to treat traveler’s diarrhea
Note: also combined with opioid anti-diarrheals to discourage drug abuse
Which antimuscarinics (4) can be used to treat urinary disorders? describe any side effects and duration of aciton
Oxybutynin - selective M3 AChR antagonist which can treat urinary urgency. Side effects include xerostomia, dry eyes, blurred vision, dizziness, constipation, and UTIs
Darifenacin, solifenacin, and tolterodine - similar in action to oxybutynin, but longer duration of action and less occurrence of constipation and xerostomia
What is an example of a ganglion blocker?
Mecamylamine
Note: this fucks your shit up
What are adverse effects of atropine administration?
When used to treat one organ system it often has adverse effects at another organ system.
High doses will block all parasympathetic function. In adults this is still safe. In children this can cause atropine fever and death.
What are contraindications for antimuscarinic use?
Glaucoma, history of prostatic hyperplasia, and peptic-acid disease
Note: selective antimuscarinics can be used to treat peptic-acid disease
