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M2 Mechanisms of Disease > Cholinomimetic Drugs (cholinergics Meds) > Flashcards

Cholinomimetic Drugs (cholinergics Meds) Flashcards

1
Q

What is a cholinomimetic? Cholinolytic? What is the difference between indirect and direct and direct receptor specific drugs? What are the principle reasons for using cholinomimetics?

A
  • cholinomimetic: mimick action of Ach (Ach agonist)
  • cholinolytic: Ach antagonist
  • indirect: increase the activity of the receptor (ie. AchE inhibitor)
  • direct: non specific to a Ach subtype (ie bladder) so more global effects
  • direct receptor subtype: bladder specific for example
  • used in treatment of glaucoma, GI/bladder dysfunction, Myasthenia Gravis, mild Alzheimer’s, muscle relaxation during surgery
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2
Q

What is the difference between a quarternary amine and a tertiary amine?

A
  • quartenary has 4 bonds to nitrogren in the drug structure (nitrogen only likes 3 bonds so it will be +). this leads to ionization and thus quarternary drugs can’t cross the blood brain barrier (no CNS effects)
  • teritary have 3 bonds to nitrogen and can cross the blood-brain barrier
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3
Q

What are the four major direct agonists cholinomimetics that we need to know for Step 1?

A

Bethanechol, carbachol, pilocarpine, methacholine

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4
Q

What receptors does bethanechol activate? What are its uses? What does it cause? What are some cautions (side effects of this drug)? How is it removed?

A
  • full agonist for M1-M3>N, with little effect to nicotinic receptors
  • produces effects of typical muscarinics (increased secretions, smooth muscle contraction, reduced heart rate
  • used post op and in nuerogenic illeus and urinary retention to stimulate bowel movement and urination
  • caution: don’t use in obstruction (can lead to backflow of urine because obstruction won’t move), and bronchospasm in asthmatics
  • low affinity for AchE so it has long half life. butyrylcholinerase is used to break them down
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5
Q

What class of drug is carbachol? uses? And action?

A
  • it is a direct agonist cholinergic drug (M, N equally)
  • used to treat glaaucoma, pupillary constriction, and relief of intraocular pressure
  • carbon copy of Ach
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6
Q

What is pilocarpine? uses? and action? structure?

A
  • potent stimulator of sweat, tears, and siliva.
  • M»»»>N
  • treatment for open angle and close angle glaucoma
  • contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed-angle glaucoma), resistant to AchE.
  • tertiary so it can cross blood-brain barrier
  • SLUDGEM affects (Salivation, lacrimation, urination, defication, gi upset, emesis, miosis)
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7
Q

What are the two nicotinic direct acting agonists ? Structure? Toxic effects? Activation of what systems?

A

nicotine
lobeline
-tertiary
-full agonists of Nn and Nm receptors that activate SANS and PANS and striated muscle
-toxicity: increased GI activity w/ nausea, vomiting, diarrhea; increased BP and potential seizures (nicotine reduced risk of parkinson’s disease

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8
Q

Describe the effects of tobacco smoke to receptors, neurotransmitters, brain function?

A
  • tobacco smoke produced monamino oxidase inhibitors that increase DA, NE, 5HT (give you euphoric effects)
  • Thru Nn receptors, works on dorsal attention network to improve focus (ventral network regulated by NE, and when dorsal usually inhibits ventral. withouth this, you would be ADHD)
  • nicotine increases dopamine in CNS through alpha4beta2 nicotinic Nn receptor located on presynaptic dopamine terminals (NANC receptor!)
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9
Q

What are all the ways that cholinergic receptors can act on a receptor?

A

-directly on receptor, presynpatic auto receptor, heterorecetpro, or non/adrenergic/non-cholineric heteroreceptor (NANC)

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10
Q

What is varenicline? (Chantix) And how does it work?

A
  • a partial agonist at the alpha4beta2 nicotinic Nn receptor
  • works to release Da release and the addictive supporting action of Da
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11
Q

What are all the indirect agonists that we need to know for Step 1? What kinda of drug is an indirect agonist of Ach? What are some general characteristics about these class of drugs?

A
  • neostigmine, pyridostigmine, physostigmine, donepezil, rivastigmine, galatamine, edrophonium
  • anticholinesterases (reduces Ach breakdown at the cleft)
  • potentiate all the effects of Ach in the periphery, can enter CNS, and produce SANS effects due to pregang synapses
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12
Q

How is Ach broken down? AchE inhibitors fall into what classes?

A
  • electrostatic binding and hydrolysis followed by a hydration of a covalent acetyl-enzyme complex re-constituting the enzyme and yielding choline and acetate
  • alcohols, carbamates, organophosphates
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13
Q

How do alcohol AchE inhibitors work? blood-brain barrier?

A
  • bind electrostatically and by hydrogen bonding similar to Ach (competitive binding for AchE between drug and Ach)
  • No covalent bond is created for drug comes off in several minutes
  • can’t cross blood brain
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14
Q

What are the carbamates drugs? How do they work? which can cross blood-brain barrier? How is each used

A
  • neostigmine and physostigmine
  • processed like Ach, but the second carbamoylation step is slowly hydrated yield longer occupancy and therefore blockade for hours
  • neostigmine can’t cross and phsostigmine can cross
  • neostigmine: post op and neurogenic ileus and urinary retention, myasthenia gravis, reversal of neuromuscular junction blockade
  • physostigmine: anticholinergic toxicity (crosses barrier) so it fixes (phyxes) atropine overdose
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15
Q

What are the organophosphate drugs? How do they work? how are they unique?

A
  • parathion, malathion, gases (sarin, soman, VX)
  • phosphorylate esteric site of AchE which ages over time
  • irreversible binders
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16
Q

What is pralidoxime?

A

can break the covalent bond and regnerate the esteric site when someone is poisoned w/ sarin gas

17
Q

What is malathion?

A

a organophosphate drug that cannot be broken down by fish and thus can kill them

18
Q

What subtype of AchE is most common in the brain? What drug actings on these subtypes? What disease does it treat?

A
  • G1, G4
  • Nootropics
  • alzheimer’s
19
Q

What are the types of different Nootropics? What do they do? Benefits to one over the other?

A

donepezil, rivastigmine, galantamine. increase endogenous Ach in treatment of Alzheimer’s

  • donepezile: non competitive, reversible inhibitor, half life of 60 hours (high bioavailability)
  • rivastigmine: pseudo-irreversible competitive inhibitor of AchE. similar to physostigmine but longer duration
  • galatamine: 5-6 hr half life, acts as Non competitive nicotinic Nn agonist
20
Q

What is SLUDGEM?

A

Salivation, lacrimation, urination, defecation, GI upset, emesis, miosis

21
Q

What is salivation? How does it work?

A
  • Causes contraction of smooth muscle of the glands and secretion of WATERY saliva.
  • vasoactive intestinal peptide (VIP) is co-localized in PANS terminals and released at higher freq of stim. VIP reduces vascular resistance, thus increasing blood flow to gland and increasing salivation and also acts at receptor to enhance Ach itself
22
Q

What protection does lacrimation provide for the eye? What medication is used when drys get dry?

A
  • oil, water, and mucin (water is the product of PANS M3 receptor)
  • cyclosporine, an antiimmune modulator that reduces immune cells and pro inflamm cytokine production that causes dry eye
23
Q

What is Sjogren syndrome? Etiology? Presentation?

A

systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs.

  • present w/ dry eyes, mouth, and large parotid gland
  • primary sjogren: absense of rheumatic disorder
  • secondary: associated w/ rheumatic disease like lupus, RA, or scleroderma
24
Q

What is micturition?

A

urination

25
Q

Describe the process of urination. Parts of brain necessary, nerves, muscles, etc

A
  • Brain centers that regulate urination are pontine micturition center, periaqueductal gray, and cerebral cortex
  • urge to urinate starts a 300-400 ccs.
  • Pelvic sensory nerves mediate the reflex
  • M3 mediates contraction of the detrussor.
  • M2 receptor are most prevalent in detrussor, but likely function presyn to inhibit NE release from SANS terminal (heteroreceptor)
  • Trigone is what allows urine to get in the bladder when its relaxes (PANS signal)
26
Q

Describe the process of defecation in regards to receptors and innervation

A
  • paristaltic contraction waves under PANS control by sacral efferents thru M3 receptors
  • muscarinic agonism can cause watery diarrhea (overcoming of voluntary control of your external sphincter)
27
Q

Describe GI-upset (cramping) in terms of receptors, neurotrasmitters, receptor, etc

A

consequence of increased peristaltic activity and increased secretions. reflexive in nature but PANs plays a role as a regulatory. Neurotransmitters 5HT and enkephalin involved in regulation of myenteric plexus. increased smooth muscle contractions, increased secretion, and leads to GI motility and diarrhea

28
Q

What areas of the brain affect emesis? neurotransmitters present in emesis? draw the vomiting reflex on pg 119 of course notes. ???

A
  • area postrema or chemoreceptor trigger zone (CTZ)

- CTZ has muscarinic receptors, but predominated by DA and 5HT receptors. Stimulation of muscarinics can cause vomiting

29
Q

What muscles and receptors are at work to cause miosis and accomondation? What type of receptor response is it? what do you call a lack of miosis?

A
  • M3 receptors cause contraction of the sphincter and ciliary muscle producing miosis and accommodation. contractions pull trabecular meshwork draining the anterior chamber and reducing intraocular pressure.
  • M3/M2 mediated (M2 inhibits NE release for SANS)
  • can’t miosis (cyclopledgia)
  • can’t accomondate (paralysis of accommodation)
30
Q

What is the PANS affect on the heart? Why can’t we see this readily? What part of the heart is effected more?

A
  • involve vasodilatation mediated by Ach-induced release of NO (M3 affect) producing transient reduction in blood pressure together w/ negative chronotropic, inotropic, and dromotropic effects (nerve conduction)
  • masked because baroreceptor reflex response occurs
  • atria more than ventricle
  • M2: affects thru Ach to increase potassium current into SA/AV nodes and lesser extent the ventricles. Ach reduces slow inward calcium current and reduces hyperpolarization activated current
31
Q

What are the net effects of cholinergic activation to the heart?

A
  • negative chronotropic effect due to reduced SA node activation
  • decreased conduction velocity (dromotropy) thru the AV node
  • negative inotropic effect on atria (a little bit of ventricle)
32
Q

What type of receptor regulation occurs in the heart with Ach?

A
  • Ach inhibiting SANS tone

- activation of M2 autoreceptors

33
Q

What affects is the cholinergic system have on respiratory system? Sweat glands?

A
  • respiratory: M3 mediated to produce smooth muscle contraction and induce secretion of mucosal cells
  • sweat glands: eccrine glands stimulated by M3 receptors to secrete sweat reducing body temp (separate from apocrine glands that secrete more viscous sweat around hair cells)
34
Q

What are the key signs of myastenia gravis? What causes it? treatment drugs? How do the work?

A
  • deficiency in Ach binding to Nm receptors
  • ptosis, blurred vision, unstable giat, weakness in extremities, change in facial expression, difficulty swallowing n SOB, impaired speech
  • pyridostigmine, neostigmine or edrophonium
  • indirect agonist that potentiate the effects of normal released Ach
35
Q

What is the tensilon test?

A

-use edrophonium (a short acting diagostic drug of myasthenia gravis). If you have admin it and symptoms get better, the pyridostigmine dose is too low. If weakness increases, pyridostigmine is too high. (weakness increasing means you have saturated the receptor and causes depolarization blockade and flaccid paralysis)

36
Q

How is myastenia gravis now diagnosed?

A

-anti-AchR Ab (anti-acetylcholine receptor antibody test)

37
Q

What body structures have SANS tone only?

A

adrenal medulla and vascular beds

M2 Mechanisms of Disease (13 decks)

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