Download adrenergic system - lec-4 2008

LECTURE : 4
CLINICAL PHARMACOLOGY AND THERAPEUTICS
ADRENERGIC SYSTEM
ADRENERGIC ANTAGONIST ( BLOCKERS ) :
Introduction :
The adrenergic antagonist ( or blockers ) bind to adrenoceptors but don't
trigger the usual pathway for production an effect .
These drugs act either by reversible or irreversible attaching to the
receptors , thus preventing the activation by endogenous catecholamines .
They are classified according to their relative affinity to alpha or beta
receptors.
1- ALPHA – ADRENERGIC BLOCKING AGENTS :
This group of drugs also subdivided in to alpha-1 blockers and alpha-2
blockers .their main effect are reduction of sympathetic tone of the blood
vessels that will cause ( specially in the first does ) hypotension specially
if the patient change his position from supine to erect position .
General clinical uses of alpha adrenoceptor antagonist ( blockers ) :
1- hypertension.
a- essential hypertension.
b- hypertension with phaeochromocytoma.
2- peripheral vascular disease .
3- benign prostates hyper atrophy .
Common side effects of alpha- blockers :
1- orthostatic hypotension.
2- tachycardia.
3- vertigo .
4- sexual dysfunction .
INDIVIDUAL DRUGS :
1- PRAZOSIN :
1- block alpha-1 receptors .
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2- has first dose effect.
3- its first dose effect may be brisk to degree that cause hypotension with
loss of consciousness.
4- the first dose should be small ( 0.5 mg ) .
5- the first dose should be given before bed time .
6- has short duration of action ( 3 hours ) .
7- because of this short duration of action plus first dose problem ,
nowadays this drug less used
.
2-DOXAZOSIN :
1- t 1/2 8 hours .
2- can be given once daily .
3- the first dose effect is less .
4- start treatment with small dose .
3- INDORAMIN :
1- it is an older alpha – 1 blocker drug .
2- less useful as antihypertensive drug .
3- still used for prostates symptoms .
4- it is taken twice or three times daily .
4- PHENTOLAMINE :
1- it is a non – selective alpha adrenoceptor blocker .
2- given intravenous for hypertensive crisis, as in phaeochromocytoma.
4- it has direct vasodilator and cardiac inotropic action .
5- less reliable in diagnosis of phaeochromocytoma .
5-PHENOXYBENZAMINE :
1- it is irreversible non-selective alpha- adrenoceptor blocking agent.
2- its effect may last 2 days . or longer .
Clinical uses :
1- it is preferred in treatment of phaeochromocytoma .
2- acute treatment of catecholamine secreting tumors of cells of adrenal
medulla .
3- chronic management of catecholamine secreting tumors .
4- sometimes used in treatment of rayuauds disease.
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5- treatment of autonomic hyperreflexia .
Side effects :
1- postural hypotension .
2- nasal stiffness .
3- nausea .
4- vomiting .
5-Inhibit ejaculation .
6- may induce tachycardia mediated by baroreceptors.
6- THYMOXAMINE :
1- it is non-selective alpha – blocker .
2- the only extant indication is rayunauds phenomena.
7- ALFUZOSIN.
8- TERAZOSIN .
BETA – ADRENOCEPTOR BLOCKING DRUGS :
introduction :
1- all the clinically available B- blockers are competitive antagonist.
2- non- selective B – blockers act at both B1 and B2 receptors .
3-cardioselctive drugs block B1 receptors .
4- they are differ in their intrinsic sympathomimetic activity .
5- although , all B- blockers lower blood pressure in hypertension but
they don’t induce postural hypotension because the alpha adrenoceptors
remain functional.
6- b- blockers are useful in treatment of angina , cardiac arrhythmias and
other clinical situation .
Note :
The names of all B – blockers end in ( olol ) except for labetalol , which
has a component of alpha-1 blocking action .
B- adrrenoceptors selectivity :
Some of b- blockers have higher affinity for cardiac B – 1 receptors and
for peripheral B-2 receptors .
The selectivity :
It is the ratio of the amount of drug required to block the two receptor
subtypes
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Pharmacokinetics :
The plasma concentration of a B adrenoceptor blocking drugs have a
complex relation ship with there effects , first order kinetic usually apply
to elimination of the drug from the plasma.
But there decline in the receptor block is zero order
Most B adrenoceptor blocking drugs can be:
1- given orally.
2- once daily.
3- either ordinary or sustained release formulation.
Lipid- soluble :
1-Agents that are extensively metabolized to water soluble substances
that can be eliminated by the kidney ,
2-the lipid soluble agents are readily cross cell membrane.
3- and so has high apparent volume of distribution .
4-Also readily enter the central nervous system
5- example propranolo reach concentration in brain 20 times than those
of water soluble like atenolol.
Water soluble :
1-These agent show more predictable plasma concentration
2- because they are less subjected to liver metabolism ,
3- being excreted unchanged by the kidney ,
4- thus their half-live are greatly prolonged in case of renal failure .
5-example atenolol t 1/2 is increased from 7 to 24 hours .
Classification of B adrenoceptor blocking drugs :
We can classify b- blockers by many classification :
1- according to pharmacokinetics to
a- lipid soluble.
b- water soluble.
2- according to selectivity in to :
a- non-selective ( B1 and B2 blockers ) like sotalol, timolo,nadolol.
b- selective ( B-1 blockers ) like atenolol, metoprolol, bisoprolol.
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General clinical uses of B – blockers :
Cardiovascular system :
1- hypertension :
They reduce rennin secretion and cardiac output.
2- cardiac tachyarrhythmia's :
They reduce drive to cardiac pacemaker.
3- myocardial infarction :
There is two strategy to use it
a- early use:
within 6 hours ( or at most 12 hours ) of onset , specially in case of
atenolol, it will protect from cardiac rupture,
contraindication :
1- braadycardia ( below 55 / min.)
2- hypotension ( systolic less than 90 mmhg ) .
3- left ventricular failure .
b- late use :
for secondary prevention of other myocardial infarction
note :
choice of the drug should be pure antagonist .
.
4-aortic dissection .
5- after subarchnoid hemorrhage.
6- obstruction of ventricular outflow.
7- hepatic portal hypertension.
8- esophageal variceal bleeding .
9- cardiac failure used in case of moderate heart failure .
But you should note the fallowing :
2-Can added anti-failure with theme.
2- starting with small dose.
Endocrine system :
1- hyperthyroidism
.
2- phaeochromocytoma.
Central nervous system :
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1- anxiety .
2- migraine prophylaxis .
3- essential tremor .
4- alcohol acute withdrawal symptoms .
5- opiods acute with drawal symptoms .
Eye :
Glaucoma ( like timolol).
General side effects of B blockers :
1- bronchoconstriction .
2- cardiac failure.
3- incapacity for vigorous exercise .
4- hypotension , when the drug given after myocardial infraction .
5- hypertension , occur when we block B receptors and allow alpha
receptor effects not opposed .
6- reduction peripheral blood flow .
7- reduction blood flow to the liver .
8- reduction blood flow to the kidneys .
9- hypoglycemia
Over dose :
Clinical features :
1- bradycardia.
2- heart block .
3- hypotension .
4- low output .
Treatment :
1- atropine .
2- glucagons.
3- if no response , give intravenous B - adrenoceptor agonist .
4- for the bronchoconstriction we can use salbutamol.
1- PROPRANOLOL( non-selective )
1- it is non-selective B-antagonist .
2-can be given in sustained release formula.
3- given i.m in cardiac arrhythmias .
4- Hypotension may occur.
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Clinical uses :
1- hypertension .
2- glaucoma .
3- migraine .
4- hyperthyroidism .
5- angina pectoris .
6- myocardial infarction .
Side effects :
1- bronchoconstriction .
2- arrhythmias .
3- sexual impairment .
4- disturbance of in metabolism .
Drug interaction :
Drugs that can interact with the metabolism of propranolol are :
1- cimetidine .( anti-gastric ulcer )
2- frusemide ( diuretic ).
3- chlorpromazine .( anti-schizophrenic ) .
2- ATENOLOL ( selective more towards B 1 ) :
1- has wide use in treatment of angina.
2- treatment of hypertension .
3- given once daily .
3- LABETALOL(alpha and Beta blocker ):
1- it has dual effect on blood vessels .
2- more B blocker than alpha blocker .
3- its effect varying with dose and route of administration .
4- postural hypotension is liable to occur
.
DRUGS AFFECTING NEUROTRANSMITTERS RELEASE OR
UPTAKE :
1- RESERPINE :
1- it is plant alkaloid .
2- it block transport pathway from the vesicles .
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3-has slow onset of action.
4- long duration of action .
2- GUANETHIDINE :
i- it inhibit the response of the adrenergic nerve to stimulation .
2- it act by blocking the release of stored nor adrenaline .
3- cause gradual lowering in the blood pressure.
4-Cause decrease in the cardiac rate
.
3- COCAINE:
Another B- adrenoceptor blocking drugs :
1- ACEBUTOLOL.
2- ESMOLOL.
3- PIDOLOL AND ACEBUTOLOL ( ANTAGONIST WITH PARTIAL
AGONIST ):
Action :
1- cardiovascular system :
a- they are not pure blockers .
b- have intrinsic sympathomimetic activity
c- decrease metabolic effects .
d- therapeutic use in treatment of hypertension
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