A5-6: Cholinergic and Adrenergic Transmission/Modification, Ganglion Blockers Flashcards Preview

Pharmacology (Dustin, Ben) > A5-6: Cholinergic and Adrenergic Transmission/Modification, Ganglion Blockers > Flashcards

Flashcards in A5-6: Cholinergic and Adrenergic Transmission/Modification, Ganglion Blockers Deck (22)
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1
Q

What are the 6 basic steps in the cholinergic transmission cycle?

(Including any important molecules, receptors, enzymes…)

A
  1. Synthesis (Ac-Coa + Choline w/ ChAT enzyme -> Ach)
  2. Storage (VAT transports into vesicle, Ach-H+ antiporter )
  3. Release (after a Calcium-influx causes action potential, Ach is released into synaptic cleft)
  4. Reception/Recognition (by postsynaptic muscarinic or nicotinic receptors + presynaptic receptors on the neuron)
  5. Termination (Ach-esterase rapidly hydrolyzes Ach)
  6. Recycling (Choline is taken back up in the neuron)
2
Q

What type of receptors are nicotinic and muscarinic acetylcholine receptors?

A
  • Nicotinic: Ionotropic (fast-acting, allowing sodium and potassium concentrations to rapidly change)
  • Muscarinic: Metabotropic (slower-acting GPCRs. M1,M3,M5 = Gq, M2,M4 = Gi).
3
Q

Cholinergic transmission is involved in which parts of the autonomic nervous system?

A
  • All preganglionic synapses (both sympathetic and parasympathetic). All are nicotinic AchR
  • Parasympathetic postganglionic synapses: Muscarinic AchR
  • Sympathetic postganglionic synapses to sweat glands: Muscarinic AchR [other sympathetic synapses are to alpha or beta receptors]

(Ach also used to trigger skeletal muscle contraction in the somatic efferent system)

4
Q

What are some important effects of different muscarinic receptor activation?

A

M2 and M3 are the most important ones

  • M1 Gq increases gastric acid secretion. Agonists are bad for peptic ulcer disease. Also have M1R in CNS.
  • M2 Gi inhibits cardiac activity. Muscarinic agonists can cause AV block.
  • M3 Gq works to contract smooth muscle in the glands, eyes, and bronchioles.
    • Muscarinic agonists can trigger asthma-like symptoms from bronchoconstriction.
    • M3 receptors on blood vessels make NO -> vasodilation. However there is no parasympathetic innervation of blood vessels, so indirect-acting agonists don’t cause vasodilation this way.
5
Q

What are some important effects of nicotinic receptor activation?

A
  • NM (muscular) type: causes excitatory post-synaptic potential (EPSP) -> stimulation of NMJ; skeletal muscle activation. Blockers used for paralysis during surgery.
  • NN (neuronal) type: preganglionic activation of both parasympethic and sympathetic nervous system. Epinephrine released from adrenal medulla. Generally not safe to modify these clinically.
6
Q

What drug can be used to inhibit the transport component of the recycling of choline?

What is the effect?

A

Hemicholinium (hemicholine)

Causes a decrease in acetylcholine production, meaning weaker activation of skeletal muscle + muscarinic and nicotinic receptors

Not used clinically

7
Q

What drug can be used to inhibit acetylcholine uptake into the vesicle?

What is the effect?

A

Vesamicol

Inhibits VAT (vesicular acetylcholine transporter)

Reduces all Ach activity

Not used clinically

8
Q

What drug blocks the presynaptic release of acetylcholine?

What is the effect?

A

Botulinum toxin (Botox)

Cleaves SNARE proteins, preventing release of Ach-containing vesicle

Effect: local flaccid paralysis when injected into a muscle, systemic paralysis if absorbed systemically. Dangerous for respiratory muscle paralysis.

Injected into facial muscles to reduce wrinkles, or clinically can be used to treat some spastic muscle disorders/dystonia

[See also topic A13]

9
Q

What toxin causes excessive release of Ach into the nerve terminal?

(Probably not too important to know, but was in lecture)

A

α-LTX: Latrotoxin (Black Widow Spider toxin)

10
Q

What are ganglion blocking agents, what are their categories, and what are some examples of ganglion blocking drugs?

A

Ganglion blockers = Neuronal-type Nicotinic receptor antagonists, including nicotine and quaternary/tertiary amines (non-depolarizing ganglion blockers). Non-specifically inhibit both parasymp + symp NS, so typically aren’t used.

  • Nicotine at high doses functions as a depolarizing ganglion blocker, causing blood pressure to fall as it inhibits the ANS.
  • Quaternary amines [N+] have + charge and so they absorb poorly in GI tract.
    • Hexamethonium: first drug shown to be effective for hypertension, but is no longer used.
    • Tetraethylammonium
  • Tertiary amines [N]: neutral charge, were developed later to absorb better in GI.
    • Mecamylamine
    • Trimetaphan
11
Q

What are the general effects of ganglion blocking agents?

A

Inhibit both parasymp and symp nervous system, so they abolish the dominant part of the ANS that is specific for each organ

  • Vasodilation: symp NS normally dominates in arterioles and veins. No symp tone -> vasodilation, hypotension. Treating hypertension was original use for ganglion blockers, but are more dangerous than modern hypertension drugs.
  • Tachycardia: parasymp tone normally has more influence on heart rate than symp tone, and so with no parasymp tone -> tachycardia
  • Other effects from blocking parasympathetic tone: mydriasis (pupil dilation), constipation, urinary retention, xerostomia (dry mouth)
  • Also from blocking sympathetic tone: anhydrosis (lack of sweat)
12
Q

What are the steps of norepinephrine (aka NE, Norepi) synthesis?

A
  1. Tyrosine is transported into adrenergic neuron, then tyrosine hydroxylase converts it into DOPA (dihydroxyphenylalanine). Rate-limiting step.
  2. DOPA is decarboxylated by aromatic amino acid decarboxylase to Dopamine (first monoamine in the process)
  3. Dopamine is transported into vesicle, then hydroxylated by dopamine ß-OHase to Norepinephrine
  4. An action potential triggers vesicle release and NE acts locally as a neurotransmitter on alpha and beta receptors.

Alternatively, in the adrenal medulla NE may be converted to epinephrine which circulates as a hormone

13
Q

What are the possibilities for norepinephrine removal/ metabolism?

A
  • NE is re-uptaken into the presynaptic cleft (most common path for NE), and then goes one of 2 ways:
    • Re-enters vesicle, being recycled
    • Broken down by MAO in mitochondria
  • Broken down in presynaptic cleft by COMT, then oxidized by MAO
14
Q

What drug can be taken to increase synthesis of dopamine, by which it also increases NE release?

A

L-DOPA (Levodopa):

bypasses the rate-limiting step of tyrosine hydroxylase, providing an intermediate to be made into dopamine and then norepinephrine

Used more to treat Parkinson’s disease (I think it will be covered again later), but also increases NE release

Usually administered with Peripheral DOPA Decarboxylase Inhibitors to allow more L-DOPA to enter the CNS without being metabolized + reduce peripheral side effects

15
Q

What drug can be used as an inhibitor of aromatic amino acid decarboxylase (aka DOPA decarboxylase)?

A

α-methyl-DOPA:

Competitive inhibitor; blocks DOPA from being converted to Dopamine

+ becomes α-methylnorepinephrine, which agonizes α2 receptors but not α1, causing presynaptic inhibition

Can be used to treat hypertension

16
Q

What drug can be used to inhibit tyrosine hydroxylase?

A

Metyrosine (or metirosine, methyltyrosine..)

Inhibits catecholamine synthesis. Used to be used to treat pheochromocytoma, now mostly in investigative studies.

17
Q

What drug inhibits uptake of dopamine into vesicles, preventing its conversion to norepinephrine?

A

Reserpine

Irreversibly blocks VMAT (vesicular monoamine transporter)

Can be used to treat hypertension, but has long-lasting effects due to irreversible binding. Rarely used.

[Note in the image that the indirect-acting sympathomimetics, covered in another topic, also block VMAT and norepinephrine reuptake]

18
Q

What drugs inhibit reuptake of norepinephrine?

A
  • Cocaine (probably more importantly it also inhibits dopamine reuptake)
  • Tricyclic Antidepressants (inhibit both serotonin and NE reuptake). Lot of side effects, less safe.
  • SNRIs: Serotonin-Norepinephrine Reuptake Inhibitors (e.g. Reboxetine, Atomoxetine) - also inhibits reuptake of both serotonin and NE

These drugs allow NE to persist in the nerve terminal for longer, signaling more of an effect from NE

19
Q

What drugs can be used to block release of NE from nerve terminals?

A

Bretylium and Guanethidine

Used as anti-hypertensive drugs

20
Q

What drugs can be used to inhibit breakdown of norepinephrine or other catecholamines?

A

MAOIs: Monoamine Oxidase Inhibitors

or COMTIs: Catecholamine Methyltransferase Inhibitors

MAOIs are in the presynaptic nerve terminal (more specific to this topic), whereas COMTIs are in the post-synaptic cell

MAOIs used to treat depression, Parkinson’s + many other uses, but can be dangerous to take with cheese or wine for risk of tyramine-induced hypertensive crisis. [Should be more in later topic]

COMTIs are newer and used to treat Parkinson’s

21
Q

What type of drugs inhibit the presynaptic noradrenergic nerve terminal?

[Will have more on this in topics 9-10]

A

α2 agonists, e.g. Clonidine

Anti-hypertensive

22
Q

Without extra details, what drugs can you list that modify the presynaptic release, metabolism, or reuptake of norepinephrine?

A

L-DOPA (+ Peripheral DDCIs)

α-methyl-DOPA

Metyrosine

Reserpine

Antihypertensive α2 agonists: Clonidine

Bretylium, Guanethidine

Reuptake Inhibitors: Cocaine, Tricyclic Antidepressants, SNRIs

MAOIs, COMTIs