Where do you find M1, M2, M3, M4 and M5 muscarinic recptors?
M1 = Nerves (think of the '1' being a long nerve)
M2 = Heart, nerves, smooth muscle
M3 = Glands, smooth muscle, endothelium
M4 and M5 = CNS
Muscarinic agonist cause the release of what from endothelial cells?
What is the physiological effect of this chemical?
- EDFR, which is largely NO
- Activates guanylyl cyclase --> increase cGMP in smooth muscle and causes relaxation
What is the effect of minimally effective doses of muscarinic agonists (ACh) on the cardiovascular system vs. Larger doses?
- Minimally effective doses cause vasodilation, resulting in decreased BP and often accompanied by reflex increase in heart rate
- Larger doses produce bradycardia and decrease AV node conduction velocity in addition to hypotension
Which muscarinic receptor type is responsible for the direct activation of smooth muscle contraction in the GI and genitourinary tracts?
Which is responsible in the reduction of relaxation caused by adrenergic effects (resulting in contraction)?
- M3 mAChR is required for direct activation of smooth muscle contraction
- M2 mAChR reduces cAMP formation and reduces relaxation caused by adrenergic effects
What are the predominate ACh receptors of the brain and in the spinal cord?
- Brain is richer in mAChRs
- Spinal cord contains predominately nAChRs
What are the effects of the nAChR agonist nicotine on both the CV system and the GI/GU tracts?
- CV system: mainly sympathomimetic (HTN and possible alternating tachycardia and bradycardia mediated by vagal discharge)
- GI/GU tracts: effects are mainly parasympathomimetic (nausea, vomiting, diarrhea, voiding of urine)
What are the major clinical uses of direct-acting cholinergic agonists?
- Glaucoma: muscarinic stimulants cause contraction of ciliary body, facilitating outflow of aqueous humor and reducing intraocular pressure
- Accomodative esotropia
- GI/GU tract disorders
What is the most widely used choline ester for GI/GU disorders, including postoperative ileus, congenital megacolon, urinary retention, and esophageal reflux?
Which 2 cholinergic drugs are used to increase salivary secretion (i.e., dry mouth associated w/ Sjorgen's syndrome)?
What are major contraindications to the use of mAChR agonists that are distributed systemically?
- Coronary insufficiency
- Acid-peptic disease
What is the treatment for acute toxicity caused by excess muscarinic stimulation from parasympathetic ganglia?
Which cholinergic drug is approved for intraocular use during surgery and causes miosis?
Which cholinergic drug is administered as an inhalant and used clinically for the diagnosis of bronchial airway hyperreactivity in patients who do not have clinically apparent asthma?
What is the clinical use of Carbachol?
Nonspecific cholinergic agonist used for tx of glaucoma or to produce miosis during surgery or opthalmic examination
What is the clinical use of the cholinergic drug, Bethanechol?
Which receptor does it act on?
- Used to treat patients with urinary retention and heartburn
- Selective mAChR agonist
What is a possible side effect from the use of Bethanechol in treating urinary retention?
May produce a UTI if sphincter fails to relax
Which cholinergic drug is used to treat dry mouth (xerostomia) in patients with Sjorgen's syndrome?
Metabolized by what enzyme?
- Metabolizd via P450 pathways and eliminated in urine
What is Pilocarpine used clinically to treat?
Which receptor does it act on?
- Xerostomia in pt's w/ Sjorgen syndrome or head and neck cancer treatment related xerostomia (PO)
- Miosis during opthalmic procedures (topical)
- Glaucoma (topical)
- Pure mAChR agonist
Which cholinergic drug has been approved to help people quit smoking and what are some potential adverse effects of this drug?
- Nausea is most common adverse effect, but serious side effects include neuropsychiatric sx's,
What are the 3 chemical groups of AChE inhibitors?
2) Carbamic acid esters (carbamates)
What are the characteristics of Quaternary and charged AChE inhibitors?
- Relatively insoluble in lipids and absorption from the conjunctive, skin, and lungs is poor
- Parenteral administration preferred
- NO CNS distribution
What are the characteristics of Tertiary and uncharged AChE inhibitors?
- Well absorbed from all sites
- CNS distribution
- More toxic than polar quaternary carbamates
What are 5 examples of Quaternary/Charged AChE inhibitors?
What are 5 examples of tertiary/uncharged AChE inhibitors?
What is the MOA of Varenicline?
- Partial agonist that binds w/ high affinity and selectivity to α4β2 nicotinic AChR located in the brain to stimulate receptor-mediated activity
- Causes moderate and sustained rlease of mesolimbic dopamine, thought to reduce craving and withdrawl symptoms associated w/ smoking cessation (reward pathway)
What is the duration of action for the AChE inhibitor, alcohol?
- Bind reversibly through electrostatic interaction and hydrogen bonding at the binding site for ACh
- Weak interactions that are short-lived and result in short duration of action (2-10 mins)
What is the duration of action for the AChE inhibitors of the Carbamic acid ester class?
- Undergo 2-step hydrolysis sequence analagous to ACh
- Second step involves formation of covalent bond betwen the enzyme and the carbamic acid group of the inhibitor that requires 30 mins - 6 hours to hydrolyze
What are the net cardiovascular effects of moderate doses of AChE inhibitors?
- Modest bradycardia
- Fall in cardiac output (due to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility)
- Modest increase in BP
Therapeutic concentration of AChE inhibitors at the NMJ cause what?
Prolong and intensify the action of ACh, which increases the strength of contraction
Which drug class is used for reversal of pharmacologic paralysis (i.e., surgical anesthesia)?
What 2 drugs in this class are preferred?
- AChE inhibitors
- Neostigmine and edrophonium
Which cholinergic drug class and specific drugs are used in the treatment of Dementia of the Alzheimer type and associated with Parkinsons disease?
- AChE inhibitors
- Donepezil, Rivastigmine, Galantamine, and Physostigmine
* "Dementia Robs Good People"
Which cholinergic drug can be used as an antidote to reverse anticholinergic intoxication caused by atropine, antihistamines, tricyclic antidepressants, sleep aids, and cold preparations?
Why is this drug preferred?
- Physostigmine (tertiary and uncharged AChE inhibitor)
- Preferred as it can cross the blood-brain barrier
What are the major therapeutic uses of AChE inhibitors?
- Diseases of eye (glaucoma, accomodative esotropia)
- GI and urinary tract (postoperative atony, neurogenic bladder)
- NMJ (myasthenia gravis, curare-induced neuromuscular paralysis
- Alzheimer disease
- Antidote (Physostigmine) for intoxication by anticholinergic agents
What are the dominant initial signs of acute intoxication by AChE inhibitors?
- Bronchial constriction
In suspected cases of deliberate AChE inhibitor poisoning with more mild signs of intoxication, measurement of what can establish the diagnosis?
AChE activity in erythrocytes and plasma
What is the antidote recommended for cholinergic poisoning with AChE inhibitors?
Will it work at the NMJ?
- Is ineffective against the peripheral neuromuscular stimulation (nAChRs), to regenerate AChE at the NMJ, cholinesterase regenerators (i.e., pralidoxime) can be administered
What is the current antidotal therapy for organophosphate exposure resulting from warfare, terrorism, or other sources?
- Parenteral atropine (cholinergic antagonist)
- An oxime (pralidoxime)
- A benzodiazepine as an anticonvulsant
Pretreatment with which drug has been shown to reduce the incapacitation and mortality associated with nerve agent poisoning?
What are the quaternary cholinergic antagonists and they are used clinically for their effects on what parts of the body?
- Ipratropium and glycopyrrolate
- Elicit antimuscarinic effects in the periphery
Atropine is a naturally occuring _______ amine alkaloid ester found in the plant _________
Atropine is a naturally occuring tertiary amine alkaloid ester found in the plant Atropa belladonna
What are the tertiary, uncharged, cholinergic antagonists and they are used clinically for their effects on what parts of the body?
- Atropine, tropicamide, and benztropine
- Eye or CNS
- Are more readily absorbed and widely distributed than charged quaternary compounds
Which muscarinic receptor types does atropine antagonize and which tissues are most sensitive to its effects?
- All 5 mAChRs and does NOT distinguish between receptor types
- Salivary, bronchial, and sweat glands
What effect do antimuscarinic compounds have on patients with Parkinson disease?
Reduce the associated tremors
Which antimuscarinic drug is effective in the prevention or reversal of the symptoms associated with vestibular distubrances (motion sickness)?
What are the CNS effects of the antimuscarinic drug, Scopolamine?
- Drowsiness an amnesia
- Toxic doses can cause excitement, agitation, hallucinations, and coma
What are the effects of antimuscarinic drugs on the eye and when are they used clinically?
- Reduce lacrimal secretion
- Blockade of papillary constrictor muscle activation (by atropine and other tertiary agents) --> unopposed sympathetic dilator activity and mydriasis (dilation)
- Weaken contraction of the ciliary muscle (cycloplegia) --> lack of accomodation and useful during opthalmic procedures
What are the effects on the CV system with low doses of atropine?
Moderate to high doses?
- Low doses result in initial bradycardia before the effects of peripheral vagal block manifest (due to the block of presynaptic M1 receptors on parasympathetic postganglionic nerve terminals in the SA node, which normally inhibit ACh release)
- Moderate to high doses cause tachycardia by blockade of vagal slowing
What are the effects of muscarinic antagonists on the respiratory system?
Blockade of airway mAChRs can cause bronchodilation and reduce secretion --> positive effects in tx of some respiratory disorders
What are the effects of antimuscarinic agents on the GI tract i.e., salivary glands, gastric, secretions, and gastric emptying time?
- Decrease salivary secretion (common side effect of these agents - dry mouth)
- Block gastric secretion only midly
- Gastric emptying time is prolonged and intestinal transit time is lengthened
What are the effects of antimuscarinic agents on the Genitourinary tract?
Make them clinically useful in the treatment of?
- Relax smooth muscle of the ureters and bladder wall and slow voiding
- Useful in tx of urinary incontinence
What is the effect of the antimuscarinic agent, Atropine, on the sweat glands?
What effect is seen in children?
- Suppresses thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (there is no parasympathetic innervation of sweat glands)
- In children, ordinary doses may produce "atropine fever"
Which antimuscarinic agents are useful as an adjunctive therapy in the treatment of Parkinson Disease?
- Benztropine and trihexyphenidyl
- Reduce tremors
What 2 uses does Atropine have as an anesthetic agent during surgery?
Which drugs are paired together during reversal of skeletal muscle relaxation post-surgery?
1) Blocks vagal reflexes induced by surgical manipulation of visceral organs
2) Atropine or glycopyrrolate is paired w/ neostigmine to block parasympathetic effects during skeletal muscle relaxation
When should antimuscarinic agents be used to elicit mydriasis during an opthalmic examination?
What is the topical drug of choice for production of mydriasis, why?
- Should never be used UNLESS cycloplegia or prolonged action is required
- α-adrenergic receptor agonists are shorter-acting and produce less adverse effects
What drug is used to prevent synechia formation in uveitis and iritis (the iris adhering to either the lens or the cornea)?
- mAChR antagonists
- Particularly long-lasting homatropine
What are the antimuscarinic agents used as a first line therapy for the treatment of COPD and asthma?
Which drug was recently approved for treatment?
- Ipratropium used as an inhalation agent (3-4x/day) is the current first-line tx
- Recently approved tiotropium has a longer bronchodilator action and only needs to be dosed once per day
What is the first drug of choice for symptomatic bradycardia in an advanced cardiac life support (ACLS) setting?
mAChR antagonists are commonly used in the treatment of which GI disorder?
- Traveler's diarrhea and other mild or self-limited conditions of hypermotility
- Often combined w/ an opioid antidiarrheal drug to discourage abuse of the opioid agent
Atropine and other antimuscarinic agents have been used to provide symptomatic relief in the treatment of which urinary disorders?
Selectivity of which receptor is preferred?
- Tx of urinary urgency caused by minor inflammatory bladder disorders
- Selectivity for the M3 subtype is preferred
Which antimuscarinic agents are used in the tx of genitourinary tract disorders, such as overactive bladder and urinary urge incontinence?
Which is the prototype and what other agents may be used?
- Prototype is oxybutynin, which is somewhat selective for M3 mAChRs
- Trospium is a nonselective antagonist that is comparable in efficacy and side effects
- Darifenacin, solifenacin, and tolterodine are selective for the M3 subtype and are advantageous due to a longer half-life and reduced incidence of xerostomia and constipation
What are side effects of treatment of urinary incontinence with the antimuscarinic agent, Oxybutynin?
Dry mouth, dizziness, constipation, blurred vision, dry eyes, and UTI's
Why is Pralidoxme, a cholinesterase regenerator compound used to treat orgagnophosphate poisoning alongside atropine?
- Breaks the bond between the organophosphate and cholinesterase enzyme
- Only effective at regenerating cholinesterase at the NMJ
Antimuscarinic agents are contraindicated in which patients and should be used with caution in whom?
- Contraindicated in patients with glaucoma (reduce secretions)
- Used w/ caution in elderly men w/ a history of prostatic hyperplasia; woul be at risk for acute urinary retention
Nonselective antimuscarinic agents (atropine) should be avoided in patients with what GI issue?
- Acid-peptic disease (potential to slow gastric emptying; increase discomfort)
- Agents that are selective, may be of benefit
Which antimuscarinic agent is use to treat peptic ulcer disease in Europe, Japan, and Canada (not the US as there are better agents available)?
This drug is selective for which receptor?
- M1 mAChR selective; inhibits gastric secretion by acting at the ganglia
All ganglion-blocking drugs are?
Which drug was developed from initial ganglion blockers and has improved GI tract absorption?
Mecamylamine (tertiary amine)
What is the MOA of ganglion-blocking agents?
Competitively block the action of ACh and similar agonists at nAChRs of both parasympathetic and sympathetic autonomic ganglia (block all autonomic outflow)
Effect of ganglion blockers on parasympathetic and sympathetic tone?
Enhance sympathetic tone
What are 2 effects of ganglion blockers on the eye?
- Cycloplegia w/ loss of accomodation
- Moderate dilation of the pupil
What are 2 effects on the CV system produced by ganglion blockers?
1) Marked decrease in arteriolar and venomotor tone, causing decrease in BP
2) Diminished contractility and moderate tachycardia
What are the effects of ganglion blockers on the GI and GU system?
- Reduced secretion and profoundly inhibited motility (GI)
- Urination hesitancy and possible urinary retention in men w/ prostatic hyperplasia (GU)
- Erection and ejaculation may be prevented (GU)
What are the clinical uses of ganglion blocking agents; which drug specifically?
Mecamylamine is approved for use to tx HTN and is being investigated for use in smoking cessation therapy