Hypertension doc by O8u17v

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									                        Project Title


                     HYPERTENSION



                      A RESEARCH   PRESENTED BY




          S TUDENT NAME : ABD ALRAUF WAEL S ULTAN

                     S TUDENT N O: 9750080




      P ROJECT SUPERVISOR D R .R AFIQ R. A. A BOU -S HAABAN



                             Jan.2001




Ajman University Of Science & Technology

Abu Dhabi Branch
UAE
   Research for this project was carried out by me during the period of Hospital
Pharmacy Training-1 no.700315 (academic year 2000-2001)



Signed                                                     Date Jan 10th 2000


                     ACKNOWLEDGMENTS


Sincere gratitude were extended to Dr. Rafeeq Abu Shaaban from the
pharmaceutical department, to the support, encouragement and fruitful
accompaniment through out the training and presentation of this project.
The author is indebted to      project supervisor Dr Asim Ahmed, for the
continuous follow up , constructive criticism , and valuable comments.
The author wishes to express special gratitude and thanks to those
contributing in this revolutionary, distinctive and advanced Hospital
Pharmacy training 1; namely Dr.Danna Sallam and the staff of the New
Medical Center Hospital.
Finally the author wishes to express heartfelt thanks to Dr. Abduelmula in-
Charge of the Central training committee for furnishing the entire Clinical
Pharmacy Services as far as this term is concerned.
INDEX


    Description                                 Page No
Section l
    1.0 Introduction
    1.1 Definition
    1.2 Pathophysiology
    1.3 Epidemology
    1.4 Classification Of Hypertension
    1.5 Clinical Manifestation
    1.6 Investigation


Section II


    2.1 Non Pharmacological Treatment
    2.2 Pharmacological Treatment
    2.3 Sympatholytics
            2.3.1 Centrally Acting
            2.3.2 Ganglionic Blockers
            2.3.3 Adrenergic Neurone Blockers
           2.3.4 Release Inhibitors
           2.3.5 Beta Receptors Blockers
           2.3.6 Alpha Receptors Blockers
     2.4 Calcium Channel Blockers
     2.5 Diuretics Therapy Of Hypertension
     2.6 Inhibitors Of Angiotensin – Aldosterone System
     2.7 Vasodilators


Section III


     3.0 Introduction
     3.1 Out-Patient Therapy
     3.2 Monotherapy vs Polypharmacy
     3.3 Algorithm For The Treatment Of Hypertension
     3.4 Management At Hypertension Emergency
     3.5 Treatment Of PheoChromocytoma
     3.6 Treatment Of Hyper Aldosteronism
     3.7 Treatment OF Pre- Eclampsia
     3.8 Patients & Their Disease State
     3.9 Conclusion


                                 GENERAL INTRODUCTION Section I


1.1Definitions:
 1.1.1- Blood pressure (BP):
Blood pressure is the pressure of the circulating blood against the walls of the arteries, the
veins, and the chambers of the heart. Overall blood pressure is kept by the complex
interaction of the volume of the blood, the walls of the arteries and arterioles, and the
force of the contraction of the heart. The pressure in the large artery of the heart (aorta)
and the other large arteries of a healthy young adult is about 120 mm Hg during
contraction (systole) and 70 mm Hg during relaxation (diastole) of the heart.


1.1.2-Hypertension :
          Hypertension is a disease of the vascular regulatory system i n which the
mechanisms that usually control arterial pressure within a certain (normal) range are
altered. The central nervous system and renal pressor system, as well as extracellular
volume, are the predominant mechanisms that control arterial pressure. Some
combination of factors effects changes in one or more of these systems, ultimately
leading to increased cardiac output and increased peripheral resistance. This elevates
the arterial pressure, reducing cerebral perfusion and the cerebral oxygen supply,
increasing the myocardial workload and oxygen consumption, and decreasing the blood
flow to and oxygenation of the kidneys.


1.2-Pahtophysiology:


1.2.1-neurosympathetic blood pressure control :
peripheral baroreceptors detect changes in the blood pressure and send appropriate
messages to the cardiovascular center in the medulla of the brain which will lead to
activation of preganglionic sypathetic neurones to the heart and stimulate B1      receptors
produce increase heart rate and increase strength of contraction , and also baroreceptors
will send messages to the vasomotor center which will lead to increases vasomotor
outflow which will cause arterial vasoconstriction .
       increase vagal activity reduces the heart rate ,but , with the exception of the
      coronary and salivary gland vascular beds there is no parasympathetic control of the
      blood vessels .
       Moment-to-moment reflex control of the circulation is via arterial baroreceptors in
      the wall of the aorta and the carotid arteries.
1.2.2-renin and angiotensin :
The renin-angiotensin-aldosterone system plays a major part in the control blood
pressure , via its control of sodium balance.
Renin secretion from granules in the juxtaglomerular apparatus is stimulated by a fall in
the plasma volume , drop in the blood pressure and sodium depletion . renin acts on
angiotensinogen to release angiotensin‫, ة‬which is convertes by angiotension converting
enzyme to angiotension²² , and this compound cause is vasoconstriction , stimulation of
the noradrenergic sympathetic nervous system , changes in the intrarenal flow patterns
and stimulate of the production of the aldosterone from the adrenals glands .so the
consequent rise in the angiotenson²² and aldosterone secretion leads to sodium and
water retention and hence restoration of sodium balance and plasma volume.
1.3-Epidemology :
Hypertension accurs in 10 to 20% of middle aged adults in developed countris and
becomes more common with increasing age.
       primary or essential hypertension accounts for approximately 95% of hypertension
      population , the remainder consisting of patients with secondary hypertension .
       urban black population have a higher incidence of hypertension than their white
      neighbors . Both environmental and genetic factors are likely to be responsible.
category                         systolic                  diastolic
normal                           Less than 130            Less than 85
High normal                      130-139                   85-89
Hypertension
         Stage 1(mild)           140-159                  90-99
         Stage 2(moderate) 160-179                        100-109
          Stage 3(sever)         180-209                  110-119
          Stage         4(very   More than 210             More than 120
sever)
                          Different stages of hypertension




1-4Classification of Hypertension:
1-     Primary or Essential Hypertension:
       In over 90% of People no identifiable - No direct cause- cause can be found .
       there are some factors may involves.
2-     Secondary Hypertension:
       In approximately 5% of Hypertensive patients a cause can be identified.

     1.4.1-Primary Hypertension:
              Primary Hypertension is not a disease, it has no symptoms and patients do
       not die directly from it. Causes and Incidence The cause of primary (essential)
       hypertension is unknown. However, known risk factors include a familial history of
       the disease, race, obesity, tobacco smoking, stress, and a high-fat or high-sodium
       diet in genetically susceptible individuals.

       1.4.1.1-Aetiology          :
       Primary or essential Hypertension has no single identifiable cause but may be
       affected by number of factors:


I-AGE:
       Blood pressure tends to increase with increasing age. This is
Probably due to decrease compliance or blood vessels which leads to an alteration in
peripheral resistance and hence an increase in blood pressure .
Deastolic blood pressure may start to fall in those over 80 years old although the systolic
blood pressure can remain elevated. ( Isolated systolic Hypertension) , this is due to
arteriosclerotic changes in major vessels of the elderly ( greater rise in systolic compared
with risk to diastolic pressure , this condition is associated with an excess risk of
morbidity through stroks , myo cardial In Fraction and congestive cardiac failure so this
condition should be vigorously treated.
II-Genetics:
   There is a tendency for Hypertension to run in families.
III-Environment:
   A- Stress : Mental and Physical stress cause transient increase in blood pressure.
   B- Sodium intake: sever dietary sodium restriction in patients who usually have a
   high salt intake dose Lead to a beneficial drop in blood pressure , however , reducing
   salt intake in patients whose consumption is not high , dos not have the same effect.
   C-Alcohol: Patients who drink large amounts of alcohol have a raised blood
   pressure which will fall if alcohol consumption is reduces.
IV-Weight:
      Obese patients have higher blood pressure than non obese patients and weight
   reduction can lead to decrease in blood pressure.
V-Race:
      In developed countries Caucasians tend to have lower blood pressure than black
   people . It may be that black people are more responsive to stress than Caucasians,
   may be also genetically geared to salt preservation as result of their hot climate.
  1.4.2-Secondary Hypertension:
             Has identifiable underlying cause however removing the cause will not
      necessarily result in a fall in blood pressure . This is because the raised blood
      pressure can damage organs such as the kidneys which relates a vicious the
      circle by causing a further rise in blood pressure and leads to more damage.


1.4.2.1- common cause of secondary hypertension :


I-Renal disease:


A-Chronic renal failure of any cause.
B- Renal arterial stenosis:
      which activities the rennin- angiotensin system and lead       to hypertension.
C- Atheromatous disease :
       (Atherosclerotic disease ) is the is the commonest form of renovascular disease ,it
is mainly affects middle-aged mal smokers.
D-Fibromuscular dysplasia :
       (a disease of younger age groups) a surgical reconstruction of renal arteries may
be very effective .
E-renovascular hypertension :
       has increased importance of diagnosing because ACE inhibitors must be avoided
in this situation . as these drugs can precipitate renal failure due to the roll to angiotensin
II in maintaining intrarenalhemodynamics in the underperfused kidney.
F-Acute and chronic glomerulonephritis .




II-Arterial disease:
  A-Atherosclerotic disease.
  B-Fibromuscular dysplasia.
  C-Embolism.
  E-Polyarteritis nodosa.
III- Endocrine disease:
       A- Hyperaldosteronism:
over production of aldosteron may be due to single or multiple autonomous adrenal
adenomas (conh’s syndrome)or bilateral micronodular hyperplasia of zona glomerulosa.
       B-phaeochromocytomas : are tumours, usually fuond in the adrenal , which
secrete a mixture of catecholamines , the majority (90%) of the tumors are benign, and
10% arise outside the adrenals.


IV-coarctiation of the arota:
       it is a congenital defects , children or young adults , present with asymptomatic
upper limb hypertension , surgery is now recommended before the age of 6, but balloon
angioplasty has recently been successfully used in this condition .
V-drug-induced hypertension:
       A-mineralocorticoid – induced hypertension with hypokalemia and alkalosis.
       B-Carbenoxolone and excessive liquorice consumption.
       C-Hypertension induced by contraceptive pill is generally mild and reversible.
       D-In general all steroids may induce hypertension.
       E-Sympathomimetic nasal decongestant and other cold preparations may also
induced blood pressure .
1.4.3-Malignant or accelerated phase hypertension :
       Malignant or accelerated phase hypertension can occur in patients with primary or
secondary hypertension in which a rapid rise in blood pressure and is often associated
with vascular fibrinoid necrosis and loss of precapillary arteriolar autoregulation as a
consequence the capillary vessel rupture which will lead to a tissue necrosis through
hemorrhage and ischaemia.
It is seen most markedly in the retina of the eye and appears as retinal exudates .the
kidney is also damaged leading to haematuria and proteinuria.
       It affects more blacks than whites. It may be caused by a variety of factors, such
as stress, a family history of the disease, being overweight, tobacco, birth control pills,
high intake of table salt (sodium chloride), an inactive life-style, and aging.




1.4.4-Hypertension in pregnancy :
       During pregnancy cardiac output rises , but blood pressure normally falls due to a
decrease in vascular resistance.
       Pre-eclampsia and eclampsia are placental syndromes. Pre-eclampsia is defined
as hypertension with proteinuria and edema . The consequence of pre-eclampsia are
placental ischaemia and infarction and in sever cases , maternal cerebral hemorrhage
treatment is elective delivery.


1.5-Clinical manifestation :
       Hypertension has no symptoms and until patients use diagnosed as hypertensive ,
most patients feel perfectly well.
       The exception to this are patients with malignant hypertension in which the rapid
rise in the blood pressure may lead to headaches .
       The symptoms usually associated with hypertension by the layman, such as
headache and nosebleeds, are probably no more frequent than found in the general
population.
       In general primary hypertension is not a disease, it has no symptoms and patients
do not die directly from it. Its importance lies in that it is the major risk factor for
cerebrovascular accidents and cardiovascular events.




1.6- Investigations:
       The diagnosis of hypertension riles solely on blood pressure reading


1.6.1-Measurement of BP:
       The blood pressure is most often measured by using a device called a
sphygmomanometer, a stethoscope, and a blood pressure cuff. The cuff is placed around
the upper arm and filled with air, tightening to stop the blood from flowing through the
artery in the arm. The stethoscope is placed over the artery in front of the elbow and the
pressure in the cuff is slowly released.
No sound is heard until the cuff pressure falls below the systolic pressure in the artery; at
that point a pulse is heard. As the cuff pressure continues to fall slowly, the pulse
continues; first becoming louder, then dull and muffled. These sounds, called the sounds
of Korotkoff, are caused by the disturbance of the blood flowing through the vessel. The
cuff pressure at which the first sound is heard is the systolic blood pressure, and the cuff
pressure at which the sounds stop is the diastolic blood pressure. The pressure in both
arms is sometimes taken. A major difference between the two readings may mean there
is a blockage of the vessels.
       The blood pressure may also be taken using the thigh with the stethoscope held
behind the knee. A larger cuff is used when taking the blood pressure of an overweight
person or when using on the thigh. Any factor that increases resistance of the vessels to
the flow of blood or that affects the amount of blood pumped by the heart will change the
blood pressure. Strong emotion, for example, tends to do both; therefore the blood
pressure reading is usually taken when the person is resting. Blood pressure increases
with age, mainly because the veins do not expand as well. As a person grows older an
increase in systolic pressure comes before an increase in diastolic pressure.
Elevated pressures on at least two occasions from measurements taken on three
separate days are needed to label a person hypertensive. Secondary causes are then
ruled out to make a determination of primary hypertension.
       It is important that the correct technique is used, with suitable equipment.
Sphygmomanometers . should be well maintained . in the case of mercury (the most
popular ) the glass should kept clean and that the mercury zeroes correctly.


1.6.2- Diagnostic Tests(further investigations)
       Biochemical , radiological ,and cardiac investigations to determines the effect of
elevated blood pressure on various organ systems(kidney and heart) and to identify a
cause(if there is a cause) of hypertension .
       I-urine testing :
              1- persistent proteinuria requires detailed testing of renal function.
             2-The discovery of haematuria should be followed by tests for inflammatory
             and neoplastic disease of the kidney.
       II- Blood testing :
             1- Raised serum urea and creatinine levels may indicate some of renal
                damage.
             2- High serum uric acid levels are common in-patients with renal
                hypertension and less common in untreated primary hypertensive
                patients.
             3- Serum potassium must be measured before treatment is started . low
                levels of potassium will notonly be aggravated by some drug treatments.
                But also suggest the presence of hyperaldosteronism .
             4- Other associated risk factor, such as hyperuricaemia or hyperlipidaemia.
             5- Anaemia due to chronic renal disease .
       III- ECG (electrocardiogram) :
                     Will indicate whether left ventricular hypertrophy has occurred.
                     Long-standing untreated, or poor treated hypertension leads to a
              strain on the heart as it tries to pump blood around the body against the
              increased peripheral resistance. This results in an enlargement of the left
              ventricular muscle. The presence of hypertrophy is an important indicator of
              poor long-term survival.
       IV- chest X-ray:
                     The chest X-ray is helpful in establishing cardiac size and may reveal
              cardiac failure.

1.7-Potential Complications of hypertension :
        Complications     include   Atherosclerotic   disease,   left   ventricular   failure,
cerebrovascular insufficiency with or without stroke, retinal hemorrhage, and renal failure.
When the pathologic process is accelerated, malignant hypertension results, the blood
pressure becomes extremely high, and nephrosclerosis, encephalopathy, and cardiac
failure rapidly ensue.


The main system which are involved in complications are :


I – Heart:
       Indirectly by promoting Atherosclerotic changes .also hypertension can promote
cardiovascular disease and increase the risk for ischemic events such as angina and
myocardial infarction.
       ventricular hypertrophy which is potent and independent risk factor for myocardial
ischaemia, MI, CHF, arrhythmias and sudden death .
       The third cardiac manifestation of hypertension is Congestive heart failure which
may be due to repeated ischaemia, excessive ventricular hypertrophy, and /or pressure
overload .


II- Brain :
       Hypertension is the most frequent causes of transient ischemic attacks(TIAs) ,
Ischemic stroke, Multipe cerebral infracts and hemarrhages.
       Prolonged increase in systemic blood pressure also can cause hypertensive
encephalopathy which is a hypertensive emergency .
III- Kidney :
       Glomerular filtration rate naturally declines with aging . however, hypertension
greatly accelerates the rate of decline of glomerular rate .
        Hypertension is associated with nephrosclerosis, which is caused by increased
intraglomerular pressures.
       Systemic hypertension directly causes Glomerular capillary damage by Increasing
intraglomerular pressure . hypertension is responsible for approximately one third of all
cases of end-stage renal disease (ESRD) requiring dialysis .
IV- Eye :
       Hypertension causes retinopathies that are characterized by narrowing of the
arterial diameter indicative of vasoconstriction, and atherosclerosis .



Section II
            Antihypertensive agents and the treatment of hypertension


2.1-Non-pharmacological treatment:
       Interest in nonpharmacological methods to lower blood pressure arises in part
from the fact that about 70% of hypertensive subjects have a mild , asymptomatic
elevation of blood pressure. So minor alterations of normal activity or diet can reduce
blood pressure to a satisfactory levels and the complications of drugs therapy can be
avoided . and increase the efficacy of drug treatment .and this include :
1-Reduction of body weight :
            obesity and hypertension are closely associated . and the degree of obesity is
       positively correlated with the incidence of hypertension . Obese hypertensives
       may lower their blood pressure by losing weight regardless of a change In salt
       consumption . the mechanism by which obesity causes hypertension is unclear ,
       but increased secretion of insulin in obese person could result in insulin-mediated
       enhancement of renal tubular reabsorption of Na+ and an expansion of
       extracellular volume . also Obesity is also associated with increased activity of the
       sympathetic nervous system all of this actions is reversed by weight loss .
2-Sodium restriction :
                  High salt diets are associated with a high prevalence of hypertension ,
       sever restriction of salt will lower the blood pressure in most hospitalized
       hypertensive patients . However , sever salt restriction is not practical from a
       standpoint of compliance . several studies have shown that moderate restriction of
       salt intake to approximately 5g per day will lower blood pressure by 12mm Hg
       systolic and 6mmHg diastolic. The higher the initial blood pressure , the greater the
       response .and subjects over 40 years age are more responsive to the hypotensive
       effect of moderate restriction of salt .than young people .An additional benefit of
       salt restriction is improved responsiveness to some antihypertensive drugs .
3-Alcohol Restriction :
              Consumption of alcohol can raise blood pressure . but it is unclear how
       much alcohol must be consumed to observe this effect . heavy consumption of
       alcohol increase the risk of cerebrovascular accidents but not coronary heart
       disease. Excessive intake of alcohol may also result in poor compliance with
       antihypertensive agents .
4-Physical Exercise :
                  Increase physical activity lowers rates of cardiovascular disease in men , it
       is not known if this beneficial effect is secondary to an antihypertensive response
       to exercise .lack of physical activity is associated with a higher incidence of
       hypertension . regular isotonic exercise reduces both systolic and diastolic blood
       pressure by approximately 10mm Hg . the mechanism by which exercise can lower
       blood pressure is not clear , regular isotonic exercise reduce blood volume and
       plasma catecholamines and elevates plasma concentrations of atrial natriuretic
       factor .
5-Relaxation and biofeedback Therapy:
                The fact that long-term stressful stimuli can sustained hypertension in
      animals . has given credence to the possibility that relaxation therapy will lower
      blood pressure in some patients . but few studies have generated positive results ,
      but generally relaxation therapy has inconsistent and modest effects on blood
      pressure .
6-Potassium therapy :
              there is a positive correlation between total body Na+ and blood pressure
      and negative correlation between total body K+ and blood pressure in
      hypertensive patients . increase intake of K+ might reduce blood pressure by
      increasing excretion of Na+ , suppressing renin secretion , causing arteriolar
      dilatation (possibly by stimulating Na+,K+-ATPase activity and decreasing
      intracellular concentration of Ca+ ) . and impairing responsiveness to endogenous
      vasoconstrictors .In hypertensive rats, supplementation with K+ decrease blood
      pressure and reduce the incidence of stroke .
7-Smoking cessation :
                All patients should be educated about the benefits of smoking cessation
      because of the association between smoking and increased risk of coronary death
      increases with the number of cigarettes smoked and is greater in patients with
      additional risk factors.
          For coronary heart disease cigarette smoking carries with it the detrimental
          effects of decreasing the oxygen-carrying capacity of the blood , increasing
          platelet adhesiveness, elevating heart rate, acutely increasing catecholamines
          and     fatty   acids,   and   increasing   myocardial   susceptibility   to   atrial
          fibrillation,chronic atheragenic effects also occur with cigarette smoking .
8-Caffeine ingestion :
              caffeine has been associated with an acute elevation in blood pressure ,
      however, this appears to be a transient effect and , therefore, dose not affect blood
      pressure control. Limitation on caffeine intake are not recommended for other
      health reasons (cardiac arrhythmias ).
9-Calcium :
                Evidence from clinical trials on the antihypertensive effect of calcium
       supplementation through dietary intake or proprietary supplements has been
       inconclusive . there appears to be a subgroup of patients who may respond to
       calcium supplementation, however, away to identify these individuals has not been
       determined .
10-Magnesium :
              the role of magnesium in hypertension is not well established. An inverse
       association between magnesium intake and blood pressure appears to exist .




2.2-Pharmacological         treatment     (drugs     used     in   the    treatment     of
hypertension):
2.2.1-Sympatholytics:
2.2.1-1centrally acting agents : ( stimulate ‫ 2ل‬receptors ):
       The two drugs in this class that are still in use are methyldopa and clonidine
they cause general sympathoplegia so they are used as second or third choise . in the
treatment of hypertension in patient resistant to other drugs .

A-methyldopa :
       mechanism of action : taken up into nerve terminal then converted to
methylnoradrenaline which is potent ‫ 2ل‬agonists so it will decrease cardiac output and BP
. and cause vasodilatation . and thus they will lead to decrease blood pressure .

Side effects :
              1- can cause orthostatic hypotension , fluid accumulation and bradycardia .
              2- fever and flulike symptoms may represent hepatic dysfunction .
              3- C.N.S effects includes sedation ,headache , nightmares , psychosis
                 and depression.
              4- Failure of ejaculation , diarrhea and nosal block .

B-clonidine :
       action : stimulates ‫ 2ل‬receptors centrally , and peripherally decreasing vasomotor
tone and heart rate , ehich will lead to decrease blood pressure ..
sadden withdrowal can cause sever hypertension ( rebound hypertension). so we have to
add another antihyretensive agent first and decrease the dose of clonidine gradually .


side effects :
             1-sedation, psychosis, drowsiness ,depression. Euphoria, And nightmares
             2-orthostatic hypotension .
             3-dry mouth, failure to ejaculation .

2.2.1-2 ganglionic blockers :
       The most important example of this group is trimethaphan , the mechanism of
lowering the blood pressure is mainly by blocking the sympathetic ganglia , thie blocking
can cause vasodilatation and bradycardia which will lead to decrease in the blood
pressure .

Side effect :
       1- constipation , urinary retension .
       2- failure to ejaculation .

clinical use :
       1- In hypertension rises .
       2- Induce hypotension during surgery.




2.2.1-3 Adrenergic neuron blockers :
       This class of antihypetensive drugs is better to avoided unless it is necessary to
treat sever refractory hypertension .it is classified to :
A)storage inhibitors ( reserpine ) :
       it prevent the storage of all catecholamins centrally and peripherally so they are
       metabolized by MAO so the drug produce general sympathoplegia .
Side effects :
       1- central effects includes , sedation , depression , parkinsonism , dizziness ,
          weakness, memory impairment and sleep disturbances .
       2- Nasal congestion and weight gain .
       3- Peptic ulcer is also is contraindicated in reserpine .


B)release inhibitors :
       Guanethidine and guanadril are the main drugs in this group , thy are uptake into
adrenergic nerve terminal then thy inhibit release of NA by local anaesthetic effect , inside
the nerve terminal they will displace NA slowly , these will result after time to deplesion of
NA storage (sympathoplegia ) so this drugs should be given at the begin in a small and
slowly increase the dose tell the maximum dose . both drugs do not have central effect
because they can not cross blood brain barrier .
Side effects :
       1- no central side effect .
       2- postural and exercise hypotension .
       3- Fluid retention .
       4- Sexual dysfunction .
Contraindications :
       1- In pheuchromocytoma .
       2- In case of treatment with MAOI .
       3- Contraindicated with uptake inhibitors like tricyclic antidepressants ,because
          they will antagonize the effect of guanethidin .
       4- Contraindicated in O.T.C that contain sympathomimetic substances (cold
          preparations ) because the combination may potentiate an acute hypertensive
          effect .




2.2.1-4 Beta-receptor blockers :
       The major difference among the many beta-blocking agents drugs is their relative
a affinities for ‫ 1آ‬and ‫ 2آ‬and their pharmacokinetic characteristics. they vary in their lipid
solubility , intrinsic sympathomimetic activity and membrane stabilizing properties.
       Many hypertensive patients will respond to a beta-blockers used alone, but the
drug is most often used with either a diuretic or vasodilator.


I-Mechanism of action:
           On the cardiovascular system beta blocking agents chronically lower blood
pressure in-patients with hypertension.
       In conventional dose, these dregs do not cause hypotension in healthy individuals
with normal blood pressure.
       Beta-receptor antagonist have prominent effects on the heart . the negative
isotropic and chronotropic effects are predictable from the role of adrenoreceptors in
regulating these function , slowed atrioventricular conduction due to blocking of
adrenoreceptors in the atrioventricular nod .
       In the vasculare system , beta –receptor blockade B2 –mediated vasodilation .this
may    results      initially   in   a   rise   in   peripheral   resistance   from   unopposed
alpha-receptor-mediated effects .
       Beta-blocking drugs antagonize the release of renin caused by sympathetic
nervous system


II-General Pharmacokinetic properties:
           Most of the drugs in this class well absorbed after oral administration , propranolol
undergoes extensive hepatic (first-pass) metabolism ; it is bioavailability is relatively low.
the beta blocking drugs are rapidly distributed and have large volume of distribution .
       Propranolol and penbutotol are quite lipophilic and readily cross the blood brain
barrier.
       Propranolol and metoprolol are extensively metabolized in the liver, with little
unchanged drug appearing in the urine.
       Atenolol, celiprolol and pindolol are less completely metabolized.
       Nadolol is excreted unchanged in the urine and has the longest half-life of any
available beta antagonist.



III-Non-selective B-adrenergic antagonists:
   A-without intrinsic sympathomimetic activity:
      This drugs produce initial reduction in cardiac output and a rise in peripheral
resistance with no net change in arterial pressure . then the peripheral resistance returns
to pretreatment values in few hours to few days , resulting in the reduction the blood
pressure .
      1-propranolol:
             is the prototype beta-blocking drug it has low bioavailability , the result of
      extensive first-pass metabolism in the liver . it is non-selective B-blocker .
      2-Nadolol :
              It has equal affinity for B1 and B2 receptors . is note worthy for its long
      duration of action ; its spectrum of action is similar to timolol , it is excreted
      unchanged in the urine. With half-life rang from 12 to 20 hours .
      3-Timolol :
             Is a short –acting , potent , nonselectiveB blocker with half-life in plasma
      about 4 hours.


   B-with sympathomimetic activity :
      1-pindolol    :
             drugs with intrinsic sympathomimetic activity produce less effect on resting
      heart rate and cardiac output , and a fall in arterial pressure is correlated with a fall
      in vascular resistance below pretreatment levels . (because of stimulation of
      vascular B2 adrenergic receptors that mediate vasodilatation ) effect they have
      partial beta-agonist activity , they are effective in the major cardiovascular
      applications of the beta – blocking group . these partial agonists may be less likely
      to cause bradycardia and abnormalities in plasma lipids than are antagonists the
      plasma half-life of pindolol is about 4 hours .. Other agents belongs to these group
      are acebutolol , carteolol , celiprolol and penbutotol .


  C- with alpha blocking activity :
    1- Labetalol :
           The antihypertensive action of these group is due to alpha 1 blockade
    which leads to relaxation of arterial smooth muscle and vasodilation . the B1
    blocking will block the reflex sympathetic stimulation of the heart. this drug is
    representative of a relatively new class of drugs. It is a reversible adrenoceptors
    antagonist available as a racemic mixture of two pairs of chiral isomers , the SS
    and RS isomers are inactive . SR is a potent alpha-blocker (mainly alpha one )and
    the RR isomer is potent nonselective beta blocker . the potency of the mixture for
    B-adrenergic blockade is five fold than alpha-adrenergic blockade . the half-life of
    the drug is 4 to 6 hours .


IV-selective B-adrenergic Antagonist :
    1-Metoprolol and atenolol :
            are members of the B1 selective blockers . they have a direct effect on the
    heart ,by blocking B1 receptors in the heart thy will decrease the cardiac out put
    and thus decrease the blood pressure . these agents may be safer in patients who
    experience bronchoconstriction response to propranolol . but because B1
    selectivity is modest, they should be used with great caution in patients with a
    history of asthma . Beta 1 –selective antagonists may be preferable in-patients
    with diabetes or peripheral vascular disease when therapy with a beta blocker is
    required. These drugs may cause change in lipid plasma less frequently, the main
    Chang between Metoprolol and atenolol is in the pharmacokinetic properties
    metoprolol subjected to first pass metabolism and is extensively metabolized . it
    half-live from 3 to 4 hours . on the other hand atenolol is excreted largely
    unchanged in the urine with half-live about 5-8 hours .
    2-Esmolol :
            Is an ultra-short acting B1 selective blocker , is administered intravenously
    and is used when B blockade of short duration is desired in critically ill patients.
V-Clinical toxicity:
     1- minor toxic effects like , rash , fever , ,and other manifestations of drug allergy
     are rare . it may cause cold extremities due to blocking of beta 2 receptors in the
     blood vessels .

     2-   central nervous system effects include sedation , sleep ditubances , and

     depression , rarely , psychotic reactions may occur .

     3-   chronic use of beta-blockers has been associated with increased plasma

     concentrations of VLDL and decreased concentration of HDL , both these changes
     are unfavorable in terms of risk of cardiovascular disease. LDL concentrations
     generally do not change.it may also increase concentration of plasma
     triglycerides.



     4-   The major adverse effect of beta-receptor antagonist drugs relate to the beta2

     receptor blocked associated with the use of nonselective agents , which cause
     worsening of preexisting asthma and other forms of airway obstruction .B1
     selective blockers drugs and beta blockers with intrinsic sympathomimetic activity
     may have less effect on airways than nonselective beta blockers . B1 selective
     blockers and beta blockers with intrinsic sympathomimetic activity, are generally
     will tolerated in patients with mild to moderate peripheral vascular disease, caution
     is required in patients with sever peripheral vascular disease or vasospastic
     disorders. Like raynoud’s phenomenon .(may become worsen ).

     5-   In patients with abnormal myocardial function , cardiac output may be

     dependent on sympathetic drive . so great caution must be exercised in using beta
     – receptor blocker       in patients with moycardial infarction or compensated
     congestive heart failure.( b-blockers may induce congestive heart failure in
     susceptible patients).

     6- In patient with partial or complete atrioventricular conduction defect ,B-blockers
     may cause life-threatening bradyarrhythmias .
      7- Beta blockers may blunt recognition of hypoglycemia by patients.
      8-   glycogenolysis in the liver is at least partially inhibited by beta blockers, so

      Beta blockers Delay the recovery from insulin induced hypoglycemic coma .in
      patients suffers from diabetes mellitus. The rate of recovery from hypoglycemic
      coma may be faster in patients receiving Beta1 – selective blockers than the
      non-selective beta-blockers .

      9- beta blockers may mask clinical signs of developing hyperthyroidism.


VI-Interactions :
      A- pharmacodynamic interactions:
      1- beta-blockers may interact with the calcium antagonist (verapamil ) , severe
           hypotension , bradycardia , congestive heart failure , and cardiac conduction
           abnormalities may be produce .
      2- sudden discontinuing beta antagonist therapy after chronic use , may produce
           sever increase in the blood pressure because of sympathetic hyperactivity ,
           due to ( up regulation ) increase number of beta receptors.
      3- Non steroidal antiinflammatory drugs such as indomethacin can blunt the
           antihypertensive effect of propranolol and probably other B-blockers . this
           effect may be related to inhibition of vascular synthesis of prostacyclin , as well
           as to retention of Na+ .
      B- pharmacokinetic interactions:
      1-Aluminum salts , cholestyramine , and colestipol may decrease the absorption
      of B blockers.
      2- Phenytoin , rifampin , phenobarbital and smoking , induce hepatic
      biotrasformation enzymes and may decreas plasma concentrations of B-blockers .


VII-Clinical properties :
      1- The B-adrenergic receptor antagonists do not cause retention of salt and water
        .
     2- The combination of a b-blocker , a diuretic and a vasodilator (minoxidil)is
        effective ; this combination can control the arterial pressure of most patients ,
        even who are resistant to other regimens.




2.2.1-5 ALPHA – RESEPTOR BLOCKING DRUGS:
 I-Mechanism of action :
                       Alpha – receptor antagonist may be reversible or irreversible.
 II-Classification :
     1-non- selective alpha blockers .
     2-selective alpha blockers .
 III-Pharmacologic Effects:
     Cardiovascular Effects: Arteriolar and venous tone are determined to a large
     extent by alpha receptors on vascular smooth muscle (by sympathetic nervous
     system ) Alpha receptors blocking drugs cause a lowering of peripheral vascular
     resistance and blood pressure . this causes a sympathetically mediates reflex
     increase in heart rate and plasma renin activity.
     So Alpha - blockers may cause postural hypotension and reflex tachycardia.
     Tachycardia by be more market with agents that block Alpha2 presynaptic
     receptors in the heart. So norepinephrine will further stimulate beta-receptors in
     the heart.
     Chronic use at Alpha-blockers may result in a compensatory increase in blood
     volume.
     During long term therapy, vasodilatation persists but cardiac out put heart rate and
     plasma renin activity return to normal. renal blood flow is unchanged during
     therapy with Alpha 1 adrenergic antagonist.
IV-SPECIFIC AGENTS:
    A-non-selective alpha blockers:

    1-Phentolamine :
           an Imidazoline derivative , is a potent competitive antagonist at Alpha
    Receptors (both alpha 1 and alpha 2 ).Phentolamine is about equally potent on
    Alpha 1 and alpha 2 . It cause a reduction in peripheral resistance through both
    alpha receptor blockade and an additional norardrenergic action on vascular
    smooth muscle.
           The   Cardiac stimulation induced by phentolamine may be reflex and
    Alpha2 receptor blocked my be involved
    Pharmacokinetic properties :
           Phentolanime is poorly absorbed after oral administration the .
    Adverse Effect:
    1-     Cardiac stimulation , tachycardia , arrhythias and angina .
    2-     Gastrointestinal stimulation may cause diarrhea and Increase gastric acid
           production.


    2- Phenoxybenzamine :
           Binds covalently to Alpha receptors , it has long duration of action , it is
    some what selective to Alpha1 receptors but less so than prazosin.
           Phenoxybenzamine causes relatively little fall in blood pressure in supine
    individual , it will reduce blood pressure when sympathetic tone is high , cardiac out
    put may be increased because of reflex effects and because of some blockade of
    presynaptic Alpha2 receptors in cardiac sympathetic nervees.
    Adverse Effetcs of phenoxybenzamine :
    1-     Postural hypotension and tachycardia .
    2-     Nosal stuffiness.
    3-     Inhibition of ejuculation .
    4-     Central effects include Fatigue , Sedation , nausea.
    Pharmacokinetics :
Phenoxybenzamine is absorbed after oral administration through bioavailability is
low.



B-Selective Alpha blockers :
       Blood pressure is reduced more in the upright than in a supine position.
Retention of salt and fluid accurse when these drugs are administrated without
diuretic.
       The drugs are more effective when used in combination with other agents,
such as Propranolol and diuretic than when use alone.


1- Prazosine
        Is effective drug in the management of hypertension. It is reversible Alpha1
antagonist . It has a low affinity for Alpha 2 . this may partially explain the relative
absence of tachycardia as compare to Phentolamine and Phenoxibenzamie
Prozosin leads relaxation of both arterial and venous smooth muscle. It reduce
Arterrial pressure by dilating both resistance and capacitance vessels.
       Prazosin does not increase heart rate, response that occurs in other
vasodilators .


Pharmacokinetics :
       prazosin is will absorbed it is boiavailability is about 70%. It is extensivly
metabolized in humans , only 50% of the drug is available after oral administration
because its undergoes first –pass metabolism in the liver .the drug is tightly boud
to plasma proteins, and only 5% of the drug is free in the circulation .the half – life
is normally about three hours but the duration of the antihypertensive effect is
longer . It is eliminated almost by metabolism. plasma concentration are increase
in patients with C.H.F.


Dosage:
       the treatment with prozosin should be initiated with a low dose (1 mg 3 times
day) to prevant postural hypotension and synoscope. Doses my be increased to
      20 or 30 mg/d.



      2-Terazosin:
              Is another reversible Alpha1 selective antahonist that is effective in
      hypertension.it is less potent than prazosin .
      It has also been approved for the use in men with urinary symptoms due to
      prostatic Hyperthophy.


      Pharmacokinetics:
             Terazosin has high biovailability , it is extensively metabolized but
      undergoes very little first – pass metabolism with only a small fraction of parent
      drug excreted in the urine , the half- life is about 6 – 12 hours.


      Dosage :
      Terazosin can often be given once dauily, with doses of 5 – 20 mg/d.


  3- Doxazosin :
       Is the third Alpha 1 selective antagonist approved for use in hypertension


  Pharmacokinetics
      It has moderate bioavailability and is extensively metabolized. With very little
  parent drug excreted in urine and feces . Doxazosin has active metabolites , through
  their contribution to the drugs effects is probably small. The parent compound has a
  half- life of about 22 hours.


  Dosage:
       Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4mg./d
  or more as needed.


V-Adverse effects of alpha blockers :
      Although long term treatment with these alpha blockers cause relatively little
  postural hypotension , a number of patients develop a precipitous drop in standing
  blood pressure shortly after the first dose is absorbed . for this reason , the first dose
  should be small and should be administered at bedtime. While the mechanism of this
  first-dose phenomenon is not clear ; it occurs more commonly in patients who are salt
  and volume depleted and also patients taking B-blockers or diuretics.
  Aside from the first dose phenomenon , the reported toxicity of the Alpha1 blockers are
  relatively in frequent and mild . these include dizziness, palpitations, headache
  ,nausea and lassitude .
  Unlike diuretics and beta-blockers , Alpha- blockers do not adversely and may even
  beneficially affect plasma lipid profiles.( administration of Alpha- bockers may reduce
  the plasma concentration of triglycerides and total LDL-cholesterol and increase
  HDL-cholecterol).

VI-Therapeutic use:
      Prazosin and terazosin can be used to treat hypertension of any degree, but these
agents are usually not effective by themselves except in patients with mild to moderate
hypertension.
      Diuretic and beta blockers enhance the efficacy the Alpha blockers .
  Prazosin      and   phenoxybenzamine       has been      used      in   the    patients   with
  pheochromocytoma.




2.2.2- calcium channel-blocking drugs:
      I-chemical classification :
             a- Dihydropyridines the prototype of this family is nifedipine , other agents
                  prolongs to this group include felodipine, amlodipine, nimodipine,
                  nitradipine. more effective on the vascular smooth muscle .
             b- Miscellaneous : have different Chemical nuclei this drugs includes
                  verapamil(phenylakylamine)        ,     Bepridil         and        Diltiazem
                  (benzothiazepines). More effective on the cardiac muscle.
II-pharmocokinetics;
       the calcium channel blockers are orally active agents , they are
characterized by high first-pass effect , high plasma protein binding ,and extensive
metabolism.


III-Pharmacologicol properties:


A-Mechanism of action:
       Current    evidence      suggest    the   existence    of   three    types   of
voltage-dependent calcium channels (in addition to receptor-operate calcium
channels)
    voltage –dependent calcium channels are categorized as L-type ,T-type and
N-type . depending on whether they are characteristically large in conductance,
transient in duration of opening or neuronal in distribution . A fourth type the P-type
, may exist in other tissues.
    The L-type calcium channel is the dominant type in cardiac and smooth
muscle and is known to contain several drug receptors . it has been demonstrated
that nifedipine and other dihydropyridines bind to one site . while verapamil and
diltazem appear to bind to closely related but not identical receptors in another
region.
    Blocking by this drugs resembles that of sodium channel blockade by local
anesthetics, the drugs act from the innerside of the membrane and bind more
effectively to channels in depolarized membranes .
    Binding of drug appears to convert the mode of aperation of the channel from
one in which opening occur consistently after depolarization to one in which such
opening are rare . the result is a marked decrease in trasmembrane calcium
current. Associated in smooth muscle with a long-lasting relaxation and in cardiac
muscle with a reduction in contractility   throughout the heart and decrease in
sinus node conduction velocity.
    Smooth muscle respnses to calcium influx through receptor operated calcium
channels are also reduced by these drugs but not as markedly .
       The block is partially reversed by elevating the concentration of calcium.
        T-and N-type calcium channels are less sensitive to blockade by calcium
   channel blockers . therefore tissues in which these channel types play a mojor role
   (neurons and most secretory glands are much less affected by these drugs than
   are cardiac and smooth tissue).


B-Systemic effects:
          1- smooth muscle : most types of smooth muscle are dependent on
   trasmembrane calcium influx for normal resting tone and contraction responses .
       These cells are relaxed by the calcium blockers. Vascular smooth muscle
   appears to be the most sensitive , but similar relaxation can be shown for
   bronchiolar, gastrointestinal and uterine smooth muscle. In the vascular system
   ,arterioles appear to be more sensitive than veins: orthostatic hypotension is not a
   common adverse effect. blood pressure can be reduced , especially with nifedine.
       Women may be         more sensitive than men to the hypotensive action of
   diltiazem.
       Important differences in vascular selectivity exist among the calcium channel
   blockers . in general the dihydropyridines have greater ratio of vascular smooth
   effects relative to cardiac effects than do diltazem and verapamil . furthermore, the
   dihydropyridines may differ in their potencey in different vascular beds. Nimodipine
   is particularly selective for cerebral blood vessels .




       2-cardiac muscle: Cardiac muscle is highly dependent upon calcium influx
   for normal function .
       Impulse generation in the sinoatrial node and conduction in the atrioventricular
   node (calcium dependent cells ) action potentials may be reduced or blocked by all
   of the calcium channel blockers.
       Excitation-contraction coupling in all cardiac cells requires calcium influx, so
   these drugs reduce cardiac contractility and cardiac output in a dose-dependent
   fashion.
          This reduction in mechanical function is another mechanism by which the
      calcium channel blocker may reduce the blood pressure .
          Cardiac sodium channels are blocked by bepridil but somewhat less
      effectively than calcium channels . sodium channel block is modest with verapamil
      and less marked with diltiazem. It is negligible with nifedipine and other
      dihydropyridines.
          Verapamil and diltiazem interact kinetically with the calcium channel receptor
      in a different manner than dihydropyridines; they block tachycardias in
      calcium-dependent      cells   in   the   heart,   more   selectively   than    do   the
      dihydropyridines.on other hand the dihydropyridines appear to block smooth
      muscle calcium channels at concentration below those required for significant
      cardiac effects; they are therefor less depressant on the heart than verapamil or
      diltiazem.
          Bepridil also has a significant potassium channel blocking effect in the heart .
      this result in prolongation of cardiac repolarization and a distinct risk of induction of
      arrhythmias.


IV-Pharmacokinetics :
      1- The absorption of these agents is nearly complete after oral administration .
         their bioavailability is reduced in some cases markedly , because of first-pass
         metabolism . peak effects of verapamil occur within 15 minutes of its
         intravenous administration.
      2- All of these agents are bound to plasma proteins to a significant extent (70 to
         99 % ) , their elimination half-life range from 1.3 to 5 hours . during repeted oral
         administration bioavailability and half-life may increase because of saturation
         of hepatic metabolism . verapamil , diltiazem has a active metabolites .
V-Clinical uses :
      1- In dihydropyridines blood pressure is lowered . contractility and ventricular
         function are improved. And heart rate and cardiac output are increased
         modestly due to sympathetic reflexes .
      2- I.V verapamil causes a decrease in arterial blood pressure due to a decrease in
          vascular resistance , but the intrinsic negative inotropic effect of verapamil is
          offset by both a decrease in afterload and the reflex increase in adrenergic tone
          .so in patients with-out congestive heart failure . ventricular performance is not
          impaired and may actually improved , in contrast , in patients with congestive
          heart failure , I.V verapamil can cause a marked decrease in contractility .
      3- All ca++ channel blockers equally effective when used alone for the treatment of
         mild to moderate hypertension .
      4- Thes drugs are usually safe in hypertensive patients with asthma ,
         hyperlipidemia , diabetes mellitus and renal dysfunction . and they do not uric
         acids , or electrolytes
VI-Oral doses    :
       Nifedipine                                 10-20 mg
       Nicardipine hydrochloride                  20-30 mg
       Nimodipine                                 30 mg
       Verapamil hydrochloride                    40mg ,80 mg ,120 mg ,240 mg
                                                  (extended release ) tablets .
       Diltiazem hydrochloride                    30 mg




VII-Toxicity :
       1- Excessive tnhibition of calcium influx can cause serious cardiac depression,
          including cardiac arrest, bradycardia, atrioventricular block . and congestive
          heart faillure.
       2- Bepridil consistently prolongs the cardiac action potential, and in susceptible
          patients may cause a dangerous torsade de pointes arrhythmia.
       3- Minor toxicity includes, flushing , edema, dizziness, hypotension, headache,
          gingival hyperplasia, nausea and constipation .


VIII-Contraindications:
       1- In patients with a history of serious arrhythmias or prolonged QT syndrom.
       2- Patients receiving beta blockers are more sensitive to the cardiac depressant
           effects of calcium channel blocke Should not used in patients with SA or AV
           nodal abnormalities .rs.
       3- Should not used in patients with SA or AV nodal abnormalities .



2.2.3- Diuretic therapy of hypertension :
        Until now the mechanism of the antihypertensive effect of the diuretics is uncertain
,this drugs first decrease extracellular volume and cardiac output . but the hypotensive
effect is maintained during long-term therapy because of reduction in vascular resistance
; cardiac output returns to pretreatment values and extracellular volume remains
somewhat reduced .



2.2.3.1-loop diuretics :
      selectively inhibit Nacl reabsorbtion in the thick ascending limb of the loop of henel.
      The most important drugs of this group are ethacrynic acid , Bumetanide and
  torsemide they are mainly sulfonamide derivatives .
  Furosemide is not asulfonamid derivative is phenoxyaceetic acid derivative.


  I-Pharmacokinetics :
         the loop agents are rapidly absorbed . they are eliminated by renal secretion as
  well as by glomerular filtration . the duration of effect is usually 2-3 hours. The half-life
  is depend on renal function .
        The bioavailability of furosemide is about 60% , wile that of bumetanide is nearly
  100% . Ethacrynic acid , furosemide and bumetanide are extensively bound to plasma
  proteins , but they are rapidly secreted by the organic acid transport system of the
  proximal tubule.
       Torsemid has a somwhat longer half-life and duration of action than furosemide or
  bumetanid. It has at least one active metabolite with a considerably longer half-life than
  that of the parent compound.
II-Mechanism of action :
       These drugs inhibit the coupled NA/K/2CL transport system in the luminal
membrane of the thick ascending limp of Henle’s loop .
By inhibiting this transporter , the loop diuretics reduce the reabsorption of Nacl and also
diminish the normal lumen-positive potential that derives from K recycling . this electrical
potential normally drives divalent cation reabsorption in the loop. Loop diuretics by
abolishing the lumen-positive potential , cause an increase in Mg and Ca excretion.
Prolonged use can cause significant hypomagnesemia in some patients. Since Ca is
actively reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause
hypocalcemia.
Addition to their diuretic activity, loop agents appear to have direct effects on bllod flow
through several vascular beds, the mechanisms for this action are not well defined.
III- Daily oral Dosage:
       Drug                                         Dose
       Bumetanide                                   0.5-2 mg
       Furosemide                                   20-80 mg
       Ethacrynic acid                              50-200mg
       Torsemide                                    2.5-20mg




IV-Toxicity :
 1- Hypokalemic metabolic Alkalosis:
                Loop diuretics increase delivery of salt and water to the collecting duct and
       thus enhance the renal secretion of K and H+ , causing hypokalemic metabolic
       alkalosis .
 2- Ototoxicity :
                loop diuretics can cause dose-related hearing loss that is usually reversible
       it is most common in patients receiving other ototoxic agents like aminoglycoside
       antibiotics . it is more common in ethacrynic acid.


3- Hyperuricemia:
                Loop diuretics can cause hyperuricemia and precipitate attacks of gout .
       this is caused by hypovolemia -associated enhancement of uric acid reabsorption
       in the proximal tubule.
4- Hypomagnesemia:
                Magnesium depletion is a predictable consequence of the chronic use of
       loop agents and occure mast often in patients with dietery defiviency of
       magnesium.
5- Allergic reaction :
                Skin rash , eosinophilia and less often interstitial nephritis are occasionally
       side effects of furosemide therapy . they are much less common with ethacrynic
       acid .
6- Other toxicities :
       I-       sever dehydration .
       II-      Hyponatremia.
7- gastrointestinal disturbances , depression of formed elements in the blood .
       paresthesias and hepatic dysfunction .


V-Contraindications:
       1-Overzealous use of any diuretic is dangerous in hepatic cirrhosis, broderline
       renal failure or congestive heart failure(C.H.F) .
       2-contraindicated in patients receiving aminoglycosides .(cause Ototoxicity).
       3-contraindicated in patients receiving cephaloridine .because it may potentate
       nephrotoxicity .


VI-interactions :
       1- Ethacrynic acid may and furosemid are bound to plasma albumin and may
       compete for sites on the protein with drugs like warfarin and clofibrate .


2.2.3.2- Thiazides :
       Thiazides and the related compounds comprise the most frequently used
antihypertensive agents in the united states .thiazides like drugs are not effective as
diuretics or antihypertensive agents in pateints who have a glmerular filtration rate below
30ml/min . one exception is metolazone , which retains efficacy in patients with this
degree of renal failure.
       Most pateints will responds to thiazides within 2 to 4 weeks .the average response
to thiazides is a reduction of blood pressure of 20/10 mmHg .
       The thiazide-type diuretics are more effective antihypertensive agents than the
loop diuretics.
       During the treatment with diuretics plasma volume remains about 5% . below
pretreatment values . and the plasma renin activity remains elevated .


I-Pharmacokinetics :
               All of the thiazides are absorbed when given            orally, but there are
       differences in their metabolism.
       Chlorothiazide is poorly absorbed from the gastrointestinal tract, the less lipid
       soluble and must be given in relatively large doses,the half-life of chlorothaizide in
       plasma is 1.5 hours.
             Chlorthalidone is slowly absorbed and has a longer duration of action .the
       half-life     about 44 hours .
       Indapamid is excreted primarily by the biliary system, enouph of the active form is
       cleared by the Kidney to exert its diuretic effect in the distal convoluted tubule.
       All thiazides vary widely In their potency as carbonic anhydrase inhibitors.
       All the thiazides are secreted by the organic acid secretory system and compete
       with the secretion of uric acid by that system .As a result , the uric acid secretory
       rate may be reduced , with a elevation in serum uric acid level.
       Several drugs in this class are known to be highly concentrated in erythrocytes .
       probably as a result of binding to carbonic anhydras , binding to plasma proteins
       varies amonge these agents .


II- Pharmacodynamics:
               Thiazides inhibit Nacl reabsorption from the luminal side of epithelial cells in
       the distal convoluted tubule. There may also be a small effect on Nacl reabsorption
       in the in the late proximal tubule .
                Relatively little is Known about the Nacl transport system that is inhibited by
      thiazides . the      mode of transport appears to be an electrically neutral Nacl
      cotransporter that is distinct from the transporter in the loop of Henle. There is also
      an active reabsorptive process for Ca in the distal concoluted tubule , which is
      modulated by parathyroid hormon(PTH) , thiazides diuretics inhance the
      absorption of Ca in the distal convoluted tubule . the mechanism for this
      enhancement is not Known, but it has been postulated to result from a lowering of
      cell Na upon blockade of Na entry by thiazides. The lower cell Na might then
      enhnce Na/Ca exchange in the basolateralmembrane , increasing overall
      reabsorption of Ca, while thiazides rarly cause hypercalcemia as the result of this
      enhanced reabsorption .
III-Dosage:
       drug                           Dose                         Duration of action
        Hydroflumethiazide            2.5-10 mg                     6-12 hours
      Chlorothiazide                  2.5-10mg                     6-12 hours
      Hydrochlorothiazide             25-100mg                     6-12 hours
      Benzthiazide                    25-100mg                     6-12 hours
      Chlorthialidone                 50-100 mg                    24-72 hours


IV-Toxicity :
      1- Hypokalemic metabolic Alkalosis and Hyperuricemia:
      These toxicities are similar to those observed with loop diuretics.
      2- Impaired carbohydrate tolerance:
        Hyperglycemia may occur in patients who are overtly diabetic or have             mildy
      abnormal glucose tolerance testd. The effect is due both to impaired pancreatic
      release of insulin and diminshed tissue utilization of glucose . Hyperglycemia may
      be patially reversible with correction of hypokalemia .
      3- Hyperlipidemia :
      Thiazides cause a 5-15% increase in serum cholesterol , increase low-density
      lipoproteins(LDL) and increase very-low denisity lipoproteins (VLDL) . These
      levels may come down toward baseline after prolonged use .so it may enhance
   coronary atherosclerosis.
   4- Hyponatremia :
   a hyponatremia is an important adverse effect of thiazide diuretics and on rare
   occasions be life-theratening. It is due to a combination of hypovolemia-induced
   elevation of ADH, reduction in the diluting capacity of the kidney , and increased
   thiret. It can be prevented by reducing the dose of the drug limiting water intake.
   5- Allergic reactions :
    The thiazides are sulfonamides and share cross-reactivity with other members of
   this chemical group. Photosensitivity or generalized dermatitis occurs rarely .
   serious allergic reactions are extremely rare but do include hemolytic
   6- Other toxicities :
    weakness, fatigability , and paresthesia may by similar to those of carbonic
   anhydrase inhibitors. Impotence has been reported but is probably related to
   volume depletion.
   7- Depression of the formed elements of the blood , acut pancreatitis and
       necrotizing vasculitis have been reported .
   8- Borderline renal or hepatic insufficiency may be unpredictably aggravated by
       the thiazides .


        All of the thiazide-like drugs cross the placenta , but they have not been found
   to have direct adverse effects on the fetus. but there are a risk of transient volume
   depletion that may result in placental hypoperfusion .
        Since appear in breast milk , they should be avoided by nursing mothers .


V-Containdications :
   Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal
failure, or congestive heart failure.


2.2.3.3- Potassium-sparing diuretics:
   A-Aldosterone antagonists
   The members of this group antagosize the effect of aldosterone at the coritical
   collecting tubule and late distal tubule. Inhibition may occur by direct pharmacologic
   antagonism of mineralocorticoid receptors (spironolactone).
      I-Pharmacodynamics:
      The potassium-sparing diuretics reduce Na absorption in the collecting tubules
   and ducts . Na absorption (and K secretion) at this site is regulated by aldosterone. At
   any given rate of Na delivery, the rate of distal K secretion is positively correlated with
   the aldosterone level. aldosterone enhances K secretion by increasing Na/K ATPase
   activity and Na and K channel activities.
   Na absorption in the collecting tubule generates a lumen-negative electrical potential,
   which enhances K secretion. Aldosterone antagonists interfere with this process.
   similar effects are observed with respect to H+ handling by the collecting tubule, in
   part explaining the metabolic acidosis seen with aldosterone antagonists.
      Spironolactone is a synthetic steroid that binds to cytoplasmic mineralocorticoid
   receptors and prevents translocation of the receptor complex to the nucleus in the
   target cell. The drug may also reduce the intracellular formation of active metabolites
   of aldosterone by inhibition of 5‫-ل‬reductase activity.
   At relatively high concentrations . spironolactone can inhibit the biosynthesis of
   aldosterone .


      II-Pharmacokinetics :
      Spironolactone is a synthetic steroid that acts as a competitive antagonist to
   aldosterone. About 70% of an oral dose of spironolactone is absorbed . binding to
   plasma proteins is extensive . substantial inactivation of spironolactone occurs in the
   liver, and there is considerable enterohepatic circulation. , Canrenone is a major
   metabolite of spironolactone and it is an active aldosterone antagonist , salicylates
   may interfere with the tubular secretion of canrenone and thereby decrease the
   effectiveness of spironolactone.     the onset of action     of spironolactone is slow,
   requiring several days before full therapeutic effect is achieved .


B- Non aldosterone antagonist potassium-sparing diuretics:
   I-Pharmacodynamics :
inhibit the Na transport through ion channels in the luminal membrane (triamterene ,
amiloride) .
   Trimterene and amiloride do not block the aldosterone receptor but instead directly
interfere with Na entry through the sodium-selective ion channels in the apical
membrane of the collecting tubule. Since K secretion is coupled with Na entry in this
segement, these agents are also effective K –sparing diuretics.


II- Pharmacokinetics :
   Amiloride and triamterene available for oral use only , about 50% of an oral dose of
each agent is absorbed .
   Triamterene is metabolized in the liver , but renal excretion is a major rout of
elimination for the active form and the metabolites .triamterene is about 60% bound to
plasma proyeins.
   Amiloride is not metabolized and it is excreted unchanged in the urine, Because
trimterene is extensivrly metabolized, it has a shorter half-life and must be given more
frequntly than amiloride.


C- Other potassium- sparing Agents:
   Converting enzyme inhibitors are discussed later . Potassium sparing effect also
seen with drugs that suppress renin or angiotensinII generation (non steroidal
anti-inflammatory agents , beta-blockers , converting enzyme inhibitors )




D-Dosage :
    Drug                                      Dose
   Spironolactone                             25mg
   Triamterene                                50mg
   Amiloride                                      5mg
E-Toxicity :
1- Hyperkalemia : unlike other diuretics these agents can cause mild, moderate, or even
   life-threatening hyperkalemia . the risk of this complication is greatly increased in the
   presence of renal disease or of other drugs that reduce renin . since most other
   diuretic agent leads to K loss , hyperkalemia is more common when aldosterone
   antagonists are used as the sole diuretic agent, especially in patients with renal
   insufficiency.
2- Hyperchloremic Metabolic Acidosis :
   BY inhibiting H+ secretion in parallel with K secretion , the potassium-sparing diuretics
   can cause acidosis similar to that seen with type IV renal tubular acidosis.
3- Gynecomastia :
      Synthetic steroids may cause endocrine abnormalities by effects on other steroid
      receptors. Gynecomastia and other adverse effects(impotence, benign prostatic
      hypertrophy) have been reported with spironolactone. Spironolactone has been
      shown to be tumorigenic when administrated for long periods to rats in high
      concentrations .
4- Acute Renal failure:
      The combination of triamterene with indomethacin has been reported to cause
      acute renal failure. This has not yet been reported with other potassium-sparing
      diuretics .
5- Kidney stones :
      Triamterene is poorly soluble and may precipitate in the urine, causing kidney
      stones.
9- Triamterene may produce :
       nausea, vomiting , leg cramps , and dizziness . slight to moderate azotemia is
      relatively common .
10- Amilorid may produce :
      Nausea , vomiting , headache , diarrhea..
F-Contraindications :
These agents can cause sever , even fatal hyperkalemia in susceptible patients. Oral K administration
should be discontinued if aldosterone antagonists are administered . patients with chronic renal
insufficiency are especially vulnerable and should rarely be treated with aldosterone antaponists.
Patients with liver disease may have impaired metabolism of triamterene and
spironolactone , and dosing must be carefully adjusted .



2.2.4- Inhibitors of angiotensin –aldosterone system
       (Renin-angiotensin-aldosterone system ):
       I-Angiotensin pathway :


       The principal steps include enzymatic cleavage of angiotensin I from
angiotensinogen by renin, conversion of angiotensin I to angiotensin II by converting
enztme , and degradation of angiotensin II by several peptidases .


           Angiotensinogen renin       Angiotensin I convrting       Angiotensin II
                                                      enzymes
                                                                       aminopeptidase
                           Angiotensinases Angiotension III
         peptide fragments




II-Renin and factors controlling renin secretion :
               Renin is an aspartyl protease that specifically catalyzes the hydrolytic
       release of the decapeptide anpiotensin I from angiotensinogen .
               Most of the renin in the circulation originates in the kidneys. Within the
       kidney, renin is synthesized and stored in a specialized area of the nephron ,the
       juxtaglomerular apparatus , which           is composed of the afferent and efferent
       arterioles and the macula densa . the afferent arterioles and to a lesser extent , the
       efferent arteriole contain specialized granular cells called juxtaglomerular cells
       that are the site of synthesis , storage. And release of renin . the macula densa is a
       specialized tubular segment closely associated with the vascular components of
       the juxtaglomerular apparatus . the vascular and tubular components of the
       juxtaglomerular cells , are innervated by adrenergic neurons .


III-Renin secretion is controlled by several factors , including :


A-Renal vascular receptor : the renal vascular receptor functions as a stretch receptor,
decreased stretch leading to increase renin release and vice versa .
B-Macula densa : the macula densa contains a different type of receptor , apparently
sensitive to the change in the rate of delivery of sodium or chloride to the distal tubule .
decreases in the distal delivery result in stimulation of renin secretion and vice versa .
C- Sympathetic nervous system : the sympathetic innervation of the juxtaglomerular
apparatus plays an important role in the control of the renin secretion . this effect is
mediated by beta adrenoceptors ( beta 1) and involves the activation of adenylyl cyclase
and the formation of cAMP .so increase renal neural activity cause stimulation of renin
secretion .
D-Angiotensin : AngiotensinII inhibits renin secretion . the inhibition of the renin
secretion , which results from a direct action of the peptide on the juxtaglomerular cells
.(negative feedback)


IV-Angiotensin II actions :
A- effects on the blood pressure :
              angiotensin II is a very potent pressor agent ( 40 times more potent than
       norepinephrine ) . the pressor response is due to direct contraction of vascular
       especially arteriolar smooth muscle . in addition angiotensin II may also increase
       blood pressure through actions on the brain and autonomic nervous system . the
       pressor response to angiotensin II may be accompanid by little or no reflex
       bradycardia. This is apparently because angiotensin acts on the brain to reset the
       baroreceptor reflex control of the heart rate to a higher pressure .
       Angiotensin II    interacts with the peripheral autonomic nervous system. It
       stinulates autonomic ganglia, increase the release of              epinephrine and
       norepinephrine from the adrenal medulla, also increase the release and reduce
          the reuptake of norepinephrine from the nerve terminals . and Angiotensin II has a
          less important direct positive inotropic action on the heart.


B- Effects on the Adrenal cortex:
             Angiotensin II acts directly on the zona glomerulosa of the adrenal cortex fo
          stimulate aldosterone biosynthesis and secretion . in higher doses , angiotensin II
          also stimulates glucocoticiod secretion.
C- Effects on the kidney :
          AngiotensinII acts directly on the kidney to cause renal vasoconstriction , increase
proximal tubular sodium reabsorption , and , as mention above , inhibit the secretion of
renin .




V-Angiotensin receptors and mechanism of action :

Angiotensin II receptors are present in a wide variety of tissue ,including vascular smooth
muscle, adrenal renal cortex , kidney , uterus and brain . like other receptors in other
peptide hormones , angiotensin II receptors are located in the plasma membrane of target
cells .
Tow distinct subtypes of angiotensin II receptors termed AT 1 and AT2 have been identified
.
Angiotensin II and saralasin bind equally to both subtypes .
    AT1 receptors are predominante in vascular smooth muscle . most of the known actions
of angiotensin II are mediated by the AT1 receptors subtype. This redeptor belongs to the
G protin-coupled receptor superfamily . binding of angiotensin II to AT 1 receptors in the
vascular smooth muscle results in the phospholipase C-mediated generation of inositol
triphosphate (IP3 ) and diacylglycerol (DAG) . IP3 mobilizes calcium from endoplasmic
reticulum , and DAG activates protein kinase C. and these two events results in the
smooth muscle contraction .



    2.2.4.1-Angiotensin II antagonist :
       I- angiotensin analogues :

      Saralasin is a peptide in nature which resemble Angiotensin II but having
antagonist effect . it is orally inactive and may exhibit agonist activity (weak partial
agonist) when circulating angiotensin II levels are low.


       II-nonpeptide angiotensin II antagonists( has an organic nucleus) :

       Losartan : Is potent and specific competitive antagonist at angiotensin AT1
receptors, losartan is orally active , dose not exhibit agonist activity , (so losartan inhibits
the constrictor effects of angiotensin II as well as prevents the release of aldosterone due
to angiotensin II) , it is used in the treatment of mild to moderate hypertension .
       These drugs can not block the metabolism of bradykinin like ACE inhibitors so it is
atihypertinsive effect is less than ACE inhibitors .

Side effect :
      1- similar to ACE inhibitors , increase in serum potassium level . hyperkalemia has
          not been reported to be sever .
      2- Cough associated with ACE inhibitors dose not appear to occur with losartan .
      Dosage : about 50 mg daily .


2.2.4.2.- Angiotensin Converting enzyme inhibitors :
It should be noted that ACE inhibitors not only block the conversion of angiotensin I to
angiotensin II but also inhibit the degradation of other substances including bradykinin ,
substance P , and enkephalins.
I- Mechanism of action :
       Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral
vascular resistance by (antagonize the actions of angiotensin II mentioned above ).
Converting enzyme inhibitors unlike to direct vasodilators do not cause reflex sympathetic
activation , so the absence of reflex tachycardia may be due to downward resetting of the
baroreceptors or to enhanced parasympathetic activity .


II-Pharmacokinetics :
       Captopril is rapidly absorbed , with a bioavailability of about 70% after fasting .
bioavailability is decreased by 30-40% if the drug is taken with food , it is metabolisd
chiefly to to disulfide conjugates with other sulfhydryl-containing molecules , less than
half of the captopril dose isexcreted unchanged in the urine . captopril is distributed to
most body tissues , with exeption of central nervous system .the half-life of captopril is
less than 3 hours .blood levels correlate poorly with clinical response.
The half life for enalaprolat is about 11hours .
Lisinopril is slowly absorbed , with half life of 12 hours.
Generally all the ACE inhibitors except fosinopril are eliminated by the kidneys .
III- Specific agents



       1-Captopril :
              inhibits the converting enzyme peptidyl dipeptidase that hydrolyzes
       angiotensin I to Angiotensin II and (under the name of kininase ) inactivates
       bradykinin , which Is a potent vasodilator .is rapidly absorbed when given oaly .
       bioavailability averages abouts 65% and is reduced significantly by food .(half-life
       of approximately 2 hours ) nearly all the drug is eliminated in the urine . about 40%
       as captopril itself and the rest as metabolites . the drug should be taken 1 hour
       before meals .
       2-Enalapril:
              is a prodrug that is converted by deesterification to a converting enzyme
       inhibitor enalaprilate , Enalapril but not enalaprilate is rapidly absorbed when given
       orally , and bioavailability is little affected by food . the onset of action after oral
       administration is slower then with captopril . the peak reduction in blood pressure
       occurs 4 to 6 hours after ingestion . by contrast enaprilate is available only for I .V
       use in the hypertensive emergencies .and the antihypertensive response occurs
       after 15 minute of the injection .it is considerably more potent than captopril , with
       prolonged duration of action , enalaprilate binds more tightly to converting enzyme
       and presistd longer in the plasma . this property allows effective treatment with a
       single daily dose . the incidence of rash and disturbance of taste appear to be
       lower , both neutropenia and proteinuria rare
       3-Lisinopril :
               is a lysine derivative of enalaprilat.unlike enalapril , lisinopril itself is active
       in addition , it has a long duration of action . lisinopril is slowly and incompletely
       absorbed (30%) after oral administration . peak concentration in plasma are
       achieved within 6 to 8 hours . it is cleared as the intact compound by the kidney ,
       and it is half-lie in plasma is about 12 hours .
       Benzaepril, fosinopril, quinapril , and ramipril are recently introduced long-acting
       members of the class , all are prodrugs .


IV-Dosage :
       Drug                                           Dose
       Captopril                                     25mg , 2or3 times each day.
       Enalapril                                     10-20mg , once daily .
       Lisinopril                                    10-80mg ,once daily.
       Enalaprilate injection                        1.25 mg/ml.



V-Toxicity:
1- sever hypotension can accur after initial doses of any ACE inhibitors in patients who
   are hypovolemic due to diuretics , salt restriction , or gastrointestinal loss .
2- other adverse effects common to all ACE inhibitors include acute renal failure (
   particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery
   of a solitary kidney ).]
3- hyperkalemia , angioedema , and dry cough , sometimes accompanide by wheezing .
4- minor toxic effects seen more typically include altered sense of taste , allergic skin
   rashes , and drug fever , which may occur in 10% of patients
5- captopril , particularly when given in high doses to patients with renal insufficiency ,
   may cause neutroenia or proteinuria


VI-Contraindications:
      The use of ACE inhibitors is contraindication during the second and third trimesters
of pregnancy because of the risk of fetal hypotension , anuria , and renal failure ,
sometimes associated with fetal malformation or death .
VII-Important drug interactions :
   1- include those with potassium supplements or potassium-sparing diuretics , which
      can result in hyperkalemia .
   2- nonsteroidal antiinflammatory drugs may impair the hypotensive effects of ACE
      inhibitors by blocking bradykinin-mediated vasodilation which at least in part,
      prostaglandin mediated.
   3- Corticosteroids, estrogens, progestogens antagonize the antihypertensive effecte
      of ACE inhibitors.


2.2.5-Vasodilators :
             Within this class of drugs are the oral vasodilator , hydralazine and
      minaxidil, which are used foe long-term outpatient therapy of hypertension and
      parenteral vasodilators , nitroprusside and diazoxide , which are used to treat
      hypertensive emergencies.
             All of the vasodilator useful in hypertension relax smooth muscle of
      arterioles ,therby decreasing systemic vascular resistance . sodium nitroprusside
      also relaxes veins, decreased arterial resistance and decreased mean arterial
      blood pressure elicit compensatory responses , mediated by baroreceptors and
      the sympathetic nervous system and renin , angiotensin , and aldosterone . these
      compansating responses oppose the antihypertensive effect of the vasodilator
      because sympathetic reflexes are intact , vasodilator therapy does not cause
      orthostatic hypotension or sexual dysfunction.
             Vasodilator work best in combination with other antihypertensive drugs that
      oppose the compensatory cardiovascular responses .



2.2.5.1-Orally active vasodilator:
      1-Hydralazine :
Hydralazine is a hydrazine derivative , dilates arterioles but not veins . hydralazine
      may be used more effectively in combination with other drugs , particularly in sever
hypertension .


I-Pharmacokinetics :
                Hydrazine is well absorbed and rapidly metabolized by the liver during the
      first pass, so bioavailability is low -25%- it is metabolized in part by acetylation , so
      rapid acetylators have greater first pass metabolism , lower availability , and less
      antihypertensive benefit than do slow acetylators , the half life of hydralazine
      ranges from 2 to 4 hours .
      Usual dosage ranges from 40 to 200 mg/d .
II-Toxicity :
      1- nausea , anorexia , palpitations , sweating , and flushing ..
      2- in patients with ischemic heart disease , reflex tachycardia and sympathetic
          stimulation may provoke angina or ischemic arrhythmias.
      3- lupus erythematosus a syndrom characterized by arthralgia , myalgia , skin
          rashes , and fever .
      4- peripheral neuropathy and drug fever are other serious but uncommon adverse
          effects .


2-minoxidil :
                is a very efficacious orally active vasodilator. Like hydralazine , minoxidil
      dilates arterioles but not veins. The effect appears to result from the opening of
      potassium channels in smooth muscle membranes by minoxidil sulfate , the active
      metabolite . this action stabilizes the membrane at its resting potential and makes
      contraction less likely .
                it is used in patients with renal failure and sever hypertension , who do not
      respond well to hydralazine .
I-Pharmacokinetics :
       Minoxidil is well absorbed from the gastrointestinal tract and is metabolized ,
primarily by conjugation in the liver with sulfate , minoxidil half life averages 4 hours .
But the hypotensive effect is longer .
Th patients are etarted on 5 or 10 mg/d in two doses and the daily dosages is then
increased to 40 mg/d .because of the compansating mechanism minoxidil must be used
in combination with beta blockers or diuretics .
II-Toxicity :
       1- tachycardia , palpitations , angina , and edema .
       2- headache, sweating , and hypertrichosis .


2.2.5.2-parenterally administered vasodilator :

1-sodium nitroprusside :
                sodium nitroprusside is a powerful parenterally administered vasodilator
       that is used in treating hypertensive emergencies as well as sever cardiac failure .
       nitroprusside dilates both arterial and venous vessels , resulting in reduced
       peripheral vascular resistance and venous return . the action occurs as a result of
       activation of guanylyl cyclase , either via release of nitric oxid or by direct
       stimulation of the enzyme. The result is increased intracellular cGMP , which
       relaxes vascular smooth muscle .
I-pharmacokinetics, metabolism, and dosage :
                Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety . it
       is rapidly metabolized by uptake into red blood cells with liberation of cyanide.
       Cyanide in turn is metabolized by the mitochondrial enzyme rhodanase,in the
       presence of a sulfur donor to thiocyanate . thiocyanate is distributed in extacllular
       fluid and slowly eliminated by the kidney .
                Nitroprussid rapidly lowers blood pressure , and its effects disappear within
       1-10 minutes after discontinuation .
                Dosage typically begins at 0.5 ug/kg/min and may be increased up to 10
       ug/kg/min .as necessary to control blood pressure.
II-Toxicity :
      The most serious toxicity is related to accumulation of cyanide ( metabolic acidosis
,arrhythmias , excessive hypotension and death have resulted ).
      Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of
cyanie. To thiocyanate .


2- Diazoxide :
                Diazoxide   is   an   effective   and   relatively   long-acting   parenterally
      administered arteriolar dilator that is used to treat hypertensive emergencies .
      injection of diazoxide results in a rapid fall in systemic vascular resistance and
      mean arterial blood pressure associated with substatial tachycardia and increase
      in cardiac output . studies of its mechanism suggest that it prevents vascular
      smooth musclecontraction by opening potassium channels and stabilizing the
      membrane potential at the resting level.


I-Pharmacokinetics and dosage :
                Diazoxide is similar chemically to the thiazide diuretics but has no diuretic
      activity . it is bound extensively to serum albumin and to vascular tissue . Diazoxide
      is in part metabolized and in part excreted unchanged , its half-life is approximately
      24 hours. The blood pressure lowering effect after a rapid injection is established
      within 5 minutes and lasts for 4-12 hours. Th dose is about 75-100 mg , the
      hypotensive effects of diazoxide are also greater if patients are pretreated with
      beta-blockers to prevent the refex tachycardia and associated increase in cardiac
      output .
II-Toxicity :
      The most significant toxicity from diazoxide has been excessive hypotension ,
resulting from the recommendation to use a fixed dose of 300mg in all patients. Such
hypotension has resulted in stroke and myocardial infarction . the reflex sympathetic
response can provoke angina .
       Diazoxide inhibits insulin release from the pancreas (probably by opening
potassium channels in the beta cell membrane ) occasionally , hyperglycemia
complicates diazoxide use , particularly in persons with renal insufficiency. and the druge
is contraindicated in diabetic persons .
       Diazoxide causes renal salt and water retention . hwever ,because the drug is
used for short periods only , this is rarely a problem .


Section III
Clinical pharmacology of Antihypertensive Agents :


3.1- Introduction :
       Hypertension presents a unique problem in therapeutics. It is usually a lifelong
disease that cause few symptoms until the advanced stage. For effective treatment,
medicines that are expensive and often produce adverse effects must be consumed daily
. thus, the physician must establish with certainty that hypertension is persistent and
requires treatment and must exclude secondary causes of hypertension that might be
treated by definitive surgical procedures. Persistence of hypertension , particularly in
persons with mild elevation of blood pressure , should be established by finding three
different office visits. Ambulatory blood pressure monitoring may be the best predictor of
risk and therefore of need for therapy in mild hypertension . Recent evidence indicates
that isolated systolic hypertension and hypertension in elderly also benefit from therapy .
       Once the presence of hypertension is established, the question of whether or not
to treat and which drugs to use must be considered . the level of blood pressure , the age
and sex of patient , the severity of organe damage (if occurs) due to high blood pressure.
       And the presence of cardiovascular risk factors must all be considered .
       Once the decision is made to treat, a therapeutic regimen must be developed and
the patient must be educated about the nature of hypertension and the importance of the
treatment . selection of drugs is dictated by the level of blood pressure , the presence
and severity of end-organ damage , and the presence of other diseases . sever high
blood pressure with life-threatening complications requires more rapid treatment with
more efficacious drugs. Most patients with essential hypertension , have had elevated
blood pressure of months of years , and therapy is best initiated in a gradual fashion.
       Successful treatment of hypertension requires that dietary instructions be followed
and medications be taken as directed . Education about the natural history of
hypertension and the importance of the treatment as well as potential side effects of
drugs is essential.
       Follow-up visits should be frequent enough to convince the patient that the
physician thinks the illness is serious. With each follow-up visit, the importance of
treatment should be reinforced and questions , particularly concerning dosing or side
effects of medication, encouraged. Other factors that may improve compliance are
simplifying dosing regimens and having the patient monitor blood pressure at home .


3.2-Outpatient therapy of hypertension :
       The initial step in treating hypertension may be nonpharmacologic. sodium
restriction may be effective treatment for as many as half patients with mild hypertension
. the average American diet contains about 200meq of sodium per day . A reasonable
dietary goal in treating hypertension is 70-100 meq of sodium per day , which can be
achieved by not salting food during or after cooking and by avoiding processed foods that
contain large amounts of sodium .compliance with sodium restriction can be assessed by
measuring 24-hours urinary excretion of sodium . which approximates sodium intake ,
before and after dietary instruction .
       Weight reduction even without sodium restriction has been shown to normalize
blood pressure in up to 75% of overweight patients with mild to moderate hypertension .
regular exercise has been shown in some but not all studies to lower blood pressure in
hypertensive patients .
       For pharmacological management of mild hypertension , blood pressure can be
normalized in most patients with a single drug such (monotherapy ) is also sufficient for
some patients wit moderate hypertension , thiazide diuretics or beta-blockers are most
commonly used for initial drug therapy in such patients results from several large clinical
trials suggest that these drugs reduce the morbidity and mortality associated with
untreated hypertension . there has been concern that diuretics and beta-blockers , by
adversely affecting the serum lipid profile or impairing glucose tolerance , may add to the
risk of coronary diseases , therapy offsetting the benefit of blood pressure reduction .
Alternative choces of initial monotherapy include ACE inhibitors , calcium channel
blockers , selective ‫ 1ل‬blockers (prazosin) , mixed alpha and beta blockers (labetalol ) ,
and central sympathoplegic agents (clonidine ) , though none of these have yet been
shown to affect long-term outcome . the presence of concomitant disease should
influence selection of antihypertensive drugs because two diseases may benefit from a
single drug. For example , beta-blockers or calcium channel blockers are particularly usful
in patients who also have angina , diuretics or ACE inhibitors in patients who also have
congestive heart failure. Race and age also affect drug selection : for example , blacks
respond well to diuretics and calcium channel blockers and less well to beta-blockers and
ACE inhibitors . older patients respond well to diuretics and beta-blockers .
       If single drug dose not adequately control blood pressure , drugs with different sits
of action can be combined to effectively lower blood pressure while minimizing toxicity
(stepped care) . if a diuretic is not used initially, it is often selected as the second drug. If
three drugs are required, combining a diuretic, a sympathoplegic agent or an ACE
inhibitors and a direct vasodilator (hydralazine or direct calcium channel blockers ) is
ofeten effective .
       Assessment of blood pressure during office visits should include measurement of
recumbent, sitting and standing pressures . An attempt should be made to normalize
blood pressure (mean blood pressure equals or less than 100 mmHg) in the posture or
activity level that is customary for the patient . the extent of orthostatic hypotension and
inhibition of reflex or exercise tachycardia are useful indicators of the effectivness of a
compliance with sumpathoplegic therapy . in addition to noncompliance with medication,
causes of failure to respond to drug therapy include excessive sodium intake and
inadequate diuretic therapy with excessive blood volume (this can be measured directly )
, and drugs such as antidepressants and over-the-counter sympathomimetics and oral
contraceptives that can interfere with actions of some antihypertensive drugs or directly
raise blood pressure .


3.3-Monotherapy versus polypharmacy in hypertension :
       Monotherapy of hypertension (treatment with a single drug ) has become more
popular since the introduction of ACE inhibitors and ‫ 1ل‬selective alpha-blockers because
compliance is likely to be better and because in some cases adverse effects are fewer.
However , moderate to sever hypertension is still commonly treated by a combination of
two or more drugs, each acting by a different mechanism (polypharmacy ). The rational
for polypharmacy is that each of the drugs acts on one of a set of interacting , mutually
compensatory regulatory mechanisms for maintaining blood pressure .


Preferred Agent                              Alternative Drugs
Diuretics                                   ACE inhibitors
Beta-blockers                               CA++ channel blockers
                                            Alpha 1- blockers
                                            Alpha-beta blockers (labetalol)


                           Agents Acceptable as monotherapy




       For example , because an adequate dose of hydralazine causes a significant
decrease in peripheral vascular resistance, there will initially be a drop in mean arterial
blood pressure, evoking a strong response in the form of compensatory tachycardia and
salt and water retention. The results is an increase in the cardiac output that is capable of
almost completely reversing the effect of hydralazine. The addition of a sympathoplegic
drug ( propranolol ) prevents the tachycardia ; addition of diuretic (Hydrochlorothiazide )
prevents the salt and water retention . in effect, all three drugs increase the sensitivity of
the cardiovascular system to each other’s actions . thus , partial impairment of one
regulatory   mechanism      (sympathetic    discharge    to   the   heart   )   increase   the
antihypertensive effect of impairing regulation by another mechanism (peripheral
vascular resistance). Finally, in some circumstances , a normal compensatory response
accounts for the toxicity of an antihypertensive agent, and the toxic effect can be
prevented by administering a second type of drug . in the case of hydralazine ,
compensatory tachycardia and increased cardiac output may precipitate angina in
patients with coronary atherosclerosis. Addition of the beta-blockers and diuretic can
prevent this toxicity in many patients .
          In patients . when hypertension dose not respond adequately to a regimen of one
drug, a second drug from different class with a different mechanism of action and
different pattern of toxicity is added. If the response is still inadequate and compliance is
known to be good , a third drug may be added. The drugs least likely to be successful as
monotherapy are hydralazine and minoxidil. It is not completely clear why other drugs
such as ‫ 1ل‬blockers and calcium channel blockers cause less marked compensatory
responses for the same amount of blood pressure lowering.

3.4-Algorithm for the treatment of hypertension :
Step I:          initiate life-style modifications:
                Reduce weight
                Moderate alcohol intake
                Begin regular physical activity
                Reduce sodium intake
                Quit smoking.


Step II:        Continue life-style modifications.
                Initiate pharmacologic therapy:
                Diuretics or B-blockers are preferred
                Because they have demonstrated
                a reduction in morbidity and mortality


step III:       Increase drug dose       or
                 substitute another drug or
                Add second agent from another class.


Step IV:        Add second or third agent
                And/or diuretic, if not already prescribed.
3.5-Management of hypertension Emergencies :
       Despite the large number of patients with chronic hypertension, hypertension
emergencies are relatively rare. Marked or sudden elevation of blood pressure may be a
serious threat to life, However and promote reduction of blood pressure is indicated. Most
commonly, hypertensive emergencies occur in patients whose hypertension is sever and
poorly controlled and in those who suddenly discontinue antihypertensive medications.
Hypertension emergencies include hypertension associated with vascular damage
(termed malignant hypertension ) and hypertension associated with hemodynamic
complications such as cardiac failure , stroke , or dissecting aneurysm . the underlying
pathologic process in malignant hypertension is a progressive arteriopathy with
inflammation and necrosis of arterioles . vascular lesions occur in the kidney , which
releases renin, which in turn stimulates production of angiotensin and aldosterone, which
further increases blood pressure .Hypertension encephalopathy is a classic feature of
malignant hypertension . its clinical presentation consists of sever headache, mental
confusion, and apprehension . Blurred vision , nausea and vomiting , and focal neurologic
deficits are common. If untreated , the syndrome may progress over a period of 12-48
hours to convulsions, stupor , coma and even death .

3.5.1-Treatment of hypertension emergencies :
       The general management of hypertension emergencies requires monitoring the
patient inan intensive care unit with continuous recording of arterial blood pressure . rapid
treatment is essential , though excessively rapid lowering of blood pressure should be
avoided since if can result in stroke or myocardial infraction . fluid intake and output must
be monitored carefully and body weight measured daily as an indicator of total body fluid
volume during the course of therapy.
       Parenteral antihypertensive medications are used to lower blood pressure rapidly
(within a few hours ) ; as soon as reasonable blood pressure control is achieved, oral
antihypertensive therapy should be substituted , because this allows smoother long-term
management of hypertension . the drugs most commonly used to treat hypertensive
emergencies are the vasodilators , sodium nitoprusside and diazoxide. Other Parenteral
drugs that may be effective include . nitroglycerin, labetalol, trimethaphan, calcium
channel blockers , hydralazine , reserpine, and methyldopa . nonparenteral therapy with
oral nifedipine, captopril, prazosin or clonidine has also been shown to be useful in the
therapy . of sever hypertension .
       Most patients with sever hypertension have a normal or contracted blood volume ,
although those with renal failure may be hypervolemic. Diuretics are administered to
prevent the volume expansion that typically occurs during administration of powerful
vasodilators. Because it is likely that the patient will have compromised renal function , a
drug that works in the presence of renal insufficiency, such as Furosemide, should be
selected .
       Dialysis may be a necessary alternative to the loop diuretics, particularly in
patients with oliguric renal failure. Dialysis can removed excess fluid, correct electrolyte
disturbances, and controls symptoms of uremia. Uremic symptoms may be confusing in
evaluating patients with hypertension encephalopathy.
3.6-Treatment of hypertension associated with phaeochromocytoma :
       Hypetensive crises in pheochromocytoma can be treated conventionally , but it is
important to avoid beta blockers befor full alpha-blockade has been achieved.
       Parenteral phentolamine can be used acutely , and longer-term control gained
with phenoxybenzamine, with the later addition of small doses of beta-blockers,such as
Propranolol . if asurgical cure cannot be effectd, long-term treatment with
alpha-methyl-tyrosine can be used , although side effects are often troublesome .


3.7-Treatment of hypertension associated with hyperaldosteronism:
       Surgical removal of the adenomas in conn’s syndrome may not always curs the
electrolyte disturbance and hypertension . in these circumstances, as in idiopathic
hyperplasia , treatment with amiloride 20-70mg daily or spironolactone 300-400 mg daily
is effective .
3.8-Treatment of pre-eclampsia :
       The treatment of pre-eclampsia requires delivery of the fetus. Nevertheless , drugs
may be neded to control the blood pressure before delivery can be achieved .
       Methyldopa is used and , if necessary, can be given parenterally. It has the
advantages of being effective and harmless to the fetus, although its sedative side-effects
can confuse neurological assessment , and its onset of action is slow.
       Hydralazine , orally or IM, is a suitable alternative although flushing , tachycardia
and vomiting may be side-effects at the higher doses. In IV administration it has rapid
onset of action which can be maintained by a constant infusion .
       Beta-blockers and calcium antagonists have been found to be effective in acute
situations.
       Diuretics are used only when cardiac failure complicates the picture .


3.9-Patients and their disease states :
       Many patient-related factors and clinical conitions influence the choice of
antihypertensive agent. Some of the clinical conditions which influence the selection of
antihypertensive agents are sumarized in the table …….
       But the most important states are : ..


1- Afro-caribbeans:
       In the mid 1980s it was noticed that a subgroup of Afro-caribbeans responded
   better to hydrochlorothiazide than to acebutolol . this lack of response to beta-blockers
   has subsequently been supported in other trials, although labetalol. Which also blocks
   alpha-receptors dose seem to be as effective as it is in the white population. Trials
   comparing calcium channel blockers to beta-receptors blockers in the two races have
   confirmed the resistance of hypertension in the black population to beta-blockade. In
   general diuretics and calcium channel blockers are more effective as monotherapy in
   Afro-caribbeans.
2- The elderly :
      Selection of appropriate antihypertensive medication in the elderly is difficult
   because of the are-related deterioration in glomerular filtration rate, hepatic mass and
   blood flow and the coexistence of other diseases. Most studies of the treatment of
   hypertension in the elderly have shown that there is no reduction in overall death rete
   although there is a reduction in cardiovascular death rate . if drug treatment is
   necessary it should be with low doses of a thiazide diuretic, with the addition of a
   potassium-sparing agent (triamterene or amiloride) , if hypokalaemia is a problem.
   However ,as renal function deteriorates with age, it should be noted that thiazides are
   less effective in the presence of compromised renal function .
      Numerous studies have demonstrated that beta-blockers are less potent in the
   elderly despite a in the drug clearlnce. Low doses of beta-blockers should be used
   probably not as first line agents unless there are associated cardiovascular
   conditions, such as angina or arrhythmias, which would benefit from beta-blockers .
      Methyldopa, a centrally acting agent, was one of the earlier antihypertensive drugs
   and many of the of the elderly were started on this drug in the past . it has numerous
   side effects including sedation, which is of particular importance in the elderly , and
   stopping this drug can often lead to a noticeable improvement in mental agility.
      Vasodilators such as the calcium channel blockers can prove extremely useful in
   the elderly in reducing blood pressure with the minimum of side effects without putting
   too much extra strain on the heart. Peripheral resistance is increased with the
   decreasing compliance of blood vessels in the elderly, thus vasodilatation of the
   arterioles by a calcium channel blocker can produce a significant reduction in blood
   pressure .
      ACE inhibitors can be effective , even though low renin levels are common in the
   elderly and a reduced effect might be expected . careful monitoring is necessary
   because of the decrease in renal function with increasing age, which could potentate
   the ability of ACE inhibitors to cause potassium retention and lead to hyperkalemia .
   ACE inhibitors are a contra-indicated in renal stenosis , condition which is difficult to
   diagnose in the elderly .
3- Diabetic patients :
      Hypertension        and     diabetes      mellitus     commonly       coincide.      In
   non-insuline-dependent diabetes (NIDDM) thiazides can furthur impair glucose
   tolerance and , whenever possible, should be avoided. In insulin-dependent diabetes
   (IDDM) , hypoglycaemic side effects have been reported with non-selective
   beta-receptors blockers this is a result of impairment of the beta            2   mediated
   breakdown of glycogen to glucose and release of glucose from the liver. In insulin
   treated patients beta 1 selective blockers (atenolol , bisoprolol, metoprolol ) may be
   used, unless the patient is particularly vulnerable to hypoglycemia. Beta-blockers also
   mask the tachycardia associated with hypoglycemia such that patients may be
   unaware that their blood glucoselevels are decreasing .
      In addition , beta-blockers can aggravate pre-existing peripheral vascular fisease
   which may be present in the diabetic patient .
4- Myocardial infraction :
      Ten different beta-blockers have been evaluated at various dosages with the aim
   of reducing post-infract mortality . those trials comparing beta-blockers with intrinsic
   sympathomimetic activity(oxprenolo, pindolol ) with placebo have shown either an
   unfavorable mortality trend or no statistically significant differences between the drug
   and placebo. In contrast , most of the trails of beta-blockers without ISA (propranolol,
   timolol) have shown a reduction in mortality . thus , in hypertensive patients surviving a
   heart attack, a beta-blocker without ISA would be beneficial not only in reducing blood
   pressure but also in reducing the risk of death and rate of non-fatal reinfarctions.
5- Asthmatic patients :
      Stimulation of bronchail beta 2 receptors is the principal mechanism by which
   bronchodilatation can be effectively produced to treat an asthma attack . blockade of
   beta 2 receptors with a beta-blockers will impair the efficacy of such treatment .
   indeed,    non-selective     beta-blockers       suchas    propranolol     can       cause
   bronchoconstriction in certain patients who have no history of asthma . all
   beta-blockers , including those with beta1 selectivity and ISA , can cause
   bronchoconstriction in asthmatic patients . although patients who develop asthma whil
   taking a beta1-selective blocker respond more readily to beta2-stimulants such as
   salbutamol, the risk of sever bronchoconstriction should preclude the use of ass
   beta-blockers in asthmatics.
6- Renal disease :
       Propranolol diminishes renal blood flow and reduces the glomerular rate by 10 to
   20% . The more selective beta-blockers , or those with ISA or an alpha-blockers
   action, produce smaller reductions in renal blood flow . However, nadolol, which is
   non-selective , can maintain renal blood flow, presumably by stimulating dopamine
   receptors in the renal vasculature. The dosage of water soluble beta-blockers , which
   are excreted in the urine , may need to be reduced in patients with impaired renal
   function .
   ACE inhibitors may cause a reduction in renal blood flow and must be used with
   caution in patients with renal disease . in renal artery stenosis ACE inhibitors are
   contra-indicated because the reduction in blood flow can be such that the affected
   kidney receives no blood at all .
7- pregnancy :
       Patients with pre-existing primary hypertension may become pregnant or
   pregnancy itself may induce gestational hypertension. In either case it is desirable to
   control blood pressure, as the hypertension is associated with complications for both
   the mother and fetus.
       Methyldopa remains the dug of choice for treating hypertension presenting in
   pregnancy. Atenolol is used but has been associated with the birth of smaller babies
   and it is excreted in breast milk .ACE inhibitors are potentially damaging to the fetus
   and inhibition of renin angiotensin system may cause problems in the neonate.
8- Aortic dissection :
                Aortic dissection is an emergency requiring prompt reduction of mean blood
       pressur to 100-110 mmHg this is usually achieved with as infusion of sodium
       nitroprisside.


   If the hypertension leads to eclampsia Parenteral hydralazine is usually
   effective, continuing until the mother recovers sufficiently to take oral medication. The
   disadvantage of using Parenteral hydralazine is the reflex tachycardia, which
                                                                         invariably occurs.




3.10-Conclusion:
Patient education
Counseling - advice
Controlling Your Blood Pressure


At present there is no cure for high blood pressure, but it can be controlled to reduce the
chances of developing problems. This takes a team effort, and you are the most important
member of the team. Mild or moderate high blood pressure can often be controlled
successfully by a low-salt diet, exercise, and weight loss.
Sodium (salt) causes your body to retain fluids, which can put extra strain on the heart
and make the blood vessels narrow. For this reason, low-sodium diets are recommended
to reduce the amount of retained water, which then helps to lower the blood pressure.
Foods that are high in potassium and calcium also help lower blood pressure.
A moderate amount of regular exercise has several benefits. It improves your overall
physical conditioning, helps with weight loss by burning extra calories, reduces blood
cholesterol, and may have a more direct effect on lowering your blood pressure.
Maintaining yourself at the right weight for your height and bone structure is important.
Extra fat makes your heart work harder. A low-fat, low-calorie diet has the further
advantage of reducing your blood cholesterol levels and delaying the beginning of
arteriosclerosis. People with high blood pressure can consume moderate amounts of
alcohol (about two drinks per day), but a heavy intake of alcohol raises blood pressure. If
you are on a weight reduction diet, keep in mind that alcohol is high in calories.
Although high blood pressure is not caused by "bad nerves," prolonged stress does
increase blood pressure. Learning to relax and taking time out to do things you enjoy
should be part of your blood pressure control program.
                Antihypertensive drugs used in emergency




Drug              Mode         of   Dose               Onset of action   Duration of action

                  administration
Diazoxide         IV bolus          50-150 mg          1-2 minutes       6-10 hours
Enalaprilat       IV                0.625-1.25 mg      15-60 minutes     12-24 hours
Esmolol           IV                500 ug/kg          2-10 minutes      10-30 minutes
Hydralazine       IM or IV          IV 10-20 mg        10 minutes        2-6 hours
                                    IM 10-40 mg        20-30 minutes
Labetalol         IV                20-50        mg    5-10 minutes      2-4 hours
                                    every         10
                                    minutes
Methyldopate      IV                250-500 mg         30-60 minutes     12-24 hours
Nitroglycerin     IV drip           5-200 ug/min       2-5 minutes       3-5 minutes
Sodium            IV drip           Titration          instantaneous     2-3      minutes
nitroprusside                       0.25-10                              after cessation
                                                  ug/kg/min                                 of drop
              Trimethaphan     Iv drip            1-4 mg/min as         2-5 minutes         5 minutes after
              camsylate                           infusion                                  cessation      of
                                                                                            drip




                        Pharmacokinetic and Phamacodynamic parameters for
                          Selected some selected antihypertensive agent .




Drug            Oral           Urinary      Bound          CL .   Vd.        Half-lif   Effective     Toxic
                Availability   Excretion.   in         L/h/70K    (L/70Kg)   e.         . Conc.       Conc.
                 ( F)            (%)        plasma     g
                                                                             (H)
                                                 (%)
Atenolol        56              94          5           10.2      67         6.1        1mg/L         _
Captopril       65              38          30          50.4      57         2.2        50ng/ml       _
Clonidine       95              62          20         12.6       150        12         0.2-2ng/ml    _
Diltiazem       44              4           78          50.4      220        3.7        _             _
Enalapril       95              90           55        9          40         3          0.5ng/ml      _
Furosemide      61              66          99          8.4       7.7        1.5        _             _
Hydralazine     40              10          87          234       105        1          100ng/ml      _
Labetalol       18              5           50          105       660        4.9        0.13mg/l      _
Metoprolol      38             10           11         63         290        3.2        25ng/ml       _
Nifedipine      50              0           96          29.4      55         1.8        47ng/ml       _
Prazosin       68        1        95     12.6   42    2.9    _         _
Propranolol    26       1         87     50.4   270    3.9   20ng/ml   _
Trimethoprim   100       69       44     9      130    11     _        _
Verapamil      22        3        90     63     350    4      _        _




           Common advers effects of drugs used to treat hypertension .
  Drug class           Adverse effects                 Drug class             Adverse effects
Thiazide Diuretics   Hypokalaemia                      Alpha blockers    Profound first dose hypotension
                     Hyperuricaemia                                      Dizziness
                     Decreased               glucose                     Headache
                     tolerance.                                          odema
                     Impotence.
                     Lethary
                     Hyperlipidaemia


Beta-blockers        Brochoconstriction                Calcium channel   Headache
                     Hyperlipidaemia                   blockres.         Dizziness
                     Impotence                                           Flushing
                     Increased insulin resistance                        Postural hypotension
                     Decreased peripheral blood                          Ankle oedema
                     flow
                     Masking of hypoglycemic
                     symptoms.


Lipophilic           Central side effects:             ACE inhibitors    Profoud first dose hypoyension
beta-blockers        Nightmares                                          Dry cough
                     Sleep disturbances                                  Hyperkalaemia
                     hallucinations                                      Taste disorders
                                                                         Angioneurotic oedema




   Summery of some antihypertensive drug used with associated disease
                  Disease                  Drug use in this situation
CHF                                     ACE inhibitors, AT1 receptor blockers
DM                                      ACE inhibitor, AT1blocjer , ca blocker
proteinuria                             ACE inhibitors , AT1 blockers
Hyperuricemia                           AT1 blocker
Bronchial Asthma                        Calcium channel blockers, diuretics,
                                       ACE inhibitors, AT1 blockers
HYperlipidemia                          ACE inhibitors, AT1 blockers, ca++
                                       blockers.
BPH                                     Alpha 1-blockers .
Anxiety, Migraine, Essential tremor     B-blockers
CVA                                    Calcium channel blocker
Peripheral vascular disease             Calcium       channel     blocker,   ACE
                                       inhibitors, AT1 blockers
Angina pectoris                        B-blockers and calcium channel, ACE
                                       inhibitors .
Liver cirrhosis                         B-blocker, ACE inhibitors
COLD                                    DIUretics, ACE inhibitors.
Thyrotoxicosis                          B-blockers
L.V.H                                   ACE inhibitors, AT1 blockers




                    Anti-Hypertensive Agents Present In UAE Markets
Trade Name           Active Constituents                    Company           Agency
Concor           Bisoprol                           Merck                  MPC
Isoptin          Verapamil                          Knoll                  Gulf Drug EST
Staril           Fosinopril                         Squibb                 MPC
Capoten          Captopril                          Squibb                 MPC
Caposil          Captopril & Hydrochlorothiazide    Squibb                 MPC
Inderal          Propranolol                        Zeneca                 MPC
Inderal LA       Prpanolol (Sustained Release)      Zeneca                 MPC
Tenoret          Atenolol & Chlorothalidone         Zeneca                 MPC
Tenoretic        Atenolol & Chlorothalidone         Zeneca                 MPC
Zestril          Lisinopril                         Zeneca                 MPC
Zestoretic       Lisinopril & Hydrochlorothiazide   Zeneca                 MPC
Tenormin         Atenolol                           Zeneca                 MPC
Micardis         Telmisartan                        Boehringer Ingelhein   Gulf Drug EST
Catapres         Clonidin                           Boehringer Ingelhein   Gulf Drug EST




     References:
           Clinical Pharmacy & Therapeutics by Roger Nalker & Slive Edwards
 Comprehensive Pharmacy Review by Leon Shargel & Alan H. Mutnick
 Basic & Clinical Pharmacology by Bertram G. Katzung
 Essential Medicine by John van John Jones & Charles R. V. Thomson
 BNF # 34 September 1997
 Textbook Of Medicine by R.L. Souhami & J. Moxham
 Applied Therapeutics & the Clinical Use Of Drugs by Lloyd Yee Young
    & Mary Anne Koba Kimble
   Basic Pharmacology for Clinical Therapeutics by Goodman
 Mosby’s Medical Encyclopedia.
 Clinesphere

								
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