PHARMACOLOGY OF PERIPHERAL NEURAL TRANSMISSION

Question 1

α-latrotoxin

Answer 1

1 - binds neurexins (TM proteins on nerve membrane) and causes massive ACh release via pore formation.
2 - black widow spider venom
3 - can cause respiratory failure.

Question 2

7-nitroindazole (7-NI)

Answer 2

1 - selectively inhibits neuron nNOS. specific to cell type not isoenzyme.
2 - doesnt effect eNOS or iNOS.

Question 3

α-methyl tyrosine

Answer 3

1 - Experimentally used to competitively inhibt TOH which converts tyrsoine to DOPA and is the rate limiting step in NA synthesis.

Question 4

α-methyldopa

Answer 4

1 - subs for NA and acts as a false transitter.
2 - converted to α-methyldopamine and α-methylNA
3 - α-methylNA has lower activity at α1 but higher at α2R.
4 - an antihypertensive due to lower α1 vasoconstriction and high negative feedback on NA release (α2?)

Question 5

Amitriptyline

Answer 5

1 - used as a tricyclic antidepressant, blocks NET (norepinephrine transport protein), blocking NA and 5HT transport.
2 - NET responsible for uptake 1

Question 6

Atenolol

Answer 6

1 - selective β1 adrenoceptor antagonist. 
2 - its selectivity reduces the risk of bronchoconstriction. 
3 - a class 2 antidysrhthmic.
4 - can be used with phenoxybenzamine to block the effects of a large release of catecholamines when a phaeochromocytoma is removed.

Question 7

ATP

Answer 7

1 - a purine
2 - natural agonist of P2XR and P2YR
3 - co-released with ACh from motor neurones
4 - P2X is ligand gated ion channel, P2Y is GPCR. many subtypes of both

Question 8

Atracurium

Answer 8

1 - competitive NACHR antagonist. NMJ block.
2 - quaternary ammonium
3 - causes tetanic fade due to autoreceptor block
4 - an ester so rapidly hydrolysed and hence short action.
5 - used in anaesthesia as a muscle relaxant. white muscle>red muscle so reduced risk of respiratory depression.
6 - reversed by anti-AChE

Question 9

Atropine

Answer 9

1 - MACHR anatagonist nonselective
2 - sympathomimetic effects as it inhibits parasympathetics
3 - tertiary ammonium
4 - from deadly nightshade
5 - mydriasis (dilates pupils)
6 - prolonged action (1 hr ish)

Question 10

Benzilylcholine mustard

Answer 10

1 - irreversible alkylates the MACHR. sympathomimetic.

2 - an ethylamine

Question 11

Bethanechol

Answer 11

1 - an analogue of ACh.
2 - non selective MACHR agonist
3 - poorly absorbed from the GI
4 - occasionally used as a laxative or to stimulate bladder emptying.

Question 12

Botulinium toxins

Answer 12

1 - irreversible antagonist.
2 - preferential to cholinergic neurons.
3 - The light chain has pepsidase activity to cleave the target SNARE.
4 - antitoxin only works within 30 mins of toxin absorption.
5 - Toxin A and E taget SNAP-25. B,D,F and G target synaptobrevin. C1 targets syntaxin and SNAP-25.
6 - somatic muscle weakness and autonomic loss - constipation, blurred vision, dry skin.

Question 13

β-Bungarotoxin

Answer 13

1 - blocks ACh release via phospholipase A2 activity.
2 - localises to the membrane via K channel binding moiety.
3 - common in Krait venoms.

Question 14

Butaxamine

Answer 14

1 - β2 blocker (some β1)

Question 15

Caffeine

Answer 15

1 - A1 (acts via Gi/o) antagonist (hence diuresis via decreased renin?) (also an A2 antagonist)
2 - nonselectively inhibits PDEs so potentiates cAMP signalling and hence rate and force of cardiac contraction along with more disposed to dysrhythmias.
3 - adenosine acts via A1 Rs in the brain to presynaptically inhibits glutamate releasing neurons causing decreased motor activity, respiration, anxiety and to induce sleep. Caffeine inhibits this.
a methylxanthine.
CNS effects due to adenosine antagonism

Question 16

Carbachol

Answer 16

1 - cholinergic agonist, nonselective

2 - quaternary ammonium

Question 17

Carbidopa

Answer 17

1 - inhibits DDC (DOPA decarboxylase)
2 - cant cross BBB so only acts peripherally.
3 - given with DOPA to raise brain DA but reduce peripheral effects
4 - benserazide is similar.

Question 18

Clonidine

Answer 18

1 - α2 (and α1) agonist

2 - antihypertensive but can cause rebound hypertension if a dose is missed. acts via hindbrain receptors

Question 19

Clorgiline

Answer 19

1 - selective MAO-A inhibitor. an antidepressant

Question 20

Cocaine

Answer 20

1 - a NET inhibitor, blocks uptake 1 of catecholamines.

Question 21

D-amphetamine

Answer 21

1 - sympathomimetic amine
2 - weakly inhibits MAO. acts as a weak base so increases pH in vesicles and decreases the pH gradient for neurot uptake.
3 - also inhibits reuptake and is long lasting as it cant be metabolised by MAO. end result is increased NA and DA activity.
4 - ritalin similar effects.
5 - response dependent upon presence of NA in vesicles therefore repeated use causes tolerance.
6 - taken up by uptake 1 NET.

Question 22

Darifenacin

Answer 22

1 - M3 specific MACHR antagonist
2 - inhibits micturition
3 - side effects dry mouth and constipation

Question 23

Decamethonium

Answer 23

1 - NMJ NACHR selective partial agonist, causes depolarisation block.

Question 24

Dipyridamole

Answer 24

1 - inhibits adenosine transporter, thus prevents inactivation.
2 - causes vasodilation and inhibits thrombus formation.

Question 25

Disulfiram

Answer 25

1 - inhibits alcohol dehydrogenase, possibly chelates the catalytic Cu2+. 2 - used to treat alcohol addiction, causes acetaldehyde build up when alcohol is consumed.

Question 26

Dobutamine

Answer 26

1 - analogue of dopamine 2 - β1 agonist. greater ionotroph than chronotroph. 3 - used in acute cardiogenic shock to raise HR and CO 4 - increases HR and O2 demand so arrhythmogenic 5 - can be used to treat heart failure in the absence of hypertension, and improve CO after open heart surgery.

Question 27

D-tubocurarine

Answer 27

1 - NACHR antagonist | 2 - quaternary ammonium compound so not orally active

Question 28

Dyflos (diisopropyl fluorophosphate/DFP)

Answer 28

1 - irreversible AChE inhibitor. phosphorylates the serine at the esteratic site. 2 - long lasting and of little use except in glaucoma. 3 - side effect of convulsions, respiratory distress and demyelination. 4 - an organophosphorus compound

Question 29

Edrophonium

Answer 29

1 - quaternary amine 2 - reversible inhibitor of AChE via electrostatic interaction with its ionic site 3 - short acting. cant enter CNS as charged 4 - used to diagnose myesthenia gravis by causing a temporary increase in muscle tension.

Question 30

Entacapone

Answer 30

1 - COMP inhibitor 2 - prevents methylation of ring hydroxyls in the liver, neuronal and non-neuronal tissues. 3 - blocks uptake 2 activity 4 - used in parkinsonism.

Question 31

Ergotamine

Answer 31

1 - α adrenoceptor and 5HT R partial agonist 2 - used for migranes probs due to 5HT activity. 3 - St Anthony's fire is the intense peripheral α1 vasoconstriction caused when ergot infected cereals are eaten and can cause gangrene.

Question 32

Guanethidine

Answer 32

1 - large doses act as sympathomimetics. 2 - competes with NA for uptake 1 and replaces in vesicles and blocks NA release in response to APs. 3 - an antihypertensive drug that reduces the release of catecholamines, such as NA. 4 - still licensed in the UK for the rapid control of blood pressure in a hypertensive emergency.

Question 33

Hemicholinium

Answer 33

1 - blocks reuptake of choline by high affinity choline transporter at the presynaptic membrane. the rate limiting step of ACh production.

Question 34

Hexamethonium

Answer 34

1 - 1st ganglion blocker to treat hypertension 2 - use dependent block of NACHR 3 - use discontinued due to loss of symp and para - hexamethonium man. 4 - mecamylamine similar

Question 35

Idazoxan

Answer 35

1 - a synthetic yohimbine 2 - both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. 3 - used experimentally.

Question 36

Imipramine

Answer 36

1 - blocks NET | 2 - used as tricyclic antidepressant blocking NA and 5HT reuptake.

Question 37

Isoprenaline

Answer 37

1 - similar to adrenaline but only β not α. | 2 - was used in asthma to relax bronchi but had side effects such as increased HR from β1.

Question 38

Isosorbide dinitrate

Answer 38

1 - an NO donor, metabolised in liver to mononitrate and used as a nitrovasodilator to treat angina..

Question 39

Labetalol

Answer 39

1 - four isomers have different actions. 2 - all 4 isomers together act as antagonists for α1, β1 and β2. 3 - used to treat hypertension in pregnancy

Question 40

L-NIO (N-iminoethyl-L-ornithine)

Answer 40

1 - potent irreversible inhibitor of iNOS in phagosytic cells

Question 41

L-NMMA

Answer 41

1 - an analogue of L-arginine 2 - non-selective inhibitor of all NOS isoforms 3 - D-isomer is inactive

Question 42

Malathion

Answer 42

1 - an organophosphate 2 - irreversible inhibitor of AChE. phosphorylates serine at the esteratic site. 3 - long lasting, little clinical use except as insecticide to kill lice.

Question 43

Mecamylamine

Answer 43

1 - Ganglionic NAChR antagonist. similar to hexamethonium.

Question 44

Methacholine

Answer 44

1 - an ACh analogue 2 - nonselective MAChR agonist 3 - +ve isomer hydrolysed by AChE, neither by BuChE. 4 - +ve isomer around 200 times more potent than -ve at muscarinic Rs.

Question 45

Muscarine

Answer 45

1 - MAChR agonist from fly agaric muschroom

Question 46

Neostigmine

Answer 46

1 - A carbamic acid ester of choline 2 - reversible inhibitor of AChE, carbamoylates the esteratic site. 3 - to treat myasthenia gravis 4 - used IV to reverse NMJ block by raising ACh conc. 5 - given orally to treat myasthenia gravis 6 - the carbamoylated serine hydrolyses much slower than the acetylated serine and thus is inactivated for several minutes.

Question 47

Nicotine

Answer 47

1 - NACHR agonist primarily at ganglion. 2 - prolonged exposure causes phase 1 depolarising block 3 - a tertiary amine

Question 48

Nitroglycerine (glyceryl trinitrate)

Answer 48

1 - Nitrovasodilator. used to treat angina. NO donor

Question 49

Octopamine

Answer 49

?

Question 50

Pancuronium

Answer 50

1 - competitive antagonist of NMJ NAChR 2 - quaternary ammonium 3 - causes tetanic fade due to autoreceptor block 4 - unlike atracurium it isnt hydrolysed and hence acts for longer. 5 - muscle relaxant in anaesthesia. 6 - effect reversed by AChE inhibitor 7 - reduced risk of severe respiratory depression.

Question 51

Phenoxybenzamine

Answer 51

1 - irreversible α blocker. 2 - blocks ENT transporter of uptake 2. also blocks uptake 1 when at 10 times higher concs. 3 - its a 2-chloroethylamine like BCM.

Question 52

Phentolamine

Answer 52

1 - non selective α anatagonist | 2 - largely obsolete as antihypertensive due to reflex tachycardia and postural hypotension.

Question 53

Phenylephrine

Answer 53

1 - selective α1 agonist. used to raise ABP in acute hypotension

Question 54

Pilocarpine

Answer 54

1 - non selective MAChR agonist 2 - poorly absorbed from GI 3 - used to treat glaucome as eyedrops, readily absorbed across conjunctival membrane 4 - contracts ciliary membrane - traction on trabecular meshwork - facilitates aqueous humour drainage - lowers intraocular pressure.

Question 55

Pirenzepine

Answer 55

1 - selective M1 antagonist 2 - M1 coupled to Gq/11, found in peripheral and central neurons. 3 - antisecretory agent for gastroduodenal ulcers, thought to act on intramural nerves serving oxyntic cells.

Question 56

Pralidoxime

Answer 56

1 - can reverse organophosphate inhibition of AChE. 2 - its oxime group is a strong nucleophile, if in close proximity to the phosphorylated serine it'll take the phosphate group. 3 - can only work within the first few hours before the complex undergoes 'ageing' and is no longer susceptible to nucleophilic attack.

Question 57

Prazosin

Answer 57

1 - selective α1 antagonist to treat hypertension 2 - causes postural hypotension 3 - α antagonists used to treat reynaud's phenomenon and reduce the hypertension caused by a phaeochromocytoma.

Question 58

Propranolol

Answer 58

``` 1 - non selective β antagonist. replaced by atenolol. 2 - class 2 antidysrhythmic 3 - non-selective so can cause bronchoconstriction 4 - β1 is linked to Gs causing a rise of cAMP, increases likelihood of opening of L types and T types hence ionotrophic and chronotrophic. ```

Question 59

Reserpine

Answer 59

1 - blocks NA and DA transport into vesicle by tightly binding amine binding site of VMAT-2 (vesicular monoamine transporter). also causes long term NA (and 5HT in brain) depletion as they leak out of vesicles and are metabolised by MAO. 2 - acts in periphery and brain. 3 - used as antihypertensive but discontinued due to profound psychological depression 4 - recovery requires synthesis of new vesicles

Question 60

salbutamol

Answer 60

1 - short acting β2 agonist used to bronchodilate in asthma. 2 - replaced the non selective isoprenaline 3 - Salmeterol is a long-acting β2 agonist prescribed for the treatment of asthma and COPD

Question 61

Selegiline

Answer 61

1 - MAO-B inhibitor. MAO-B metabolises DA so inhibitor used in Parkinson's.

Question 62

Sildenafil

Answer 62

1 - selective inhibitor of PDE5 which selectively breaks down cGMP. PKG activated by cGMP and causes S.M. relaxation inc in vessels. 2 - used to treat impotence.

Question 63

Suxamethonium

Answer 63

1 - NMJ NAChR agonist, causes depolarising block. the only one in clinical use. 2 - v.short duration of action so used for short procedures ie intubation 3 - an ester so rapidly metabolised by plasma BuChE. 4 - 0.1-0.2% of pop has BuChE deficiency causing prolonged action

Question 64

Tetanus toxin

Answer 64

Degrades Synaptobrevin. Retrograde transport up the motor neuron, trasferred to an inhibitory interneuron where it acts, hence causing motoneuron hyperexcitability. prevents NeuroT release.

Question 65

Tranylcypromine

Answer 65

1 - non selective reversible inhibitor of MAO,used to treat refractory depression

Question 66

Trimetaphan

Answer 66

1 - Blocks ganglionic NACHR. | 2 - Competitive antagonist

Question 67

Tyramine

Answer 67

1 - found in many foodstuffs 2 - indirectly acting sympathomimetic amine 3 - displaces NA from vesicles, some metabolised but some reaches adrenoceptors 4 - taken up via NET uptake 1 5 - large ingestion causes NA out, widespread vasoconstriction and ABP rise which can be fatal. the cheese effect. those taking MAOI are vulnerable

Question 68

Vesamicol

Answer 68

1 - inhibits the transport of acetylcholine into synaptic vesicles in cholinergic nerve terminals. non competitive and reversible.

Question 69

Xylazine

Answer 69

1 - more selective version of clonidine | 2 - vet med for sedation via CNS α2

Question 70

Yohimbine

Answer 70

1 - α antagonist. α2 > α1