Flashcards in EXAM #1: ANS PHARMACOLOGY - CHOLINERGICS Deck (94):
What is a direct acting cholinomimetics?
Drugs that bind directly to and activate muscarinic or nicotinic cholinoceptors
What is a indirect acting cholinomimetics?
Drugs that produce their effects by inhibiting AChE i.e. preventing the destruction of endogenous ACh
What are the two classes of indirect acting cholinomimetics? What are their basic clinical and commerical applications?
- Reversible= used to treat Alzheimer's Disease or Myasthenia Gravis
- Irreversible= Organophosphates, commerical insecticides
What are the different types of direct-acting cholinomimetics?
1) Choline esters
2) Natural alkaloids
3) Synthetic analogs
List the choline esters. Generally, what type of drug are these?
*****These are all "choline esters," which are direct cholinoceptor agonists.*****
Describe ACh's: 1) susceptibility to cholinesterase, 2) muscarinic action, and 3) nicotinic action.
1) High susceptibility to cholinesterase
2) Equally high muscarinic and nicotinic action
Describe Methacholine's: 1) susceptibility to cholinesterase, 2) muscarinic action, and 3) nicotinic action.
1) Low susceptibility to cholinesterase
2) High muscarinic action (greater than ACh)
3) Low nicotinic action
Describe Carbachol's: 1) susceptibility to cholinesterase, 2) muscarinic action, and 3) nicotinic action.
1) NO susceptibility to cholinesterase
2) Moderate muscarinic action
3) Moderately high nicotinic action
Describe Bethanechol's: 1) susceptibility to cholinesterase, 2) muscarinic action, and 3) nicotinic action.
1) NO susceptibility to cholinesterase
2) Moderate muscarinic action
3) NO nicotinic action
What are the cardiovascular effects of the choline esters?
- Hypotension from direct vasodilation
- Slowed conduction/ prolonged refractory period of AV node
What are the gastrointestinal effects of the choline esters? What symptoms seen with choline esters?
- Increased tone and contractility of the gut
- Increased acid secretion
*****Nausea, vomiting, diarrhea, and cramps*****
What are the genitourinary effects of the choline esters?
- Increased bladder motility and relaxation of sphincter resulting in involuntary urination
- Little or NO effect on UTERUS
What are the ocular effects of the choline esters?
- Miosis (sphincter m.)
- Decreased intraocular pressure and accomodation (ciliary m.)
What are the respiratory effects of the choline esters?
What are the effects of choline esters on glands?
Increased secretory activity resulting in:
How does acetylcholine need to be administered? Why?
IV b/c it is rapidly destroyed by AChE
What are the effects of ACh on the cardiovascular system at low doses vs. high doses?
- Decreased TPR b/c of M3 receptor activation on vascular endothelium
--> "Reflex tachycardia"
- Decreased AV conduction
- Negative ionotope
What are the nicotinic effects of ACh?
None--does NOT penetrate fat surrounding skeletal muscle and ANS ganglia
What are the clinical uses of ACh?
B/c of rapid degradation, clinical use is limited, but it can be used for:
1) Eye surgery for short-lasting miosis
2) Provocation test in coronary angiography
*****Provocation test assists in the diagnosis of coronary vasospasm*****
What are the respiratory effects of ACh administration?
2) Increased bronchial secretion
*****Thus, ACh should NOT be given to ASTHMATICS*****
What is the clinical use of methacholine?
Diagnosis of bronchiolar hypersensitivity
*****This is called a "methacholine challenge"-->M3 activation leads to transient bronchoconstriction patients with bronchiolar hypersensitivity at much lower doses than normal population*****
How does Methacholine differ from ACh?
Longer half-life b/c of methyl group
What is the clinical cuse of Carbachol?
Treatment of Glaucoma; it contracts the ciliary muscle, which:
1) Enlarges canal of Schlemm
2) Increases drainage of aqueous humor
3) Decreases intraocular pressure
What receptors are activated by therapeutic doses of Carbachol?
BOTH nicotinic and muscarinic cholinoreceptors
What is the danger associated with high doses of Carbachol?
May induce cardiac arrest
What are the clinical indications for Bethanechol?
1) Gastric atony
2) Gastric emptying abnormalities
3) Urinary retention (w/out obstruction)
Bethanechol increases Lower Esophageal Sphincter (LES) tone; this can reduce symptoms of reflux s/p vagotomy
What are the predominate Gu and GI effects of Bethanechol? Drug interaction with which type of receptor mediates these effects?
- Increased detrusor tone
- Decreased outlet resistance of internal sphincter
GI= increased motility and secretion
*****M3 receptor mediated*****
What are the two direct acting muscarininc alkaloids?
What are the symptoms of muscarine poisoning?
- Salivation, lacrimation, and sweating initially
- Abdominal pain, nausea, diarrhea, blurred vision, and dyspnea
*****Effects typically subside within 2 hours*****
What are the clinical uses of Pilocarpine?
- *Glaucoma- this is the drug of choice* (topically)
- Xerostomia (orally)
- Test on autonomic state/ PNS dysfunction
What effects of Pilocarpine predominate? What receptor type are these effects mediated by?
What the mechanism of action of Pilocarpine on the eye?
1) Contracts sphincter muscle to produce MIOSIS
2) Contracts ciliary m. to free entrance into Canal of Schlemm (narrow angle Glaucoma)
3) Enhances tone of trabecular network (wide angle glaucoma)
What are the contraindciations to direct-acting cholinoceptor agonists?
1) Peptic ulcers
2) GI tract disorders
What drugs interact with direct-acting cholinoceptor agonists?
Drugs with antimuscarinic properties:
- Quinidine (antiarrhythmic)
- Procainamide (antiarrhythmic)
- Tricyclic antidepressants
All can block the intended effects of cholinoceptor agonists
What are the two nicotinic alkaloids?
These are direct acting nicotinic receptor agonists. Note that b/c of dramatic long term receptor activation, Succinylcholine function as a nicotinic receptor antagonist
What are the actions of nicotine on Nm receptors?
- Skeletal muscle contraction
- Fasiculations/ spasm
- Depolarizing blockade (similar to succinylcholine)
Generally, what is the action of nicotine on Nn receptors?
Stimulation of BOTH SNS and PNS post-ganglionic neurons
What is the action of nicotine on Nn subtype receptors in the heart?
Increased heart rate
What is the action of nicotine on Nn subtype receptors in the vascular system?
What is the action of nicotine on Nn subtype receptors in the GI tract?
Increased gut motility and secretion
What is the action of nicotine on Nn subtype receptors in the carotid bodies?
Increased respiratory rate
What is the action of nicotine on Nn subtype receptors in the medullary emetic chemoreceptors?
Nausea and vomiting
What is the clinical indication for nicotine prescription?
To assist with smoking cessation
List the reversible cholinesterase inhibitors.
What is the important characteristic of Edrophonium?
What is the clinical use of Edrophonium?
Diagnosis of Myasthenia Gravis
*****It can be difficult to differentiate the symptoms/ etiology of myasthenia gravis. Blocking AChE leads to the specific improvement of MG symptoms and can thus be useful diagnostically.
What is are important characteristics of Neostigmine and Pyridostigmine?
- Quaternary amines= no CNS entry
*****Inability to penetrate the CNS keeps the action of these drugs confined to the periphery hence their utility in treating MG.****
What are the clinical uses of Neostigmine and Pyridostigmine?
These are the standard AChE inhibitors used to treat Myasthenia Gravis. Other uses include:
2) Urinary retention
4) Reversal of non-depolarizing NM blockers
What are the important characteristic of Physostigmine?
- Tertiary amine= ENTERS CNS
- Intermediate acting
What are the clinical uses of Physostigmine?
- Antidote in atropine overdose
What is the important characteristic of Donepezil and Tacrine?
Lipid soluble i.e. enters the CNS
What is the clinical use of Donepezil and Tacrine?
There is a deficiency in intact cholinergic neurons in AD; thus these drugs, which DO cross the BBB are used.
What are the important characteristics of Organophosphates?
3) Irreversible inhibitors of AChE
What are the clinical uses for the Organophosphates?
3) Nerve gas
What is the mnemonic to remember the symptoms of cholinesterase inhibitor intoxication?
List the muscarinic receptor antagnoists.
What are the characteristics of atropine?
- Tertiary amine; thus, it enters the CNS (but not readily at therapeutic doses)
- Competes with ACh at M receptors
- Does NOT distinguish between M1, M2, and M3 receptors
What are the pharmacologic effects of atropine?
1) Decreased secretions
2) Mydriasis and cycloplegia
6) Urinary retention and constipation
7) Behavioral excitation and hallucinations
*****Note that these effects are listed in order of increasing dose.
What drug will completely counteract peripheral vasodilation caused by choline esters?
Does atropine effect blood pressure when given alone?
This is due to lack of significant cholinergic innervation most vascular beds
What are the indications for atropine?
- Management of AChE inhibitor overdose
- Prevention of vagal reaction e.g. in pericardiocentesis
What drug can be used to counteract acute intoxication of atropine?
What are the clinical uses of Ipratropium?
1) *First line therapy for COPD*
2) Asthma (2nd line)
What are the properties of Ipratropium?
- Nonselective muscarinic antagonist
- Mainly acts on bronchial SMC/ glandular M3 receptors when inhaled
- Quaternary amine= no CNS effects
What are the effects of Ipratropium?
1) Decreased bronchoconstriction
2) Decreased bronchial secretions
What are the clinical uses of Benztropine?
- Parkinson's Disease (2nd or 3rd line therapy)
- PD secondary to an antipsychotic medication
What are the properties of Benztropine?
- Tertiary amine= CNS absorption
- Acts on muscarinic receptors in the brain
What are the effects of Benztropine?
1) Re-establishment of DA-ACh balance in patients with PD
- Decreased GI/GU secretions and motility
- Increased HR
What are the two nicotinic receptor antagonists?
What are the pharmacologic effects of nicotinic receptor antagonists?
- Reduce the predominant ANS tone
- Prevent baroreceptor reflex changes in HR
****Most are no longer available clinically b/c of toxicity
What is the effect of nicotinic receptor antagonists on the arterioles? Which system (PNS or SNS) is being antagonized?
- Vasodilation and hypotension
What is the effect of nicotinic receptor antagonists on the veins? Which system (PNS or SNS) is being antagonized?
- Decreased venous return
- Decreased CO
What is the effect of nicotinic receptor antagonists on the heart? Which system (PNS or SNS) is being antagonized?
What is the effect of nicotinic receptor antagonists on the iris? Which system (PNS or SNS) is being antagonized?
What is the effect of nicotinic receptor antagonists on the ciliary muscle? Which system (PNS or SNS) is being antagonized?
Cycloplegia is the paralysis of the ciliary muscle of the eye, which results in a loss of accommodation.
What is the effect of nicotinic receptor antagonists on the GI tract? Which system (PNS or SNS) is being antagonized?
- Decreased tone and motility
What is the effect of nicotinic receptor antagonists on the bladder? Which system (PNS or SNS) is being antagonized?
- Urinary retention
What is the effect of nicotinic receptor antagonists on the salivary glands? Which system (PNS or SNS) is being antagonized?
What is the effect of nicotinic receptor antagonists on the sweat glands? Which system (PNS or SNS) is being antagonized?
Ahidrosis is the abnormal lack of a sweating response.
What is the non-depolarizing neuromuscular blocking agent?
What is the depolarizing neuromuscular blocking agent?
What are the neuromuscular blocking drugs clinically used for?
Used as adjuncts during general anesthesia to:
1) Facilitate tracheal intubation
2) Optimize surgical conditions while ensuring adequate ventilation
What is D-tubocurarine's mechanism of action? What is the difference between small and large doses?
Prevention of ion channel opening when bound to the Nm receptor
- Low dose= compete with ACh
- High dose= enters the Nm channel pore
What is phase 1 of depolarizing neuromuscular blocking agents?
1) Drug binds Nm receptor causing depolarization
2) Persistent depolarization leads to paralysis
*****Note that this effect can be augmented by the administration of AChE inhibitors
What is Phase 2 blockade of depolarizing neuromuscular blocking agents?
Repolarized occurs but the receptor is "desensitized" and not easily depolarized again
In what sequence do muscles respond Succinylcholine administration? In what order do they recover?
- Larger muscles are more resistant than smaller ones
- Diaphragm responds last
- Larger muscles recover first
Aside from facilitating airway management, what else can neuromuscular blocking agents be used for?
Treatment of convulsions
*****Note that these agents DO NOT enter the CNS and thus only decrease the MUSCULAR manifestations of a seizure*****
What are the side effects of the neuromusclar blockers?
- Increased intraocular pressure
- Increase intragastric pressure
- Muscle pain
Why does hypotension follow neuromuscular blocker administration? What can be given to prevent this?
- Tubocurarine can produce systemic histamine release that results in hypotension
- Anti-histamines can prevent this effect
Describe the structure of the choline esters. What is clinically important about their structure?
All are "cationic quaternary ammonium compounds"
*****Thus, all are INSOLUBLE in lipids and DO NOT enter the CNS
Which two choline esters have an extended half-life compared to ACh? What is the structural basis for this difference?
BOTH have a longer half life b/c of the addition of a methyl group
Outline the management of cholinesterase inhibitor intoxication.
1) Symptom management including:
- Airway support
- Cardiovascular support
2) Antidote= ATROPINE
3) PRALIDOXIM (2-PAM)= regeneration of AChE
Atropine is a a muscarinic receptor antagonist that can block M receptors from high ACh conentrations. AChE inhibitors phosphorylate AChE. 2-PAM reverses that phosphorylation.
What is Myasthenia Gravis?
NM disorder caused by autoimmune attack of the ACh receptor on post-junctional endplate, which causes:
- Fagitability of skeletal muscle
Fgitability is an increased susceptibility to fatigue.