block 2- 4. Adrenergic autonomic drugs

all made from ai didn't double check it.

Q: Which receptors are present at the different points in the simplified ANS? (diagram on slide 3)

A: N1; N2 and muscarinic receptors; N2, α and β adrenoceptors.

Q: Why were physiologists puzzled by sympathetic nerve stimulation?

A: It could produce both excitatory and inhibitory effects.

Q: What did Cannon and Rosenblueth postulate in the 1940s?

A: Two adrenergic mediator substances, sympathin E and sympathin I, accounting for inhibitory and excitatory effects.

Q: What did Ahlquist investigate?

A: The effects of catecholamines on blood vessels, uterus, pupillary muscle and GI muscle.

Q: What was the potency order for vasoconstrictor responses?

A: Adrenaline had the greatest potency and isoproterenol the least.

Q: What was the potency order for vasodilation and cardiac stimulation?

A: Isoproterenol was most potent and adrenaline least.

Q: What did Ahlquist propose?

A: The existence of α and β adrenoceptors and only one sympathetic adrenergic mediator.

Q: What was the significance of Ahlquist's discovery?

A: It provided the basis for developing drugs as antagonists of these receptors.

Q: What do NA, Adr and Iso stand for?

A: NA = noradrenaline; Adr = adrenaline; Iso = isoprenaline.

Q: What is isoprenaline?

A: A nonselective β agonist.

Q: Who identified noradrenaline as the sympathetic neurotransmitter, and when?

A: U. von Euler, in 1946.

Q: What did Ahlquist's 1948 study identify? (diagram on slide 6)

A: α and β adrenoceptors, based on differences in catecholamine potency.

Q: What observation did Irwin Slater make in 1957?

A: Adrenaline could not relax tracheal strips in the presence of dichloroisoprenaline (DCI).

Q: What was Sir James Black trying to develop?

A: A drug similar to DCI but without intrinsic activity.

Q: What therapeutic potential did Black identify?

A: Protecting the heart from adrenaline release during stress or emotion.

Q: What was the first beta blocker developed by Black?

A: Pronethalol, produced in 1960.

Q: Why was pronethalol replaced?

A: Because of side effects in patients and animals.

Q: When did James Black receive the Nobel Prize, and for what?

A: 1988, for developing beta blockers and anti-ulcer drugs.

Q: Which adrenergic receptor subtypes have drugs used therapeutically?

A: α1, β1 and β2 receptors.

Q: Which additional adrenergic receptor subtypes are considered?

A: α2 and β3 receptors.

Q: Where are β3 adrenoceptors found, and what do they do? (diagram on slide 10)

A: In adipose tissue, they trigger lipolysis to generate heat (thermogenesis).

Q: What do β3 adrenoceptors do in the bladder?

A: Relax bladder muscle, allowing greater filling and reducing the urge to urinate.

Q: What effect can β3 adrenoceptors have in the heart and blood vessels?

A: Help counteract overactive sympathetic stimulation.

Q: Why is β3 sometimes called the atypical β-adrenoceptor?

A: It is not blocked by drugs like propranolol.

Q: Which β3 agonist is used for overactive bladder syndrome?

A: Mirabegron.

Q: What other potential uses may β3 agonists have?

A: Weight loss and diabetes.

Q: How can α2 adrenoceptors modulate neurotransmitter release?

A: Through a negative feedback inhibitory mechanism that modulates noradrenaline release.

Q: What happens when α2 receptors are blocked during exercise?

A: Noradrenaline release increases, augmenting β-adrenergic effects on heart rate and contractility.

Q: Which drugs are mentioned as α2 receptor blockers?

A: Phentolamine and yohimbine.

Q: How does clonidine work?

A: Centrally in the brain stem to modulate autonomic output.

Q: What organs does clonidine affect?

A: Blood vessels and the heart.

Q: What important adverse effect can clonidine cause?

A: Rebound hypertension.

Q: What other conditions can clonidine be used for?

A: Migraine and menopausal hot flushes.

Q: What happens to urinary noradrenaline and plasma renin activity with clonidine?

A: Urinary noradrenaline increases, but plasma renin activity does not change.

Q: Why can drugs targeting ANS activity have multiple therapeutic uses?

A: The ANS has neuronal projections to many organs.

Q: Which ANS targets can drugs act on?

A: Adrenoceptors, nicotinic cholinoceptors, muscarinic subtypes, and neurotransmitter release or reuptake.

Q: Which topic is covered in another lecture?

A: Drugs affecting the neuromuscular junction (NMJ) of the somatic nervous system.

Q: Which topic is covered by Dr Moult?

A: Drugs targeting cholinoceptors.

Q: What does the remainder of this lecture focus on?

A: Adrenergic receptors and neurotransmitter synthesis and release, particularly in the eye and bladder.

Q: Where does noradrenaline synthesis begin, and where is NA stored? (diagram on slide 15)

A: Synthesis begins in the cytoplasm of the presynaptic nerve terminal; NA is stored in vesicles.

Q: How does tyrosine enter the axon?

A: It is transported from the bloodstream.

Q: Which enzyme converts tyrosine into L-DOPA?

A: Tyrosine hydroxylase (TH).

Q: What is the rate-limiting step in noradrenaline synthesis?

A: Conversion of tyrosine into L-DOPA by tyrosine hydroxylase.

Q: Which enzyme converts L-DOPA into dopamine?

A: Aromatic L-amino acid decarboxylase (DOPA decarboxylase).

Q: What does VMAT do?

A: Moves dopamine into the vesicle.

Q: Which enzyme converts dopamine into noradrenaline?

A: Dopamine β-hydroxylase (DBH).

Q: How does metyrosine affect noradrenaline synthesis?

A: Blocks TH, preventing tyrosine conversion to L-DOPA and reducing NA synthesis.

Q: What is metyrosine sometimes used to treat?

A: Phaeochromocytoma (adrenal gland tumours).

Q: How does reserpine affect noradrenaline storage?

A: Blocks VMAT, preventing NA storage in vesicles and reducing its release when stimulated.

Q: What were the serious side effects of reserpine?

A: Nasal congestion, drowsiness and serious depression.

Q: How do benserazide and carbidopa work?

A: They inhibit peripheral DOPA decarboxylase, blocking dopamine production in peripheral neurones and blood.

Q: Why are benserazide and carbidopa used in Parkinson's disease?

A: To lower the dose of L-DOPA needed.

Q: What proportion of released NA is removed by neuronal uptake (Uptake 1)?

A: About 90%.

Q: Which transporter carries out Uptake 1?

A: The noradrenaline transporter (NET), moving NA against a concentration gradient.

Q: What is Uptake 2?

A: Extraneuronal uptake, accounting for about 5%, into surrounding postjunctional or non-neuronal tissues.

Q: What happens to the remainder of released NA?

A: It diffuses into capillaries and is removed into the systemic circulation.

Q: Which two enzymes metabolise NA?

A: Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

Q: Where is MAO found, and what does it produce from NA?

A: On the mitochondrial membrane; it metabolises cytoplasmic NA into DHPG.

Q: Where is COMT found, and what does it produce from NA?

A: Outside the neuron and in the liver; it methylates NA to produce normetanephrine.

Q: Which further metabolites are excreted in urine?

A: Vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG).

Q: What conditions are many drugs affecting NA reuptake or inactivation used for?

A: CNS conditions, including depression.

Q: Which MAO inhibitors are mentioned for depression?

A: Phenelzine and iproniazid.

Q: What dietary interaction is associated with MAO inhibitors?

A: Potential interactions with foods containing tyramine.

Q: What question does the lecture raise about excessive NA release?

A: Why is there too much NA release?

Q: Why can reserpine cause nasal congestion?

A: Reduced NA in nerves indirectly dilates blood vessels in the nose.

Q: How can nasal congestion be relieved using sympathomimetic drugs?

A: By constricting nasal blood vessels.

Q: Which drugs are used for nasal congestion?

A: Pseudoephedrine, phenylephrine, oxymetazoline and xylometazoline.

Q: How do these decongestants act?

A: Some are α agonists, while others act indirectly.

Q: How does menthol act as a decongestant?

A: Through a cooling action on the TRPM8 channel and a local anaesthetic action.

Q: What problems are associated with cocaine as a decongestant?

A: Nasal septal and palate ischaemia, coronary constriction and pro-arrhythmic effects.

Q: What is mydriasis?

A: Dilatation of the pupil.

Q: How do sympathomimetics cause mydriasis?

A: α1 receptor stimulation contracts the iris dilator muscle; phenylephrine has a quick onset.

Q: How do antimuscarinics cause mydriasis?

A: They relax the iris sphincter muscle and paralyse focusing muscles.

Q: Which antimuscarinics are used to cause mydriasis?

A: Tropicamide and cyclopentolate.

Q: Where does atropine come from?

A: Atropa belladonna (Deadly Nightshade).

Q: What were the historical cosmetic uses of belladonna?

A: Women applied belladonna berry juice to the eyes to enlarge their pupils.

Q: What visual side effects can atropine cause?

A: Blurred near vision and extreme light sensitivity (photophobia); effects can be long-lasting.

Q: What systemic side effects can atropine cause?

A: Rapid heart rate, dry mouth, hallucinations and occasionally death.

Q: What is glaucoma?

A: A build-up of excess pressure within the eyes.

Q: What proportion of glaucoma cases are primary open-angle glaucoma (POAG)?

A: About 90%.

Q: What happens in POAG?

A: Drainage remains open, but channels become progressively blocked; symptoms develop slowly and painlessly.

Q: What causes angle-closure glaucoma?

A: The iris physically blocks the drainage channel.

Q: What are the symptoms of acute angle-closure glaucoma?

A: Sudden pain, headache, blurred vision and nausea.

Q: How does chronic angle-closure glaucoma develop?

A: The angle closes gradually over time, with no early warning signs.

Q: What may cause normal-tension glaucoma?

A: Unknown causes, possibly optic nerve sensitivity or poor blood flow.

Q: How can ANS dysfunction affect glaucoma?

A: It can cause faster development of glaucoma.

Q: What is the sympathetic input to the eye? (diagram on slide 24)

A: Via the superior cervical ganglion; noradrenaline and NPY control vasoconstriction of the choroid and optic nerve head.

Q: How does sympathetic input dilate the pupil?

A: Noradrenaline acts on α1 receptors on the dilator pupillae.

Q: What is the parasympathetic input to the eye?

A: Via the ciliary and pterygopalatine ganglia.

Q: What does ACh acting on muscarinic receptors control in the eye?

A: Accommodation and pupil constriction; it also causes vasodilation in the ocular microcirculation.

Q: What is the objective of glaucoma treatment?

A: Lower intraocular pressure (IOP) by reducing aqueous humour production or increasing its outflow.

Q: How do beta blockers treat glaucoma?

A: Timolol and betaxolol slow aqueous fluid production in the eye.

Q: How do α2 agonists treat glaucoma?

A: Brimonidine and apraclonidine reduce fluid production and improve drainage.

Q: How do muscarinic agonists treat glaucoma?

A: Pilocarpine constricts the pupil, opening drainage pathways and increasing outflow.

Q: Why is pilocarpine not first-line treatment?

A: Miosis is poorly tolerated.

Q: What other drug groups are used to treat glaucoma?

A: Prostaglandin analogues and carbonic anhydrase inhibitors.

Q: How can α1 blockers be used to treat hypertension?

A: They block α1 adrenoceptors on blood vessels.

Q: How do doxazosin and prazosin differ in dosing?

A: Doxazosin is long-acting and taken once daily; prazosin requires 2–3 doses per day.

Q: Why are α1 blockers not used first-line for hypertension?

A: Postural hypotension and reflex tachycardia.

Q: How can α1 blockers treat benign prostatic hyperplasia (BPH)?

A: They widen the urethral lumen, reducing obstruction and improving peak urinary flow rates.