LECTURE : 2
CLINICAL PHARMACOLOGY AND THERAPEUTICS
ADRENERGIC SYSTEM
Classification of sympathomimetic ( adrenergic agonist ) drugs
according to mechanism of action :
They can be classified according to the way that can act through it to
three types :
1- direct – acting adrenoceptor agonists:
This group of drugs act directly on alpha or beta receptors producing
effects similar to those that occur following stimulation of sympathetic
nerves or release of the hormone adrenaline( epinephrine ) from the
adrenal medulla
includes :
1- adrenaline.
2- nor-adrenaline.
3- isoprenaline ( isoproterenol ) .
4-methoxamine .
5- phenylephrine .
2- indirect- acting adrenoceptor agonist :
These agents are taken up in to the presynaptic neurons and cause the
release of nor adrenaline from the cytoplasmic pools or vesicles of the
adrenergic neuron as with neuronal stimulation
Includes :
1- amphetamines.
2- tyramine .
3- ephedrine .
3- mixed acting adrenoceptor agonist :
These agents have the capacity both to directly stimulate adrenoceptors
and to release nor adrenaline from the adrenergic neuron .
Includes :
1- metaraminol.
Organ system effects of sympathomimetic drugs :
cardiovascular system :
a-blood vessels:
1- control peripheral vascular resistance .
2- control venous capacitance .
3- increase arterial resistance ( through alpha receptors ).
4- promote smooth muscle relaxation ( through Beta – 2 receptors ).
5- promote coronary vasodilatation ( through D-1 receptors ).
b- heart :
1-increase calcium influx in cardiac cells ( through Beta receptors ) .
2- increase electrical activity ( positive chronotropic effect ).
3- tend to increase coronary blood flow .
Eye :
1- cause mydriasis ( through alpha receptors ) .
2- alpha agonist increase the out flow of aquis humor from the eye (
through alpha receptors ).
3- decrease the production of aquis humor ( through Beta receptors ) .
Respiratory system :
1- relaxation of bronchial smooth muscle and bronchodiltation ( through
Beta-2 receptors ) .
2-decongestion of upper respiratory tract area ( through alpha-1-receptors
).
Gastrointestinal tract :
1- relaxation of GIT smooth muscle ( through both alpha and beta
receptors ) .
2- decrease the salt and water flux in to the lumen of the intestine (
through alpha-2 receptors ) .
Genitourinary tract :
1- relaxation of the uterus , useful in pregnancy ( through Beta receptors).
2- cause contraction of the bladder base and urethral sphincter therefore
promote urinary continence ( ( through alpha receptors ) .
Exocrine glands :
1- cause symptoms of dry mouth ( through what ? still uncertain ).
2- increase sweat production especially in palms of the hands and few
other areas , usually associated with psychological stress .
Metabolic effects :
1- increase lipolysis ( through Beta receptors ) .
2- enhance glycogenolysis in the liver .which lead to increase glucose
release in to the circulation ( mainly through Beta receptors , but alpha- 1
receptors may also play a role ) .
3- catecholamine in high concentration may cause metabolic acidosis .
4- promote the uptake of potassium into cells lead to fall in the extra
cellular potassium which may cause fall in the plasma potassium
concentration ( through Beta- 2 receptors ).
Effects on endocrine function and leukocytosis :
1- increase insulin secretion ( through Beta receptors ) .
2- inhibition of insulin secretion ( through alpha – 2 receptors ) .
3- stimulation rennin secretion ( through Beta- 1 receptors ) .
4- modulation the secretion of parathyroid hormone, calcitonin ,
thyroxine and gastrin hormone .
5- cause leukocytosis ( in high concentration ) .
Central nervous system :
Its action varies dramatically depending on their ability to cross blood
brain barrier .this effect range from nervousness to feeling of disaster
which is undesirable sensation .
2- anxiety and tremor .
3- insomnia.
4- psychotic behaviors .
5- anorexia
.
ADRENERGIC AGONISTS :
1- ADRENALINE
:
1- it has alpha and Beta adrenoceptor effect .
2- it is one of the most commonly used catecholamine in the therapy (
adrenaline , nor adrenaline , dopamine , dobutamine and isoproterenol ) .
3- it occur naturally ( not synthetic compound ) .
4- the use of adrenaline should be with high caution to obtain high degree
of safety .
Pharmacokinetics :
1- it has rapid onset but brief duration of action .
2- in emergency it is given intravenously .
3- it also may be given subcutaneously, by endotrachial tube, by
inhalation or topically to the eye.
4- oral administration is ineffective because it inactivated by intestinal
enzymes .
5- the metabolites only are excreted in the urine .
clinical uses :
1-treatment of acute asthma ( to relive bronchospasm ) .
2- treatment of anaphylactic shock( type one hypersensitivity reaction in
response to allergens ) ( very effective , it is the drug of choice ) .
3- treatment of open angle glaucoma ( as 2 % ophthalmic solution ).
4- combination with local anesthetic drugs .( because it produce
vasoconstriction at the site of injection allow local anesthetic drug to act
as longer as possible before being absorbed to the circulation and
metabolized ) .
5-very weak solution of adrenaline can be used topically to
vasoconstrictor mucous membrane to control oozing of capillary blood .
6- used as topical mydriatic agent .
7- for sever allergic reaction
.
ADVERSE EFFECTS :
1- CNS disturbance :
It can produce anxiety , fear , tension , headache and tremor .
2- Hemorrhage :
The drug may induce cerebral hemorrhage as a result of marked elevation
of blood pressure .
3- Cardiac arrhythmias :
It can trigger cardiac arrhythmias particularly in patient receive digitalis.
4- pulmonary edema :
DRUG INTERACTION :
1- hyperthyroidism:
Adrenalin may enhance d cardiovascular action in patient with
hyperthyroidism , if adrenalines is required in such patient , the dose must
be reduced .
2- cocaine :
In the presence of cocaine , adrenaline produces exaggerated
cardiovascular \ action . this is due to ability of cocaine to prevent reuptake of catecholamine in to the adrenergic neuron .
BIOTRANSFORMATION :
Adrenaline like other catecholamines is metabolized by two enzymatic
pathway , COMT and MAO .
ACCIDENTAL OVERDOSE :
Accidental overdose with adrenaline occur occasionally , it is treated by
propranolol to block the cardiac B- effect ( cardiac arrhythmias ) and
phentolamine or chlorpromazine to control the effect of peripheral
circulation that will be prominent when B effect are abolished . labetalol (
alpha and beta block ) would be un alternative .
2- NOR- ADRENALINE :
1- it is one of the most commonly used adrenergic agonist drug in therapy
.2- it is mainly alpha adrenoceptor agonist , but also affect Beta-1 .
Pharmacokinetic :
1- it is given by intravenous infusion to obtained a gradual sustained
response .
2- the effect of a single dose would last only a minute or so .
3- should be used with high caution .
Clinical uses :
1-it s used to treat shock because it increase vascular resistance and ,
therefore increase blood pressure , however , dopamine is better because
it does not reduce blood flow to the kidney as does nor adrenaline .
2- it is used where peripheral vasoconstriction is specifically desired like
in vasodilatation of septic shock
.
SIDE EFFECTS :
1- peripheral gangrene .
2- local necrosis .
3- tachyphylaxis occur and withdrawal must be gradual.
Note :
Tachyphylaxis is a rapidly diminishing response to repeated
administration .
3- ISOPRENALINE ( ISOPROTERENOL ):
1-it is a direct – acting catecholamine ..
2- it is a synthetic .
3 – it is non- selective B- receptors agonist ( stimulate B1- and B2 ,
insignificant stimulation to alpha receptors ) .
Pharmacokinetic :
1- it can be absorbed systemically by the sublingual mucosa .
2- it is more reliably absorbed when given parentrally .
3- good absorption when given as an inhaled aerosol .
4- it is a marginal substrate for COMT and is stable to MAO action .
Clinical uses :
1- its principle uses in complete heart block .
2- occasionally in cardiogenic shock ( hypotension ) .
3- it is not used in the treatment of bronchial asthma because it has
vigorous stimulant effect on the heart .
SIDE EFFECTS :
Its adverse effect are similar to that of adrenaline which include :
1- CNS disturbance : like anxiety , fear , tension headache and tremor .
2- hemorrhage like cerebral hemorrhage .
3- cardiac arrhythmias.
4- pulmonary edema