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Mechanism of Drug Action > Pharmacology of Peripheral Neural Transmission (Pharmacology) > Flashcards

Pharmacology of Peripheral Neural Transmission (Pharmacology) Flashcards

1
Q

What are the key steps in cholinergic transmission that can be modified by drugs?

A
  1. ACh synthesis
  2. Transport of ACh into vesicles
  3. Release of ACh
  4. Binding of ACh to cholinergic receptors
  5. Breakdown of ACh
  6. Re-uptake of ACh degradation products into pre-synaptic terminal
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2
Q

What is the process of ACh synthesis?

A

Choline + Acetyl-CoA → ACh + CoA

Reaction catalysed by choline acetyltransferase (CAT)

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3
Q

What is the process of ACh breakdown and re-uptake?

A
  1. ACh is broken down in synaptic cleft by acetylcholinesterase (AChE) within 1 ms of release into choline + acetate.
  2. Choline transported back into pre-synaptic terminal through Na+-dependent choline transporter (ChT).
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4
Q

What is the significance of choline re-uptake in ACh synthesis?

A

Choline re-uptake is the limiting step of ACh synthesis.

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5
Q

What is the process of ACh transport into vesicles?

A
  • ACh transport into vesicles mediated by vesicular ACh transporter (VAChT).
  • VAChT relies on secondary active transport and H+ gradient generated by H+-ATPase.
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6
Q

What are the types of NMJ blockers?

A
  1. Depolarising agents
  2. Non-depolarising agents
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7
Q

What is the mechanism of action of depolarising NMJ blockers?

A

They are nAChR agonists and cause sustained depolarisation of post-synaptic terminal, causing inhibition of ACh action via 2 mechanisms:

  1. Phase I: Depolarisation of muscle fibres cause inactivation of Navs, making it inexcitable.
  2. Phase II: After Navs recover, nAChRs are desensitised due to sustained stimulation, so subsequent ACh binding produces little effect.
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8
Q

What are the side-effects of suxamethonium?

A
  1. Bradycardia: Muscarinic action
  2. Increased serum [K+]: Increased K+ permeability
  3. Increased intraocular pressure: Contraction of extraocular muscles
  4. Malignant hyperthermia: Uncontrolled release of Ca2+ from SR and futile cycle of re-sequestration.
  5. Prolonged paralysis
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9
Q

What is the benefit of depolarising agents over non-depolarising agents?

A

Depolarising agents have quicker recovery times.

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10
Q

What factors may extend effective time of suxamethonium and cause prolonged paralysis?

A
  1. Genetic variation leading to reduced AChE efficiency
  2. Use in conjunction with cholinesterase inhibitors (e.g. treating glaucoma)
  3. Longer effect in individuals with reduced liver function (e.g. neonates)
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11
Q

What is the mechanism of action of non-depolarising NMJ blockers?

A
  • Competitive antagonism of nAChRs
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12
Q

What is the significance of therapeutic dosage of non-depolarising NMJ blockers?

A
  • Dosage is large
  • Over 80% of receptors need to be blocked in order for NMJ transmission to be blocked (large amount of spare receptors)
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13
Q

What are the side-effects of non-depolarising NMJ blockers?

A
  • Hypotension (atracurium, mivacurium): Due to SNS block + histamine release from mast cells.
  • Tachycardia (pancuronium): Cardiac mAChR inhibition.
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14
Q

What is the pharmacokinetics of non-depolarising NMJ blockers?

A
  • Charged so cannot cross gut epithelium
  • Needs to be administered through IV
  • Cannot cross placenta so is safe as obstetric anaesthetic
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15
Q

How can non-depolarising NMJ block be reversed quickly?

A
  • Neostigmine (AChE inhibitor) administration in conjunction with atropine (counters parasympathomimetic effects)
  • Sugammadex: Reverses blocking by rocuronium (steroidal blocker) by binding to it and forming inactivating complex
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16
Q

How are non-depolarising NMJ blockers generally metabolised?

A
  • Excreted unchanged in urine
  • Metabolised in liver
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17
Q

How is atracurium metabolised?

A

Spontaneous hydrolysis in plasma pH

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18
Q

How is mivacurium metabolised?

A

Hydrolysis by plasma BuChE

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19
Q

What is the mechanism of action of ganglionic stimulants?

A

nAChR agonists that act selectively in ganglionic N2 nAChRs

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20
Q

What is the mechanism of action of ganglionic blockers?

A
  • nAChR agonists that stimulate post-ganglionic terminal and cause depolarising block (Type I).
  • Ganglionic nAChR antagonists (Type II).
  • Molecules that block synthesis/release of ACh in ganglia.
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21
Q

What is the G-protein signalling pathway used by M1 ACh receptors and what are its functions?

A

Signalling pathway: αq/11

Functions:

  1. Mediates synaptic transmission in CNS/PNS
  2. Found in post-ganglionic ANS neurones (binding of ACh causes slow EPSP through Kv inhibition [M-current])
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22
Q

What is the G-protein signalling pathway used by M2 ACh receptors and what are its functions?

A

Signalling pathway: αi/o

Functions:

  1. Parasympathetic control of heart
  2. Pre-synaptic inhibition at nerve terminals
  3. αi causes ↓ intracellular [cAMP] → ↓ Cav phosphorylation → Ca2+ conductance → ↓ Heart contractility and heart rate
  4. Gβγ opens GIRK channels in pacemaker tissue → Hyperpolarisation → ↓Rate of spontaneous depolarisation pacemaker rate → ↓Heart rate
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23
Q

What is the G-protein signalling pathway used by M3 ACh receptors and what are its functions?

A

Signalling pathway: αq/11

Functions:

  1. Mediates glandular secretion (e.g. sweat, oxyntic glands)
  2. Mediates smooth muscle contraction (GI tract, VSM)
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24
Q

How do M3 ACh receptors cause vascular smooth muscle relaxation and vasodilation?

A

M3 →(endothelium)→ eNOS → ↑[NO] → Guanylyl cyclase → cGMP → PKG → Relaxation

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25
Q

What are the signalling pathways of M4/M5?

A

M4: αi/o

M5: αq/11

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26
Q

What are the effects of muscarinic agonists on the heart?

A

↓ Contractility

↓ Heart rate

↓ Conduction velocity at AV node

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27
Q

What are the effects of muscarinic agonists on the vascular system?

A

Vasodilation

↓ Blood pressure

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28
Q

What are the effects of muscarinic agonists on non-vascular smooth muscle?

A

Contraction

Increased gut mobility

Contraction of bladder smooth muscle

Contraction of bronchial smooth muscle

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29
Q

What are the effects of muscarinic agonists on exocrine glands?

A

↑ Sweating

↑ Lacrimation

↑ Nasophayngeal secretion

↑ Salivation

↑ Bronchial mucous secretion

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30
Q

What are the effects of muscarinic agonists on the eyes?

A

Contraction of constrictor pupillae, resulting in:

  1. Pupil constrction
  2. Decreased intraocular pressure

Contraction of ciliary muscles

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31
Q

How do muscarinic agonists decrease intraocular pressure?

A

When pupils dilated, folds of iris inhibits aqueous humour drainage. Constriction of pupils improves drainage and decreases intraocular pressure.

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32
Q

What is the structure of parasympatholytics (muscarinic antagonists)?

A
  1. Basic group
  2. Ester group
  3. Aromatic group
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33
Q

What are the types of cholinesterases and their distributions?

A
  • Acetylcholinesterase (AChE): Free in pre-synptic membrane and bound to post-synpatic membrane in PNS
  • Butyrylcholinesterase (BuChE): Free in plasma and bound in tissues (e.g. skin, liver…)
34
Q

What is the structure of AChE in synaptic cleft?

A
  • Trimer of tetramer of AChE
  • Attached by disulfide bonds to collagen tail anchoring them to post-synpatic membrane
35
Q

What type of enzymes are AChE and BuChE?

A

Serine hydrolases

36
Q

What is the catalytic triad in AChE?

A

Glu334

His447

Ser203

37
Q

What is the structural elements of the AChE active site?

A
  • Anionic site (Glu334): Where ACh binds to active site.
  • Esteratic site (His447 + Ser203): Catalytic region of enzyme.
38
Q

What is a significant difference between AChE and BuChE active sites?

A

BuChE lacks anionic site so has lower affinity for cholinesters than AChE.

39
Q

What is the reaction mechanism of AChE?

A
  1. Quaternary nitrogen of ACh binds to Glu334.
  2. Ester bond in ACh undergoes nucleophilic attack by Ser203.
  3. Acetyl group transferred from choline to Ser203.
  4. Choline is freed and bond between acetyl group and Ser203 undergoes spontaneous hydrolysis.
40
Q

What are the classes of anticholinesterase drugs?

A
  1. Short-term (non-covalent)
  2. Medium-term (covalent, reversible)
  3. Long-term (covalent, irreversible)
41
Q

What is the mechanism of action of medium-acting (covalent) anticholinesterases?

A

Transfers carbamyl group to Ser203, which is much more stable and takes longer to hydrolyse than acetyl group in ACh

42
Q

What is the mechanism of action of irreversible (covalent) anticholinesterases?

A

Phosphorylates Ser203 and deactivates the enzyme

43
Q

What is the process of ageing in irreversible covalent inhibition of AChE and its significance?

A
  • Process whereby the O-P bond between Ser and inhibitor rarranges and becomes more stable
  • After this point, inhibtion cannot be reversed
44
Q

What are the main catecholamines found in the body?

A
  • Noradrenaline (NA)
  • Adrenaline (Adr)
  • Dopamine (DA)
45
Q

What is the process of catecholamine synthesis?

A
46
Q

What is the localisation of enzymes involved in synthesis of NA?

A
  1. TOH: Restricted to cells synthesising catecholamines
  2. DDC: Ubiquitous and found in many cells
  3. DBH: Restricted to cells synthesising catecholamines (found in NA vesicles of noradrenergic neurones)
  4. PNMT: Adr cells of adrenal medulla
47
Q

What are the key steps in noradrenergic transmission that can be modified by drugs?

A
  1. NA synthesis
  2. Uptake into vesicles
  3. Release of NA
  4. Binding to adrenergic receptors
  5. Breakdown of NA
48
Q

How do α2 adrenoreceptors mediate NA release?

A
  1. Binding of NA causes activation of associated G-protein with αi subunit.
  2. αi inhibits activity of adenylyl cyclase.
  3. Intracellular [cAMP] decreases.
  4. PKA activity decreases.
  5. Number of phosphorylated Cavs and Ca2+ current during APs.
  6. Reduced Ca2+-mediated exocytosis.
  7. βγ subunit binds to and activates GIRK channels, causing K+ efflux and hyperpolarisation.
49
Q

What is the function of L-DOPA/Carbidopa combination therapy?

A
  • L-DOPA can croos BBB and enters CNS to increase dopamine production.
  • Carbidopa cannot cross CNS and remains in periphery to prevent peripheral side-effects.
  • Used to treak Parkinson’s.
50
Q

What is the function of oxidopamine (6-OHDA)?

A
  • Enters noradrenergic nerve terminals via NA transporters.
  • Selectively destroys noradrenergic/dopaminergic nerve terminals.
51
Q

What are the mechanisms of NA vesicular storage?

A
  1. NA/DA transported into vesicles through VMAT via secondary active transport.
  2. Energy derived from H+ gradient set up by V-type H+-ATPase, using ATP (4 NA per ATP).
52
Q

What are the routes of NA re-uptake?

A

Uptake 1: Mediated by NET (Norepinephrine transporter) and is responsible for ~75% of NA re-uptake.

Uptake 2: Mediated by EMT (Extrneuronal monoamine transporter) and is responsible for ~25% of NA re-uptake.

53
Q

What are the differences between NET and EMT?

A
  • Transporter type: NET is part of the Solute Carrier (SLC) family while EMT is part of the Organic Cation Transporter (OCT) family.
  • Affinity (specificity): NET has higher specificity that EMT, meaning that while NET only transports NA, EMT transports other monoamines such as dopamine and serotonin.
  • Capacity: NET has low capacity (rate of NA transport) while EMT has high capacity.
  • Na+ dependence: NET is Na+-dependent (cotransports Na+ and Cl-) while EMT is Na+-independent.
54
Q

Which heteroreceptors can mediate NA release?

A
  • δ-opioid receptors
  • M2 muscarinic receptors
  • Prostaglandin E2 receptor 3 (EP3)
55
Q

Which enzymes are responsible for NA breakdown?

A
  • Monoamine oxidase (MAO)
  • Catechol-O-methyl transferase (COMT)
56
Q

What is the main mechanism by which NA action is terminated?

A

Re-uptake by uptake 1 (NET)

57
Q

What is the function of MAO?

A
  • Modulates amount of NA in pre-synaptic terminal available for release
  • Breaks down NA that leaks from pre-synaptic vesicles to prevent un-stimulated release of NA into synaptic cleft
58
Q

What are the functions of COMT?

A

Breakdown of circulating catecholamines (absent in noradrenergic neurones)

59
Q

What are the main clinical uses of MAO and COMT inhibitors?

A

Inhibitors of MAO (e.g. phenelzine) and COMT (e.g. entacapone) alter levels of dopamine in CNS and thus are mainly used as antidepressants and to treat Parkinson’s disease.

60
Q

What are the effects of NA on blood pressure?

A
  • ↑Systolic pressure: Increased heart rate and contractility
  • ↑Diastolic pressure: Systemic vasoconstriction
61
Q

What are the effects of Adr on blood pressure?

A
  • ↑Systolic pressure: Increased heart rate and contractility
  • ↓Diastolic pressure: Vasodilation of skeletal muscle arterioles
62
Q

Where are α1 adrenorecptors found and what signalling pathway does it use?

A

Location: Smooth muscle

Signalling pathway: Gq/11

63
Q

Where are α2 adrenorecptors found and what signalling pathway does it use?

A

Location:

  • Pre-synaptic terminals
  • Platelets
  • Lipocytes
  • Smooth muscle

Signalling pathway: Gi

64
Q

Where are β1​ adrenorecptors found and what signalling pathway does it use?

A

Location:

  • Cardiac myocytes
  • Lipocytes
  • Juxtaglomerular apparatus

Signalling pathway: Gs

65
Q

Where are β2​ adrenorecptors found and what signalling pathway does it use?

A

Location:

  • Bronchial smooth muscle
  • Vascular smooth muscle
  • Cardiac myocyte
  • Uterine smooth muscle

Signalling pathway: Gs

66
Q

Where are β3 adrenorecptors found and what signalling pathway does it use?

A

Location:

  • Lipocytes
  • Smooth muscle

Signalling pathway: Gs

67
Q

What are the functions of α1 adrenoreceptors?

A
  • Pupil dilation
  • Vasoconstrction
  • Salivary secretion
  • Decreased GI motility
  • Piloerection
  • Contraction of bladder smooth muscle
  • Ejaculation
  • Increased glycogenolysis and gluconeogenesis
68
Q

What are the functions of α2 adrenoreceptors?

A
  • Decreased NT (e.g. NA) release
  • Platelet aggregation
  • Inhibition of insulin release
69
Q

How do α2 receptors mediate insulin release?

A

Causes dephosphorylation of Cavs in pancratic islets, resulting in decreased Ca2+ current on stimulation and decreased insulin release

70
Q

What are the functions of β1 adrenoreceptors?

A
  • Increased force of cardiac contraction
  • Increased heart rate
71
Q

What are the functions of β2 adrenoreceptors?

A
  • Bronchodilation
  • Vasodilation in myocardium/skeletal muscle
  • Relaxation of uterine smooth muscle
  • Gluconeogenesis
72
Q

What are the functions of β3 adrenoreceptors?

A
  • Lipolysis
  • Thermogenesis
  • Relaxation of bladder smooth muscle
73
Q

What are the clinical uses of non-selective adrenoreceptor agonists?

A
  • Acute asthma: Relieves bronchospasms (β2)
  • Anaphylaxtic shock:
    1. Vasoconstriction (α1): Increases blood pressure
    2. Reduces histamine secretion from mast cells (β2)
  • Acute heart failure: Increases heart rate and contractility (β1)
74
Q

What are the clinical uses of α1 agonists?

A
  • Nasal decongestion
  • Increases blood pressure by vasoconstriction
75
Q

What are the clinical uses of α2 agonists?

A
  • Hypertension (reduces sympathetic tone release)
76
Q

What are the clinical uses of β1 agonists?

A

Heart failure

77
Q

What are the clinical uses of β2 agonists?

A

Asthma

78
Q

What are the clinical uses of β3 agonists?

A

Over-reactive bladder

79
Q

What are the clinical uses of non-selective α antagonists?

A
  • Hypertension (e.g. phentolamine)
  • Phaeochromocytoma (e.g. phenoxybenzamine)
80
Q

What are the clinical uses of α1 antagonists?

A
  • Hyerrtension
  • Benign prostatic hypertrophy
81
Q

What are the clinical uses of non-selective β antagonists?

A
  • Hypertension
  • Ischaemic heart disease
  • Congestive heart failure
  • Cardiac dysrhythmias
82
Q

What are the clinical uses of β1 antagonists?

A
  • Hypertension
  • Cardiac dysrhythmias

Mechanism of Drug Action (28 decks)

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