Adrenergic pharmacology II

Question 1

What are ergot alkaloids ?

Answer 1

he ergot alkaloids are mycotoxins produced by several species of parasitic fungi in the genus Claviceps that grow on rye and other grains. There are four main groups of ergot alkaloids: the clavines, the lysergic acids, the lysergic acid amides, and the ergopeptides.

Question 2

AT which receptors do ergot alkaloids act ?

Answer 2

Alpha-ARs, 5-HT Rs, DA Rs.

Ergot alkaloids also have “oxytocin-like” action.

Question 3

Different preparations of ergot alkaloids exits, such as ergotamine, ergometrine and “hydergine”.
What are these different preperations used for ?

Answer 3

Ergotamine –> migraine in acute attack
Ergometrine –> postpartum/postnatal haemorrhage
“Hydergine” –> cerebral vasodilator; Dementia … ?

Question 4

Some ergot alkaloids have no alpha-adrenoreceptor actions.

Give 3 examples of such coumpounds.

Answer 4

1) Lysergic acid diethylamide (LSD)
2) Methysergide = 5-HT receptor antagonist/agonist (an antagonist at the 5-HT2C receptor and a 5-HT1A partial agonist) –> treatment of migraine
3) Bromocriptine = DA receptor agonist (D2) –> treatment of galactorrhea & parkinsonism

Question 5

What is phenoxybenzamine (beta-haloalkylamine) ?

Answer 5

A non-selective, non-competitive (and thus irreversible) alpha adrenergic blocker.

Question 6

Can beta-AR antagonists be partial agonists ?

Support your answer with 2 examples.

Answer 6

Some adrenergic antagonists have Intrinsic Sympathomimetic Activity (ISA).
Pindolol is a non-selective beta blocker w/ partial agonist activity and also possesses ISA. This means that pindolol, particularly in high doses, exerts effects like AD or isoprenaline (increased pulse rate, increased blood pressure, bronchodilation), but these effects are limited.
Similarly, oxprenolol is a non-selective beta blocker with some intrinsic sympathomimetic activity. It is used for the treatment of angina pectoris, abnormal heart rhythms and high blood pressure.

Question 7

What are the similarities and differences between phenoxybenzamine and phentolamine ?

Answer 7

Both are non selective alpha blockers.
Phenoxybenzamine = long acting
Phentolamine = i.v. short acting

Question 8

Prazosin and doxazosin and adrenegric antagonists selective for :

• alpha-1
• alpha-2
• beta-1
• beta-2
• beta-3

Answer 8

Alpha-1 ARs.

Question 9

What are the physiological consequence of alpha-AR blockade ?

Answer 9

• fall in BP
• postural hypotension
• nasal stufiness
• failure of ejaculation
• miosis (constriction of the pupil - weak effects)

Question 10

How does the human body respond to a fall in BP ?

Answer 10

• reflex tachycardia

- sodium + water retention (renin)

Question 11

What is the function of renin in the renin-angiotensin aldosterone system (RAAS) ?

Answer 11

Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure. Renin’s primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.

Question 12

What is hexamethonium and how does it work ?

Answer 12

Hexamethonium is a non-depolarising ganglionic blocker, a nAChR antagonist that acts in autonomic ganglia by binding mostly in or on the receptor, and not the ACh binding site itself.

Question 13

How are alpha-AR blockers used therapeutically ?

Answer 13

Hypertension (phaeochromocytoma), benign prostatic hyperplasia (BPH)

Question 14

Name a beta-AR antagonist for each of the following properties :

• Cardio-selective beta-1
• Non-selective
• ISA
• Local anaesthetic action
• alpha-AR antagonist properties

Answer 14

• Cardio-selective beta-1 = atenolol
• Non-selective = propranolol
• ISA = pindolol
• Local anaesthetic action = sotalol
• alpha-AR antagonist properties = carvedilol, labetatol

Question 15

What are the therapeutic uses of beta-blockers ?

Answer 15

Angina, Hypertension, Glaucoma, Myocardial infarction,

Arrhythmias, Thyrotoxicosis, Congestive Heart failure, Anxiety, prophylaxis of migraine

Question 16

What are the contra-indications against the use of beta-blockers ?

Answer 16

Asthma, AV (Atrioventricular) block, severe peripheral vascular disease, diabetes … ?

Question 17

What are some of the unwanted effects of beta-blockers ?

Answer 17

Fatigue, bradycardia, cold extremities, breathlessness, sleep disturbance + nightmares.

Question 18

What are the different sites at which drugs may interfere
with the release of sympathetic transmission ?
Give examples for each specific site you mention.

Answer 18

Ganglia = Hexamethoniumganglion --> blockers/nicotinic antagonists
Synthesis = Disulfiram --> DA beta-hydroxylase
Storage = Reserpine --> depletes vesicular storage
Release = Guanethidine --> adrenergic neuron blocking drug + Clonidine = pre-junctional alpha-2 ARs
Uptake = Desmethylimipramine --> neuronal uptake  uptake 1
Metabolism = Phenelzine --> MAO-inhibitor

Question 19

What are the different steps for the biosynthesis of NA ?

Answer 19

1. L-Phenylalanine –> L-Tyrosine by PH (oustide the cell)
2. L-Tyrosine –> L-Dopa by TH w/ tetrahydrobiopterin (=rate limiting step, happens in the cell) inhibited by alpha-methyltyrosine (metirosine), then converted to alpha-methyldopa and then to alpha-methylINA
3. L-Dopa –> DA by L-Dopa D w/ pyridoxal phosphate
4. DA –> NA bu DA beta-H w/ acrobic acid (inside the vesicle), inhibited by disulfiram

Question 20

How does reserpine work ?

How can its effects be reversed ?

Answer 20

Reserpine irreversibly blocks the VMAT. Unprotected NTs are metabolized by MAO (as well as by COMT) in the cytoplasm and consequently never excite the post-synaptic cell. Thus, reserpine not only decreases metabolic rate of monoamine NTs but also decreases magnitude of monoamine release.
Effects can be reversed by MAO-I.

Question 21

How does guanethidine (Gu) work ?

Answer 21

Guanethidine is transported by uptake into the presynaptic terminal transported by NET. (In this it competes with NA so can potentiate exogenously applied NA.) It becomes concentrated in norepinephrine transmitter vesicles, replacing norepinephrine in these vesicles. This leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the release of norepinephrine in response to arrival of an action potential. Spontaneous release is not affected.

Question 22

How does clonidine work ?

Answer 22

Clonidine works by stimulating α2 receptors in the brain, which decreases peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels, thus inhibiting the release of NA. The net effect is a decrease in sympathetic tone.

Question 23

How does tricyclic antidepressants (TCAs) work ?

Answer 23

The majority of the TCAs act on NET, which results in an elevation of the synaptic concentrations of NA/AD.

Question 24

How does entacapone work ?

Answer 24

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT eliminates biologically active catechols present in catecholamines (DA, NA and AD) and their hydroxylated metabolites.