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Pharmacology > Autonomic Nervous System: Cholinergic and Adrenergic Agents > Flashcards

Autonomic Nervous System: Cholinergic and Adrenergic Agents Flashcards

1
Q

Mecamylamine

A

A ganglionic blocking drug of both parasympathetic and sympathetic (Nn) receptors.

Used as an antihypertensive drug (peripheral vasodilator) and tobacco smoking cessation (blocks Nn receptors in reward center of brain).

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2
Q

What is the rate-limiting step of Ach synthesis?

A

The transport of choline into the pre-synaptic nerve endings by Na+-choline co-transporter

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3
Q

Steps of Ach synthesis

A
  1. Choline transported into pre-synaptic nerve endings by Na+-choline co-transporter
  2. Choline + Acetyl CoA–> Ach by a cytosolic choline acetyltransferase (ChAT)
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4
Q

Ach storage

A

In the nerve terminal vesicles

Active vesicular uptake by a H-Ach antiporter, Ach is ion trapped (+charged) in the vesicle

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5
Q

Ach Release

A

AP–> Ca influx –> docking of vesicle with plasma membrane –> release of Ach by exocytosis – Ach is always charged and therefore can’t cross membranes

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6
Q

Presynaptic Inhibition of Cholinergic Transmission is done by _______.

A

Botulinum toxin (deadly nightshade) - prevents the release of Ach

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7
Q

Hemicholinium

A

Prevents choline from entering the pre-synaptic nerve ending

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8
Q

Vesamicol

A

Prevents the storage of Ach into vesicles

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9
Q

onabotulinumtoxinA (Botox)

Mechanism

A

PRE SYNAPTIC DRUG

Mechanism: inactivates SNAP-25 required for docking of the vesicle with the presynaptic membrane

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10
Q

onabotulinumtoxin A (Theraputic uses)

A
  1. Muscle spasms/dystonias (strabismus aka lazy eye–inject into dominant eye), blepharospasm (eyelid muscle spasm that shuts eyelids)
  2. Cosmetic - reduce glabellar, forehead, and lateral canthus lines, given IM
  3. Axillary hyperhidrosis (prevent sweating) - intradermal
  4. Chronic migraines, IM
  5. Overactive bladder disorder, intra-detrusor muscle
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11
Q

Onabotulinumtoxin A (side effects)

A
  1. Dysphagia and breathing difficulties (boxed warning) - from distant spread beyond injection site
  2. Muscle weakness (ptosis), urinary retention, pain
  3. Allergic reaction (due to it being a protein coming from a foreign bacteria)
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12
Q

Onabotulinumtoxin A (drug action)

A

Drug action: flaccid paralysis of skeletal muscle softens facial wrinkles and relaxes muscle spasms; inactivates sweat glands

Restoration of function requires sprouting of new nerve terminals; duration 3-4 months (irreversible inactivation)

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13
Q

Cholinergic Receptor Subtypes

A

Muscarinic: GPCRs
Nictonic

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14
Q

M3

A

(Smooth muscle, gland, endothelium)
Mediates excitation/contraction/secretion

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15
Q

M2

A

(heart) - Gi –> signals cellular inhibition

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16
Q

Muscarine

A

PRE-SYNAPTIC DRUG

Prototype AGonist of Botulin Toxin; activates all M subtypes

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17
Q

Atropine

A

PRE SYNAPTIC DRUG

Prototype ANTAGonist of Botulism Toxin: blocks M subtypes

Sits on receptor to block but activates opposing response due to blocking

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18
Q

Nicotinic Receptors

A

Ligated ion channels with a fast response time

Stimulation increases permeability to Na+ causing membrane depolarization; persistent stimulation causes destimulation of receptor

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19
Q

Nn

A
  • neuronal (ganglia, adrenal medulla-Epi)
  • high-affinity agonist - Nicotine (stimulation followed by desensitization)
  • Prototype antagonist - Mecamylamine (anti-hypertensive agent)
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20
Q

Nm

A

-musculoskeletal; NMJ
- low-affinity agonist - Nicotine (stimulating –> densensitized –> skeletal muscle paralysis)
-prototype antagonist - d-tubocurarine (produces non-depolarizing (competitive) neuromuscular blockade

21
Q

Nicotine

A

PRE SYNAPTIC DRUG

High affinity agonist to Nn, low affinity agonist to Nm

Can look like an antagonist due to how tightly it binds

22
Q

d-tubocurarine

A

PRE SYNAPTIC DRUG

A prototype ANTAGonist for Nm that produces a depolarizing (competitive) neuromuscular blockade

23
Q

Acetylcholinesterase (AChE)

A

rapidly terminates cholinergic NT by hydrolysis of ACh

24
Q

Butyrylcholinesterase (BuChE)

A

expressed mainly in the plasma and liver. Is a drug-metabolizing enzyme of choline ester drugs (ACh). – only does Ach when injected –

25
Q

Steps for synthesis of Catecholamines - DA, NE, Epi

A

Tyrosine –(Tyrosine hydroxylase)–> Dopa – (LAAAD)–> Dopamine –(Dopamine beta hydroxylase) –> NE –(PNMT)–> Epi

Tyrosine –> Dopa is the rate-limiting step

26
Q

CNS basal ganglia and renal vasculature release…

A

Dopamine

27
Q

Adrenergic neurons release…

A

Norepinephrine

28
Q

Adrenal medulla releases…

A

Epinephrine because it has all four converting enzymes to convert NEpi–> Epi

29
Q

The release of cortisol in the cortex stimulates ______ and ______ release in the adrenal medulla.

A

Epi and NE

30
Q

Monoamine oxidase (MAO)

A
  • Degrades any catecholamine molecule that isn’t stored
  • In sympathetic nerve terminals, liver, and brain
  • ## Two isoforms: A , B; degrade tyramine (A), and histamine (B)
31
Q

Vesicular Monoamine Transporter (VMAT-2)

A

Actively transports catecholamines into vesicles – which are then passively diffused out of the storage vesicles

32
Q

Reserpine (Mechanism)

A

Inhibits VMAT-2 thus depleting catecholamines from being stored in vesicles and reduces CNS sympathetic outflow (Dopamine)

33
Q

Reserpine (therapeutic use)

A

Used as an old hypertensive: caused sedation, psychotic depression, and orthostatic hypotension

34
Q

Release of catecholamines

A

Same process as with cholinergic neurons (AP, Ca2+ influx, exocytosis)

35
Q

alpha-2 auto-receptors

A

Stimulation causes negative feedback inhibition of NE release – Gi inhibition of Ca2+ influx

36
Q

Antagonists of alpha-2 auto-receptors do what

A

Increase NE release

37
Q

Tyramine

A

PRE SYNAPTIC DRUG

Toxic amino acid in food (aged cheese, beer/wine, cured meat) that stimulates NE release – can cause hypertensive crisis by increasing sympathetic nerve terminal activity at heart and vasculature

38
Q

Tyramine (Mechanism)

A

Displaces NE from storage vesicles; elevated cytosolic NE triggers non-vesicular release by reverse transport through NET

39
Q

(Norepinephrine Transporter) NET

A

An intra-membranous transporter that can transport NE in either direction

40
Q

Why would a patient be at risk if they are on an MAOI (Monoamine Oxidase Inhibitor) and they consume Tyramine?

A

MAO degrades unstored NE and a MAOI will inhibit MAO from degrading free NE. Since tyramine displaces NE from storage vesicles, without MAO, NE will cause a hypertensive crisis. — therefore patient’s on MAOIs must have dietary restrictions

41
Q

Methyldopa (Therapeutic)

A

Gestational hypertension (safe for developing fetus) – side effects are dry mouth, edema, elevated risk of autoimmune hemolytic anemia (+Coombs’ test) with long-term use

42
Q

Methyldopa (Mechanism)

A

PRE SYNAPTIC DRUG

Alpha-2 agonist prodrug converted by DOPA decarboxylase –> methyl-dopamine and then by dopamine beta-hydroxylase –> methyl-NE (active form). - Methyl-NE binds to alpha-2 to halt release of NE.

Inhibits NE release and thus lowers blood pressure by decreasing sympathetic outflow from CNS to the heart, vasculature, and kidneys

43
Q

Adrenergic Receptor Subtypes

A

All coupled to G-proteins (GPCRs)

Pre-synaptic:
alpha 2 - Gi: decrease cAMP, M2 receptor in heart to slow HR

Postsynaptic:
alpha 1 - Gq: M3 receptor for vasoconstriction
beta 1 - Gs: increases cAMP; excitatory/contraction
beta 2 - Gs: relaxation of smooth muscle
beta 3 - Gs: relaxation of smooth muscle, lipolysis

44
Q

Cocaine

A

-PRE-SYNAPTIC DRUG
blocks reuptake of NE from NET.
- a local anesthetic for pain similar to lidocaine, novocaine etc. – but only one to block reuptake of NE – thus NE continuously fires in NMJ

45
Q

What are MAOIs used for therapeutically?

A

Depression and Parkinson’s disease

46
Q

Catechol-O-methyltansferase (COMT)

A
  • In the liver and kidney
  • Methylates and clears catecholamines (metabolism)
  • COMT inhibitors are used for Parkinson’s disease
47
Q

Both MAO and COMT do what?

A

They both metabolize NE and result in the production of VMA

48
Q

VMA

A
  • End results from metabolism of NE by COMT and MAO.
  • Major metabolite excreted in the urine; basis of clinical tests for pheochromocytoma (tumor of the adrenal medulla)
  • elevated in a hypertensive crisis when sympathetic nervous system is over activated
49
Q

Cholinergic Agonists and Antagonists

A

Agonists: “A big python came”
Acetylcholine (prototype)
- Bethanechol, pilocarpine, cevimeline

Antagonists: “And snuck by two Irish toddlers”
Atropine (prototype)
- scopolamine, ipratropium bromide, tolterodine, tropicamide

Pharmacology (2 decks)

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