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Neuropsych > 5,6 - Autonomic Pharmacology > Flashcards

5,6 - Autonomic Pharmacology Flashcards

1
Q

basic organization of the autonomic nervous sytem (diagram)

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2
Q

common autonomic nervous system transmission pathways

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3
Q

Neurochemical Transmission of the Autonomic Nervous System:
Parasympathetic and Sympathetic

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  • In both the parasympathetic and sympathetic divisions, the preganglionic neurotransmitter released at autonomic ganglia is acetylcholine (ACh).
  • ACh activates nicotinic cholinergic receptors on postganglionic neurons, generating action potentials propagated to target tissues.
    -Parasympathetic neurons primarily release ACh to activate muscarinic cholinergic receptors on effector organs.
    →ACh is rapidly broken down by enzymes
  • Sympathetic postganglionic neurons chiefly release norepinephrine (NE) to stimulate adrenergic receptors on target tissues .
    -Most NE is transported back into the nerve terminal and some NE is then broken down
  • The parasympathetic or sympathetic outflow refers to the pathways and activation of these autonomic nervous system.
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4
Q

Schematic of the autonomic nervous system and major organs that they effect

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  • The neurotransmitter released by most postganglionic sympathetic nerves is norepinephrine (NorEpi), which stimulates postsynaptic α & β receptors on target organs.
  • The expression of different α & β receptors and their subtypes (e.g. α1,α2,β1,β2,β3) is tissue specific.
  • One exception to the rule are sweat glands, which are innervated by postganglionic sympathetic nerves that release acetylcholine (ACh).
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5
Q

(diagram) describe the pathway of Ganglionic Receptors: Nicotinic NN Receptors

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6
Q

Nicotinic Receptors: NN and NM

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  • Structurally, the nicotinic acetylcholine (Ach) receptor comprises five subunits, each of which has a mass of approximately 40 kDa
  • Subunits identified are: α, β, γ, δ, and ε. All of these subunits share 35–50% homology with one another.
  • There are two types of nicotinic cholinergic receptors:
    -At autonomic ganglia are called N2 or NN (only composed of α and β subunits)
    -At neuromuscular junction are called N1 or NM (composed of are: α, β, γ, δ, and ε subunits)
  • Activation of two ACh molecules will trigger their activation.
  • Activation of these ionotropic receptors (ion channels) trigger a sodium influx (depolarization)
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7
Q

Ganglionic Receptors: Drug Interventions?

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Ganglionic Stimulants/ Ganglionic Agonists
– No Signicant clinical applications.

* Ganglionic Blockers / Ganglionic Antagonists
– They interrupt the neural transmission at nicotinic receptors on postganglionic autonomic neurons (Block NN receptors for para- and sympathetic fibers).

– Trimethapan is rarely used severe hypertension and to induce hypotension during surgery (adjuvant), and in aortic dissection.

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8
Q

Cholinergic Synapse : Muscarinic Receptors

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9
Q

Cholinergic Synapse (with both Muscarinic and Nicotinic Receptors)

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  • Nicotinic Receptors are not present in main muscarinic synapses.
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10
Q

Muscarinic acetylcholine receptors (mACHr)

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11
Q

Selected Effects of Direct-Action Cholinergic Agonists

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12
Q

Cholinergic transmission: Summary of Drug Interventions

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13
Q

Cholinergic transmission: Drug Interventions - Disruptor of Cholinergic Synapse

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14
Q

Botulinum Toxin A (Botox)

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  • degrades SNAP-25 and prevents synaptic vesicle fusion with the inner cell membrane.
  • It inhibits exocytosis and prevents ACh release but it’s not specific to Ach, just snap25.
  • Used to treat facial dystonias due to increased muscle tone, cosmetic treatment of wrinkles (local administration) and headache syndromes (intratechal administration)
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15
Q

Cholinergic transmission: Drug Interventions - Cholinergic Agonists Cholinomimetics

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16
Q

Direct Muscarinic Agonists
* Cholinomimetics: Selected Clinical Applications

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Cholinomimetics: Adverse Effects:
– Bronchoconstrictor action could precipitate an asthma attack (by activation of M3 receptors in the lung)
– Bradycardia and Hypotension by activation of M2 receptors in heart and M3 receptors in endothelial cells. These can severely reduce coronary blood flow, especially if it is already compromised.
– The gastric acid secretion produced by the choline esters can aggravate the symptoms of acid-peptic disease.

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17
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18
Q

Cholinergic Drugs: Questions to ask

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Many clinically used cholinergic drugs lack strong selectivity for specific receptor subtypes. However, some degree of selectivity can be achieved in vivo based on administration route and distribution. A drug’s ionization influences absorption and brain penetration - permanently charged quaternary
ammonium compounds do not cross the blood-brain barrier, while more lipid-soluble tertiary amines often do.
Acetylcholine itself has no clinical use due to rapid hydrolysis. Among cholinesterase-resistant muscarinic agonists, lipid solubility affects absorption and distribution. Quaternary drugs like bethanechol are poorly absorbed orally and cannot enter the brain. Thus, oral dosing restricts bethanechol’s actions to the gastrointestinal tract,
where it enhances motility.

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19
Q
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20
Q

Cholinergic transmission: Drug Interventions
Cholinergic Agonists: Cholinomimetics - AChE inhibitors

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21
Q

Acetylcholinesterase (AChE) Inhibitors
Degradation of acetylcholine by acetylcholinesterase (AchE)

A
  • They will affect ALL Cholinergic Synapses (NN, NM, and M receptors)
  • Irreversible AChE Inhibitors: Mostly used as insecticides
    -Clinical Applications: Malathion is a scabicide
    -Metrifonate is an antihelminthic
  • Reversible AChE Inhibitors: (Carbamates) neostigmine, physostigmine
    Clinical Applications: - increasing transmission at the neuromuscular junction (neostigmine, physostigmine)
    -increasing central cholinergic activity (e.g.,
    rivastigmine used in Alzheimer’s Disease).

Adverse Effects
* Mild or moderate (resembles parasympathetic stimulation)
-Miosis, Salivation, Lacrimation, Diaphoresis, Vomiting & Diarrhea

  • Serious and Poisoning (insecticides, tabun, sarin, soman, ethyl sarin, and cyclosarin)
    -Same as those described above but with compromise of the Central Nervous System (convulsions, etc)

The spectrum of toxicity can be remembered with the aid of the mnemonic “DUMBBELSS”: Diarrhea, Urination, Miosis,
Bronchoconstriction, Bradycardia, Excitation [skeletal muscle and CNS], Lacrimation, Salivation and Sweating.

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22
Q

Cholinergic transmission: Drug Interventions
Cholinergic Antagonists

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23
Q

Muscarinic Antagonists: Clinical Applications

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24
Q

Muscarinic Antagonists (Antimuscarinics)
Effect of Muscarinic Blocking Drugs

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25
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26
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Cholinergic transmission: Drug Interventions
Cholinergic Antagonists

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27
Q

Neuromuscular Junction: Neuromuscular Blockers

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  1. Competitive Antagonists of the NM Receptor.
    Mechanism: They bind to the NM receptor and prevent their activation by Ach and cholinomimetics
    e.g. curare (d-tubocurarine), vecuronium, pancuronium, atracurium.
    Long Duration Effect (30, 60 minutes to several hours depending on the agent)
    Clinical Uses: Adjuvant (intubation) in surgical anesthesia

2. Depolarizing Blockers:
Mechanism: They binds the NM receptor and produce the following events:
1. They cause the opening of the NM channel and induce a short depolarization. (Onset 60 seconds)
2. They are slowly metabolized by pseudocholinosterases but not AChE. Pseducholinosterases are slower
3. Therefore, they remain bound to the NM receptor for a longer duration (blocking its reactivaton).
e.g. succinylcholine, decamethonium
Clinical Uses:
-Adjuvant in surgical anesthesia
-Orthopedic procedures for alignment of fractures

28
Q

Neuromuscular Junction: Neuromuscular Blockers (diagram of action)

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29
Q

What are the receptors of the Autonomic System used in the parasympathetic division?

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30
Q

Drug Interventions in the Cholinergic Synapse (diagram)

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31
Q

Cholinergic transmission: Summary of Drug Interventions

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32
Q

Adrenergic System - Neurotransmission pathways (diagram)

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33
Q

Schematic of the autonomic nervous system and major organs that they effect

A
  • The neurotransmitter released by most postganglionic sympathetic nerves is norepinephrine (NorEpi), which stimulates postsynaptic α & β receptors on target organs.
  • The expression of different α & β receptors and their subtypes (e.g. α1,α2,β1,β2,β3) is tissue specific.
  • One exception to the rule are sweat glands, which are innervated by postganglionic sympathetic nerves that release acetylcholine (ACh).
34
Q

Synthesis of Catecholamines

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35
Q

Adrenergic Synapse (diagram)

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36
Q

Adrenergic Synapse: Norepinephrine (NE) Metabolism COMT and MAO

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37
Q

Signaling properties of adrenergic receptors

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38
Q

What are the main endogenous neurotransmitters of the Sympathetic Nervous System?

A
  • Norepinephrine (Noradrenaline, NE) mainly released by postganglionic sympathetic nerve terminals
  • Epinephrine (Adrenaline, Epi) released by the adrenal medulla
39
Q

What is the significance of having both Epinephrine and Norepinephrine?

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40
Q

What is the significance of having both Epinephrine and Norepinephrine?

In the context of managing severe allergic reactions in asthma patients, which catecholamine is most likely to bind to and activate Beta-2 receptors on the lungs, leading to bronchodilation?

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41
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42
Q

Adrenergic Synapse: Drug Interventions

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43
Q

Direct Acting ⍺1 Agonists: Clinical applications
(Phenylephrine, methoxamine, metaraminol)

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44
Q

Direct Acting ⍺1 Agonists: Adverse Effects

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  1. ⍺1 receptors on blood vessels
    – Reduce peripheral blood flow (pallor)
    – Marked elevation of blood pressure
  2. Excessive contraction of blood vessels at infusion site
    – Ischemia/Necrosis
  3. Rebound nasal congestion (Desensitization of adrenergic receptors after repeated activation)
    – Topical agents (nasal sprays)
  4. Mydriasis or pupil dilation
    – Photophobia
45
Q

Direct Acting ⍺2 Agonists: Clinical applications
(Clonidine, Methyldopa, Guanefacine, Bromidine)

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46
Q

Adrenergic Synapse: Drug Interventions

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47
Q

β1-Receptor Agonists: Isoproterenol (Non-Selective) and Dobutamine (selective)

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Isoproterenol (Isoprenaline)
* Agonist for β1 and β2 receptors in the heart
* Increase heart activity (cardiac output) by activation of β1
receptors
* Used in clinic to treat cardiac arrhythmias

Dobutamine
* β1 agonist
* Increase heart rate (chronotropic effect) and heart contraction
(inotropic effect) by activation of β1 receptors
* Clinically used in heart failure and cardiogenic shock (heart
cannot pump enough)

48
Q

Selective β2 Receptor Agonists: Albuterol and Salmeterol

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  • Mechanism of Action: Inhibition of Myosin Light Chain Kinase (MLCK)
  • Albuterol (SABA: Short acting β agonist)
  • Salmeterol (LABA: Long acting β agonist)
    -Clinical Use: Bronchodilation (relaxation of bronchial smooth muscle)
    -In blood vessels smooth muscle produces vasodilation (physiology)
  • Adverse effects: Tachycardia (non-selective activation of β1 receptors)
49
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50
Q

Adrenergic Synapse: Drug Interventions - indirect

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51
Q

Indirect Acting Sympathomimetics

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52
Q

Indirect Acting Sympathomimetics - transmitters

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Ephedrine
It is a direct and indirect sympathomimetic amine.
* As a direct effect, ephedrine activates alpha-adrenergic and beta-adrenergic receptors.
* As an indirect effect, it inhibits norepinephrine reuptake and increases the release of norepinephrine from
vesicles in nerve cells.
* Was available as OTC
* OTC status removed due to safety concerns

Pseudoephedrine
– One of four ephedrine enantiomers
– Clinical uses:
* Decongestant
– Adverse effects
* Hypertension, tachycardia
– limited and restricted sale of pseudoephedrine by pharmacies

53
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54
Q

Adrenergic Synapse: Drug Interventions - Sympathethic antagonists (diagram)

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55
Q

α1 and α2 Receptor Antagonists

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56
Q

β-Receptor Antagonists

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β adrenergic receptors are divided into three main subtypes - β1, β 2, and β3.
* β -1 receptors are abundant in cardiac tissue and stimulate heart function when activated.
* β -2 receptors have wider distribution; their activation increases metabolic activity and promotes smooth muscle relaxation.
* β -3 receptors break down fat cells but currently have limited clinical relevance. There are 3 generations of β adrenergic blockers or β adrenergic anatagonists

57
Q

What are the receptors of the Autonomic nervous system? sympathetic and parasympathetic

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58
Q

Adrenergic Synapse: Drug Interventions (all, diagram)

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59
Q

Adrenergic Synapse: Summary Drug Interventions (all, diagram)

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Neuropsych (15 decks)

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