topic 20 Flashcards
What are 6 types of cholinergic drug agents?
Directly acting muscarinic agonists
Muscarinic Antagonists
Anticholinesterases
Ganglionic Stimulant
ganglionic Antagonist
Neuromuscular blockers
What are two types of directly acting ACh agonists? Name 4 examples of one and 2 examples of the other.
Choline Esters: ACh, Methacholine, Carbachol, Bethanechol
Alkaloids: Pilocarpine, Cevimeline
What is the susceptibility to cholinesterases of the 4 choline esters? What is each primarily used for? Do they stimulate nicotinic receptors?
ACh-Very susceptible to Ach. the others not as much.
Methacholine-Used to diagnose bronchial hyperreactivity (not used in much else, acts strongly on heart)
Carbachol-Used mainly in research. Acts strongly on nicotinic receptors and thus can be used for that.
Bethanechol-The main one used clinically. It is not hydrolyzed by AChE. It is used to stimulate the motility of GI tract and contract the urinary bladder, often post-operatively.
What are the 2 alkaloids used?
Pilocarpine and Cevimeline
How is Bethanechol taken? What is its absorption? Distribution? What receptor does it favor? What does it do?
SC or PO
Poor lipid solubility
Does not cross BBB
Favors M3
Enhances function of GI tract and urinary bladder, especially post-op
How is Pilocarpine taken? What is its absorption? Distribution? What does it do? What is it used to treat?
PO or eyedrops
Well absorbed
Good lipid solubility
Marked stimulation of saliva and sweat
Used in both narrow angle and wide angle glaucoma
What receptor does Cevimeline work on? What drug is it simliar to? What does it do? What is sjogrens syndrome? Treatment of it?
Synthetic M3 selective agonist
Similar to Pilocarpine
Used for treatment of dry mouth associated with Sjogrens Syndrome (autoimmune where moisture producing glands are destroyed) or radiation damage of salivary glands.
Pilocarpine also used to treat sjogrens syndrome.
What is glaucoma? What are the two types? How are each treated?
Ocular disease characterized by an elevation of intraocular pressure leading to possible retinal damage
Primary open angle Glaucoma: More common. Problem in trabecular network so aqueous humor cant get out into schlemms canal. But angle is intact. This is usually treated step-wise with drugs. Pilocarpine is part of the 3rd step.
Narrow angle glaucoma: Less common. Iris bows forward and makes contact with cornea so aqueous humor cant get to anterior chamber. Emergency increased pressure. Pilocarpine used immediately followed by surgery.
What are the side effects of muscarinic agonists
Salivation, Lacrimation, Nausea and vomiting, bradycardia, diarrhea, sweating, urination, hypotension, bronchospasm, CNS activation, Headache and visual disturbances, Pupils constricted
What are the contraindications of muscarinic agonists?
Asthma/COPD, Hyperthyroidism, Coronary insufficiency, Peptic Ulcer Disease, Obstruction of urinary bladder or Gi tract.
What are 5 muscarinic antagonists or belladonna alkaloids? What are the prototypes? How do they work? What happens w/o parasymp tone?
Atropine, Scopolamine, Ipratropium, Tolterodine/Oxybutynin
They are competetive antagonists at muscarinic receptors. The more parasymp tone at a receptor, the greater their effect.
What are the routes of admin. of atropine? How is it absorbed orally? What is it distribution? How is it metabolized?
PO, IM, IV, SC, opthalmic drops
Well absorbed orally
Well distributed, crosses BBB
40% hydrolyzed and conjugated
60% excreted
What are the routes of admin. of Scopolamine? What is it distribution? How is it metabolized?
PO, IM, IV, SC, eyedrops,patches
Crosses BBB
Metabolism similar to atropine
What are the routes of admin. of Ipatropium? Absorption? What is it distribution? ?
Only inhaled
Poorly absorbed, doesn’t cross membranes well
Doesn’t cross BBB
What is the effect of muscarinic antagonists on the CNS? What are some therapeutic uses? How do scopolamine and atropine differ in their effects?
Atropine stimulates CNS and causes hallucinations. Scopolamine depresses CNA (drowsiness, euphoria). Antitremor in parkinsons.
Sleeping pills (scopolamine)
Motion sickness (scopolamine)
Parkinson’s
Sedation prior to surgery (scop)
Sedation during labor (scop-truth serum)
What is the effect of muscarinic antagonists on the eye? What are some therapeutic uses?
Dilation and paralyzes accomodation (looking close) (cycloplegia).
Opthalmalgic use (eye exams)
mydriatics and cycloplegics
What is the effect of muscarinic antagonists on the respiratory system? SM in general? glands in general? What are some therapeutic uses?
SM in general is relaxed, so bronchioles are relaxed (opening airway). Gland secretions are inhibited, so resp tract gland secretion is inhibited.
Inhibition of secretions
Reduce or prevent vagal overactivity
Cold Remedies
Asthma
COPD
What is the effect of muscarinic antagonists on the Heart/BP? What are some therapeutic uses in CV system?
In heart, low doses—>slight bradycardia (due to vagal stimulation in CNS), but most tachycardia via blockage of SA node. No great effect on BP.
Atropine always in crash cart. After MI, it combats symptoms such as
Sinus Bradycardia
SA Arrest and SA Block
What is the effect of muscarinic antagonists on the GI Tract? Sphincters in general? What are some therapeutic uses?
Since SM is relaxed–>less motility and tone, less gall bladder secretion. Sphincters are blocked in general.
Inflammation (IBS and acute enterocolitis)
Travelers diarrhea
What is the effect of muscarinic antagonists on the bladder? What are some therapeutic uses?
Urinary incontinence in elderly using tolterodine and oxybutyin
Child enuresis
What are some side effects of Atropine and other muscarinic antagonists in order of when they appear with increasing doses
Less salivation (dry mouth), inhibition of sweating, Micturition speed lowered, acceleration of heart, dilation of pupil, blurring of vision, speech disturbed, headache, restlessness and fatigue, hot skin, difficulty swallowing, reduced peristalsis, ataxia, hallucinations, delirium, death.
What are atropine, scopolamine, ipratropium, tolterodine, and oxybutynin primarily used for? Why do some have less side effects?
Atropine-counteract muscarinic toxicity, mydriatic, reversal of bradycardia or cardiac arrest
Scopolamine-motion sickness
Ipratropium-Bronchodilator in asthma and copd
tolterodine/oxybutynin-reduce involuntary voiding.
The last 3 are used locally and have poor penetration across membranes and thus have fewer side effects.
What are the two types of cholinesterases? Where are they primarily located? What is their substrate selectivity? How are indirect ACh agonists different from direct?
AChE: Located in all cholinergic synapses (therefore it works in CNS and Neuromuscular synapses as well unlike the direct agonists). Specific for ACh.
Plasma Cholinesterase: Located in plasma (also intestines, etc.). Selective for ACh, succinylcholine, and local anesthetics
What are 7 Reversible AChE inhibitors?
Edrophonium, Physostigmine, Neostigmine, Pyridostigmine, Tacrine/Donepezil (alzheimers), demecarium (opthalmic)
What is edrophonium? How is it administered/distribution? How is it excreted? Which site does it bind to? How long does it stay on the enzyme/what type of interaction? How is it used?
IM or IV
No CNS Effects
Excreted in Urine
Non-covalent/very rapidly unattaches/binds to anionic site
Used to differentiate between myasthenia crisis and excess cholinergic excitation.
What are tacrine and donepezil used for? How are they administered? How are they metabolized? Distribution?
PO
Enter CNS
P450
Treatment of alzheimers
How is physostigmine administered? How is it hydrolyzed? How is it used clinically? How is it different from neostigmine?
IM, IV, Opthalmic
Hydrolyzed by ChE
Different in that it enters CNS
applied topically to treat wide angle glaucoma
Treatment of CNS toxicity due to anticholinergic poisoning
How is neostigmine administered? How is it hydrolyzed? How is it used clinically?
IM, IV, SC, PO
Hydrolyzed by ChE
Drug of choice for paralytic ileus and atony of bladder after surgery
Rx and diagnosis of myasthenia
Reversal of NM Blockade
How is Pyridostigmine administered? How is it hydrolyzed? How is it used clinically?
IM, IV, PO
Hydrolyzed by ChE
Pretreatment to reduce risk of mortality due to nerve gases
Rx of myasthenia
Reversal of NM Blockade
What are the 3 main drugs we use? Where do they bind to AChE? How long are they bound to AChE?
Physostigmine, Pyridostigmine, Neostigmine,
Bind to both anionic and esteric sites
2-8 hours
What are two types of Organophosphate AChE inhibitors that are irreversible that are used clinically (not totally irreversible)? What are they used to treat? What other organophosphate AChE inhibitors are there and what are there purposes? Where do they bind AChE? How are the organophosphates absorbed
Isoflourophate and Echothiophate-treats glaucoma
Nerve Gases-Serin and Soman
Insectisides-parathion
They bind to esteric site
They are absorbed well through skin, lung, gut and conjuctiva
What side effects are common to all AChE inhibitors including the clinically used ones? What side effects are caused by organophosphates (mainly Nicotinic and CNS effects)?
Muscarinic Effects: ciliary spasm, Miosis, bronchoconstriction, bradycardia, increased bronchial secretion, sweating, salivation, hypotension, involutary defecation and urination
Nicotinic effects: weakness, muscle fasciculation (twitching), muscular paralysis (too much ACh)
CNS: Confusion, ataxia, convulsions, Coma, respiratory depression, CV
What are general clinical uses of AChE inhibitors? What is myasthenia gravis? What can be given to combat the muscarinic side effects of these drugs?
Used to reverse NM blockade after surgery
Used to get bladder and GI going
Used to treat glaucoma (ectothiopate and Demecarium)
Used to treat Myasthenia gravis (PO Neostygmine and Pyridostigmine). Pyridostigmine lasts a little longer than neostigmine. The muscarinic side effects wear off with time, but atropine can be given. The cholinergic effects can become excessive leading to paralysis. To test between excessive cholinergic effects or myasthenia crisis, physostigmine is used. If it gets better=crisis, worse=excessive cholinergic.
Myasthenia gravis is autoimmune in which lymphocytes destroy nicotinic cholinergic receptors.
What can be used to treat poisining by organophosphates (nerve gasses or insectisides)? How is it made most effective? How does it work?
Atropine can help with the muscarinic effects.
To help with the nicotinic effects, Pralidoxime is used. It binds to anionic site and then binds to the organophosphate stronger than the enzyme does and thus releases it.
It should be used within a few hours b/c the bound enzymes can age.
What does demecarium used to treat? How is it administered
Glaucoma
Opthalmic
What happens at a ganglionic synapse?
ACh is released.
ACh mainly binds to a nicotinic receptor causing a F-EPSP (fast)
It can also bind to a muscarinic receptor on the postsynap. cell causing an S-EPSP (slow)
It can also bind to a muscarinic receptor on an interneuron causing it to releasing dopamine which binds to a dopamine receptor on the postsyn. cell causing an S-IPSP (inhibitory)…sometimes the interneuron isn’t used and the ACh binds directly to a muscar. receptor on the post synap cell causing an S-IPSP.
Lastly, Autacoids from the blood stream (angiotension, etc.) can bind to an autacoid receptor on the post synap cell causing a late S-EPSP (very slow).
What is the main ganglionic stimulant? What are the sites of action of it and what does it do there?
Nicotine
CV System-Increases BP and heart rate due to release of NE and E from adrenal medulla and nerves
GI Tract-increase tone and motor activity
Exocrine glands- increased salivation and bronchial secretion
respiratory system-stimulates respiration
skeletal muscle-increase muscle fasiculations
CNS-stimulation, release of vasopressin, ADH, Emesis…increase in psychomotor, memory consolidation, attention, sensorimotor, and cognitive
Autonomic ganglia-increased depolarization
What are the withdrawal symptoms of nicotine?
craving, irritability, anxiety, anger, restlessness, difficulty concentrating, impatience, increased appetite, insomnia
What is the absorption, distributino, and excretion of nicotine?
Well absorbed from all tissues (especially oral, lungs, GI). Quickly is absorbed and distributes to brain. Metabolized P450 in liver, but also in kidney and lung and excreted in kidney
What are some possible ways to help people stop smoking?
Withdrawal symptoms, diagnose other conditions, treat other conditions, reduce drug craving, prevent relapse
Nicotine gum, inhalers, patches, nasal sprays, verinicline, antidepressants
Psychotherapy
What does verinicline do? How does it work? What are its side effects
partial agonist of nicotinic receptor.
Blocks nicotine from binding but activates the receptor much less than nicotine
Sx=GI related, altered dreams, but generally well tolerated.
What mechanism of action do the clinically useful ganglionic antagonists use? What is the prototype drug? What are two other drugs? What can these drugs be used for? Why aren’t they used much today? What are they used for sparingly today?
They are competitive inhibitors of Acetylcholine, preventing it from binding.
Prototype is Hexamethonium
Trimethaphan and mecamylamine can be used for vasodilation, lower bp.
They are only used in emergencies to lower BP today because of severe sx.
What are the side effects of ganglionic antagonists due to ganglionic blockade of organs and tissues under parasymp tone and symp tone?
parasympathetic: Tachycardia, mydriasis, cycloplegia, decrease in tone and motility of GI tract (constipation), urinary retention, dry mouth, decrease in secretion of sweat glands
symp: decrease in contractile force of heart, vasodilation, increase in peripheral blood flow, hypotension, pooling of blood in veins, decrease in venous return, decrease in cardiac output
How does BoTOX work? What are some clinical uses?
Blocks the SNARE system from releasing ACh.
Used to treat ocular conditions( spasms, cross eyes) and other muscle spasms (spasm of lower esophogeal sphincter, achalasia). Used dermatologocialy (hyperhidrosis, or excessive sweating, on palms and armpits AND facial wrinkles)
What are 3 types of NM blocking agents? What is the prototype of each?
BoTox-itself
NOndepolarizing agents (competitive agents)-curare
Depolarizing agents-succinylcholine, the only one
How do nondepolarizing agents work? How can they be combated? How do the different drugs differ?
They are basically competitive antagonists of ACh at the receptor. They block them from binding. Therefore, they can be overcome by adding more ACh through the use of AChE inhibitors (Edrophonium, Neostigmine, Pyridostigmine).
They differ basically in how long the effect lasts.
Which non depolarizing NM blockers have a short to intermediate duration b/c they are either metabolized by plasma ChE or spontaneously in order from shortest to longest?
Mivacurium, Atracurium, Cisatracurium
Which non depolarizing NM blockers has an intermediate duration due to largely hepatic elimination?
Vecuronium
Which non depol. NM blockers have a long duration due to primarily having renal elimination?
Pipercurium and Tubocurarine
What is the only depolarizing agent? How does it work? What is its duration? Its speed of onset? Can it be counteracted with more Ach
Succinylcholine.
Its duration is very short and so is speed of onset and thus is used for short procedures
It is basically a partial agonist of ACh. it causes the initial depolarization and thus some fasiculations but then it doesn’t repolarize b/c it isn’t broken down in the NM junction by AChE and the enzyme that breaks it down isn’t there. B/c it doesn’t repolarize, nothing else can stimulate the motor end plate during that period.
Can’t be counteractedw ith more ACh.
What do the competitive NM blockade agents do to the respiratory system? What is their onset and duration? What do they do to the CNS? What are the side effects of Tubocurarine, gallamine, pancuronium? What are the drug interactions of them?
Competitive:
Resp. system: depression
Onset: 1-2 minutes
duration: 30-60 minutes
No CNS Effect
SX Tubocurarine: Hypotension, ganglionic blockade, bronchospasm, histamine release
SX Gallamine: Tachycardia, atropine like effect
SX Pancuronium: Very little side effects, some high BP
Other SX: block autonomic ganglia at high doses,
Drug interactions: Antagonized by AChE inhibitor, enhanced by some general anesthetics and certain antibiotics (NM Blockade)
What does succinylcholine do to the respiratory system? What is their onset and duration? What do they do to the CNS? What are the side effects of Tubocurarine, gallamine, pancuronium? What are the drug interactions of them?
Resp. system: depression
Onset: 20-40 sec.
duration: 2-5 minutes
No CNS Effect
SX: Intraocular pressure, muscle soreness, liberates potassium from cell–>cardiac arrythmias, prolonged apnea, Malignant hyperthermia
Drug interactions: Not antagonized by AChE inhibitors
What causes malignant hyperthermia? What drug is used to treat it? How does it work?
Hereditary impairment of ability of SR to sequester Ca2+—>massive muscle contracction, lactic acid, potass. in plasma, increase in body temp.
Treated with datrolene to decrease release of calcium.
What are NM Blockers used for clinically?
endotracheal intubation
muscle relaxation in surgery
maintain controlled ventillation
