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PHARMCOL201 2005: Lecture 16

Learning Objectives
Lecture 16 Describe the classification of adrenoceptors,
adrenoceptors, their
ANS Lecture 3 effectors and second messengers
Describe the synthesis, storage and release of NA
and Adrenaline and points where drug action (with
Noradrenergic examples) can occur.
Describe the mechanism by which NA’s actions are

Transmission terminated and the key enzymes involved in its


metabolism
Describe the actions of adrenoceptor agonists on
smooth muscle, the heart and metabolism.
Chapter 11, 5th Edition, Rang, Describe, with examples, the key clinical uses of
adrenoceptor agonists & antagonists.
Dale and Ritter. Differentiate direct and indirect acting
sympathomimetics
Describe and predict the effects of drugs that inhibit
NA uptake transporters

Chemistry of the Peripheral Synthesis


Nervous System
Methyl tyrosine - used in the
Tyrosine -ve treatment of phaeochromocytoma
SMOOTH MUSCLE
SYMP. ACh N NA CARDIAC Tyrosine hydroxylase
Methyl dopa -false substrate, decarboxylated
GLANDS DOPA and hydroxylated to form -methyl NA a false
trasmitter, which is not a substrate for MAO,
Dopa decarboxylase
so accumulates and displaces NA from vesicles
- less active on -1 receptors
Dopamine -more active on -2.
SWEAT GLANDS USED AS AN ANTIHYPERTENSIVE
SYMP. ACh N ACh M PILOERECTOR Dopamine- -hydroxylase
-ve
Noradrenaline
Carbidopa-used as an adjunct therapy in PD
Does not enter the brain

Storage and Release


depolarisation
Uptake and Degradation
Ca2+ in
Ca2+
No synaptically localised enzyme to degrade NA
Ca2+
NA Vesicle (or other catecholamines)
catecholamines)
cAMP ATP exocytosis
Action is terminated by REUPTAKE
AC Gi Release of NA UPTAKE I:
I: High affinity system with a relatively
α2 and ATP (1:4) low maxmium rate of uptake (neuronal)

NA
UPTAKE 2:2: Low affinity for NA, but high
ATP Action at post-
and pre-synaptic maximum rate: Smooth muscle, cardiac muscle,
receptors endothelium (non-
(non-neuronal)
PHARMCOL201 2005: Lecture 16

Metabolism
Adrenoceptor Agonists
Subtype selective drugs exist:
-α1-agonists – phenylephrine,
phenylephrine, oxymetazoline
- α2-agonists - clonidine – cause fall in blood
pressure partly due to decreased NA
release,major central actions.
-β1-agonists – dobutamine – increased cardiac
contractility, but cause dysrhythmias
-β2-agonists – salbutamol – bronchodilater -
asthma

Agonists of α1 on Smooth Agonists of β-receptors on


Muscle Smooth Muscle
NA α1 Gq/11 IP3 Ca2+ contraction Produce relaxation of smooth muscle
Main effect is on vascular smooth muscle -β 2 cAMP PKA inhibition of MLCK
decreased vascular compliance inhibits contraction
increased central venous pressure -β2 agonists e.g. salbutamol are used in the
increased peripheral resistance treatment of asthma (brochodilation
(brochodilation),
), or to cause
relaxation of uterine smooth muscle during
Increased systolic and diastolic arterial pressure, premature labour
triggering baroreceptor reflexes reflex Adrenaline is used in anaphylactic reaction to
bradycardia and inhibition of respiration
help breathing

Metabolism
Heart
β-receptor activation

Heart rate (chronotropic


(chronotropic))
Force of contaction (inotropic)
inotropic)

Cardiac output
Oxygen consumption

Clinically: adrenaline iv for cardiac arrest


Beta agonists encourage the conversion of energy
Dalbutomol (β1 agonist) IV in cardiogenic shock into freely available fuels causing an increase in
plasma concentration of glucose and free fatty acids.
PHARMCOL201 2005: Lecture 16

Alpha Adrenoceptor Antagonists Non-


Non-Selective -AR Antagonists
Phenoxybenzamine (irreversible) – used
Non-
Non-selective -antagonists to treat pheochromocytoma but non-
non-
– Haloalkylamines (eg phenoxybenzamine)
phenoxybenzamine)
specific for alpha adrenoceptors (also
5HT, His & Ach)
1-
1-selective antagonists
Phentolamine – binds to both alpha 1 and
– Prazosin,
Prazosin, 2-
2-selective antagonists
alpha 2.
– Yohimbine
These drugs cause a fall in blood pressure
– Ergot derivatives
but baroreceptor reflexive increase in
cardiac output and heart rate.

α-1 Selective Antagonists α-2 Selective Antagonists.


PRAZOSIN e.g. Yohimbine (naturally occurring alkal
alkaloid
oid))
Cause vasodilation and a fall in arterial Block presynaptic -2 receptors, therefore
increase release of NA - sympathomimetic
pressure (hypotensive
(hypotensive))
Also block post-
post-synaptic -2 receptors so
Used in the treatment of mild responses are complex
hypertension. – Dominant effects - vasodilation,
vasodilation, drop in blood
Major side effects - postural hypotension, pressure.
impotence No therapeutic use but useful pharmacological
tool

β-Adrenoceptor Antagonists Cardiac Effects


Propranolol ( 1 and 2) Beta blocker use lowers blood pressure in
Atenolol 1-
1-selective antagonist patients with hypertension.
Effects depend on the degree of sympathetic complex mechanism involving:
activity - very little effect at rest. Most important – Reduction in cardiac output
effects are on the cardiovascular system and on – Reduced sympathetic activity
bronchial smooth muscle – Reduction of renin release from the kidney
Propranolol - at rest, very little change in heart – Central actions
rate, cardiac output or blood pressure. But the Beta blockers do not cause hypotension in
effects of exercise on these variables is reduced. normotensive patients.
PHARMCOL201 2005: Lecture 16

Other Clinical Uses Adverse Effects


Beta-
Beta-antagonists reduce intraocular For propranolol,
propranolol, 2 receptor blockade of
pressure due to decreased aqueous bronchial smooth muscle relaxation leads to
humor production-
production- used in glaucoma increased airway resistance.
– Delivered directly to eye-
eye- timolol may have – Inconsequential in healthy individuals but very
cardiovascular effects if absorbed serious in asthmatics. Other adverse effects are bad
dreams - probably centrally mediated
Also used to treat the peripheral
Cold extremities due to loss of beta receptor
symptoms of anxiety - racing heart, tremor
mediated vasodilatation in cutaneous vessels
etc
Fatigue - probably due to reduced muscle
perfusion

Drugs That Affect Noradrenergic


Other Effects
Storage - Reserpine
Only minor metabolic changes in healthy
patients From the shrub Rauwolfia
– Inhibition of sympathetic stimulation of lipolysis.
lipolysis. At low concentrations blocks the transport of
– May inhibit glucose response in diabetic patients in noradrenaline and other amines into vesicles
response to adrenaline -increased likelihood of NA accumulates in the cytoplasm where it is
exercise induced hypoglycemia because normal broken down by MAO
adrenaline induced release of glucose from liver is Decreased NA levels in tissue - blockade of
diminished sympathetic transmission
– Decreased sympathetic reflexes so hypoglycemia is Also depletes 5HT and dopamine levels
more likely to go unnoticed. Has anti-
anti-hypertensive effects - but not used due
to side effects - what are the likely side effects?

Drugs That Affect NA Release Guanethidine


Multiple sites of action to abolish response
1. Prevent exocytosis e.g. guanethidine
of tissue to sympathetic nerve stimulation
2. Evoke NA release in the absence of
Transported by uptake 1 into NA nerve
nerve terminal depolarisation (indirectly
terminals
acting sympathomimetics)
sympathomimetics)
Stored in synaptic vesicles displacing NA
3. Interact with -2 presynaptic receptors to
inhibit or enhance depolarisation evoked Produces a slowly developing, but long
release lasting depletion of NA in nerve terminals
4. Increase or decrease available stores of Prevents fusion of vesicles with cell
NA, e.g. reserpine or MAO inhibitors. membrane
PHARMCOL201 2005: Lecture 16

Indirectly Acting Indirectly Acting


Sympathomimetic Agents Sympathomimetic Agents
Tyramine,
Tyramine, amphetamines and ephedrine
Effects abolished by reserpine (as
Transported into nerve terminals by uptake terminals will be depleted of NA)
I Effects potentiated by MAO inhibitors
Displace NA from vesicles (prevent breakdown of NA displaced from
vesicles)
broken down by MAO Diffuses out of nerve Uptake 1 inhibitors e.g. imipramine
terminal to activate
So effects are caused by: post-synaptic receptors prevent uptake of sympathomimetic
1. Activation of receptors amines so prevent their actions
2. Inhibition of uptake 1

Indirectly Acting
Inhibitors of NA Uptake 1
Sympathomimetic Agents
The effects of these drugs are similar to NA, but What effect will this have on NA activity?
longer lasting.
Tricyclic antidepressants e.g. desipramine
– Bronchodilation
– Increased arterial pressure Cocaine - local anesthetic
– Peripheral vasoconstriction – Tachycardia, increased arterial pressure
– Tachycardia – CNS effects - euphoria, excitement.
– Inhibition of gut motility.
Amphetamine, guanethidine.
guanethidine.
Many central effects are due to effects on 5HT
and DA terminals e.g. amphetamine - euphoria,
excitement, wakefulness and increased
attentiveness, loss of appetite.