Chemical Mediators NA 2

Question 1

What is Nonadrenaline (NA)

Answer 1

Is a cathecolamine
Is the main neurotransmitter in the sympathetic nervous system
Found both in the periphery and CNS
Is released from varicosities on adrenergic neurones.
Is also released by the adrenal medulla along with adrenaline (Ad).
NA and Ad both act on adrenoceptors and mediate a wide range of effects.

Question 2

What is catecholamines?

Answer 2

Catecholamines are compounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side-chain.
Pharmacologically, the most important ones are:
Noradrenaline (norepinephrine), a transmitter released by sympathetic nerve terminals
Adrenaline (epinephrine), a hormone secreted by the adrenal medulla
Dopamine, the metabolic precursor of noradrenaline and adrenaline, also a transmitter/neuromodulator in the central nervous system
Isoproterenol (previously isoprenaline), a synthetic derivative of noradrenaline, not present in the body.

Question 3

Nonadrenaline process:

Answer 3

Noradrenaline is manufactured in terminal and put into vesicles

After release it can bind to α/β receptors

A specific ‘reuptake’ mechanism exists for NAdr, taking it back into the pre-synaptic cell where it is broken down by MAO (mono-amine oxidase) enzyme.

Recycling then occurs.

Question 4

What is adrenergic transmission?

Answer 4

Transmitter synthesis involves the following:
l-tyrosine is converted to dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (rate-limiting step).
Tyrosine hydroxylase occurs only in catecholaminergic neurones.
Dopa is converted to dopamine by dopa decarboxylase.
Dopamine is converted to noradrenaline by dopamine β-hydroxylase (DBH), located in synaptic vesicles.

Question 5

Feedback control of noradrenaline release?

Answer 5

The presynaptic α2 receptor inhibits adenylate cyclase, thereby reducing intracellular cAMP. cAMP acts to promote Ca2+ influx in response to membrane depolarisation, and hence to promote the release of noradrenaline and ATP.

Question 6

Transmitter storage:

Answer 6

Noradrenaline is stored at high concentration in synaptic vesicles, together with ATP, chromogranin and DBH (dopamine β-hydroxylase), all of which are released by exocytosis.
Transport of noradrenaline into vesicles occurs by a reserpine-sensitive transporter.

Noradrenaline content of cytosol is normally low due to monoamine oxidase in nerve terminals.

Question 7

Transmitter release:

Answer 7

Occurs normally by Ca2+-mediated exocytosis from varicosities on the terminal network.
Non-exocytotic release occurs in response to indirectly acting sympathomimetic drugs (e.g. amphetamine), which displace noradrenaline from vesicles.
Noradrenaline escapes via uptake 1 (reverse transport/neuronal uptake).
Noradrenaline release is controlled by autoinhibitory feedback mediated by α2 receptors.

Question 8

What transmitter action terminated:

Answer 8

Mainly by transporter-mediated reuptake of noradrenaline into nerve terminals (uptake 1), to a lesser extend also by uptake 2 (extraneuronal uptake).
NA is then degraded by the enzyme monoamine oxidase (MAO) or cathecol-O-methyl transferase (COMT)
Uptake 1 is blocked by tricyclic antidepressant drugs and cocaine.

Question 9

Nonadrenaline receptors:

Answer 9

All belong to G-protein-coupled receptors.
There are two main groups of adrenergic receptors:
α and β, with several subtypes.

Question 10

α receptors:

Answer 10

Have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor).
Phenylephrine is a selective agonist of the α receptor.

α1 receptors are coupled to PLC activation causing breakdown of membrane phosphoinositides to inisitol phosphates leading to mobilisation of Ca2+.
Activation of α1 receptors causes contraction of smooth muscle cells.
Locations of α1 receptors : For example, blood vessels of gut and skin, sphincters of bladder and gut.

Question 11

α2 receptors:

Answer 11

Coupled to adenylate cyclase.
Location: Nerve endings, isles of pancreas and platelets
Mainly cause inhibition by inhibiting transmitter release, platelet aggregation.

Question 12

α-Adrenoceptors:

Answer 12

Order of potency:
Agonists: NA ≥Ad»Isoprenaline
Antagonist: Phentolamine (competitive)

Question 13

β receptors subtypes

Answer 13

β1 ( heart), increased cardiac rate and force
β2 (blood vessels of skeletal muscles, bronchi), bronchodilatation, vasodilatation, relaxation of visceral smooth muscle, hepatic glycogenolysis and muscle tremor
β3 (liver, fat/adipose tissue), lipolysis. .

All three are linked to Gs proteins, which in turn are linked to adenylyl cyclase.

Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP and also protein kinase A (PKA).

Question 14

Isoprenaline:

Answer 14

Isoprenaline is a selective agonist. Order of Potency:
Agonist: Isoprenaline >Ad≥NA
Antagonist: Propranolol

Question 15

Drugs affecting the synthesis and storage of noradrenaline:

Answer 15

α-methyltyrosine, which inhibits tyrosine hydroxylase (used rarely to treat phaeochromocytoma)

Carbidopa, a hydrazine derivative of dopa, which inhibits dopa decarboxylase and is used in the treatment of parkinsonism

Methyldopa, a drug still used in the treatment of hypertension during pregnancy, taken up by noradrenergic neurons, where it is converted to the false transmitter α-methylnoradrenaline

Reserpine, at very low concentration, blocks the transport of noradrenaline and other amines into synaptic vesicles, by blocking the vesicular monoamine transporter.

Question 16

Drugs that affect NA release 1

Answer 16

NA neuron-blocking drugs (e.g. guanethidine)
The action is complex. It is selectively accumulated by noradrenergic nerve terminals, being a substrate for uptake 1. Its initial blocking activity is due to block of impulse conduction in the nerve terminals that selectively accumulate the drug. Its action is prevented by drugs, such as tricyclic antidepressants, which block uptake 1.
In addition, accumulation in synaptic vesicles may interfere with their ability to undergo exocytosis, and also displacing noradrenaline.

Indirectly acting sympathomimetics:
Eg.tyramine, amphetamine and ephedrine, cocaine
They are taken up into the vesicles by the vesicular monoamine transporter, in exchange for noradrenaline, which escapes into the cytosol. Some of the cytosolic noradrenaline is degraded by MAO, while the rest escapes via uptake 1, in exchange for the foreign monoamine, to act on postsynaptic receptors

Question 17

The mode of action of amphetamine, an indirectly acting sympathomimetic amine:

Answer 17

Amphetamine enters the nerve terminal via the NA transporter (uptake 1) and enters synaptic vesicles via the vesicular monoamine transporter (VMAT), in exchange for NA, which accumulates in the cytosol.
Some of the NA is degraded by monoamine oxidase (MAO) within the nerve terminal and some escapes, in exchange for amphetamine via the noradrenaline transporter, to act on postsynaptic receptors.
Amphetamine also reduces NA reuptake via the transporter, so enhancing the action of the released NA.
Causes inc in extracellular neurotransmitter concentration

Question 18

Effects on the CNS
;

Answer 18

These drugs, especially amphetamine, have important effects on the central nervous system that depend on their ability to release not only noradrenaline, but also 5-HT and dopamine from nerve terminals in the brain.
An important characteristic of the effects of indirectly acting sympathomimetic amines is that marked tolerance develops.
Repeated doses of amphetamine or tyramine, for example, produce progressively smaller responses.
This is probably caused by a depletion of the releasable store of noradrenaline.
A similar tolerance to the central effects also develops with repeated administration, which partly accounts for the liability of amphetamine and related drugs to cause dependence.

Question 19

Amphethamines:

Answer 19

Methamphetamine is metabolised by P450 in liver
25% are eliminated by renal mechanisms
t1/2 ~ 10-12 h
Cardiac stimulation due to increase in extracellular NA concentrations
Effects include tachycardia, chest pain, palpitations, arrhythmias, hypertension, headache and stroke
At high amphetamine doses, MAO activity is also inhibited.

Question 20

Ephedrine & Pseudoephedrine:

Answer 20

Has mixed sympathomimetic action (both direct and indirect actions)
Mechanism of action:
Direct effects: weak agonist activity at alpha and beta adrenergic receptors
Indirect effects: blocks reuptake of NA
Have amphetamine-like properties but less potent than d-amphetamine

Question 21

Sudafed:

Answer 21

Sudafed past
Pseudoephedrine Sinus and Allergy
Works on both sympathetic nerves and on smooth muscles, alpha receptors

Sudafed PE present
Phenylephrine, alpha -1 agonist, works on the smooth muscle
Nasal decongestion

Question 22

Cocaine:

Answer 22

A natural plant alkaloid that is an indirectly acting sympathomimetic in the periphery and CNS. Its high lipophilicity accounts for its stimulant properties in the CNS.
Cardiovascular actions due to inc in NA in the synapse
Stimulation of beta-1 receptors inc heart rate, contractility

Stimulation of alpha-1 receptors inc BP
Cocaine inc O2 demand which sill not match O2 supply as alpha-1 mediated vasoconstriction of both epicardial and resistance vessels results in reduced O2 supply cocaine decreases O2 supply.
Cacaine has local anaesthetic properties by blocking Na+ channels and disturbing depolarisation
Cardiovascular effects can result in angina, arrhythmias and cardiac arrest.

Question 23

Drugs inhibiting NA uptake:

Answer 23

Neuronal reuptake of released NA (uptake 1) is the most important mechanism by which its action is brought to an end.
Many drugs inhibit this transport, and thereby enhance the effects of both sympathetic nerve activity and circulating NA.
Uptake 1 is not responsible for clearing circulating Ad, so these drugs do not affect responses to this amine.
The main class of drugs whose primary action is inhibition of uptake 1 are the tricyclic antidepressants, for example desipramine. These drugs have their major effect on the CNS but also cause tachycardia and cardiac dysrhythmias, reflecting their peripheral effect on sympathetic transmission.
Cocaine, known mainly for its abuse liability and local anaesthetic activity, enhances sympathetic transmission, causing tachycardia and increased arterial pressure. Its central effects of euphoria and excitement are probably a manifestation of the same mechanism acting in the brain.

Question 24

Adrenoceptor agonists:

Answer 24

Noradrenaline and adrenaline show relatively little receptor selectivity.
Selective α1 agonists include phenylephrine and oxymetazoline.
Selective α2 agonists include clonidine and α-methylnoradrenaline. They cause a fall in blood pressure, partly by inhibition of noradrenaline release and partly by a central action. Methylnoradrenaline is formed as a false transmitter from methyldopa, developed as a hypotensive drug (now largely obsolete).
Selective β1 agonists include dobutamine. Increased cardiac contractility may be useful clinically, but all β1 agonists can cause cardiac dysrhythmias.
Selective β2 agonists include salbutamol, terbutaline and salmeterol, used mainly for their bronchodilator action in asthma.
Selective β3 agonists may be developed for the control of obesity.

Question 25

Clinical uses of adrenoceptor agonists:

Answer 25

Cardiovascular system:
cardiac arrest: adrenaline
cardiogenic shock: dobutamine (β1 agonist)
Anaphylaxis (acute hypersensitivity, adrenaline).
Respiratory system:
asthma: selective β2-receptor agonists (salbutamol, terbutaline, salmeterol, formoterol)
nasal decongestion: drops containing xylometazoline or ephedrine for short-term use.
Miscellaneous indications:
adrenaline: with local anaesthetics to prolong their action premature labour (salbutamol)
α2 agonists (e.g. clonidine): to lower blood pressure and intraocular pressure; as an adjunct during drug withdrawal in addicts; to reduce menopausal flushing; and to reduce frequency of migraine attacks.

Question 26

α-Adrenoceptor antagonists:

Answer 26

Drugs that block α1 and α2 adrenoceptors (e.g. phenoxybenzamine and phentolamine) were once used to produce vasodilatation in the treatment of peripheral vascular disease, but this use is now largely obsolete.
Selective α1 antagonists (e.g. prazosin, doxazosin, terazosin) are used in treating hypertension. Postural hypotension and impotence are unwanted effects.
Yohimbine is a selective α2 antagonist. It is not used clinically.
Tamsulosin is α1A-selective and acts mainly on the urogenital tract.
Some drugs (e.g. labetolol, carvedilol) block both α and β adrenoceptors.

Question 27

Clinical uses of α-adrenoceptor antagonists:

Answer 27

Severe hypertension: α1-selective antagonists (e.g. doxazosin) in combination with other drugs.
Benign prostatic hypertrophy (e.g. tamsulosin, a selective α1A-receptor antagonist).
Phaeochromocytoma: phenoxybenzamine (irreversible antagonist) in preparation for surgery.

Question 28

β-Adrenoceptor antagonists:

Answer 28

Non-selective between β1 and β2 adrenoceptors: propranolol, alprenolol, oxprenolol.

β1-selective: atenolol, nebivolol. Fewer side effects, β1>β2 receptor antagonism for this class of drug but the selectivity can be lost with high doses.

Question 29

Alprenolol and oxprenolol

Answer 29

have partial agonist activity.
Important hazards are bronchoconstriction, and bradycardia and cardiac failure (possibly less with partial agonists).
Side effects include cold extremities, insomnia, depression, fatigue.
Some show rapid first-pass metabolism, hence poor bioavailability.

Question 30

Clinical uses of β-adrenoceptor antagonists:

Answer 30

Cardiovascular :
angina pectoris
myocardial infarction
dysrhythmias
heart failure
hypertension (no longer first choice)
Other uses:
glaucoma (e.g. timolol eye drops)
thyrotoxicosis, as adjunct to definitive treatment (e.g. preoperatively)
anxiety, to control somatic symptoms (e.g. palpitations, tremor)
migraine prophylaxis
benign essential tremor (a familial disorder).

Question 31

Post-synaptic actions of noradrenaline (NA)

Answer 31

Noradrenaline(NA)acts on receptors located both pre- and post-synaptically.
The presynaptic receptors can modulate the amount of transmitter released by the axon.
Released NA binds to post-synaptic alpha or beta receptors which are metabotropic. They are linked to a cAMP second messenger system.