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 NORADRENERGIC
NEUROEFFECTOR
TRANSMISSION AS A
TARGET OF DRUG ACTION
 PART III
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AGONISTS AT THE BETAADRENOCEPTOR
 All types of beta-adrenoceptors seem to
be coupled to a stimulatory G-protein that
activates adenylyl cyclase.
 Thus, in many effectors, the activation of
beta adrenoceptors is accompanied by
an increase in cellular content of cyclic
AMP.
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EFFECTS OF AGONISTS THAT ARE
MEDIATED BY 1 AND 2
ADRENOCEPTORS..
 BETAI ADRENOCEPTORS.
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HEART
 SA node
 AV node
Increased firing rate.
Reduced refractory
period.
 Conducting myocardium- Reduced refractory
period and
Increased automaticity.
 Ventricular myocardium - Increased
contractile force.
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BETAI ADRENOCEPTORS...
GUT, STOMACH TO RECTUM
 Propulsive smooth musculature
Inhibited.
KIDNEY
 Juxtaglomerular cells -Renin release.
 Adipocytes
-lipolysis.
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BETA2 ADRENOCEPTORS
RESPIRATORY TRACT.
 Airway smooth muscle -Relaxed.
GENITAL APPARATUS SMOOTH
MUSCLE.
 Uterus
-Relaxed.
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BETA2 ADRENOCEPTORS…
BLOOD VASCULAR SYSTEM SMOOTH
MUSCLE
 Arterioles
-Dilated.
 Liver cells
-Glycogenolysis.
 Skeletal muscle cells -Tremor,
glycogenolysis,
Uptake of K+
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THE BETA ADRENOCEPTOR:
RELATIVE ORDERS OF
POTENCY
Non-selective agonists.
 Isoprenaline > Adrenaline >
Noradrenaline.
 Agonist selective for subtypes of betaadrenoceptor
Beta1-Dobutamine.
Beta2-Salbutamol
Non-selective antagonists
Propranolol
>>
Phentolamine
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Antagonist selective for
subtype of beta adrenoceptor
 Beta1 – Atenolol.
 An alternative name for 1,2
dihydrobenzene is catechol, therefore
3,4-dihydroxyphenylethylamines are
catecholamines.
 The physiological compounds, NA and
adrenaline, have relatively low selectivity
and therefore elicit effects mediated by
both alpha and beta adrenoceptors.
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 The synthetic agonist agent isoprenaline elicit
only the effects mediated by betaadrenoceptors.
 In general, increasing the size of the alkyl
substituent on the nitrogen atom of the 3,4dihydroxyphenylethanolamine molecule
increases selectivity first for beta rather than
alpha adrenoceptors and then for 2-rather
than 1-adrenoceptors.
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 Provided that excessive concentrations are
avoided, the synthetic agonist drug
Phenylephrine elicit only the effects mediated
by 1-adrenoceptors and synthetic agonist
drug Salbutamol elicit only the effect mediated
by 2-adrenoceptors.
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 Dopamine has complex peripheral actions on
noradrenergic mechanisms.
 It is a precursor in the synthesis of NA.
 When exogenously administered, it is an
agonist at both 1-and 1-adrenoceptors.
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 Dopamine is also an agonist at renal
vascular dopamine receptors, mediating
vasodilatation, and it is an indirectly acting
sympathomimetic agent.
 Dobutamine is an analoque of Isoprenaline
that is an agonist at both 1 and 1adrenoceptors.
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THERAPEUTIC USES
 Phenylephrine eye drops produces mydriasis,
which is useful as an aid in diagnostic
retinoscopy.
 Adrenaline eye drops are effective in reducing
intraocular pressure.
 Adrenaline is included in the formulation of
some local anaesthetic agents for injection.
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 By causing vasoconstriction at the injection
site it prolongs the local anaesthesia.
 Adrenaline is given i/m or i/v in the control of
anaphylaxis.
 It usefully evokes vasoconstriction,
bronchodilatation and a reduction in the
protein permeability of the endothelium of
postcapillary venules.
 Salbutamol is useful for reducing airway
resistance in bronchial asthma.
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 It can relax bronchial smooth muscles at
doses that have little or no cardiac stimulant
activity.
 Most of the agonists selective at 2adrenoceptors that are used as
bronchodilator drugs are neither substrates
for uptake nor for enzymatic degradation by
MAO or COMT
 Salbutamol is also useful as a relaxant of
uterine smooth muscle when attempting to
suppress premature labour.
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 Salmeterol is useful as bronchodilator in
bronchial asthma, the action of which
persists for 12 hours.
 Dopamine and Dobutamine are useful, by i/v
infusion, to increase the force of contraction
of the failing heart.
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ANTAGONISTS AT
ADRENOCEPTORS
ANTAGONISTS AT THE ALPHA
ADRENOCEPTORS.
 By combining with the -adrenoceptors, these
agents reduce the access of agonists.
 They thereby reduce those effects of
noradrenergic nerve activity or
sympathomimetic drug (both directly and
indirectly acting) action that are mediated by
alpha-adrenoceptors.
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THERAPEUTIC USES
 Phentolamine is occasionally a useful aid in
diagnostic of phaeochromocytoma.
 The diagnosis is supported when an i/v
injection produces a dramatic but brief
reduction in BP to near or below normal by
antagonizing the catecholamines that are
circulating in excessive concentrations.
 Phenoxybenzamine protects vascular
smooth muscle from large circulating
concentration of catecholamines produced
by
phaeochromocytoma.
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 Also useful in providing protection during
surgical removal of such tumour or as
symptomatic treatment in inoperable cases.
 In both circumstances it should be combined
with antagonist at beta adrenoceptors.
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 Neither Phentolamine nor phenoxybenzamine
has proved useful in the treatment of essential
hypertension, despite the fact that each
produces a marked decrease in peripheral
resistance.
 This is because the resultant reduction in BP
is accompanied by an unacceptable degree of
reflex tachycardia.
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 Prazosin, however, produces much less
tachycardia than phentolamine for the same
reduction in peripheral resistance and as a
result has proved more useful in treating
hypertension.
 Phentolamine generates an excessive
amount of reflex tachycardia because the
normal feedback inhibition of NA release from
cardiac noradrenergic nerves by released NA
is abolished, due to occupation of
prejunctional alpha2 adrenoceptors.
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 Prazosin, because it is able to inhibit
contraction of smooth muscles of the trigone,
urethra and perhaps prostate gland, has been
exploited to reduce the symptoms of benign
hypertrophy- obstruction of urine flow through
the bladder neck.
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NON-SELECTIVE ADRENOCEPTORS
 Propranolol, while very selective for beta
– as opposed to alpha-adrenoceptors,
has equal potency at 1 and 2
adrenoceptor subtypes.
 Propranolol is a competitive antagonist at
beta receptors.
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 In a concentration greater than required for
blockade of beta adrenoceptors, it can directly
stabilize the membrane of excitable cells,
prolonging the action potential and effective
refractory period of cardiac muscle.
 With Sotalol this latter action is more
prominent.
 Labetalol has affinity for both  and adrenoceptors.
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 It exhibit no selectivity between the 1 and 2
– adrenoceptor subtypes but is selective for
1-adrenoceptors, reducing the arteriolar
response to NA without affecting the neuronal
negative feedback mechanism mediated by
2-adrenoceptors.
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SELECTIVE FOR BETA1ADRENOCEPTORS
 Atenolol is a competitive antagonist that
is very selective for beta as opposed to
alpha-adrenoceptors and also has a
greater affinity for 1-than 2adrenoceptors.
 That is, it can antagonize NA on the heart
at doses that have little or no effect on
the relaxant action of NA on respiratory
tract smooth muscle.
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 Atenolol does not directly stabilize the
membranes of excitable cells.
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OTHER PROPERTIES OF
ANTAGONISTS AT ADRENOCEPTORS.
 Oxprenolol exhibits some intrinsic
efficacy at -adrenoceptors, that is it is a
partial agonist.
 In situations where there is little
noradrenergic tone to an organ ( e.g. the
heart in healthy person at rest ) the
agonist action can be seen.
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 Where there is significant NA tone to an organ
(e.g. the heart in a person undergoing
vigorous exercise ) the antagonist action
predominates.
 Atenolol and Sotalol are relatively water
soluble compared to other antagonists.
Hence, they penetrate less into CNS.
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THERAPEUTIC USES
1) Antagonists at beta adrenoceptors
reduce the heart rate by occupying
cardiac pacemaker beta-adrenoceptors.
This prolongs diastole and reduce
myocardial oxygen demand, thereby
increasing the exercise tolerance of
patients with angina pectoris.
2) Useful to reduce BP of hypertensive
patients.
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3) Are effective in the correction of certain
cardiac dysrhythmias, especially those due
to digoxin toxicity or thyrotoxicosis.
4) Useful in protecting cardiac beta
adrenoceptors from large concentrations of
circulating catecholamines, prior to, or
during surgical removal of a
phaeochromocytoma.
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5) Some symptoms of thyrotoxicosis
(tachycardia, palpitations, tremor ) can be
controlled by antagonist at beta
adrenoceptors.
6) Useful prophylactically in migraine.
7) Eye-drops containing an antagonist at beta
adrenoceptors provide useful control of
intraocular pressure in chronic open-angle
glaucoma, by reducing the rate of secretion
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UNWANTED EFFECTS
 Include excessive bradycardia and
precipitation of cardiac failure in patients
with a small cardiac reserve.
 Many patients experience easy
fatiguability, stemming from reduced
ability to increase the cardiac output,
and coldness of the extremities either from
the same source or from antagonism of
a vasodilator response to a small
concentration of circulating adrenaline.
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 There is aggravation of bronchoconstriction in
asthmatic patients.
 The risk less likely with atenolol than with nonselective beta antagonists.
 Sleep disturbance and unpleasant dreams are
experienced with the more lipid soluble agents
( e.g. propranolol ).
 Unwanted effects of Labetalol also include
those mediated at alpha-adrenoceptors ( e.g.
postural hypotension, failure of ejaculation ).
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 Read: Rang and Dale’s Pharmacology (7th
edition Chapter 14)
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THANK YOU!
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