Lecture 14: Nerves III Flashcards
*Outline the 6 steps involved in neurotransmission at the adrenergic neuron.
- SYNTHESIS of noradrenaline: Tyrosine is transported into the adrenergic neuron where it is first converted to DOPA then to dopamine
- STORAGE of vesicular noradrenaline: Dopamine is transported to synaptic vesicles where it is converted to noradrenaline.
- RELEASE of noradrenaline: An action potential arriving at the nerve junction triggers calcium influx. The influx causes vesicles to fuse with cell membrane and expel their contents into the synapse.
- RECEPTOR BINDING: The released noradrenaline binds to presynaptic receptors on the nerve ending or to postsynaptic receptors on the effector organ.
- REMOVAL of noradrenaline: Noradrenaline can (a) diffuse out of the synapse and enter the general circulation (b) be metabolised by COMT in the synaptic space (c) be recaptured by the neuron.
- Fate of RECAPTURED norepinephrine: either metabolised by COMT and MAO or recycled and reused.
*Give examples of drugs that affect neurotransmission at the adrenergic neuron.
Drugs that affect the six steps of
neurotransmission include:
1. Synthesis of noradrenaline: None
2. Storage of vesicular noradrenaline: RESERPINE
3. Release of noradrenaline: GUANETHIDINE, BRETYLIUM
4. Receptor binding: ADRENERGIC ANTAGONISTS
5. Removal of noradrenaline: IMIPRAMINE, COCAINE
6. Fate of recaptured norepinephrine: None
*Compare and contrast the cellular roles of β1 and β2 adrenoceptors.
β1 (equal affinities for adrenaline and noradrenaline )
β2 (higher affinity for adrenaline than for noradrenaline)
Tissues with a predominance of β2 receptors (e.g. vasculature of smooth muscle) are particularly responsive to circulating adrenaline from the adrenal gland. All β adrenoceptors are coupled to Gs, activate adenylyl cyclase and increase intracellular levels of cyclic AMP.
β adrenoceptor location is an indicator of the cellular function of that receptor. Thus β1 receptors, found predominantly in heart tissue, cause cardiac stimulation whereas β2, found predominantly in smooth muscle causes vasodilation and bronchiolar relaxation.
*Compare and contrast the catecholamine and non-catecholamine agonists.
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*Describe in detail the three mechanisms of action of the adrenergic agonists.
- DIRECT acting – act directly on α or β
adrenoceptors. Similar effects to those that
occur following stimulation of sympthetic
nerves or release of adrenaline from the
adrenal medulla. Examples include
adrenaline, noradrenaline, isoproterenol,
phenylephrine. - INDIRECT acting – These agents are taken up
into the presynaptic neuron and cause the
release of noradrenaline from cytoplasmic
pools or vesicles of the adrenergic neuron.
The noradrenaline crosses the synapse and
binds to the α and β receptors. Examples
include amphetamine and tyramine. - MIXED action – Some agonists have the
ability to both stimulate adrenoreceptors
directly and to release noradrenaline from
the adrenergic neuron. Examples include
ephedrine and metaraminol.
*Describe in detail the systemic effects, therapeutic uses and adverse events of ADRENALINE.
SYSTEMIC EFFECT =
1. Respiratory – adrenaline causes bronchodilation in
airways smooth muscle via β2 receptors.
2. Hyperglycaemia – due to increase in glycogenolysis in
the liver (β2), increased release of glucagon (β2), and
decreased release of insulin (α2).
3. Lipolysis – promotes triglyceride breakdown to glycerol
and free fatty acids via β receptors on adipose tissue.
4. Cardiovascular – acts as a positive inotrope (β1)
increasing force and rate of cardiac contraction.
THERAPEUTIC USES =
=> Bronchospasm - (used in emergency treatment though β2 agonists (albuterol preferred due to longer half life)
=> Glaucoma - (reduces intraocular pressure in open angle glaucoma by reducing production of aqueous humour by vasoconstriction of the ciliary blood vessels.
=> Anaphylactic shock - (adrenaline is the drug of choice for treatment of type I hypersensitivity reactions in response to allergens.
ADVERSE EVENTS =
- CNS disturbances (can produce effects such as anxiety, fear, tension, headache, tremor)
- Haemorrhage (cause cerebral haemorrhage as a result of elevated blood pressure)
- Cardiac arrhythmias (particularly if patient is receiving digitalis)
- Pulmonary oedema
*Describe in detail the systemic effects, therapeutic uses and adverse events of ISOPROTERENOL.
= non selective β agonist. Its actions on α receptors
is not significant
SYSTEMIC EFFECT =
Cardiovascular actions:
1. Increase in rate and force of contraction (β1).
2. Dilation of the arterioles of skeletal muscle (β2) resulting in decreased peripheral resistance.
3. Systolic BP rises because of increase in cardiac output but decrease in peripheral resistance means that mean arterial and diastolic BP is greatly reduced.
- Pulmonary – a profound and rapid bronchodilation (β2)
- Actions on sugar metabolism similar to
adrenaline - rarely used as a bronchodilator in asthma. It can be used
to stimulate the heart in emergency situations.
THERAPEUTIC USES =
Treating certain heart problems (eg, heart attack, congestive heart failure), blood vessel problems (eg, shock), and certain types of irregular heartbeat (eg, heart block). It is also used during anesthesia to treat airway constriction.
ADVERSE EVENTS =
Nervousness, headache, dizziness, restlessness, insomnia, anxiety, tension, blurring of vision, fear, excitement, tachycardia, palpitations, angina, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias, flushing of the skin, diaphoresis, mild tremors, weakness.
*Outline, with examples, how drugs can act as indirect acting adrenergic agonists.
- AMPHETAMINE- As well as its CNS effects, amphetamines can increase blood pressure by α agonist action on the vasculature as well as β-stimulatory actions
on the heart. - TYRAMINE- Not a drug as such but a chemical found in
fermented food such as ripe cheese and chianti wine. It is a
normal by product of tyrosine metabolism and is normally
oxidised by MAO. If the patient is taking MAOIs then it can enter the nerve terminal and displace noradrenaline which is released and acts on adrenoceptors.
*Compare and contrast the cellular roles of α1 and α2 adrenoceptors.
α1 (specific agonist – PHENYLEPHRINE) receptors are found
postsynaptically in the membranes of the effector organs.
They mediate a number of physiological responses including smooth muscle contraction, increased blood pressure, mydriasis. They mediate their action through the G protein, Gq, which activates phospholipase C to generate inositol 1,4,5 trisphosphate and diacylglycerol second messengers.
α2 (specific agonist – CLONIDINE) receptors are found
presynaptically in nerve endings and on other cells such as
the β cells of the pancreas where it mediates insulin output.
Presynaptically these receptors control noradrenalinemediated feedback inhibition of noradrenaline release into the synapse. They work via Gi to inhibit adenylyl cyclase and reduce intracellular levels of cyclic AMP.