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IC > Cholinergic Pharmacology I > Flashcards

Cholinergic Pharmacology I Flashcards

1
Q

Cholinoreceptor-activatnig and cholinesterase-inhibiting drugs

A

mimic acetylcholine

-muscarinic or nicotinic receptors

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2
Q

direct acting cholinomemetic agents

A

-directly bind and activate muscarinic or nicotinic receptors

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3
Q

indirect acting agents

A

inhibit acetylcholinesterase

  • reduce hydrolysis of acetylcholine, inc endogenous Ach concentration in synaptic cleft, excess ach stimulates cholinoreceptors to evoke increased responses
  • drugs act primarily where acetylcholine is physiologically released
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4
Q

Cholinoreceptors are either

A

g protein linked (muscarinic) or ion channel (nicotinic)

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5
Q

G protein linked receptors

A
  • muscarinic
  • 7 transmembrane domains
  • located in CNS, tissues targeted by PNS, vascular endothelium
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6
Q

Ion channel (nicotinic)

A

four subunits form cation-selective ion channels
-located on all ANS post ganglionic cells, muscles (neuronal type), muscles innervated by somatic motor fibers (NMJ type), some CNS neurons

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7
Q

direct acting cholinoreceptor agonists are classified as

A 
esters of choline (including Ach)
or alkaloids (such as muscarine and nicotine)
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8
Q

choline esters

A
  • acetylcholine, methacholane, carbachol, and bethanechol
  • poorly absorbed and poorly distributed into CNS
  • adding a methyl group reduces potency at nicotinic receptors (methacholine, bethanechol)
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9
Q

Methacholine

A

-Add methyl group to first carbon of choline, which makes it resistant to hydrolysis and gives it muscarinic specificity

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10
Q

Acetylcholine

A

rapidly hydrolyzed and active towards both muscarinic and nicotinic

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11
Q

Carbachol and Bethanochol

A

-adding a nitrogen to acetate, makes it even very resistant to hydrolysis

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12
Q

Bethanochol

A

-Has nitrogen group, making it resistant to hydrolysis and has a methyl group, making it muscarinic specific

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13
Q

Tertiary natural cholinomimetic alkaloids

A

Muscarine (quaternary amine), nicotine

  • Pilocarpine, lobeline
  • A lot more lipophilic
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14
Q

Muscarinic receptors

A
  • G protein coupled
  • Activates IP3, DAG cascade, increases potassium flux, some tissues will inhibit adenylyl cyclase activity and open K channels (Gi)
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15
Q

Nicotinic receptor activation

A
  • electrical and ionic changes
  • depolarization of nerve cell or neuromuscular end plate membrane
  • prolonged agonist occupancy can abolish effector response, cause depolarizing blockade, and can produce muscle paralysis
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16
Q

Prolonged nicotinic agonist occupancy can

A

abolish effector response, cause depolarizing blockade, and can produce muscle paralysis

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17
Q

Muscarinic cholinoreceptor effects

A
  • parasympathetic nerve stimulation

- At the distribution of muscarinic receptors

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18
Q

Nicotinic agonist effects

A

-autonomic ganglia and skeletal muscle motor end plate

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19
Q

Eye- muscarinic agonists produce

A

contraction of iris sphincter (miosis), contraction of ciliary muscle (accomodation) which facilitates acqueous humor outflow

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20
Q

Muscarinic agonist affect CV system by

A
  • reducing peripheral vascular resistance (if delivered IV; via release of NO)
  • direct effect is to slow heart rate
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21
Q

IV infusions of ACh

A
  • Cause vasodilation and reduce blood pressure
  • ACh induced vasodilation requires intact endothelium which releases NO (relaxes smooth muscle)

-This will evoke a SNS reflex and result in tachycardia; larger ACh will mask this reflex (bradycardia)

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22
Q

Respiratory system cholinergec effects

A
  • Contracts smooth muscle of bronchial tree, glands of mucosa stimulated to secrete
  • Exacerbates symptoms of asthma
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23
Q

GI tract

A
  • Increases secretion, increase peristaltic activity

- Contraction of longitudinal muscle, relaxation of sphincters

24
Q

GU tract

A

Contracts detrusor muscle, relaxes trigone and sphincter muscles
-promotes voiding (but micturition is it’s own reflex, so may just make it easier)

25
Q

Secretory glands

A
  • sympathetic

- stimulates secretion of sweat from thermoregulatory sweat glands

26
Q

Nicotinic agonists

A
  • Autonomic ganglia are major site of action
  • Simultaneous SNS and PNS discharge
  • Tissue where effects are balanced (like eye)- may intermediate response
  • Peripheral vasculature, which has no parasympathetic innervation, will have solely sympathetic effect
  • GI tract- cholinergic ending of myenteric plexus, will inhibit parasympathetic outflow–> see GI motility and secretion
27
Q

Effects on NMJ by nicotinic agaonists

A
  • produce muscle fasciculations because it’s an overall increase in activity, not specifically one muscle
  • subsequent development of depolarization blockage (flaccid paralysis)
28
Q

Low dose Ach

A
  • only activates vascular muscarinic receptors (endothelium)
  • not high enough of a dose to escape peripheral vasculature
  • evokes synthesis and release of NO, produces vasodilation (decrease in BP), reflex tachycardia
29
Q

Direct effect of Ach on muscarinic receptors on vascular smooth muscle is

A

contraction (usually masked by effects of NO)

-Can be seen in vasculature stripped of endothelium

30
Q

Effects of low dose Ach blocked by

A

atropine (muscarinic antagnost)

31
Q

In the presence of ganglionic blockade or other elimination of baroreceptor mediated reflexes, a low dose ACh might

A

decrease both blood pressure and heart rate

only direct effects of drugs observed with ganglionic blockade

32
Q

HIgh dose ACh

A
  • high enough dose to escape vascular space and affect muscarinic and nicotinic receptors
  • muscarinic receptors on vascular endothelial cells are activated evoking synthesis and release of NO and producing vasodilation (dec BP)
  • cardiac muscarinic receptors activated- produces direct bradycardia, slows rate of diastolic depol of SA node, slows AV conduction, reduces force of myocardial contractions, shortened atrial refractory period which can lead to atrial flutter
33
Q

Indirect acting cholinomimetics

A

ACh effects terminated by acetylcholinesterase
-these inhibit this enzyme
-acetylcholinesterase and butyrylcholinesterase inhibited
3 groups:
-simple alcohols (brief overactivity) , carbamic acid esters of alcohols (longer duration effect), organic derivatives of phosphoric acid (organophosphates)

34
Q

simple alcohol -cholinesterase inhibitor

A

Edrophonium

  • bears quaternary ammonium group
  • reversibly bind to active site, inhibition is short lived (2-10 mins)
35
Q

Carbamic acid esters of alcohol- cholinesterase inhibitors

A
  • neostigmine (quaternary, not lipid soluble)
  • physostigmine and carbaryl (high lipid solubility, will have CNS effects)
  • undergo two step hydrolysis: covalent bond of carbamoylated enzyme resistant to hydration, inhibition is longer (30 min- 6 hrs)
36
Q

organophosphates- cholinesterase inhibitors

A
  • echothiophate, soman, sarin, malathion, parathion
  • malathion and parathion are used as insecticides
  • well absorbed topically and distributed to all parts of body, including CNS
  • organophosphates bind and are hydrolyzed– results in phosphorylated AChE active site
  • inhibition lasts hundreds of hours (lifetime of enzyme protein)
  • aging strengthens phosphorous-enzyme bond
37
Q

Pralidoxime (2-PAM)

A

restores AChE function when given before aging caused by organophosphates

38
Q

cholinesterase inhibitors- organ system effects

A

CV and GI systems mainly effected, eye and skeletal muscle as well

  • actions amplify endogenous acetylcholine
  • little effect on vascular smooth muscle and blood pressure
  • modifies tone of PNS (not peripheral vasculature because it is not innervated by PNS)
39
Q

Effects of cholinesterase inhibitors on NMJ

A

low (therapeutic) concentrations increase force of contraction
-higher doses produce depolarizing neuromuscular blockade

40
Q

Clinical use of cholinesterase inhibitors on eye

A

Eye: closed angle glaucoma, promotes outflow of aqueous humor by reducing intraoculuar pressure and contraction of ciliary body

41
Q

Clinical use of cholinesterase inhibitors on GI and UT

A
  • disorders related to inactivity of smooth muscle
  • postop ileus, congenital megacolon, urinary retention, neurogenic bladder, reflux esophagitis, insufficient salivary secretion
42
Q

Clinical use of cholinesterase inhibitors at NMJ

A

For myasthenia gravis
Can be used as therapy and
-Edrophonium as diagnostic test–> improvement in muscle strength

43
Q

Clinical use of cholinesterase inhibitors - atropine and other anticholinergic intoxication

A

-reversal of competitive blockade by cholinomimetics

44
Q

Clinical use of cholinesterase inhibitors- CNS

A

Alzheimer’s

45
Q

Toxicity of cholinesterase inhibitors

A 
SLUDGE
Salivation
Lacrimation
Urinary incontinence
Diarrhea
Gastrointestinal cramps
Emesis
  • Parasympathetic like activities
  • Can be reversed by atropine (muscarinic agonist)
46
Q

Cholinesterase inhibitor poisoning treated by

A

large doses of Atropine

  • Maintenance of vital signs (respiration- because it causes paralysis of diaphragm), decontamination,
  • pralidoxime to rescue unaged inhibited enzyme
47
Q

Nicotinic toxicity

A
  • usually produced by nicotine
  • fatal dose is 440 mg
  • amt in 2 regular cigarettes but most is destroyed by burning
  • ingestion is usually followed by vomiting (emesis)
  • limits absorbed dose

effects: overactivity of entire ANS, and stimulation of CNS- convulsions, coma,respiratory arrest
- htn, cardiac arrythmias,

48
Q

Tx of nicotinic toxicity

A

-symptom mediated
-muscarinic and adrenergic antagonists and mechanical respiration
Most significant toxicity is due to chronic use

49
Q

Choline esters

A

ACh, bethanechol, carbachol, cevimeline

50
Q

Alkaloids

A

muscarine, pilocarpine

51
Q

direct nicotinic agonist

A

nicotine, varenicline

52
Q

Carbamates

A

neostigmine, physostigmine, pyridostigmine, rivastigmine, ambenomium, demecarium, carbaryl

53
Q

simple alcohol ester cholinesterase

A

edrophonium

54
Q

organophosphates

A

echothiophate, soman, sarin, parathion, malathion, isoflurophate, diisopropylfluorophosphate

55
Q

other cholinesterase inh

A

donepezil, tacrine, galantamine

IC (31 decks)

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