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Pharm Exam 1 > Mattingly - Cholinergic Pharmacology II > Flashcards

Mattingly - Cholinergic Pharmacology II Flashcards

1
Q

What drug can inhibit sodium-dep choline transporter (CHT)?

A

Hemicholinium

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2
Q

What does ChAT do?

A

Acetylcholine is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase (ChAT).

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3
Q

What does VAT do? What inhibits VAT?

A

ACh is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol.

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4
Q

What are SNAPs and VAMPs?

A

SNAPs, synaptosome associated proteins; VAMPs, vesicle-associated membrane proteins]

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5
Q

General Cholinergic Synapse: 7 steps

A
  1. Choline transported into presynaptic nerve terminal by Na-dependent choline transporter (CHT)
    o Blocked by hemicholinium drugs
  2. ACh is synthesized in the cytoplasm from choline and acetyl CoA by ChAT
  3. ACh transported into the storage vesicle by the vesicle associated transporter (VAT)
    o VAT inhibited by vesamicol
  4. Peptides, ATP and proteoglycan also stored in the vesicle
  5. Voltage sensitive Ca++ channels in terminal membrane open, Ca++ enters nerve terminal
  6. Increase in Ca++ causes fusion of vesicles with surface of membrane and exocytosis of ACh and co-transmitters
    o Blocked by botulinum toxin
    o Receptors on presynaptic nerve terminal regulate transmitter release (SNAPs, VAMPs)
  7. ACh action terminated by AChE
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6
Q

Direct Acting Agonist: (3)

A

Direct Acting Agonist: mimic ACh at AChR (produce same conformational changes in AChR)

o Muscarinic: pilocarpine, methacholine, bethanechol

o Muscarinic and Nicotinic: ACh, carbachol

o Nicotinic: nicotine, varenicline (partial nicotinic agonist)

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7
Q

Direct Acting Agonist:

Muscarinic (3)

A

Muscarinic: pilocarpine, methacholine, bethanechol

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8
Q

Direct Acting Agonist: 2

Muscarinic and Nicotinic (2)

A

Muscarinic and Nicotinic: ACh, carbachol

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9
Q

Direct Acting Agonist: 2

Nicotinic (2)

A

Nicotinic: nicotine, varenicline (partial nicotinic agonist)

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10
Q

Black widow spider venom

A
  • Promote release of NT by acting presynaptically:

Black widow spider venom: promotes sustained release of ACh causing skeletal muscle twitching; if systemic, produces other signs of cholinergic activity (sweating, abdominal cramps, bradycardia)

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11
Q

Anticholinesterase:

A

Anticholinesterase (Cholinesterase Inhibitors/Indirectly-Acting Cholinomimetics): agents occupy ACh binding sites on cholinesterases to prevent destruction of ACh

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12
Q

Anticholinesterase:

Reversible (8 Examples)

A

Reversible:

Metabolized or removed from binding sites within minutes to a few hours

Ex:
Physostigmine, rivastigmine
Neostigmine, pyridostigmine

Simple, competitive inhibitors of ACh binding to active site

Ex:
Edrophonium*, tacrine, donezepil, galantamine

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13
Q

Anticholinesterase:

Irreversible (3 Examples)

A

Irreversible: stable covalent binding to esterases and remain on the binding site for hours to days

Echothiophate
Sarin (nerve gas)
Malthion, parathion (insecticides)

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14
Q

AChR Antagonists:

A

AChR Antagonists: agent with little/no intrinsic activity occupies AChR, preventing ACh from reaching it

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15
Q

Reversible Anti-Muscarinic:

Exs:

A

Reversible Anti-Muscarinic: competitive antagonist

Atropine*, scopolamine, tolterodine, oxybutynin, tropicamide, benzotropine, iptratropium, tiotropium, propantheline

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16
Q

Reversible Anti-Nicotinic:

Exs:

A

Reversible Anti-Nicotinic: competitive antagonist

D-tubocurarine, atracurium, pancuronium, vecuronium, rocuronium
Mecamylamine

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17
Q

What blocks synthesis of ACh presynaptically?

A

Blocking synthesis of ACh presynaptically:

Hemicholinium 3: blocks the transport of choline into the nerve terminal, causing gradual depletion of ACh (no therapeutic use)

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18
Q

What prevents release of NT from presynaptic site? (3)

A

Botulinum Toxin A
Aminolycoside Abx
High serum Mg

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19
Q

Botulinum Toxin A (Botox): only therapeutic agent for this use

Local injection to treats:

Effects last:

A

Prevent release of NT from presynaptic site
Botulinum Toxin A (Botox): only therapeutic agent for this use

Local injection to treat spastic disorders (ie. strabismus or spasmodic torticollis) and wrinkles

Effects last a few months, with restoration of neurotransmission via establishment of new neuroeffector junctions

Subsequent treatments may be less effective due to production of neutralizing Abs

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20
Q

Amingoglycoside Abx:

A

Prevent release of NT from presynaptic site

Inhibit Ca++ movement through cholinergic nerve terminals, reducing exocytosis of ACh

21
Q

High Serum Mg++:

A

Prevent release of NT from presynaptic site

High Serum Mg++: due to competitive interference with Ca++ entry into presynaptic terminal

22
Q

Depolarizing Blockade:

Examples

A

Excessive cholinergic agonist stimulation of nicotinic R at NMJ results in depolarization of motor end plate and blocks transmission to the skeletal muscle sarcolemma (paralysis)

Succinylcholine: used therapeutically for this reason

Nicotine: depolarizing blockade can be a toxic effect

23
Q

Muscarinic Pharmacology:

Effect of ACh:

Effect of longer acting analogs
Types:

A

ACh: direct agonist with limited therapeutic use because of rapid hydrolysis in plasma by psedocholinesterases

Longer acting analogs of ACh: metabolized more slowly and can be employed for systemic effects

  • Tertiary Amines: can be employed orally for systemic effects
  • Quaternary Amines: need to be applied directly to the appropriate site or administered parenterally for systemic effects
24
Q

Muscarinic pharmacology in the CNS:
Muscarinic Agonists:

Toxicity:

Clinical Trials:

A

Muscarinic Agonists: most of the clinically used agonists are quaternary amines and do no cross the BBB

Toxicity: CNS symptoms may occur in poisoning with mushrooms containing muscarine

Clinical Trials: selective M1 agonist that crosses BBB for used in AD

25
Q

Atropine:

MOA:

CNS effects:

Toxic?

Effects due to:

A

Atropine: prototype; natural alkaloid; tertiary amine

MOA: competitive antagonist of ACh at muscarinic receptor sites (can therefore be displaced by muscarinic agonists)

CNS Effects: only seen at toxic levels (coma and death may follow)

Significantly toxic (“red as a beet, dry as a bone, blind as a bat, mad as a hatter”)

Effects due to blocking of MR in brainstem and cortex (has a less depressing effect on ascending reticular core than scopolamine)

26
Q

Atropine: use and pharmacokinetics

A

Use: Treatment of mushroom poisoning (muscarine) and organophophate poisoning

Alleviates some motor symptoms of Parkinson’s Disease

Pharmacokinetics:
Absorption: well absorbed orally, parenterally, and topically (through skin)

Distribution: widely ( to all body compartments)

Metabolism: liver

Excretion: some excreted unchanged in the urine

27
Q

Scopolamine:

MOA:

CNS effects: (4)

A

Scopolamine: natural alkaloid; tertiary amine

MOA: same as atropine

CNS Effects: has effects at therapeutic levels (not just toxic levels)

  1. Effects due to blocking MR in brainstem and cortex (has 100x more depressing effect on ascending reticular core than atropine)
  2. Hypnotic activity with amnesia
  3. Occasionally produce delirium and hallucinations at therapeutic levels
  4. Very effective anti-motion sickness drug (transdermal patch)
    o Note: site of action in brain stem between semicircular canals of inner ear and emetic center in medulla; will not block emetic action of agents triggering CTZ
28
Q

Scopolamine: pharmacokinetics

A

Absorption: well absorbed orally, parenterally; very good topical absorption

Distribution/Metabolism/Excretion: same as atropine

29
Q

Benzotropine:
Use:

A

Use: adjunct in oral treatment of Parkinsonian tremor and ridgidity (including those produced by anti-psychotics)

Used a lot in nursing homes (possibly due to sedative action)

30
Q

Muscarinic pharmacology in the eye

Muscarinic Agonists:

Primary target:

What does contraction result in?

Exs:

A

Primary Therapeutic Target: sphincter pupillae muscle of the iris (circularly-oriented and controlled by PS innervation)

Acts in concert with radially-oriented group of muscle fibers controlled by SS neurons to control the amount of light admitted into the posterior chamber of the eye

Contraction (ie. due to application of muscarinic agonist) results in pupillary constriction (miosis) to reduce light entering the eye

Piliocarpine and Carbachol

31
Q

Pilocarpine:

Structure:

Application:

Use: standard and emergency

Mechanism of Use in Glaucoma:

A

Muscarinic Agonist
Structure: tertiary amine from a plant

Application: primarily topical for ophthalmology application

Use:

  • Standard cholinergic direct agonist for management of open-angle glaucoma (still second like to other drugs)
  • Emergency therapy of a narrow-angle glaucoma attack

Mechanism of Use in Glaucoma: enhance drainage of intraocular fluid from anterior chamber of the eye to reduce abnormally high intraocular pressure
- Contraction of sphincter pupillae opens canal of Schlemm and other drainage routes around the periphery of the iris

32
Q

Carbachol:

Structure:

Activity:

Metabolism:

Use:

What is used as a miotic agent during eye surgery?

A

(aka carbamylcholine)
Muscarinic Agonist

Structure: synthetic quaternary amine

Activity: agonist activity at ALL cholinoreceptors (muscarinic and nicotinic)

Due to widespread activity, usually only employed topically as a miotic agent

Metabolism: not degraded by cholinesterases

Use:
Miotic agent during eye surgery such as lens replacement (acetylcholine used for this as well; NOT pilocarpine)

33
Q

Muscarinic pharmacology in the eye

Muscarinic Antagonists:
Primary target:

Cholinergic agonists vs antagonists

A

Primary Thearapeutic Target: ciliary muscle that controls the shape of the lens

Contracts to increase convexity of lens to focus on near objects

Cholinergic AGONISTS can produce transitory blurring of distance vision

Cholinergic ANTAGONISTS (ie. atropine) cause inability to focus on near objects

34
Q

Muscarinic pharmacology in the eye

Muscarinic Antagonists:

Actions:

Uses:

A

Action: Cause cycloplegia (paralysis of the ciliary muscle) resulting in a FIXED LENS that only focuses at a DISTANCE
- Cause mydriasis (dilation of the pupil)

Use:
- Prescribing corrective lenses for the eye (short-acting agent tropicamide)

35
Q

Muscarinic pharmacology in the eye

Muscarinic Antagonists:

Issues, side effects, and contraindications

A

General Issues: Atropine and scopolamine are READILY absorbed through sclera and cornea (topical), but produce long-lasting effects (several days)
- Oral or parenteral administration produces lesser and shorter duration effects on the eye

Side Effects:

  • Photophobia (dilated pupil)
  • Difficulty with near vision
  • Potentially elevated intracocular pressure to dangerous levels*

Contraindications:

  • Do not use long acting agents in people with glaucoma or a predisposition to glaucoma (ie. shallow anterior eye chamber)
  • This is why atropine/scopolamine are not routinely uses to examine the eyes for corrective lenses (use tropicamide instead)
36
Q

What is routinely used instead of atropine and scopolamine in the eye?

A

tropicamide

37
Q

Muscarinic Agonists and the Heart:
Type of receptors used:
Results:

A

M2

Decreases cellular activity when stimulated

38
Q

Mechanism of M2-R in heart

Effects of Gi beta/gamma:
alpha:

A

Increase plasma membrane K+ permeability (hyperpolarization)

Gi beta/gamma subunits act directly on K+ channels

Gi alpha subunit inhibits adenylate cyclase to decrease cAMP (counteracts stimulator effects of beta-adrenoceptor stimulation

39
Q

Muscarinic Agonist Action on the Heart:

Targets:

Effects of M2 activation

A

Targets: SA node, atria and AV node

Effects of M2 activation:
• slows heart rate (negative chronotropic action)
• decreases the force of contraction (negative inotropic action)
• suppresses AV conduction (negative dromotropy).

40
Q

Muscarinic agonists in the heart:

chronotropic, inotropic, dromotropic effects

A

Negative Chronotropic Action: slows heart rate
o Effects on pacemaker cells due to effects on AP and diastolic depolarization phases of the cycle
o Reduced slope of diastolic depolarization (due to hyperpolarization because of K+ permeability)
o Shortened AP (due to increased K+ permeability during repolarization)

Negative Inotropic Action: decreases force of contraction
o Shortened AP –> less Ca++ influx and release –> less Ca++ available for contractile elements in the cell –> weaker contraction

Negative Dromotropic Action: suppresses AV conduction

41
Q

Muscarinic Agonists and the Vascular System

Vascular Effects:

Cholinergic nerve stimulation of vascular system limited to:

All vascular beds have:

A

Muscarinic Agonists and the Vascular System:

Vascular Effects: most prominent with ACh administered by IV (experiemental)

Cholinergic nerve stimulation of vascular system limited to ONLY sympathetic fibers that supply resistance vessels of skeletal muscle

However, all vascular beds have M3 receptors on endothelium that promote vessel dilation.

42
Q

Mechanism of Vessel Dilation:

Activation of M3 receptors via:

Gq protein activation causes

Ca+ stimulated NO synthase to produce:

A

Muscarinic agonists in the vascular system:

Mechanism of Vessel Dilation:

Activation of M3 receptors via ACh in blood stream

Gq protein activation causes release of intracellular Ca++

Ca+ stimulated NO synthase to produce NO/EDRF (endothelial-derived relaxing factor)

43
Q

Muscarinic agonists in the vascular system:

Result of ACh Administration:

low dose, higher dose, even higher dose:

A

Low Dose by IV: metabolized quickly by plasma cholinesterases so the only actions are on the vascular system
- Vasodilation –> Decreased blood pressure –> Triggers baroreceptor reflex –> Increase in SS tone to the heart –> Reflex tachycardia

Higher Dose by IV: causes cardiac depression via direct action of ACh on the cardiac M2 receptors

Even Higher Doses by IV: complex results because of additional cardiac stimulation from activation of SS ganglia nAChR and release of NE

44
Q

If Atropine Given before ACh in the vascular system:

A

If Atropine Given First: will always get tachycardia, regardless of dose

Atropine blocks all the muscarinic receptors, leaving only nicotinic receptors for ACh to act on

ACh stimulates nicotinic receptors to cause release of catecholamines

45
Q

Use of Acetylcholine in Diagnostic Angiography:

A

Direct intracoronary injection of ACh

Normal Response: vasodilation subsequent to NO/EDRF release from endothelium

Patients with Vasospastic Angina Pectoris: results in spasm of coronary artery

46
Q

Atropine (Muscarinic Antagonist) Cardiac and Vascular Effects:

A

Atropine (Muscarinic Antagonist) Cardiac and

Vascular Effects:

Cardiac Effects: produces prominent and prolonged tachycardia and increased AV conduction

  • Blocks all cardiac effects of the vagus
  • Blocks all depressant effects of exogenously administered cholinomimetic drugs
  • Recall that low doses of atropine may cause paradoxical bradycardia
47
Q

Cardiac Uses of Atropine: (2)

A

Sinus bradycardia occurring after MI

Individuals with hyperactive carotid sinus reflexes (rare)

48
Q

Vascular Effects of Atropine:

Location:

Sign of toxicity:

A

Vascular Effects: has little effect on BP but does promote some cutaneous vasodilation via reflex mechanism (red as a beet)

Location: blush areas and upper thorax (more pronounced and more deadly in children)

Sign of toxicity: at toxic levels of atropine, skin becomes very red, warm and dry (“atropine flush”); related to thermoregulation because atropine blocks formation of sweat

Pharm Exam 1 (23 decks)

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