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Pharmacology Drug Flashcards > Pharm 2013.09.05 Cholinergic 2 > Flashcards

Pharm 2013.09.05 Cholinergic 2 Flashcards

1
Q

What is the difference between muscarinic and nicotinic receptors in terms of overstimulation?

A
  • Muscarinic overstimulation leads to more effect

* Nicotinic overstimulation leads to reduced effect

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2
Q

What are the ACh NON-SPECIFIC drugs?

A

ACh

Carbachol

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3
Q

What are the Muscarinic agonists?

A

Methacoline
Bethanechol
Pilocarpine

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4
Q

What are the Nicotinic agonists?

A

Nicotine

Varenicline (Chantix)

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5
Q

What are the categories of Indirect cholinergics?

A 
Cholinesterase inhibitors (short, medium, and long acting)
Presynaptic release stimulator of ACh (metoclopramide)
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6
Q

What are the short acting Cholinergics?

A

Edrophonium

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7
Q

What are the intermediate acting cholinergics?

A

Neostigmine

Physostigmine

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8
Q

What are the long acting cholinergics?

A 
Echothiophate
Parathion
Malathion
Sarin
Soman
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9
Q

What is the presynaptic ACh releasing drug?

A

Metoclopramide

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10
Q

Where are the muscarinic receptors?

Where are the nicotinic recptors?

A

Musc: Brain, CNS, all of para effector sites ie post ganglionic targets (visceral), sweat glands (sympa), endothelium (non-innervated tissue)

Nicotinic: Brain, CNS, all sympa ganglia, adrenal medulla, skeletal muscles

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11
Q

What would happen if we gave I.V. ACh?

A

1) CNS, but actually penetrates the blood-brain-barrier (BBB) poorly
2) Skeletal muscle mediated at the MNJ
3) Parasympathetic nervous system from two sites:
* Parasympathetic ganglia
* Postganglionic termini
4) Sympathetic nervous system from two sites:
* Sympathetic ganglia including the adrenal gland
* Postganglionic sympathetic-cholinergic fibers
5) Vascular endothelial cells (noninnervated receptors)

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12
Q

What is the hierarchy of accessibility from blood of I.V. ACh?

A 
The hierarchy of accessibility from blood:
Endothelial cell 
Para & sympathetic effector tissues
NMJ
Ganglia
(CNS)

Note: ACh is rapidly cleared from blood
Plasma psuedocholinesterase
Further limits access to less perfused site, so really just the first two need to be considered.

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13
Q

What is Cholinergic Sydrome?

What are the two mneumonics?

A

1) DUMBBELSS

2) SLUDGE

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14
Q

What is SLUDGE in cholinergic syndrome?

Note: this is a combination of muscarinic and nicotinic activation.

A

Salivation, Lacrimation, Urination, Defication, GI upset, Emesis

Lacrimation is detrusor muscle
Defication is anal sphincter

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15
Q

What is DUMBBELSS in Cholinergic Syndrome?

Note: this is due to muscarinic activation.

A

Diarrhea (increased gut motility)
Urination (contraction of the detrusor muscle)
Miosis (contraction of sphincter muscle of the iris)
Bronchorrhea (increased secretions) Bronchoconstriction (wheezing)
Bradycardia (as above)
Emesis (increased and uncoordinated stomach and GI tone)
Lacrimation (tearing)
Salivation
Sweating (sympathetic-cholinergic)

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16
Q

What causes hypotension of endothelial cells from muscarinic stimulation?

A
  • Activation of noninnervated M3/M5 on endothelial cells
  • Rapid activation of endothelial nitric oxide (NO) synthase (eNOS) (arginine → citrulline and NO)
  • NO diffuses into vascular smooth muscle cells (vSMCs)
  • NO stimulates guanylate cyclase (GTP → cGMP)
  • cGMP binds to myosin light chains to relax vSMCs → vasodilation → reduced BP
  • Clinical note: nitroglycerin releases NO to reduce vascular resistance
  • Clinical note: sildenafil (Viagra™) blocks cGMP degradation, potentates NO vasodilation
  • Nomenclature note: NO previously referred to as endothelial derived relaxing factor (EDRF)
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17
Q

What are the HR effects of muscarinic stimulation?

A

Eventhough there is hypotension, there is bradycardia due to the muscarinic receptors on the SA node

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18
Q

Why are Muscarine and ACh not good therapeutic agents?

A

Side effects
Don’t arrive at effectors in organized fashion
AChEsterase

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19
Q

What are the three types of AChE?

A

True AChE at the cholinergic junctions
Pseudo ACheE in the blood plasma
RBC AChE

Note: there are rare genetic disorders without pseudo AChE

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20
Q

What are the modified Muscarine ACh Agonists?

A

Methacholine
Bethanechol
Pilocarpine

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21
Q

What is Methacholine?

What is it used for?

A

Poorly absorbed, but used in the Dx of Bronchial Hyperreactivity (asthma)
Hyperreactive airways always respond with bronchoconstriction to lower concentrations of Methacholine

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22
Q

What is Bethanechol?

What is it used for?

A

Relieves GI dysmotility syndromes, such as postsurgical ileus

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23
Q

What has replaced Bethanechol?

What receptors does this replacment stimulate?

A

Largely replaced by metoclopramide which stimulates presynaptic D2 receptors that trigger the release of ACh

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24
Q

What is Pilocarpine?

A

Used in Glaucoma
See the additional “Self-Study” lecture
Note: this is a plant alkaloid

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25
Q

What are the two basic flavors of Nicotinic receptors?

A

Nn for nerves

Nm for muscles at NMJ

26
Q

Where are Nn Nicotinic receptors found?

A

Post synaptic, on efferents to soma of postganglionic neurons
Also in the CNS

27
Q

What is the receptor mechanism of Nicotinic receptors?

A

Ligand gated Na+/K+ channels
When pore is open, Na+ goes into cell, K+ comes out
More Na+ goes in than K+ comes out, net +ve charge in → membrane depolarizes
Depolarization triggers action potential

28
Q

What is the mechanism of Nicotine addiction?

A

Nicotinic receptors in NUCLEUS ACCUMBENS and PREFRONTAL CORTEX
Stimulation of these receptors elevates MESOLIMBIC DOPAMINE
When dopamine falls cravings develop

29
Q

Note: toddlers can overdose on nicotine gum and patches

A

…

30
Q

What are the effects of Nicotine receptor overactivation?

A

1) ACh interaction with nicotinic receptors is very different from competitive-reversible actions on muscarinic receptors
2) Initial activation → subsequent deactivation
3) Initial depolarization leads to muscle fasciculations
4) Prolonged receptor occupancy with ACh leads to receptor phosphorylation and inactivation (termed: depolarization-desensitization blockade)
5) Result is a paradoxical flaccid paralysis which cannot be practically reversed; have to wait until agonist is cleared
6) Most critical concern is skeletal muscle/diagphram

31
Q

What are the initial mechanisms of nicotine poisoning?

A

Initially, stimulation of parasympathetic/sympathetic ganglia and adrenals, then depolarization-desensitization blockade

32
Q

What are the major signs of nicotine poisoning?

A 
tachycardial
hypertension
nausea/vomitting/diarrhea/salivation
urinary incontinence
cold sweat
syncopy, collapse, unconsciousness
flaccid paralysis (may need respiratory support)
33
Q 
Varenicline (Chantix)
The whole shabang
Drug Class?
Pharmacodynamics?
Pharmacokinetics?
Toxicity?
Interactions?
Special Considerations?
Indications and Dose/route?
Monitor?
A

Drug class: Very selective and potent competative partial agonist of a2-b4 nicotinic receptors, for smoking cessation
Pharmacodynamics: CNS mesolimbic dopamine, partial a4-b2 stimulation prevents low dopamine and cravings; also prevents nicotine from creating dopamine surges, No chemical reward
Pharmacokinetics: well absorbed; peak 4 h, t1/2 = 24 h; excreted primarily in urine as unchanged drug
Toxicity: N/A
Interactions: No direct interactions identified
Special considerations: Reports of suicidal thoughts and aggressive and erratic behavior → patients and caregivers should be instructed about the importance of monitoring for neuropsychiatric symptoms, and to communicate immediately with the prescriber the emergence of agitation, depression, unusual changes in behavior, or suicidality. Psychiatric patients – use extreme caution. Contraindicated in pregnancy/lactation. Causes drowsiness, caution operating machinery
Indications and dose/route: 1 mg PO BID for healthy adults, 0.5 mg PO BID for renal impairment CrCl < 50 ml/min
Monitor: neuropsychiatric symptoms

34
Q

Varenicline

What is the drug class?

A

Very selective and potent competative partial agonist of a2-b4 nicotinic receptors, for smoking cessation

35
Q

Varenicline

What are the pharmacodynamics?

A

CNS mesolimbic dopamine, partial a4-b2 stimulation prevents low dopamine and cravings; also prevents nicotine from creating dopamine surges, No chemical reward

36
Q 
Varenicline
Pharmacokinetics
How absorbable?
What is peak time?
What is half life?
How is the drug removed from the body?
A

well absorbed
peak 4 h
t1/2 = 24 h
excreted primarily in urine as unchanged drug

37
Q

Varenicline
What is the toxicity?
What are the interactions with other drugs?

A

Toxicity: N/A
Interactions: No direct interactions identified

38
Q

Varenicline
What are special considerations?
What are side effects?

A

Reports of suicidal thoughts and aggressive and erratic behavior
Psychiatric patients – use extreme caution.
Contraindicated in pregnancy/lactation.
Causes drowsiness, caution operating machinery

39
Q

Varenicline

What are indications and dose/route?

A

1 mg PO BID for healthy adults

0.5 mg PO BID for renal impairment CrCl < 50 ml/min

40
Q

Varenicline

What needs to be monitored?

A

neuropsychiatric symptoms

DO NOT GIVE TO A PATIENT LIVING ALONE

41
Q

What are the general considerations of AChE inhibitors?

A

Short, Intermediate, and Long acting
Affect both muscarinic and nicotinic
Only affect synapses when ACh is released
Effects True (synaptic) AChE, Plasma AChE, and RBC AChE

42
Q

What is the hierarchy of effects of the three types of AChE?

A

Plasma AChE is affected first and neutralizes some of the inhibitors in order to protect neural AChE

Note: can test for plasma and RBC AChE levels if suspecting an AChE Inhibitor poisoning

43
Q

What are the effects of AChE inhibitor poisoning?

A

Major hazard is respiratory inundation

  • Paralysis of intercostal muscles & diaphragm (nicotinic depolarization desensitization blockade)
  • increased bronchial secretions & bronchoconstriction (muscarinic)
  • Central respiratory arrest
  • Respiratory support is essential
44
Q

What is the AChE mechanism?

A

1) Anionic site binds quaternary ammonium cation
2) Esteric site is catalytic, hydrolyzes ACh ester bond
* * Ester Bonding to acetyl group → liberate choline
* * Rapid hydrolysis releases acetate
3) Enzyme ready for next ACh

45
Q

What are the short acting Cholinergics?

A

Edrophonium

46
Q 
Edrophonium
What is it?
What is mechanism?
Does it cross the BBB?
What is the dose?
How long are the effects?
What is it used for in Dx?
A

1) Short acting AChE are competitive inhibitors, do NOT form ester bond to AChE (temporarily blocks ACh from AChE)
2) Highly charged, does not cross BBB
3) Given I.V. (onset 1 min) or I.M. (onset 2 – 10 min)
4) Extremely short lived effects (5-10 min IV; 5-30 min IM)
5) Dx of myasthenia gravis (90-95% accuracy)

47
Q

What is Myasthenia Gravis?

A

1) Autoimmune disease
2) Antibodies against a thymocyte epitope cross react with NMJ
3) Attack and distruction of motor end plates, over months/years, causing impairment of neurotransmission
4) Patients complain of muscle weakness and rapid muscle fatigue
5) By transiently inhibiting ChE, edrophonium makes more ACh available in the synapse to restore transmission
6) Patients note rapid increase in muscle strength

48
Q

What are the intermediate acting cholinergics aka Carbamates?

A

Neostigmine

Physostigmine

49
Q

What is the mechanism of the Carbamates?

A

1) Bind anionic and esteric sites
2) AChE forms an ester bond to the carbamoyl group
3) This bond hydrolyzes slowly, over hours
4) Effects last much longer than those of edrophonium

50
Q

What are the Carbamates used for?

A

Insecticide
Tx for Myasthenia gravis
Tx to Reverse the paralytic effects of nondepolarizing blockers of the NMJ (Nicotinic antagonists – NOT nicotinic agonists) (See Lecture C-5)

51
Q

Physostigmine
Does it cross the BBB?
Is it used to Tx Myasthenia gravis?
What is it used for?

A

1) Uncharged and lipid soluble so it DOES cross the BBB
* * Note: ChE inhibitors in the CNS have dangerous effects
2) Not useful in myastenia gravis (strictly a peripheral disease)
3) Occasionally used to treat CNS signs of muscarinic blockers (See Lecture C-5)

52
Q 
Neostigmine
Does it cross the BBB?
Is it used to Tx Myasthenia gravis?
What is the delicate nature of Tx?
What other drug can monitor Tx?
A

1) Designed with quaternary ammonium group to keep it out of the CNS
2) Just peripheral effects so useful for myasthenia gravis
3) Treatment is an exercise in brinksmanship
* * Too little drug is inadequate to restore transmission → myasthenic crisis (respiratory paralysis, flacid paralysis)
* * Too much results in depolarization-desensitization blockade → cholinergic crisis (respiratory paralysis, flacid paralysis)
4) IV edrophonium can distinguish between the two states

53
Q

Compare Physostigmine and Neostigmine in terms of the BBB and Myasthenia gravis.

A

Physostigmine DOES cross the BBB and DOES NOT treat Myasthenia gravis
Neostigmine DOES NOT cross the BBB and DOES treat Myasthenia gravis

54
Q

What are the long acting cholinergics aka Organophosphates?

A 
Echothiophate
Parathion
Malathion
Sarin
Soman
55
Q

What are the general mechanisms of the long acting cholinergics aka organophosphates?

A

1) Over 50,000 organophoshpate AChE inhibitors
2) Covalently bond the esteric site → phosphorylated enzyme
3) Bond may require hundreds of hours to hydrolyze
4) Some of the agents split off an alkyl group at which point the phosphorylation is essentially irreversible (aging)

56
Q

1) Drugs, Echothiophate
* * Once used to treat narrow angle glaucoma
* * Largely replaced by other types of agents
2) Insecticides:
* * A frequent source of poisoning
* * Parathion, extremely toxic insecticide, poorly metabolized
* * Malathion, “mammal friendly” insecticide
3) Nerve gas, weapons of mass destruction
* * Sarin
* * Soman

A

…

57
Q

What is the antidote to organophosphate poisoning?

A

Pralidoxime 2-PAM

58
Q

What does Pralidoximne 2-PAM do?
When is it effective?
When is it contraindicated?

A

1) Can reactivate phosphorylated enzymes if given soon enough (within a few h)
2) Most effective if “aging” has not occurred
3) Rescues muscular function
4) Contraindicated in poisoning by carbamate ChE inhibitors (makes worse due to competitive inhibition of AChE)

59
Q

What are other Tx for organophosphate poisoning?

A

Manage DUMBBELSS/SLUDGE with muscurinic blockers (e.g. atropine)
Aggressive respiratory support

60
Q

.

A

Receptor Nonspecific
ACh (topical for glaucoma)
Carbachol (topical for glaucoma)
Muscarinic agonists (DUMBBELSS)
Methacholine (Inhalation for Dx of asthma, clinical research)
Bethanechol (Oral for neurogenic illeus)
Pilocarpine (topical for glaucoma)
Nicotinic agonists
Nicotine (oral/patch for smoking cessation)
But can lead to depolarization desensitization blockade
Varenicline (Chantix™) (oral for smoking cessation)

61
Q

.

A

Cholinesterase inhibitors
Short acting (Competitive inhibitors)
Edrophonium (IV/IM for Dx of myasthenia gravis)
Intermediate acting (Carbamates)
Physostigmine (IV, Rx for CNS side effects of muscurinic antagonist)
Neostigmine (PO, Rx for myasthenia gravis)
Long acting (Organophosphates)
Echothiophate (topical for glaucoma)
Parathion, extremely toxic insecticide
Malathion, “mammal friendly” insecticide
Sarin – nerve gas (hopefully not common)
Soman – nerve gas (hopefully not common)
Presynaptic
Metoclopramide (PO/IV/IM, Rx neurogenic illeus, nausea)
Binds presynaptic D2 receptors to stimulate ACh release
Has largely replaced bethanecol

Pharmacology Drug Flashcards (4 decks)

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