tutorial questions

Question 1

autonomic nervous system: name the neurotransmitter: released from synaptic nerve terminal and activates adrenoceptors:

Answer 1

noradrenaline

Question 2

autonomic nervous system: name the neurotransmitter: released from parasympathetic nerve terminals and activates muscarinic receptors:

Answer 2

acetylcholine

Question 3

autonomic nervous system: name the neurotransmitter: released from pre-ganglionic receptors and activates nicotinic receptors:

Answer 3

acetylcholine

Question 4

autonomic nervous system: name the neurotransmitter: is a substrate for SLC6A2:

Answer 4

noradrenaline

Question 5

autonomic nervous system: name the neurotransmitter: synthesized from dopamine by dopamine beta-hydroxylase

Answer 5

noradrenaline -> adrenaline

Question 6

2 Which answer is correct?

a – Choline is acetylated by acetylcholinesterase in parasympathetic nerve terminals to produce
acetylcholine

b – The effect of released choline is terminated by acetylcholinesterase

c – Free choline within parasympathetic nerve terminals is acetylated by choline acetyltransferase which transfers the acetyl group from acetyl coenzyme A

d – The effect of released acetylcholine is terminated by choline acetyltransferase

e – Free acetate within parasympathetic nerve terminals is acetylated by acetate acetyltransferase to produce acetylacetylcholine

Answer 6

C

Question 7

3 Botulinum toxin

a – facilitates acetylcholine release from sympathetic nerve terminals

b – causes progressive sympathetic nerve ‘paralysis

c – facilitates acetylcholine release from parasympathetic nerve terminals

d – prevents exocytosis of acetylchloline from storage vesicles

e – is indicated for management of underactive bladder syndrome

Answer 7

D

Question 8

4 Anticholinesterase drugs:-

a – inhibit acetylcholine release from cholinergic neurons

b – metabolize acetylcholine to choline and acetate

c – increase synaptic acetylcholine levels

d – are indicated for bradycardia

e – prevent acetylcholine uptake into parasympathetic nerves

Answer 8

C

Question 9

5 Hexamethonium:-
a – is a nicotinic receptor agonist
b – is an adrenoceptor antagonist
c – is an irreversible nicotinic receptor antagonist
d – causes hypotension and loss of cardiovascular reflexes
e – activates muscarinic receptors

Answer 9

D

Question 10

6 Nicotinic receptors:-

a – are activated by noradrenaline on sympathetic ganglia

b – are activated by acetycholine released from pre-ganglionic nerves

c – are blocked by nicotine released from post-ganglionic parasympathetic nerves

d – are blocked by propranolol

e – are activated by nicotine released form pre- ganglionic parasympathetic nerves

Answer 10

B

Question 11

16. Describe pharmacological properties of clonidine and effects on blood pressure.

Answer 11

Clonidine is a prototype of centrally acting antihypertensive drugs, originally synthesized in an attempt to produce a nasal decongestant. Effective in treating moderate to severe forms of hypertension. They produce centrally mediated reductions in blood pressure. Their mechanisms include reducing the release of sympathetic transmitter (noradrenaline) to decrease vascular resistance, heart rate and force of contraction.

Question 12

17. which are the main effects of the parasympathetic nervous system.

Answer 12

Along with sympathetic nervous system, they provide a link between peripheral organs and the central nervous system. Parasympathetic nerves consist of cranial and sacral sections of the spinal cord, with long pre-ganglionic nerves. In parasympathetic nerves, acetylcholine activates muscarinic receptors.

Parasympathetic nervous system is related to “rest and digest”, which have effects such as decreasing heart rate and force of atrial and ventricular contraction, relaxation of blood vessels and contraction (smooth muscle dependent), and also associated with lower blood pressure. Additionally, increased peristaltic activity in the gastrointestinal tract and bronchial constriction. Increased glandular secretions and acid release. Constriction of pupil and decrease in IOP.

Question 13

19. explain the effects of muscarinic receptor agonists on the constrictor pupillae muscle and ciliary body.

Answer 13

Muscarinic receptor agonists have many effects on the eye. Relating to the constrictor pupillae muscle, it constricts the pupil and adjusts for light, whilst lowering IOP through facilitation of aqueous humour flow into canal of Schlemm (for glaucoma patients). It also induces ciliary body contraction, decreasing tension on suspensory ligament of the lens. This results in increased accommodation (lens bulges more) and decrease in focal length. Focus near objects.

Question 14

20. What are the main effects of muscarinic receptor antagonists.

Answer 14

Increased in heart rate and decrease in motility and acid release in gastrointestinal tract smooth muscles. On other smooth muscles, relaxation of bronchial, biliary and urinary tract smooth muscle. Decrease in secretions, such as salivary, lacrimal, bronchial and sweat glands, resulting in dry mouth and skin.

Question 15

21. explain the effects of muscarinic receptor antagonists on the constrictor pupillae muscle and ciliary body.

Answer 15

Effects on the eye: constrictor pupillae muscle. Dilates pupil and adjusts for light (darkness), lose ability to respond to light. Increased intraocular pressure for glaucoma patients through restricting aqueous flow into canal of Schlemm. With the ciliary body, causes relaxation which increases tension on suspensory ligaments of the lens. Resulting in less accommodation as lens becomes flatter. Increase in focal length, focus on far away objects.

Question 16

22. What are the indications (what are drugs used to treat) of muscarinic receptor antagonists?

Answer 16

Peripheral indications include: bradyarrhythmia (atropine). Homatropine is used as eye drops for mydriasis and cycloplegia. Ipratropium is used for asthma, COPD, and rhinitis. Hyoscine used for motion sickness. Hyoscine N-butylbromide for GIT spasm, renal and biliary spasm. Aid in GIT radiology or endoscopy and IBS.

Question 17

23. compare and contrast muscarinic orthosteric and allosteric binding sites. Include in your answer ‘selectivity’ with reference to affinity.

Answer 17

Orthosteric: conventional muscarinic receptor ligands bind to orthosteric receptor site. Found on the primary, classical binding site on muscarinic receptor. Ligands binding directly influence receptor activity. Affinity at this site determines the selectivity of a ligand for specific receptor subtype. Drugs with high affinity for the site will selectively bind to and activate specific muscarinic receptor subtypes. Ligands which bind to orthosteric site often show high selectivity for specific subtype of the receptor.

Allosteric: newer compound can bind to allosteric, or both orthosteric and allosteric binding sites simultaneously (bitopic ligands). Promote conformational changes in the receptor than alters properties of ligand bound to classical orthosteric site. Three types: positive allosteric modulators PAM, negative allosteric modulators NAM, neutral allosteric ligands NAL. Allosteric ligands may or may not exhibit the same level of subtype selectivity as orthosteric ligands. But allosteric modulators provide more selective muscarinic ligands than those currently available –> fewer side effects.

Question 18

Explain the mechanism of G-protein-receptor coupling. Use the beta2-adrenoceptor as an example. Include in you answer adrenaline, G-protein, alpha, beta, γ subunits, GDP, GTP, adenylate cyclase, GTPase.

Answer 18

When adrenaline binds to the β2-adrenoceptor, a conformational change occurs, activating the receptor and facilitating its interaction with the G-protein. This G-protein consists of three subunits: α, β, and γ. Upon binding, the G-protein undergoes GDP-GTP exchange with the alpha subunit, leading to the dissociation of the Gsα subunit from the βγ subunits. The freed Gsα subunit activates adenylate cyclase, located on the inner cell membrane, promoting the conversion of ATP to cyclic AMP (cAMP).
Acting as a second messenger, cAMP activates protein kinase A (PKA) by releasing its catalytic subunits. PKA then phosphorylates target proteins, eliciting specific cellular responses such as bronchodilation or increased heart rate and contractility. The signal is terminated by GTP hydrolysis on the Gsα subunit, facilitated by its intrinsic GTPase activity. The inactive Gsα-GDP complex reassociates with the βγ subunits, ready for another activation cycle. This G-protein-coupled receptor (GPCR) signalling pathway efficiently transduces extracellular signals to intracellular responses, allowing cells to respond appropriately to diverse stimuli.
(Notes: g alpha subunit is associated with GDP in its inactive state. Ligand binding causes conformational change in GPCR, promoting exchange GDP to GTP, allowing the G alpha subunit to dissociate from the beta-gamma subunits).

Question 19

Describe the main effects of ET-1 on vascular smooth muscle

Answer 19

Endothelin-1 (ET-1) has significant effects on vascular smooth muscle. It primarily acts as a potent vasoconstrictor, leading to the narrowing of blood vessels. The vasoconstrictive effects are mediated through the activation of endothelin receptors, particularly the ETA receptors located on vascular smooth muscle cells. This activation triggers intracellular signalling pathways, resulting in an increase in intracellular calcium and the activation of contractile elements, ultimately causing smooth muscle contraction and vasoconstriction. Additionally, the dysregulation of ET-1 levels is associated with conditions like pulmonary artery hypertension and heart failure, where elevated ET-1 levels contribute to abnormal vascular tone and function. The ETA receptors, along with ETB receptors, play a role in maintaining vascular tone, and their distribution on both smooth muscle cells and endothelial cells highlights the complexity of the endothelin system in regulating vascular physiology.
It should be noted that with ETB in endothelial cells, ET-1 induces smooth muscle relaxation and vasodilation, with the release of NO and PGI2 by ETB.

Question 20

Write notes about ET. Include the three classifications.

Answer 20

The pharmacology guide on endothelin (ET) explains the discovery and classification of three peptidic vasoconstrictors: ET-1, ET-2, and ET-3.
ET-1, acting as a paracrine mediator, shows elevated plasma levels in conditions like pulmonary artery hypertension and heart failure. ET-1 is a potent vasoconstrictor. The receptors, ETA and ETB, present in the human heart, regulate vascular tone. ETA and ETB on smooth muscle (with ET-1) induces vasoconstriction, , while ETB, when located on endothelial cells, releases nitric oxide (NO) and prostacyclin (PGI2), causing smooth muscle relaxation, vasodilation. Both receptors can couple to G proteins, with ETA coupling to Gq and ETB to both Gq and Gi.
ETA less potent to ET-3, while ETB all equipotent (ET-1,2,3)
The antagonist Bosentan blocks ET-1 effects at both receptor types and is used to manage pulmonary artery hypertension, improving exercise endurance and patient survival. The endothelin system is vital for vascular homeostasis, and its dysregulation is linked to various cardiovascular conditions.