Adrenergic pharmacology I

Question 1

What is an axon varicosity ?

Answer 1

A type of synapse in which the presynaptic cell releases neurotransmitter at a series of swellings along the axon.

Question 2

What NTs are released at sympathetic varicosities ?

Answer 2

• mostly NA, ATP and sometimes other co-transmitters e.g. NPY
• ACh at sweat glands

Question 3

One major problem in pharmacology was the ability of sympathetic nerves and AD to have excitatory and inhibitory response.
What did R Ahlquist propose in 1848 as a consequence ?

Answer 3

In 1848, Ahlquist proposed the existence of 2 types of receptors alpha and beta-adrenoceptors.

Question 4

What were the first observations on alpha and beta ARs ?

Answer 4

Stimulation of alpha-ARs caused contraction of smooth muscle (except in the gut) :
AD > NA&raquo_space;> Isoprenaline
Stimulation of beta-ARs caused relaxation of smooth muscle :
Isoprenaline > AD&raquo_space;> NA

Question 5

Where are the innervated beta-1, 2 and 3 receptors located ?

What effect do they have upon stimulation ?

Answer 5

Beta-1 = heart (+ve inotropic/chronotropic effect)
Beta-2 = Juxtoglomerular apparatus --> release of renin
Beta-3 = Adipose Tissue Brown --> lypolysis

Question 6

What kinds of beta-ARs are not innervated ?
Where are they located ?
What effect do they have upon stimulation by circulating AD ?

Answer 6

Some beta-2 ARs are not innervated, they all have inhibitory effects :

• bronchial smooth muscle (treatment of asthma)
• uterine smooth muscle (treatment of premature labour)
• skeletal muscle vasculature

Question 7

Give an example of a beta-2 AR agonist.

Answer 7

Salbutamol.

Question 8

What are the metabolic effects of AR activation ?

Answer 8

• mainly beta-2 activation AC
• in the liver –> glycogenolysis
• in muscle –> glycogen converted to lactic acid, can cause hyper-lactic acidaemia + activation of Na+/K+ ATP ase –> hypokalaemia (decrease in blood K+)
• in the liver, alpha-1 –> release of K+ (hyperkalaemia)
• in the pancreas, alpha 2 –> insulin release
• in adipocyte, beta-3 –> lipolysis, release of FFA (Free Fatty Acids)

Question 9

How are alpha-ARs sub-divided ?

Answer 9

α1 - post-junctional/synaptic (heteroreceptor)
α2 - pre-junctional/synaptic (autoreceptors) –> -ve feedback, but can also be post-junctional and cause platelet aggregation

Question 10

For which ARs are AD, NA and isoprenaline selective for ?

Answer 10

AD is selective for α1, α2, β1, β2
NA is selective for α1, α2, β1
Isoprenaline is selective for β1, β2

Question 11

How are alpha-2 agonists used clinically ?

Give an example.

Answer 11

α1-ARs agonists e.g. phenylephrine are used as nasal decongestants

Question 12

What are the effects of AD given i.v. or i.m. ?

Answer 12

BP - effect depends on dose
Skeletal Muscle - tremor
Uterine smooth muscle - relax
Mast Cell - “stabilisation”
Bronchial smooth muscle - relax
CNS effects - (foreboding)

Question 13

What are the clinical used of AD ?

Answer 13

• Anaphylactic shock “physiological antagonism”
• Glaucoma
• Cardiac arrest (Cardiopulmonary resuscitation)
• Prolongation of the action of local anaesthetics (vasoconstriction)
• Acute anaphylactic reactions (e.g. to a bee sting)
• Laryngeal oedema, bronchospasm and hypotension systemic release of histamine

Question 14

Why can AD be used t treat laryngeal oedema ?

What kind of antagonism is this an example of ?

Answer 14

i.m. of adrenaline = vasoconstriction caused by α1-AR stimulation –> reduces laryngeal oedema + increases BP ; + bronchodilatation caused by beta2-AR stimulation
This is an example of physiological antagonism i.e. the effects of the bee sting are prevented not by blocking the receptors mediating these effects but by the drug acting on different receptors which have opposite effect.

Question 15

What is dipivefrine ?

What is it used for ?

Answer 15

Dipivefrine = esterification of AD and pivalic acid - more lipid solube (allows AD to be used as a pro-drug)
This can be used to treat “simple” open angle (the filtration angle formed between the iris and the cornea) glaucoma when the intra-ocular pressure in above 21 mmHg.

Question 16

Why id dipivefrine useful for the treatment of glaucoma ?

Answer 16

Dipivefrine (AD + pivalic acid) :
- binds alpha-2 ARs, causes vasoconstriction of afferent arterioles, which diminishes aqueous humour production
- α2-ARs on the veins that drain the canal of Schlemm
facilate absorption of aqueous humour

Question 17

When is dipivevrine contra-indicated ?

Answer 17

In closed angle because of mydriatic action (dilation)

• radial muscle on the iris is contracted .
• NB circular muscle is cholinergic

Question 18

What is brimonidine and what is it used for ?

Answer 18

Brimonidine is an α2 adrenergic agonist and is used in open-angle glaucoma.
α2 agonists, through the activation of a G protein-coupled receptor, inhibit the activity of adenylate cyclase. This reduces cAMP and hence aqueous humour production by the ciliary body.

Question 19

Name a beta-1 sympathomimetic.

What is its clinical use.

Answer 19

Dobutamine = inotrope, used for treatment of heart failure and cardiogenic shock

Question 20

Name a beta-2 sympathomimetic.

What is its clinical use.

Answer 20

Salbutamol –> used to treat asthma and premature labour

Question 21

Name a beta-3 sympathomimetic.

What is its clinical use.

Answer 21

Mirabegron –> used to treat oevractive bladders

Question 22

What are the unwanted effects of beta-2 agonists ?

Answer 22

Hypokalaemia, tremor, preipheral vasodilation and reflex tachycardia.

Question 23

Name 3 indirect acting sympathomimetics.

How do these amines work ?

Answer 23

Tyramine, ephedrine and amphetamine.

1) Have only weak actions on ARs
2) Resemble noradrenaline so they are transported into nerve terminals by NET (NE Transporter)
3) Inside the nerve terminals, they are taken up into the vesicles by the vesicular monoamine transporter (VMAT), in exchange for NA, which escapes into the cytosol
4) Some of the cytosolic NA is degraded by MAO, while the rest escapes via NET, in exchange for the foreign monoamine, to act on postsynaptic receptors, i.e it is pumped out
5) Exocytosis is not involved in the release process, so their actions do not require the presence of Ca2+

Question 24

What is phentolamine ?

Answer 24

A non-selective alpha-adrenergic antagonist.

Question 25

What is AD reversal ?

Answer 25

AD reversal is the fall in blood pressure produced by AD when given following blockage of α-adrenergic receptors by an appropriate drug such as phantolamine or phenoxybenzamine. The vasodilation reflects the ability of AD to activate β-adrenergic receptors that, in vascular smooth muscle, are inhibitory. In the absence of α-receptor blockade, the β-receptor activation by AD is masked by its predominant action on vascular α-receptors, which causes vasoconstriction.