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My Pharm > Cholinergic > Flashcards

Cholinergic Flashcards

1
Q

Nicotinic: what kind of channels?

A

Ligand-gated ion channels.

transduction mechanism –> alter ionic permeability (increased Na+ - Ca2+ conductance)

Nn- autonomic ganglia and CNS

NM- neuromuscular junction

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2
Q

Muscarinic, what time of coupled receptors?

A

Super family of G protein coupled receptors

Transdunction mechanism –> alter enzyme activity

Gq –> increase phospholipase C [M1 neuronal (CNS-ENS)/GI glands, M3: Exocrine glands/smooth muscle)

Gi–> decrease adenyl cylcase [M2, M4 - hearts and lungs, CNS]

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3
Q

What are different selectivity mechanisms of Cholingeric drugs?

A

Receptor subtype selectivity - Muscarinic vs Nicotinic

Receptor subtype selectivity Nn( neuronal ganglion) Nm (neuromuscular junction)

Pharmcokinetic selectivity - ability to cross BBB, Lipid soluble tertiary - agenst enter CNS

Pharmacokinetic selectivity - Quaternary agents are prevented due to permanent positive charge on the drug molecule

Pharmacokinetic selectivity: organ selectivity - appropriate routes of administration can limit drug exposure (inhalting vs topical (eye))

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4
Q

Direct acting cholingergic agosnists interact with?

A

Interact with various cholinergic receptor subtypes themselves - most clinically useful

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5
Q

Indirect-acting cholingeric agonists work by?

A

Inhibitors of acetylcholinesterase (AChE)

Cause ACh accumulation at cholinergic synapses - effects resemble those of excessive cholinergic stimulation

Minimal selectivity - regardless of postsynaptic receptor subtype.

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6
Q

Indirect-acting cholinergic agonist receptor locations? M, Nn, Nm, M and Nn

A

M - at PNS end organs

Nn - at ANS ganglia

Nm - at NMJ

M and Nn - in CNS (if drug crosses BBB)

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7
Q

Cholinergic antagonists effects?

A

Block effects of ACh at cholinergic receptors at varoius anatomic locations.

At parasympathetic end organs known as antimuscarinic or anticholinergic agents

At NMJ - neuromuscular blockers

At the autonomic ganglia known as ganglionic blockers

Block effects of ACh at cholinergic receptors at various anatomic locations.

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8
Q

Antimuscarinic agents effect?

A

All are reversible (competitive) blockers at postganglionic muscarinic receptors in the parasympathetic NS.

Greatest clinical utility of cholingeric antagonists - thus antimuscarinic often used synonymously with anticholinergic

Some agents have dose-dependent selective effects

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9
Q

antimuscarinic receptors?

A

M1 (CNS, gastric parietal cells)

M2 (cardiac cells)

M3 ( smooth muscle organs and glands)

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10
Q

Which of the following organs or organ systems has muscarinic receptors present, but lacks cholingeric innervation?

a) Eye
b) Heart
c) Blood vessels (resistance)
d) urinary bladder muscle
e) lungs

A

C) Blood vessels (resistance)

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11
Q

Cholingeric agonist have what mode of action? Cholingeric antagonists have what mode of action?

A

Agonist - direct or indirect

Antagonist - parasympatholytic - or more more commonly receptor blocker

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12
Q

What are the direct-acting cholinergic drugs?

A

Choline esters - Bethanecol (quatenary ion - NH4+)

Alkaloids - Pilocarpine (tertiary ions - NH3+ - weak base) (CNS)

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13
Q

What are the indirect acting cholingeric agonists?

A

Acetylcholinesterase -

Nerve gas - insecticides (organophosphates - very long acting)

Physostigimine - Neostigmine (carbamates - intermediate lacting)

Edophonium (short acting)

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14
Q

Nicotinic ganglionic direct agonist effect? Periphery and CNS

A

Nicotine’s peripheral actions are complex –> activate both the PNS and SNS via stimulation of ganglionic Nn receptors

Initially causes stimulation as agonist (levels obtained from cigarette smoking)

  • Periphery -
    • increases in BP, Hr, vasoconstriction –> via epinephrine released from the adrenal gland (SNS)
    • Increased GI motility –> via ganglionic stimulation (PNS)
  • CNS
    • Euphoria, arousal, relaxation, increased attention/learning
    • Stimulation of emetic chemoreceptor trigger zone -
      • At toxic doses - tremors and convulsions
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15
Q

Glaucoma is treated with?

A

Treated with longer acting topical agents - PILOCARPINE, echotiophate

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16
Q

Urinary retention or paralytic ileus without obstruction (post op, post partum, s.c injury) is treated with?

A

Treated with oral agents (bethanecol, neostigmine)

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17
Q

Smoking deterrence is treated by?

A

Nicotine - (gum- transdermal delivery stystem), used to allieviate withdrawal symptoms in smoking cessation

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18
Q

Drugs used in open angle glaucoma, mechanism.

BB - Timolol, others

Prostaglandins – latanoprost, others

Cholinomimetics- pilocarpine, others

Alpha agonists - epinephrine, dipivefrin

Alpha 2 selective -apraclonidine, brimonidine

Diuretics - acetazolamide, dorzolamide

A

BB - decreased aqueous secretion from the ciliary epithelium - topical drops

Prostaglandins - increased aqueous outflow - topical drops

Cholinomimetics - Cililary muscle contraction, opening of trabecular meshwork, increased outflow

Alpha agonists - increased outflow, probably via the uveoscleral veins

Alpha 2 selective - decrease aqueous secretion

diuretics - decreased secretion due to lack of HCO3 - Oral -A or Topical - D

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19
Q

Adverse reactions of direct acting cholinergics? How do you treat the adverse effects?

A

SLUDGE - side effects seen in therapuetic dosage range are primary muscarinic receptor effects of “Sludge”

S- salivation

L- lacrimation

U - urination

d - defecation

G - Gi –> cramping, emesis

E - eye - Miosis

tX: atropine (to block excessive muscarinic receptor stimulation)

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20
Q

Direct acting - parasympathetic agonists are used in the treatment of?

a) asthma
b) peptic ulcers
c) xerostomia
d) diarrhea

E) bradycardia

F) alzheimer’s disease

A

c) Xerostomia

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21
Q

The most common mechanism of action for indirect acting cholinergic agonists is?

a) inhibition of acetylcholine metabolism in the presynaptic neruons
b) inhibition of acetylcholine reuptake from the synapse into the presynaptic neuron.
d) inhibition of acetylcholine metabolism in the synapse
e) enhancement of acetylcholine synthesis and storage in presynaptic neurons.

A

d) inhibition of acetylcholine metabolism in the synapse (acetylcholinesterases)

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22
Q

Cholinesterase inhibitors mechanism of action?

A

Cause ACh accumulation at cholinergic synapses - effect resemble those of excessive cholinergic stimulation

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23
Q

What category of cholinesterase inhibitors is used therapeutically?

A

Intermediate to long-acting - used therapuetically

Short - used diagnostically

Very long acting - used as nerve gas or insecticide

These categories are related to the nature of the drug interaction with AChE, ionic or covalent bonds, and reversible or irreversible bonds.

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24
Q

Reversible AChE inhibitors at the therapuetic dose do what to muscles?

A

Cause increase in muscle contraction

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25
Q

Short acting indirect cholingeric agonist drug?

A

Edrophonium (tensilon) - ionic bining, reversible inhibitors, in vivo duration of about 5-30 minutes

Rapidly reversible

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26
Q

Intermediate to long acting indirect cholingeric agonist?

A

Physostigmine (Antilirium): Tertiary amine, crosses the BBB

Neostigmine (Prostigmin) - Quatenary amine - NO CNS action

This bind via covalent actions - reversible inhibitors, in vivo duration of about 3-4 hours.

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27
Q

Very long acting indirect cholingeric agonist?

A

Organophosphates - Covalent - irreversible

Insecticides (isoflurophate malathion, parathion)

Nerve gases (soman, tabun, sarin)

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28
Q

What is a reactivator of AChE?

A

If inactivated by organophosphates exerts an anticholinergic effect

Pralidoxime

  • Directed to anionic site
  • Attracts the phosphate group away from the serine site, leading to reactivation of the enzyme.
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29
Q

Cholinesterase inhibitors - Pharmacokinetics

A
  • Physostigmine (tertiary) -
    • intermediate - well absorbed, distributed to CNS
  • Quatenary carbamates (neostigmine-pyridostigmine)
    • Absorption from conjunctiva, skin, lungs is poor; neglible penetration into the CNS
  • Organophosphates (insecticides - nerve gas)
    • Well asorbed from skin, lung, gut and conjunctiva
    • Very lipid soluble - reach CNS, malathion (not parathion) rapidly metabolized to inactive products in mammals
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30
Q

What is the clincal use of the indirect cholinergic agonists?

A

Myasthenia gravis: immunologic therapies are now mainstays of treatment - AChEIs used as adjunctive therapy

Edrophonium (diagnostic in Tensilon test)

Neostigmine, pyridostigmine

31
Q

What do you use if you need rapid reversal of neuromuscular blockade (paralysis)

A

Neostigmine - increases ACh,

Shortens post-op recovery time following surgical procedures

Occasionally give atropine if needed to block muscarinic receptor side effects (BB-sludge)

32
Q

What drug is used in the treatment of Alzheimer’s disease?

A

AChE inhibitors usch as tacrine (cognex), donepezil (aricept)

These are used in mild to moderate disease.

33
Q

What drug do you use in antimuscarinic drug intoxication? (with atropine, tricyclic antidepressants)

A

Physostigmine - entesr the CNS but narrow therpauetic index, rarely used today.

34
Q

What are the side effects of the indirect cholinergic agonists in the therapeutic dosage range? What do you use to treat OD?

A

Side effects seen in the therapeutic dosage range are primarily muscarinic recepotr effects of “SLUDGE” - salivation, lacrimation, urination, defecation, GI (cramping emesis), eye –> miosis

Treatment: atropine to block excessive muscarinic receptor stimulation

35
Q

What are the s/e of the indirect cholinergic agonists at lethal exposures?

A

Initial signs –> muscarinic excess, and double vision (via NMJ depolarization block)

BB SLUDGE - for muscarinic receptor signs

Bradycardia and Bronchospasm, salivation, lacrimation, urination, defecation, gi cramping, emesis, eye (miosis)

WITH TOXIC EXPOSURES MUSCARINIC SIGNS OF BRADYCARDIA AND HYPOTENSION PREDOMINATE –> REQUIRE EMERGENT TREATMENT

36
Q

Other than BB SLudge what other s/e can you see from lethal exposures to AChEIs?

A

ACh EIs also act at the autonomic ganglia and NMJ - can see a complex mix of effects

seizures, by stimulation of Nn receptors

Fasiculations - cramping initially as ACh accumulates, then WEAKNESS as excessive ACh leads to depolarization block and muscle paralysis

Progression to respiratory paralysis –> hypoxia –> death within 5 minutes -24 hours depending on exposure (dose and route)

37
Q

Nerve Gas Poisoning Antidotes and treatment?

A

Pralidoxime (parental-IM) regenerates AChE –> anticholingergic actions via facilitating ACh breakdown

Atropine (parenteral-IM) –> anticholinergic actions to block bradycardia-bronchospasm-bronchorrhea

Diazepam (parenteral-IM) to prevent or treat convulsions

Mechanical ventilation to support respiration

38
Q

Side effects that can be seen with a cholinesterase inhibitor include? (2)

a) blurred vision
b) diarrhea
c) drowsiness
d) tachycardia
e) urinary retention
f) bradycardia

G) constipation

A

B) diarrhea, F) bradycardia

39
Q

A number of therapies are utilized in the treatment of nerve gas poisoning. which of the following treatments acts more specifically to block effects of excessive ACh at the muscarinic receptors? (ie SLUDGE)

a) Atropine

B) Diazepam

c) Pralidoxime (2-PAM)

D Succinylcholine

A

a) Atropine

Pralidoxime regenerates AChE –> anticholinergic actions via facilitating ACh breakdown

ATropine –> anticholinergic actions to block Bradycardia, bronchospasm-bronchorrhea (BB sludge)

Diazepam - prevents or treats convulsios (not part of BB sludge)

40
Q

A patient presents in the emergency room with nausea, vomiting, miosis, decreased heart rate, urinary incontinence, drooling, and a runny nose. Which of the following agents is most likely to have caused these symptoms?

a) scopolamine (muscarinic receptor antagonist)
b) Curare (competitive neuromuscular blocker
c) Nerve gas (organophophaste cholineseterase inhibitor)
d) Pilocarpine (muscarinic receptor agonist)
e) Propanolol (beta-adrenergic receptor antagonist

A

C) Nerve gas (organophophaste cholineseterase inhibitor)

d) pilocarpine (muscarinic receptor agonist)

41
Q

A patient presents in the emergency room with nausea, vomiting, miosis, decreased heart rate, urinary incontinence, drooling and a runny nose PLUS double vision, skeletal muscle weakness, and restlessness. Which of the following agents is most likely to have caused these symptoms?

a) scopolamine (muscarinic receptor antagonist)

B) curare (competitive nueromuscular blocker)

c) nerve gas (organophosphate cholinesetrase inhibitor)

D) pilocarpine (muscarinic receptor agonist)

E) Propranolol (beta-adrenergic receptor antagonist)

A

C) Nerve gas (organophosphate cholinesterase inhibitor)

42
Q

Cholinergic antagnoist categories

A

Antimuscarinic

Antinicotinic

Cholineseterase regenerator

43
Q

Antimuscarinic non-selective drugs?

A

Atropine, scopolamine, oxybutynin, tolterodine

44
Q

Antinicotinic neuromuscular blocker drugs?

A

Atracurium, rocuronium

succinylcholine

45
Q

Cholinesterase regenerator drug?

A

Pralidoxime

46
Q

Atropine MOA? What does it preferentially affect? (Also absorbtion, distribution, elimination)

A

Little central depressant action, generally excitatory. Very high affinity and specificity for muscarinic receptors.

Preferentially affects the heart, intestine, bronchial muscle

Absorption: Well asborbed from GI and conjunctiva

Distribution: rapidly into the CNS - can diminish tolerability when used for peripheral effects

Elimination: combination of hepatic metabolism and renal excretion of unchanged drugs.

47
Q

Scopolamine (hysocine) mechanism of action? What does it preferentially effect?

A

Similar MOA to atropine - CNS effects prominent (especially on vestibibular apparatus)

Can cause drowsiness, euphoria, block of short term memory

Preferentially effects the iris, ciliary body, secretory glands.

  • Absorption: well absorbed from GI and conjunctiva - scopolamine absorbed across skin transdermally
  • Distribution: rapidly into CNS - can diminish tolerability when used for peripheral effects
  • Elimination: combination of hepatic metabolism and renal excretion of unchanged drug
48
Q

Synthetic antimuscarinic agents improve in what category? What are the tertiary compounds that we need to know?

A

Selectivity of antagonism - of a particular parasympathetic function - ie bladder function

oxybutynin, tolterodine - 3^ have potential to exert actions in the CNS

49
Q

All of the following side effects are associated with drugs that block muscarinic receptors EXCEPT:

A.Tachycardia

B.Blurred vision

C.Diarrhea

D.Sedation

E.Dry Mouth

F.Urinary retention

G.Bradycardia

A

c) diarrhea

G) bradycardia

Effects are essentially opposite of BB sludge. So BB sludge effects would be the right answer here.

50
Q

What two anticholinergic drugs are used in COPD and asthma?

A

Ipratropium and tiotropium

51
Q

What two anticholinergic drugs are used in GI hypermotility (ie cramping)

A

Dicyclomine, propantheline

52
Q

What anticholinergic drug would you use in acute, severe bradycardia in coronary care unit?

A

Atropine

53
Q

What anticholinergic drug would you use for rhinorrhea?

A

Ipratropium

54
Q

What anticholinergic drug would you use in treatment of overactive bladder?

A

Oxybutynin- tolterodine

55
Q

What drug would you use to block neostigmine-induced cholinergic excess - IN ANS following use to revere skeletal muscle relaxants?

A

Atropine

56
Q

What would you use to treat cholinesterase inhibitor toxicity (nerve gas) and muscarine (mushroom toxicity)

A

Atropine

57
Q

What drugs would you use as a preanesthetic medication to reduce salivary and bronchial secretions?

A

Atropine, scopolamine, glycopyrrolate

58
Q

What anticholinergic would you use to treat mydriasis-paralysis of accomodation for eye exams?

A

Tropicamide

59
Q

Select the optimal receptor action for producing mydriasis and cycloplegia for eye exams

A.Alpha-1 adrenergic agonist

B.Beta-2 adrenergic agonist

C.Muscarinic antagonist

D.Muscarinic agonist

A

c) Muscarinic antagonist (tropicamide)

60
Q

What anticholinergic would you use as adjunctive treatment for parkinson’s disease?

A

Benztropine

61
Q

What anticholinergic would you use to prevent motion sickness (transdermal)? Is there a preferred tx?

A

Could use transdermal scopolamine

Antihistamines such as dimenhydrinate are preferred if motion sickness is milder and of longer duration.

62
Q

Adverse reactions to anticholinergic drugs?

A

Known as antihcolinergic or antimuscarinic side effects

Urinary rentention –> no pee

Blurred vision –> no see (cycloplegia –> block of accomodation)

Dry mouth –> no spit

constipation –> no shit

Tachycardia –> But - minimal effect on blood pressure because of the lack of muscarinic tone in the vasculature

CNS effects (drowsiness, sedation, delirium)

63
Q

Therapeutic uses of muscarinic receptor antagonists include all of the following EXCEPT:

A.Treatment of Parkinson’s disease

B.Prevention of motion sickness

C.Treatment of asthma and COPD

D.Treatment of narrow angle glaucoma

A

d) treatment of narrow angle glaucoma

64
Q

Ganglionic blocking agents MOA? Effects?

A

Antagonists at nicotinic nueronal (Nn) cholinergic receptors on ganglion neuron cell bodies

Widespread effects predictable form knowledge of which ANS branch exerts dominant contorl over each target organ.

Effects from blockade of predominant tone at effector site

PNS- controls tone in most organs –> ganglionic blockade leads to array of anticholinergic (antimuscarinic) effects

SNS – controls only arteriole and venous tone –> ganglionic block leads to vasodilation and hypotension (reflex tachycardia)

No therapeutic usefulness because agents are no longer available

65
Q

Voltage-sensitive sodium channels in the action potential (VSSC) can be blocked by?

A

Local anesthetics - lidocaine

66
Q

Synaptobrevinis lysed by what at the NMJ? What does this cause?

A

Synaptobrevins is lysed by botulinum toxin at the NMJ –> this blocks vesicle fusion and stops ACh release –> leads to flaccid paralysis

Synaptobrevin is also lysed by tetanus toxin –> transported in retrograde fashion to spinal cord synapses. Blocks release of inhibitory GABA or glycine –> no reflex inhibition –> excessive contractions –> spastic paralysis

67
Q

Black widow spider venom (a-latrotoxin) has what effect?

A

Forms pores in the terminal membraens –> excessive Ca2+ influx, clumping of vesicles and explosive release of ACh

This results in flaccid parlaysis. Similar to botox just a different mechanism.

68
Q

Neuromuscular blocking agents bind to the Nm receptor. What do receptor antagonists do (curare)? What do receptor agonists do(SuCh)?

A

Antagonists (curare) - bind and prevent ACh channel from opening and EPP –> flaccid paralysis

Receptor agonist (SuCh) - binds and opens channels –> depolarizatoin EPP and initial contraction (fasiculations) - depolarization is prolonged becuase SuCH is not degraded by AChE. Repolarizatoin of VSSC doesn’t occur and subsequent APs are prevented –> flaccid paralysis

69
Q

What is a inhibitor of Ca2+ release (ryanodine receptor inhibitor)? What is this used for?

A

Dontrolene sodium is an inhibitor of Ca2+ release channel (RYR)

Used for GA-induced malignant hyperthermia.

70
Q

Cholineseterase inhibitors in the NMJ synapse have what effect at a therapeutic range and what effect at a toxic overdose range?

A

Prolongs life of ACh in the synapse, –> increase binding to the Nm

In physiological therapeutic ranges this is an increase in strength of muscle contraction

In toxic-overdose ranges this prolonged stimulation can cause a depolarization block as seen with SuCh.

71
Q

Flaccid (vs spastic) paralysis of skeletal muscles would be produced by:

A.Administration of rocuronium

B.Administration of succinylcholine

C.Exposure to organophosphate nerve gases

D.Administration of botulinum toxin

E.Tetanus toxin

A

Answer is a, b, c, d

72
Q

Neuromuscular function can be restored most safely and effectively following surgical use of skeletal muscle relaxants with:

A.Acetylcholine

B.Succinylcholine (AnectineÒ)

C.Tubocurarine (Curare)

D.Neostigmine (Prostigmin®)

E.Pralidoxime (2-PAM)

A

d) neostigmine

73
Q

Which of the following statements concerning AChEIs is FALSE?

A.Pralidoxime (2-PAM) regenerates cholinesterase enzymes that have been inactivated by organophosphate nerve gases.

B.Cholinesterase inhibitors can be used to reverse neuromuscular blockade caused by administration of curare-like drugs during surgery.

C.They can reverse the depolarizing neuromuscular block produced by succinylcholine.

D.Organophosphate cholinesterase inhibitors cause death via respiratory paralysis and hypoxia.

E.The symptoms of cholinesterase inhibitor poisoning are similar to those produced by atropine overdose.

A

Answer is C and E

AChEIs will worsen the block by increasing ACh-induced depolarization - similar to succinylcholine (depolarization block)

Symptoms are treated with atropine

74
Q

In the NMJ the following have what effect?

Curare drugs –>

AChEIs –>

SuCh –>

AChEIs (OD) –>

A

Curare drugs –> competitive block

AChEIs –> reverse competitive block by allowing more acetylcholine

SuCh –> binds to ach receptor and causes prolonged depolarization leading to depolarization block

AChEIs overdose –> increases ACh too much –> causes depolarization block

ACHEis –> worsen depolarization block (treat with atropine)

My Pharm (6 decks)

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