3.0 Peripheral Nervous System Flashcards
1
Q
Where does PSNS originate from?
A
Craniosacral<br></br>(CNs III, VII, IX and X + pelvic splanchnics)
2
Q
Where does the SNS originate from?
A
Thoracolumbar<br></br><br></br>(T1 → L2/3)
3
Q
What neurotransmitter is the exception by not being stored in vesicles?
A
NO
4
Q
What is the releasable pool?
A
Vesicles that are already docked to the release sites. Able to release contents very quickly (200μs)
5
Q
What is the reserve pool?
A
Vesicles that are associated with the cytoskeleton. Can augment vesicle population if more than releasable pool is needed
6
Q
What are the different SNAREs?
A
<b>v-SNARE</b><br></br>Synaptobrevin<br></br><br></br><b>t-SNARE</b><br></br>SNAP-25<br></br>Syntaxin
7
Q
How many α helices do the following SNAREs have?<br></br>1) Synaptobrevin<br></br>2) SNAP-25<br></br>3) Syntaxin
A
1) Synaptobrevin - 1<br></br>2) SNAP-25 - 2<br></br>3) Syntaxin - 1
8
Q
What is the core complex?
A
Complex of: <br></br>1) Synaptobrevin<br></br>2) SNAP-25<br></br>3) Syntaxin<br></br><br></br>The four α helices come together and form a leucine zipper to bring plasma membranes together
9
Q
What is synaptotagmin?
A
<b>Ca²⁺ sensor on vesicle</b><br></br><br></br>Transmembrane region (N terminus)<br></br>Sequence homology with PKC<br></br><br></br>Binds <b>several</b> Ca²⁺ with <b>low affinity</b>
10
Q
What are synapsins?
A
Found on surface of vesicles<br></br>Link vesicle to cytoskeleton <br></br><b>Non-phosphorylated</b> → vesicles are immobile<br></br><b>Phosphorylated</b> (by PKA + CaM kinase II) → dissociation → vesicles are free to move
11
Q
What are the symptoms of botulinum poisoning?
A
- Somatic muscle weakness (can lead to need for respiratory support)<br></br>2. Loss of cholinergic activity (consitipation, blurred vision, dry skin, urine retention)<br></br>3. Noradrenergic nerve actions (heart rate slowed)
12
Q
What is the mechanism of Botulinum toxin?
A
- Preferentially effects cholinergic neurons <br></br>- Has a light chain and heavy chain<br></br>- C-terminus (heavy chain) binds ganglioside receptor (GT1b) ⟶ endocytosis of complex<br></br>- N-terminus translocates light chain from the endosomal lumen ⟶ cell cytoplasm (Does so by making a channel in endosomal membrane)<br></br>- Light chain has peptidase activity ⟶ cleaves target SNARE
13
Q
What is the mechanism of tetanus toxin?
A
- Does not act directly on motor neuron<br></br>- Retrogradely transported to the cell body ⟶ transfers to inhibitory interneuron ⟶ disables interneuron from releasing its transmitter ⟶ motor neuron becomes more excitable
14
Q
What are the SNARE targets for botulinum and tetanus toxin?
A
“<div><img></img></div>”
15
Q
What is the rate limiting step in ACh production?
A
Supply of choline
16
Q
What protein transports ACh into vesicles?
A
VAChT (vesicular ACh transporter)
17
Q
What other neurotransmitters are found in ACh vesicles?
A
ACh + ATP (10:1)<br></br><br></br>Also some VIP sometimes
18
Q
Whats the structure of AChE?
A
3 x tetramer of AChE bind to a tail via <b>disulphide bonds</b><br></br>Tail binds to basement membrane via <b>heparin sulphate proteoglycan</b>
19
Q
What is the mechanism of action of cholinesterases?
A
AChE + BuChE = <b>Serine hydrolases</b><br></br><br></br><b>AChE</b><br></br>2 binding sites:<br></br>1) Anionic site (contains glutamate. Binds choline)<br></br>2) Esteratic site (Contains Serine + histidine)<br></br><br></br><b>BuChE</b><br></br>Lacks anionic site therefore ↓ affinity for ACh
20
Q
What is the structure of nAChR?
A
Pentamer<br></br>2 x α + combination of 3 other subunits (e.g. βγδ)
21
Q
What are the different muscarinic receptors?
A
Several different types. Important ones:<br></br><br></br><b>M1</b><br></br>- Location = Peripheral and central neurons<br></br>- G-protein = G₁₁/q<br></br><br></br><b>M2</b><br></br>- Location = Heart + pre-synaptic terminals<br></br>- G-protein = Gi<br></br><br></br><b>M3</b><br></br>- Location = Secretory glands + smooth muscle<br></br>- G-protein = G₁₁/q
22
Q
What is the synthesis pathway for catecholamines?
A
Tyrosine → DOPA → Dopamine → NA → A<br></br><br></br>1) Tyrosine hyroxylase<br></br>2) Dopa decarboxylase<br></br>3) Dopamine beta-hydroxylase<br></br>4) PNMT
23
Q
What is the rate limiting step in catecholamine synthesis?
A
Tyrosine hydroxylase
24
Q
What is the ratio of NA:ATP in noradrenaline vesicles?
A
4:1<br></br>NA:ATP
25
What transporter transports DA and NA into vesicles?
Vesicular monoamine transporter (VMAT2)
H⁺ = energy source (2H⁺ extruded for every amine taken into vesicle) ← ATP dependent
H⁺ = energy source (2H⁺ extruded for every amine taken into vesicle) ← ATP dependent
26
Which two adrenoreceptors act as auto receptors?
α2
- Main one
- Activation → ↓ NA release (main effect is via G protein gated K⁺ channel
β2
- Activation → ↑ NA synthesis
- Main one
- Activation → ↓ NA release (main effect is via G protein gated K⁺ channel
β2
- Activation → ↑ NA synthesis
27
What are the different types of uptake for inactivation of catecholamines?
Uptake 1
- Uptake into presynaptic neuron
- Affects response
- High affinity/low capacity
- Transporter = NET
-Na+ dependent
- NA > Adr
Uptake 2
- Uptake into postsynaptic neuron
- No effect on response
- Low affinity/High capacity
- Transporter = ENT (OCT3)
- Not Na+ dependent
- Adr > NA
- Uptake into presynaptic neuron
- Affects response
- High affinity/low capacity
- Transporter = NET
-Na+ dependent
- NA > Adr
Uptake 2
- Uptake into postsynaptic neuron
- No effect on response
- Low affinity/High capacity
- Transporter = ENT (OCT3)
- Not Na+ dependent
- Adr > NA
28
What enzymes are involved in metabolism of catecholamines?
1) MAO
- On outer mitochondrial membrane
- MAO-A → NA, Adr, DA + 5-HT
- MAO-B → DA
2) COMT
- In liver and neuronal tissues
- Associated with uptake 2
- On outer mitochondrial membrane
- MAO-A → NA, Adr, DA + 5-HT
- MAO-B → DA
2) COMT
- In liver and neuronal tissues
- Associated with uptake 2
29
What are the G-proteins coupled to the different adrenoreceptors? What are their effects?
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30
What are the affinities for Adr and NA at the different adrenoreceptors?
α1 - NA > Adr
α2 - Adr > NA
β1 - Same
β2 - Adr > NA
β3 - Same
α2 - Adr > NA
β1 - Same
β2 - Adr > NA
β3 - Same
31
As well as primary neurotransmitter, what transmitters are also released from:
1) Cholinergic nerves
2) Noradrenergic nerves
1) Cholinergic nerves
2) Noradrenergic nerves
1) VIP + NO + ATP
2) ATP + Neuropeptide Y
2) ATP + Neuropeptide Y
32
What are the purinoceptors (purinergic receptors)?
P1
Adenosine > AMP > ADP > ATP
These are the adenosine receptors
P2
ATP > ADP > AMP > Adenosine
Divided into:
- 1) P2X (ligand gated ion channel)
- 2) P2Y (G-protein coupled)
Adenosine > AMP > ADP > ATP
These are the adenosine receptors
P2
ATP > ADP > AMP > Adenosine
Divided into:
- 1) P2X (ligand gated ion channel)
- 2) P2Y (G-protein coupled)
33
What is the structure of P2X receptor?
- Trimer of P2X subunit
- Non-selective cation channel
Important role in fertility
- Non-selective cation channel
Important role in fertility
34
What are the different adenosine receptors?
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35
Give examples of peptide neurotransmitters:
1) Substance P
2) VIP
3) Neuropeptide Y
4) CGRP
5) Opioids
6) Vasopressin (ADH)
2) VIP
3) Neuropeptide Y
4) CGRP
5) Opioids
6) Vasopressin (ADH)
36
What are different about peptide vesicles?
1) Much larger
2) Vesicles are further away from plasma membrane, thus require larger APs to generate a large enough ↑[Ca²⁺]i
2) Vesicles are further away from plasma membrane, thus require larger APs to generate a large enough ↑[Ca²⁺]i
37
How is NO synthesised?
Mainly on endothelial cells and neutrons
Ca²⁺ dependent
L-arginine → NO + L-ciltrulline (enzyme = NOS)
Ca²⁺ dependent
L-arginine → NO + L-ciltrulline (enzyme = NOS)
38
What are the three types of NOS?
1) Neuronal NOS (nNOS/NOS I)
CNS + NANC neurons
2) Inducible NOS (iNOS/NOS II)
Induced by macrophages etc (IFN-Y + chemokines)
3) Endothelial NOS (eNOS/NOS III)
In platelets and endothelial cells
CNS + NANC neurons
2) Inducible NOS (iNOS/NOS II)
Induced by macrophages etc (IFN-Y + chemokines)
3) Endothelial NOS (eNOS/NOS III)
In platelets and endothelial cells
39
Mechanism of action for NO:
Interacts with soluble guanylyl cyclase (GC) → ↑ cGMP → activation of cGMP dependent protein kinase G → relaxation of smooth muscle (esp. blood vessels)
40
How is NO inactivated?
1) Combined with haem in Hb
2) Oxidated to nitrite and nitrate → excreted in urine
2) Oxidated to nitrite and nitrate → excreted in urine
41
ADMA (asymmetric dimethyl arginine)
- Class = -
- Target = Nitric oxide synthase
- Mechanism = Endogenous inhibitor
- Steps:
- Info:
• equipotent to synthetic L-NMMA
• its concentration is increased in hypercholesterolaemia, aenemia and renal failure
- Target = Nitric oxide synthase
- Mechanism = Endogenous inhibitor
- Steps:
- Info:
• equipotent to synthetic L-NMMA
• its concentration is increased in hypercholesterolaemia, aenemia and renal failure
42
Alpha-latrotoxin
- Class = Toxin
- Target = Neurexins (transmembrane proteins on plasma membrane of nerves)
- Mechanism = Causes massive release of ACh
- Steps:
Bind to neurexins ⟶ formation of Ca²⁺ channels ⟶ massive release of ACh
- Info:
From black widow spider
- Target = Neurexins (transmembrane proteins on plasma membrane of nerves)
- Mechanism = Causes massive release of ACh
- Steps:
Bind to neurexins ⟶ formation of Ca²⁺ channels ⟶ massive release of ACh
- Info:
From black widow spider
43
alpha-methyldopa [methyldopa]
- Class = Precursor to false transmitter
- Target = -
- Mechanism = Becomes false transmitter α-methylnoradrenaline
- Steps:
• α-methyldopa is taken into noradrenergic nerve ending
• Converted by DDC and DBH ⟶ α-methyldopamine and α-methylnoradrenaline
• α-methylnoradrenaline is stored in vesibles ⟶ release in place of NA
• α-methylnoradrenaline = false transmitter
(Less active than NA on α1 but more active on on α2 ∴ less vasoconstriction following SNS stimulation)
- Info:
Functions as an anti-hypertensive by preferential competitive inhibition on α1 receptors
- Target = -
- Mechanism = Becomes false transmitter α-methylnoradrenaline
- Steps:
• α-methyldopa is taken into noradrenergic nerve ending
• Converted by DDC and DBH ⟶ α-methyldopamine and α-methylnoradrenaline
• α-methylnoradrenaline is stored in vesibles ⟶ release in place of NA
• α-methylnoradrenaline = false transmitter
(Less active than NA on α1 but more active on on α2 ∴ less vasoconstriction following SNS stimulation)
- Info:
Functions as an anti-hypertensive by preferential competitive inhibition on α1 receptors
44
Amitriptyline
- Class = Tricyclic antidepressant
- Target = NET
- Mechanism = Blocker
- Steps:
1) Blocks NET to prevent uptake of norepinephrine and 5-HT through uptake 1
- Info:
- replaced by SSRIs, which only blocks specific 5-HT transporter
-side effects: sedation due to H1 receptor block, postural hypotension, dry mouth, constipation, ventricular dysrythmias
- Target = NET
- Mechanism = Blocker
- Steps:
1) Blocks NET to prevent uptake of norepinephrine and 5-HT through uptake 1
- Info:
- replaced by SSRIs, which only blocks specific 5-HT transporter
-side effects: sedation due to H1 receptor block, postural hypotension, dry mouth, constipation, ventricular dysrythmias
45
Atenolol
- Class = Selective β1 antagonist
- Target = Selective β1 antagonist
- Mechanism = Antagonist
- Steps:
- Info:
Used in Hypertension
Less likely to cause bronchoconstriction (compared to propranolol ∵ selective to β1)
Also treat dysrhythmias and angina
Does not cross BBB (hydrophilic)
- Target = Selective β1 antagonist
- Mechanism = Antagonist
- Steps:
- Info:
Used in Hypertension
Less likely to cause bronchoconstriction (compared to propranolol ∵ selective to β1)
Also treat dysrhythmias and angina
Does not cross BBB (hydrophilic)
46
Atracurium
- Class = Quaternary ammonium
- Target = nAChR at NMJ
- Mechanism = competitive antagonism
- Steps:
1. Block end-plate potential in response to nerve stimulation
2. Antagonise the effects of directly applied ACh/other agonist
3. Tetanic fade - in presence of drug teatanus in response to high freq. stimulation is not maintained. This is due to block of autoreceptors which give +ve feedback to maintain transmitter release
- Info:
-Charged ∴ not orally active
-Broken down by plasma esterases
(∴ shorter duration of action than pancuronium)
- Used in anaesthetics
---Produce muscle relaxation
---Affect fast (white) muscles > slow (red)
(thought to ↓ respiratory depression ∵ respiratory muscles are slow twitch)
-Blocking can be reversed by anticholinesterases
- Target = nAChR at NMJ
- Mechanism = competitive antagonism
- Steps:
1. Block end-plate potential in response to nerve stimulation
2. Antagonise the effects of directly applied ACh/other agonist
3. Tetanic fade - in presence of drug teatanus in response to high freq. stimulation is not maintained. This is due to block of autoreceptors which give +ve feedback to maintain transmitter release
- Info:
-Charged ∴ not orally active
-Broken down by plasma esterases
(∴ shorter duration of action than pancuronium)
- Used in anaesthetics
---Produce muscle relaxation
---Affect fast (white) muscles > slow (red)
(thought to ↓ respiratory depression ∵ respiratory muscles are slow twitch)
-Blocking can be reversed by anticholinesterases
47
Atropine
- Class =
- Target = mAChR receptor (non-selective)
- Mechanism = Antagonist
- Steps:
- Info:
Used to be used to induce pupil dilation (but too long lasting, thus now sympathetic agonists used instead)
- Target = mAChR receptor (non-selective)
- Mechanism = Antagonist
- Steps:
- Info:
Used to be used to induce pupil dilation (but too long lasting, thus now sympathetic agonists used instead)
48
Bethanechol
- Class =
- Target = mAChR (non-specific)
- Mechanism = Agonist
- Steps:
- Info:
Used for urinary retention
Poor oral absorption
- Target = mAChR (non-specific)
- Mechanism = Agonist
- Steps:
- Info:
Used for urinary retention
Poor oral absorption
49
Botulinum toxins
- Class = Toxin
- Target = SNARE (mainly cholinergic neurons)
- Mechanism = Inhibits neurotransmitter release
- Steps:
1) Has a light and heavy chain
2) Heavy chain (C-terminus) binds to ganglioside receptor (GT1b) → endocytosis
3) N terminus translocates light chain from endosomal lumen → light chain now in cytoplasm
4) Light chain has peptidase activity and targets its SNARE
- Info:
Botox B, D, F + G → Synaptobrevin
Botox A + E → SNAP-25
Botox C1 → SNAP-25 and Syntaxin
- Target = SNARE (mainly cholinergic neurons)
- Mechanism = Inhibits neurotransmitter release
- Steps:
1) Has a light and heavy chain
2) Heavy chain (C-terminus) binds to ganglioside receptor (GT1b) → endocytosis
3) N terminus translocates light chain from endosomal lumen → light chain now in cytoplasm
4) Light chain has peptidase activity and targets its SNARE
- Info:
Botox B, D, F + G → Synaptobrevin
Botox A + E → SNAP-25
Botox C1 → SNAP-25 and Syntaxin
50
beta-Bungarotoxin
- Class = Toxin
- Target = Nerve ending and K⁺ ion channels
- Mechanism = Blocks ACh released by destroying nicotinic nerve endings
- Steps:
Consists of two chains:
Chain 1 ⟶ binds to K⁺ ion channels, targeting 2nd chain to nerve terminal
Chain 2 ⟶ a phospholipase A₂ which destroys the terminal
- Info:
Released from krait snake
- Target = Nerve ending and K⁺ ion channels
- Mechanism = Blocks ACh released by destroying nicotinic nerve endings
- Steps:
Consists of two chains:
Chain 1 ⟶ binds to K⁺ ion channels, targeting 2nd chain to nerve terminal
Chain 2 ⟶ a phospholipase A₂ which destroys the terminal
- Info:
Released from krait snake
51
Butaxamine/Butoxamine
- Class = β1 and β2 blocker
- Target = β1 and β2 adrenoreceptors
- Mechanism = antagonist
- Steps:
- Info:
• >selectivity for β2
• No clinical use
- Target = β1 and β2 adrenoreceptors
- Mechanism = antagonist
- Steps:
- Info:
• >selectivity for β2
• No clinical use
52
Caffeine
- Class = A1 receptor antagonist /PDE inhibitor
- Target = Non-selective drug: A1 receptor and phosphodiesterase (PDE)
- Mechanism = Antagonist/Inhibitor
- Steps:
Antagonism of A1 ⟶ wakefulness + increase heart rate
Inhibition of PDE ⟶ ↓ break down of cyclic nucleotides ⟶ ↑ rate and force of heart contractions (mainly due to cAMP)
- Info:
Waking action is most prominent after prolonged wakefulness
- Target = Non-selective drug: A1 receptor and phosphodiesterase (PDE)
- Mechanism = Antagonist/Inhibitor
- Steps:
Antagonism of A1 ⟶ wakefulness + increase heart rate
Inhibition of PDE ⟶ ↓ break down of cyclic nucleotides ⟶ ↑ rate and force of heart contractions (mainly due to cAMP)
- Info:
Waking action is most prominent after prolonged wakefulness
53
Carbidopa
- Class = -
- Target = DOPA decarboxylase
- Mechanism = Antagonist
- Steps:
1) Given with L-DOPA in treatment of Parkinsons disease
2) L-DOPA is given as it can cross blood-brain barrier (DA cannot)
3) L-DOPA alone gives off-target side effects ∵ ↑ DA in periphery
4) Carbidopa cannot cross BBB ∴ inhibits DOPA decarboxylase peripherally to prevent peripheral side effects of L-DOPA
- Target = DOPA decarboxylase
- Mechanism = Antagonist
- Steps:
1) Given with L-DOPA in treatment of Parkinsons disease
2) L-DOPA is given as it can cross blood-brain barrier (DA cannot)
3) L-DOPA alone gives off-target side effects ∵ ↑ DA in periphery
4) Carbidopa cannot cross BBB ∴ inhibits DOPA decarboxylase peripherally to prevent peripheral side effects of L-DOPA
54
Clonidine
- Class = Adrenoreceptor agonist
- Target = Slightly selective α2/l1 agonist
- Mechanism = Agonist
- Steps:
• stimulation of presynaptic alpha2 receptors reduces NA release (by downregulating PKA activity presynaptically) and thereby reduces blood pressure
-it also stimulates I1 receptors (in brain), which may have a more predominant role in clonidine's ability to act as an anti-hyerpertensive
- Info:
• Has been used as an antihypertensive (effect is achieved by stimulating receptors in hind brain)
• Missing one dose ⟶ rebound hypertension
Not used in UK
- Target = Slightly selective α2/l1 agonist
- Mechanism = Agonist
- Steps:
• stimulation of presynaptic alpha2 receptors reduces NA release (by downregulating PKA activity presynaptically) and thereby reduces blood pressure
-it also stimulates I1 receptors (in brain), which may have a more predominant role in clonidine's ability to act as an anti-hyerpertensive
- Info:
• Has been used as an antihypertensive (effect is achieved by stimulating receptors in hind brain)
• Missing one dose ⟶ rebound hypertension
Not used in UK
55
Clorgiline [clorgyline]
- Class = MAO inhibitor
- Target = MAO-A
- Mechanism = Inhibitor
- Steps:
- Info:
-selective blocker of MAO-A, thereby preventing breakdown of presynaptic 5-HT
-used in the treatment of depression
-exacerbation of the cheese effect from tyramine-containing foodstuffs
- excessive stimulation causing tremor and insomnia, muscarinic effects (dry mouth, constipation).
- Target = MAO-A
- Mechanism = Inhibitor
- Steps:
- Info:
-selective blocker of MAO-A, thereby preventing breakdown of presynaptic 5-HT
-used in the treatment of depression
-exacerbation of the cheese effect from tyramine-containing foodstuffs
- excessive stimulation causing tremor and insomnia, muscarinic effects (dry mouth, constipation).
56
Cocaine
- Class =
- Target = NET
- Mechanism = Blocker
- Steps:
1) Blocks NET to prevent uptake of norepinephrine through uptake 1
2) This results in prolonged NA-dependent signalling
- Info:
- Target = NET
- Mechanism = Blocker
- Steps:
1) Blocks NET to prevent uptake of norepinephrine through uptake 1
2) This results in prolonged NA-dependent signalling
- Info:
57
D-amphetamine [dexamfetamine]
- Class = Indirectly acting sympathomimetic amines
- Target = -
- Mechanism = Displaces NA from vesicles
- Steps:
• Taken up into storage vesicles
• ∵ it is a weak base ⟶ ↑vesicular pH ⟶ ↓ pH gradient that is required for VMAT2 to function ⟶ prevention of uptake of further NA to vesicle
• Displaced NA leaves cell through nerve endings ⟶ stimulate receptors
- Info:
• Substrate for uptake 1
• Dexamfetamine has an α-methyl group ∴ it is • not metabolized by MAO (it is actually a weak inhibitor)
• Can reduce appetite
- Target = -
- Mechanism = Displaces NA from vesicles
- Steps:
• Taken up into storage vesicles
• ∵ it is a weak base ⟶ ↑vesicular pH ⟶ ↓ pH gradient that is required for VMAT2 to function ⟶ prevention of uptake of further NA to vesicle
• Displaced NA leaves cell through nerve endings ⟶ stimulate receptors
- Info:
• Substrate for uptake 1
• Dexamfetamine has an α-methyl group ∴ it is • not metabolized by MAO (it is actually a weak inhibitor)
• Can reduce appetite
58
Darifenacin
- Class =
- Target = Selective M3 muscarinic receptor
- Mechanism = Reversible antagonist
- Steps:
- Info:
Reduces bladder constriction in the treatment of urinary incontinence to decrease the urge to urinate
- Target = Selective M3 muscarinic receptor
- Mechanism = Reversible antagonist
- Steps:
- Info:
Reduces bladder constriction in the treatment of urinary incontinence to decrease the urge to urinate
59
Dipyridamole
- Class =
- Target = Adenosine uptake mechanism/PDE V
- Mechanism = Prevents adenosine uptake into cells
- Steps:
- Info:
• Blocks adenosine uptake to prevent termination of adenosine-dependent signalling
• By amplifying the effects of endogenous adenosine on A2A and A2B receptors, dypyridamole is a potent vasodilator
• PDE V inhibition → ↑ cGMP
Causes coronary steal
- Target = Adenosine uptake mechanism/PDE V
- Mechanism = Prevents adenosine uptake into cells
- Steps:
- Info:
• Blocks adenosine uptake to prevent termination of adenosine-dependent signalling
• By amplifying the effects of endogenous adenosine on A2A and A2B receptors, dypyridamole is a potent vasodilator
• PDE V inhibition → ↑ cGMP
Causes coronary steal
60
Dobutamine
- Class = Beta agonist (β1)
- Target = Selective β1 agonist
- Mechanism = Agonist
- Steps: Effects on β1 ⟶ ↑ heart rate + ↑ inotropy (effect on isotropy > chronotropy)
- Info:
Used in cardiogenic shock
Post heart surgery
In heart failure (without HTN)
- Target = Selective β1 agonist
- Mechanism = Agonist
- Steps: Effects on β1 ⟶ ↑ heart rate + ↑ inotropy (effect on isotropy > chronotropy)
- Info:
Used in cardiogenic shock
Post heart surgery
In heart failure (without HTN)
61
D-tubocurarine [curare/tubocurarine]
- Class =
- Target = nAChR (non-selective between ganglion and NMJ)
- Mechanism = Antagonist
- Info:
Generated through purification of curare
Charged ∴ not orally active
- Target = nAChR (non-selective between ganglion and NMJ)
- Mechanism = Antagonist
- Info:
Generated through purification of curare
Charged ∴ not orally active
62
Dyflos [diisopropyl fluorophosphate/DFP]
- Class = Long acting antiChE
- Target = acetylcholinesterase (AChE)
- Mechanism = Irreversible inhibitor of AChE
- Steps:
• Organophosphorous compound
• Forms strong covalent bond between phosphorous atom and the serine residue at esteratic site
- Info:
Used to treat glaucoma
- Target = acetylcholinesterase (AChE)
- Mechanism = Irreversible inhibitor of AChE
- Steps:
• Organophosphorous compound
• Forms strong covalent bond between phosphorous atom and the serine residue at esteratic site
- Info:
Used to treat glaucoma
63
Edrophonium
- Class = Short acting antiChE
- Target = acetylcholinesterase (AChE)
- Mechanism = Reversible inhibitor of AChE
- Steps:
• Quaternary compound
• Binds to anionic site in the active site of AChE through electrostatic intereactions
- Info:
Used to diagnose myasthenia gravis
- Target = acetylcholinesterase (AChE)
- Mechanism = Reversible inhibitor of AChE
- Steps:
• Quaternary compound
• Binds to anionic site in the active site of AChE through electrostatic intereactions
- Info:
Used to diagnose myasthenia gravis
64
Entacapone
- Class = COMT inhibitor
- Target = COMT
- Mechanism = Inhibitor
- Steps:
- Info:
Used in Parkinson's disease
- Target = COMT
- Mechanism = Inhibitor
- Steps:
- Info:
Used in Parkinson's disease
65
Guanethidine
- Class =
- Target =
- Mechanism = Blocks release of NA
- Steps:
•Taken into nerve by Uptake 1 ∴ compete with NA
• ∴ can potentiate exogenously applied NA
• Large doses ⟶ behave as indirectly acting sympathomimetic amines (as described above)
• Repeated low doses ⟶ block the release of NA evoked by APs (spontaneous release is unaffected, showing that vesicle release processes are intact)
- Info:
Used to be used for HTN not any more
- Target =
- Mechanism = Blocks release of NA
- Steps:
•Taken into nerve by Uptake 1 ∴ compete with NA
• ∴ can potentiate exogenously applied NA
• Large doses ⟶ behave as indirectly acting sympathomimetic amines (as described above)
• Repeated low doses ⟶ block the release of NA evoked by APs (spontaneous release is unaffected, showing that vesicle release processes are intact)
- Info:
Used to be used for HTN not any more
66
Hemicholinium
- Class = -
- Target = Na⁺/Choline cotransporter
- Mechanism = Blocker
- Steps:
Hemicholinium blocks the symporter →↓ ACh production in pre-synaptic terminal
- Info:
Only reduces neurotransmission with high rates of stimulation
- Target = Na⁺/Choline cotransporter
- Mechanism = Blocker
- Steps:
Hemicholinium blocks the symporter →↓ ACh production in pre-synaptic terminal
- Info:
Only reduces neurotransmission with high rates of stimulation
67
Hexamethonium
- Class =
- Target = nAChR at autonomic ganglion
- Mechanism = Channel pore blocker
- Steps:
Use-dependent blocker of open channel pore
- Info:
Previously used for treatment of HTN but discontinued ∵
1. Caused loss of both SNS (wanted effect ⟶ ↓ vascular tone) and PSNS (lead to Hexamethonium man)
2. It has a double positive charge ∴ needed frequent administration via injection
- Target = nAChR at autonomic ganglion
- Mechanism = Channel pore blocker
- Steps:
Use-dependent blocker of open channel pore
- Info:
Previously used for treatment of HTN but discontinued ∵
1. Caused loss of both SNS (wanted effect ⟶ ↓ vascular tone) and PSNS (lead to Hexamethonium man)
2. It has a double positive charge ∴ needed frequent administration via injection
68
Idazoxan
- Class = α1 and α2 blocker
- Target = α1 and α2 adrenoreceptors
- Mechanism = antagonist
- Steps:
- Info:
• >selectivity for α2
- Target = α1 and α2 adrenoreceptors
- Mechanism = antagonist
- Steps:
- Info:
• >selectivity for α2
69
Imipramine
- Class = Tricyclic antidepressant
- Target = NET
- Mechanism = Blocker
- Steps:
1) Blocks NET to prevent uptake of norepinephrine and 5-HT through uptake 1
- Info:
- replaced by SSRIs, which only blocks specific 5-HT transporter
-side effects: sedation due to H1 receptor block, postural hypotension, dry mouth, constipation, ventricular dysrhythmias
- Target = NET
- Mechanism = Blocker
- Steps:
1) Blocks NET to prevent uptake of norepinephrine and 5-HT through uptake 1
- Info:
- replaced by SSRIs, which only blocks specific 5-HT transporter
-side effects: sedation due to H1 receptor block, postural hypotension, dry mouth, constipation, ventricular dysrhythmias
70
Isoprenaline
- Class = Beta agonist
- Target = Non-selective β agonist
- Mechanism = Agonist
- Steps:
causes bronchodilatation through an action on B2 and increased heart rate through B1
- Info:
Was used more in asthma (replaced now by β2 selective agonists)
Effects on β2 ⟶ bronchodilation but effects on β1 ⟶ ↑ heart rate which was undesired
10x more potent than adrenaline
NOT A SUBSTRATE FOR UPTAKE 1
- Target = Non-selective β agonist
- Mechanism = Agonist
- Steps:
causes bronchodilatation through an action on B2 and increased heart rate through B1
- Info:
Was used more in asthma (replaced now by β2 selective agonists)
Effects on β2 ⟶ bronchodilation but effects on β1 ⟶ ↑ heart rate which was undesired
10x more potent than adrenaline
NOT A SUBSTRATE FOR UPTAKE 1
71
Labetalol
- Class = Combined α and β blocker
- Target = alpha1, beta1, beta2 adrenoreceptors
- Mechanism = antagonist
- Steps:
Has 4 isomers with different actions:
1. R,R - β blocker + weak α1 blocker
2. R,S - no activity
3. S,R - α1 blocker + very weak β blocker
4. S,S - α1 blocker
- Info:
Used to treat hypertension in pregnancy
- Target = alpha1, beta1, beta2 adrenoreceptors
- Mechanism = antagonist
- Steps:
Has 4 isomers with different actions:
1. R,R - β blocker + weak α1 blocker
2. R,S - no activity
3. S,R - α1 blocker + very weak β blocker
4. S,S - α1 blocker
- Info:
Used to treat hypertension in pregnancy
72
Malathion
- Class = Long acting antiChE
- Target = acetylcholinesterase (AChE)
- Mechanism = Irreversible inhibitor of AChE
- Steps:
• Organophosphorous compound
• Forms strong covalent bond between phosphorous atom and the serine residue at esteratic site
- Info:
Used as an insecticide to kill lice
- Target = acetylcholinesterase (AChE)
- Mechanism = Irreversible inhibitor of AChE
- Steps:
• Organophosphorous compound
• Forms strong covalent bond between phosphorous atom and the serine residue at esteratic site
- Info:
Used as an insecticide to kill lice
73
Mecamylamine
- Class =
- Target = nAChR at autonomic ganglion
- Mechanism = Antagonist
- Steps: Use-dependent blocker of open channel pore
- Info:
Use-dependent, as mecamylamine requires access to the channel
- Target = nAChR at autonomic ganglion
- Mechanism = Antagonist
- Steps: Use-dependent blocker of open channel pore
- Info:
Use-dependent, as mecamylamine requires access to the channel
74
Muscarine
- Class =
- Target = mAChR (non-specific)
- Mechanism = Agonist
- Steps:
- Info:
No clinical use
- Target = mAChR (non-specific)
- Mechanism = Agonist
- Steps:
- Info:
No clinical use
75
Neostigmine
- Class = Medium acting antiChE
- Target = acetylcholinesterase (AChE)
- Mechanism = Reversible inhibitor of AChE
- Steps:
• Binds to the esteratic site and carbomylates the enzyme
• It is hydrolysed by the enzyme (but much slower than ACh ∴ enzyme is inactivated for many minutes)
- Info:
Orally ⟶ myasthenia gravis
IV ⟶ reverse neuromuscular blockade after surgery
- Target = acetylcholinesterase (AChE)
- Mechanism = Reversible inhibitor of AChE
- Steps:
• Binds to the esteratic site and carbomylates the enzyme
• It is hydrolysed by the enzyme (but much slower than ACh ∴ enzyme is inactivated for many minutes)
- Info:
Orally ⟶ myasthenia gravis
IV ⟶ reverse neuromuscular blockade after surgery
76
Nicotine
- Class = -
- Target = nAChR
- Mechanism = Agonist (can cause depolarising block)
- Steps:
Two phases of block
1) Phase I block
Long lasting nature of stimulation ⟶ inactivation of voltage gated Na⁺ channels on post-synaptic cell ∴ post-synaptic cells cannot be stimulated
2) Phase II block
Membrane repolarised as nictonic receptors become desensitised ∴ stimulation of preganglionic nerve will not excite postganglionic cell
Because Na⁺ channels are relieved from inactivation, postganglionic cell can be directly stimulated by electrical means
- Info:
- Target = nAChR
- Mechanism = Agonist (can cause depolarising block)
- Steps:
Two phases of block
1) Phase I block
Long lasting nature of stimulation ⟶ inactivation of voltage gated Na⁺ channels on post-synaptic cell ∴ post-synaptic cells cannot be stimulated
2) Phase II block
Membrane repolarised as nictonic receptors become desensitised ∴ stimulation of preganglionic nerve will not excite postganglionic cell
Because Na⁺ channels are relieved from inactivation, postganglionic cell can be directly stimulated by electrical means
- Info:
77
Nitroglycerin [glyceryl trinitrate]
- Class = NO donor
- Target = soluble guanylyl cyclase
- Mechanism = Activator
- Steps:
- Info:
• Causes actiation of sGC in vascular smooth muscle, leading to smooth muscle relaxation and vasular dilatation
• Preferentially causes dilatation in collateral vessles. This reduces the amount of ischaemic myocardial tissue.
• Used in acute angina
• Must be taken sublingually
- Target = soluble guanylyl cyclase
- Mechanism = Activator
- Steps:
- Info:
• Causes actiation of sGC in vascular smooth muscle, leading to smooth muscle relaxation and vasular dilatation
• Preferentially causes dilatation in collateral vessles. This reduces the amount of ischaemic myocardial tissue.
• Used in acute angina
• Must be taken sublingually
78
Pancuronium
- Class = Quaternary ammonium
- Target = nAChR at NMJ
- Mechanism = competitive antagonism
- Steps:
1. Block end-plate potential in response to nerve stimulation
2. Antagonise the effects of directly applied ACh/other agonist
3. Tetanic fade - in presence of drug teatanus in response to high freq. stimulation is not maintained. This is due to block of autoreceptors which give +ve feedback to maintain transmitter release
- Info:
-Charged ∴ not orally active
-Not broken down by plasma esterases
(∴ longer duration of action than atracurium)
- Used in anaesthetics (∵ longer duration)
---Produce muscle relaxation
---Affect fast (white) muscles > slow (red)
(thought to ↓ respiratory depression ∵ respiratory muscles are slow twitch)
-Blocking can be reversed by anticholinesterases
- Target = nAChR at NMJ
- Mechanism = competitive antagonism
- Steps:
1. Block end-plate potential in response to nerve stimulation
2. Antagonise the effects of directly applied ACh/other agonist
3. Tetanic fade - in presence of drug teatanus in response to high freq. stimulation is not maintained. This is due to block of autoreceptors which give +ve feedback to maintain transmitter release
- Info:
-Charged ∴ not orally active
-Not broken down by plasma esterases
(∴ longer duration of action than atracurium)
- Used in anaesthetics (∵ longer duration)
---Produce muscle relaxation
---Affect fast (white) muscles > slow (red)
(thought to ↓ respiratory depression ∵ respiratory muscles are slow twitch)
-Blocking can be reversed by anticholinesterases
79
Phentolamine
- Class = Alpha antagonist
- Target = Non-selective α antagonist
- Mechanism = Non-selective α antagonist
- Steps:
- Info:
Obsolete in hypertensive treatment ∵ cause reflex tachycardia
Can cause reflex hypotension
- Target = Non-selective α antagonist
- Mechanism = Non-selective α antagonist
- Steps:
- Info:
Obsolete in hypertensive treatment ∵ cause reflex tachycardia
Can cause reflex hypotension
80
Phenylephrine
- Class = Adrenoreceptor agonist
- Target = Selective α1 agonist
- Mechanism = Agonist
- Steps:
- Info:
Used to ↑ BP in acute hypotension
- Target = Selective α1 agonist
- Mechanism = Agonist
- Steps:
- Info:
Used to ↑ BP in acute hypotension
81
Pilocarpine
- Class =
- Target = mAChR (non-selective)
- Mechanism = Agonist
- Steps:
- Info:
Used in treatment of glaucoma
Causes contraction of ciliary body ⟶ produces traction on trabecular meshwork ⟶ facilitates aqueous humour drainage ⟶ ↓ intraocular pressure
- Target = mAChR (non-selective)
- Mechanism = Agonist
- Steps:
- Info:
Used in treatment of glaucoma
Causes contraction of ciliary body ⟶ produces traction on trabecular meshwork ⟶ facilitates aqueous humour drainage ⟶ ↓ intraocular pressure
82
Pralidoxime
- Class = -
- Target = acetylcholinesterase (AChE)
- Mechanism = Reverses inhibition of AChE imposed by organophosphates
- Steps:
• Phosphate group on the serine residue (of inhibited enzyme) is transferred to the oxime group of pralidoxime ⟶ relieving inhibition
• This reversal can only occur before the process of 'aging' occurs of the acetycholinesterase-inhibitor complex (occurs after a few hours ⟶ chemical rearrangement meaning that the bond is no longer susceptible to nucleophilic attack)
- Target = acetylcholinesterase (AChE)
- Mechanism = Reverses inhibition of AChE imposed by organophosphates
- Steps:
• Phosphate group on the serine residue (of inhibited enzyme) is transferred to the oxime group of pralidoxime ⟶ relieving inhibition
• This reversal can only occur before the process of 'aging' occurs of the acetycholinesterase-inhibitor complex (occurs after a few hours ⟶ chemical rearrangement meaning that the bond is no longer susceptible to nucleophilic attack)
83
Prazosin
- Class = Alpha antagonist (α1)
- Target = Selective α1 antagonist
- Mechanism = Antagonist
- Steps:
- Info:
Used in hypertension
Can cause postural hypotension
- Target = Selective α1 antagonist
- Mechanism = Antagonist
- Steps:
- Info:
Used in hypertension
Can cause postural hypotension
84
Propranolol
- Class = Non-selective β antagonist
- Target = β1 and β2 antagonist
- Mechanism = Antagonist
- Steps:
- Info:
Was used for hypertension but replaced by β1 selective blockers
- Target = β1 and β2 antagonist
- Mechanism = Antagonist
- Steps:
- Info:
Was used for hypertension but replaced by β1 selective blockers
85
Reserpine
- Class = -
- Target = VMAT2
- Mechanism = Blocks amine binding site on VMAT2
- Steps:
• Blocks amine binding site ⟶ prevention of uptake of NA ⟶ depletion of stored NA (and 5-HT in brain)
• Depletion occurs ∵ there is some leak and MAO in cytoplasm metabolises the neurotransmitters
• Acts on periphery and CNS
• Recovery requires synthesis of new vesicles
- Info:
Use as a hypertensive stopped ∵ lead to profound depression (5-HT depletion)
- Target = VMAT2
- Mechanism = Blocks amine binding site on VMAT2
- Steps:
• Blocks amine binding site ⟶ prevention of uptake of NA ⟶ depletion of stored NA (and 5-HT in brain)
• Depletion occurs ∵ there is some leak and MAO in cytoplasm metabolises the neurotransmitters
• Acts on periphery and CNS
• Recovery requires synthesis of new vesicles
- Info:
Use as a hypertensive stopped ∵ lead to profound depression (5-HT depletion)
86
Salbutamol
- Class = Beta agonist (β2)
- Target = Selective β2 agonist
- Mechanism = Agonist
- Steps:
Effects on β2 ⟶ bronchodilation
- Info:
Used in asthma
- Target = Selective β2 agonist
- Mechanism = Agonist
- Steps:
Effects on β2 ⟶ bronchodilation
- Info:
Used in asthma
87
Selegiline
- Class = MAO inhibitor
- Target = MAO-B
- Mechanism = Inhibitor
- Steps:
- Info:
- used in the treatment of parkinson's disease, since is it MOA-B that is responsible for dopamine metabolism in the substantia nigra
- Target = MAO-B
- Mechanism = Inhibitor
- Steps:
- Info:
- used in the treatment of parkinson's disease, since is it MOA-B that is responsible for dopamine metabolism in the substantia nigra
88
Sildenafil
- Class = PDE inhibitor
- Target = PDE V
- Mechanism = Inhibition
- Steps:
- Info:
• Inhibition of PDE V ⟶ persistence of cGMP in smooth muscle cells ⟶ smooth muscle relaxation, specifically of vascular smooth muscle in the penis
• It is used in treating impotence and can also be used in pulmonary arterial hypertension
- Target = PDE V
- Mechanism = Inhibition
- Steps:
- Info:
• Inhibition of PDE V ⟶ persistence of cGMP in smooth muscle cells ⟶ smooth muscle relaxation, specifically of vascular smooth muscle in the penis
• It is used in treating impotence and can also be used in pulmonary arterial hypertension
89
Suxamethonium
- Class = Depolarising blocking agent
- Target = nAChR at NMJ
- Mechanism = Agonsit but causes depolarising blockage
- Steps:
1. Phase I
Anitcholinesterases ⟶ deepen bloackade ∵ prolonged ACh signal ⟶ enhanced depolarisation ⟶ blockade of transmission at more junctions
Non-depolarising blockers can be used in this phase to reverse blockade
2. Phase II
Anitcholinesterases ⟶ reverse blockade
- Info:
- Only depolarising blocker with clinical use
- Duration of action = short ∴ used for short procedures (e.g. intubation)
- Ester ∴ rapidly broken down by plasma BuChE
- Some people have deficiency of this enzyme ⟶ prolonged action
- Target = nAChR at NMJ
- Mechanism = Agonsit but causes depolarising blockage
- Steps:
1. Phase I
Anitcholinesterases ⟶ deepen bloackade ∵ prolonged ACh signal ⟶ enhanced depolarisation ⟶ blockade of transmission at more junctions
Non-depolarising blockers can be used in this phase to reverse blockade
2. Phase II
Anitcholinesterases ⟶ reverse blockade
- Info:
- Only depolarising blocker with clinical use
- Duration of action = short ∴ used for short procedures (e.g. intubation)
- Ester ∴ rapidly broken down by plasma BuChE
- Some people have deficiency of this enzyme ⟶ prolonged action
90
Tetanus toxin
- Class = Toxin
- Target = Synaptobrevin
- Mechanism = Inhibits neurotransmitter release
- Steps:
Indirectly affects motor neurons
Retrograde transport to cell → disables inhibitory interneuron
Causes motor neuron to be more excitable
- Info:
- Target = Synaptobrevin
- Mechanism = Inhibits neurotransmitter release
- Steps:
Indirectly affects motor neurons
Retrograde transport to cell → disables inhibitory interneuron
Causes motor neuron to be more excitable
- Info:
91
Tranylcypromine
- Class =MAO inhibitor
- Target = MAO-A and MAO-B
- Mechanism = Inhibitor (irreversible)
- Steps:
- Info:
- non-selective MOA inhibitor → preventing the breakdown of adrenaline, noradrenaline, dopamine and histamine
-used in the treatment of refractory depression
- Target = MAO-A and MAO-B
- Mechanism = Inhibitor (irreversible)
- Steps:
- Info:
- non-selective MOA inhibitor → preventing the breakdown of adrenaline, noradrenaline, dopamine and histamine
-used in the treatment of refractory depression
92
Tyramine
- Class = Indirectly acting sympathomimetic amines
- Target = -
- Mechanism = Displaces endogenous NA from vesicles
- Steps:
• Transported to nerve endings and vesicles
• Displaces NA from vesicles
• Some NA escape MAO action and reach extracellular space ⟶ activate adrenoreceptors
- Info:
• Substrate for uptake 1
• Found in food (cheese, red wine, pickled herring, yeast [marmite], soya beans)
• Large ingestion ⟶ large NA release ⟶ widespread vasoconstriction ⟶ HTN
• HTN can be fatal (cheese effect)
Especially likely in people taking MAO inhibitors (MAOI) ⟵ warned about high tyramine foods
Can be converted to octopamine by DBH (octopamine = false transmitter)
- Target = -
- Mechanism = Displaces endogenous NA from vesicles
- Steps:
• Transported to nerve endings and vesicles
• Displaces NA from vesicles
• Some NA escape MAO action and reach extracellular space ⟶ activate adrenoreceptors
- Info:
• Substrate for uptake 1
• Found in food (cheese, red wine, pickled herring, yeast [marmite], soya beans)
• Large ingestion ⟶ large NA release ⟶ widespread vasoconstriction ⟶ HTN
• HTN can be fatal (cheese effect)
Especially likely in people taking MAO inhibitors (MAOI) ⟵ warned about high tyramine foods
Can be converted to octopamine by DBH (octopamine = false transmitter)
93
Xylazine
- Class = -
- Target = Selective α2 agonist
- Mechanism = Agonist
- Steps:
- Info:
Used in vetinary medicine for sedation (effect is on receptors in CNS)
- Target = Selective α2 agonist
- Mechanism = Agonist
- Steps:
- Info:
Used in vetinary medicine for sedation (effect is on receptors in CNS)
