Download Therapy of systemic hypertension

Therapy of systemic
hypertension
By
Dr.Mohamed Abd Almoneim
Drug therapy (antihypertensive drugs):
•
►First choice groups (commonly used drugs): ABCD
Angiotensin-converting enzyme inhibitors (ACEIs).
Beta-blockers.
Calcium channel blockers.
Diuretics.
►Second choice groups:
α1-adrenergic blockers: e.g. prazosin and doxasosin.
Combined α and β-blockers: e.g. labetalol.
Adrenergic neuron blockers: e.g. α-methyldopa and reserpine.
Direct vasodilators: e.g. hydralazine and diazoxide.
Central α2 stimulants: e.g. clonidine and guanfacine.
Serotonin receptor blockers: e.g. ketanserine.
Dopamine (D1) receptor agonists: e.g. fenoldopam.
Beta blockers (LoL)
* Pharmacokinetics
Most of beta-blockers are absorbed orally:
1-Lipophilic (fat-soluble) beta-blockers:
They are well absorbed, but undergo extensive hepatic
metabolism (first pass effect).
They are preferred in patients with renal failure.
They can also cross the BBB and produce CNS effects.
e.g. propranolol, …….
2-Hydrophilic (water-soluble) beta-blockers:
They are less well absorbed and slowly eliminated by the
kidney.
They are not preferred in patients with renal failure and cannot
cross to CNS.
e.g. atenolol, ………………etc.
Mechanism of Action
1-Beta blocking action:
2-Intrinsic sympathomimetic action (ISA):= stimulate action.
3-Local anaesthetic, or quinidine-like action or
membrane stabilizing activity.
3-CNS depressant action.
4-Direct vasodilator action.(recent drugs only)
Not all beta-blockers have the above-mentioned
actions but they differ in their mechanism of
action.
Classification
1- NON SELECTIVE BETA-BLOCKERS (1st
GENERATION)=block 1, 2, 3
Liable to cause side effects.(propranolol)
2- BETA-1 SELECTIVE BLOCKERS "CARDIOSELECTIVE"
(2nd GENERATION)= block 1 only (atenolol,
bisoprolol)
3- BETA-BLOCKERS WITH V.D. ACTION (3rd
GENERATION)e.g carvidelol
Pharmacological Effects
Cardiovascular system
*Decreases heart rate and myocardial contractility.(B1)
*Slow A-V conduction because the vagal action on the A.V. node predominates(B1).
* Decreases total coronary blood flow(B2) and oxygen consumption(B1).
*Quindine like action suppresses ectopic foci in the heart.
*Decrease blood flow to most tissues by the unopposed alpha effect in response to
reduced COP.
*Decrease platelet aggregation.
Lowers blood pressure by:********
1-Negative inotropic and chronotropic effects lead to decreased COP
2-Decrease renin release
3-Blocks presynaptic 2 receptors lead to decreased NE release.
4-Decrease central sympathetic outflow.
5-Resetting of baroreceptors downwards.
6-May act through vascular prostaglandins.
7-Some blockers have vasodilator properties.
Respiratory system
Bronchospasm and increased airway resistance in susceptible patients
Eye
Decreases aqueous humor formation and reduce intra-ocular pressure.
Metabolic effects:
In normal individual : no effect on blood glucose. But in patient with
diabetes:
Augment hypoglycemic effects of insulin by blocking glycogenolsis and
gluconeogenesis.
Mask the hypoglycemic symptoms except sweating.
Increase triglycerides and decrease H.D.L.
CNS
Antianxiety effect
Insomnia, lethargy, night mares, vivid dreams and depression
Others
Salt and water retention secondary to the decrease in COP.
Therapeutic Uses
A- Cardiovascular
1-Treatment of hypertension with a diuretic.
2-Ischaemic heart diseases :(angina and infarction)
3-Cardiac arrhythmias:
*Supraventricular arrhythmias especially those
produced by exercise, thyrotoxicosis and
pheochromocytoma.
*Digitalis induced arrhythmias.
*Arrhythmias induced during surgery (I.V. esmolol).
4-Hypertrophic obstructive cardiomyopathy:
by their negative inotropic action.
GIT
Cases of gastrointestinal bleeding by decreasing COP and enhancing
splanchenic vasoconstriction.
Endocrine
Hyperthyroidism.
Pheochromocytoma. (Must be combined with alpha-blockers).
C- Eye
Open angle glaucoma. (Timolol)
D- CNS
Prophylaxis of migraine
Anxiety and essential tremors.
Carvedilol is nonselective beta blocker with antioxidant and alpha mediated
vasodilator properties used in CHF, postinfarct LV Dysfunction and
hypertension not for angin (combined beta and alpha blocker)
Combined alpha and beta-blockers: labetalol
It is selective 1 blocker and non-selective betablocker.
It has rapid onset of action.
It is used to control severe hypertension associated
with pheochromocytoma and hypertension in
pregnant patient.
Adverse Effects
1-Heart failure, bradycardia, hypotension.
2-Bronchospasm in susceptible patients.
3-Potentiation of the hypoglycaemic effect of insulin and oral
hypoglycemic drugs and masking of the hypoglycaemic
symptoms.
4-Peripheral ischaemia, intermittent claudication and cold
extremities.
5-Reduced blood flow to the liver and kidney reducing metabolism
of drugs.
6-Hyperkalaemia..
7-Nightmares, vivid dreams and depression.
8-Nausea, vomiting, diarrhea or constipation.
9-Increased plasma triglycerides and decrease HDL.
10-Allergic reactions (rash fever)
11-Sudden withdrawal leads to aggravation of the disease under
treatment due to up regulation of beta-receptors.
12-Decrease sexual function.
Contraindications
1-Congestive heart failure.
2-Heart block.
3-Variant angina.
4-Hypotension.
5-Peripheral vascular diseases.
6-Bronchial asthma.
7-With verapamil (Negative chronotropic and
inotropic).
8-Alone in pheochromocytoma (Severe hypertension).
9-Never stopped suddenly (Especially in case of angina)
10-Diabetes mellitus.
►Indications of beta-blockers in hypertension:
1-Hypertension associated with: IHD, cardiac
arrhythmia, or thyrotoxicosis.
2-Hypertension associated with high plasma renin
(hyperreninemic hypertension).
3-In patients with increased sympathetic overactivity
e.g. young age, hyperkinetic circulation, etc.
4-As a part of combined therapy.
What are the criteria of ideal beta-blocker in
hypertension? It should be:
(1) β1-cardioselective,
(2) Has long duration of action; and
(3) Has improved pharmacokinetic profile e.g.
atenolol, bisoprolol…...
Alpha blockers :PRAZOSIN
Mechanism of Action (Selective 1 blocker and Direct V.D. at high doses).
Pharmacological Effects
V.D. of arteries and veins lowering the blood pressure.
It does not produce any change in C.O.P., renal blood flow and GFR thus; it could be
used in renal failure.
Salt and water retention.
Therapeutic Uses
Treatment of mild to moderate hypertension.
Treatment of acute congestive heart failure (decreases pre- and after-load).
Impaired bladder emptying due to prostate obstruction (decreased the tone of
trigone) leads to decreased resistance to flow of urine.
Adverse Effects
First dose effect:
1-The initial dose especially if large can produce postural hypotension and syncope.
It occurs most commonly in salt and water depleted patients (start with a small dose
and at bedtime).
2-Dizziness, headache, drowsiness, and palpitation (disappears with continued
treatment).
3-False positive tests for antinuclear factor.
4-Salt and water retention.
TERAZOSIN and TRIMAZOCIN Similar to prazosin but it does not produce first-dose
syncope.
Centrally acting antihypertensive drugs
1-Adrenergic neuron blockers: reserpine .
Reserpine :
*Adrenergic neurone blocking action by preventing the granular uptake of
catecholamines where it stays outside the granules (in the cytoplasm) to be
inactivated by MAO enzyme. Now, the nerve has to synthesize more and
more NE to keep the stores constant. As this process is limited, with
frequent sympathetic stimulation the granules are depleted and the
released NE becomes less, leading to decreased sympathetic tone. This
process of depletion needs about seven days to be completed.
Depletion of tissues e.g. brain, heart, and adrenal medulla from their
catecholamine and 5HT content.
*Parasympathomimetic action.
The hypotension effect is due to:
*Adrenergic neurone blocking action.
*Central action (inhibition of VMC and tranquilization)
*Depletion of suprarenal medulla.
Adverse Effects:
1-Bradycardia, flushing and nasal stuffiness.
2-Hyperacidity, peptic ulceration, salivation and diarrhea.
3-Loss of libido and impotence in males.
4-Salt and water retention.
5-Psychic depression, suicidal attempts, parkinsonian-like rigidity and
nightmares, cancer breast.
Uses : Less common nowadays due its side effects.
Not alone but as part of combination therapy for treatment of
hypertension.
2-Alpha methyl dopa:
Pharmacological actions
1-In the CNS it is transformed to alpha methyl NE.
which activates inhibitory 2 receptor in the
medullary region leading to inhibition of the
sympathetic outflow.
2-Inhibits plasma renin activity.
3-Adrenergic neurone blocking action by:
*Inhibition of dopa decarboxylase enzyme.
*Competes with dopa for dopa decarboxylase enzyme
leading to formation of alpha methyl
norepinephrine (false chemical transmitter)
ineffective on the adrenergic receptors.
Pharmacological effects
Antihypertensive.
Therapeutic Uses
Treatment of hypertension. (in pregnant female and in chronic renal
failure) because it does not affect the heart rate, COP, renal,
cerebral or myocardial blood flow.
Adverse effects
Drowsiness (common and disappears with continued treatment).
Depression (Less than reserpine).
Nasal stuffiness.
Drug fever.
Salt and water retention.
Liver damage.
Bone marrow depression.
Positive Commb's test.
3-Beta-Blockers: propranolol .
4-Central α2 stimulants: Clonidine and guanfacine.
Mechanism:
It stimulates presynaptic α2 receptors → inhibition of NA release.
It inhibits dopamine hydroxylase enzyme → inhibition of NA synthesis.
Inhibition of central sympathetic outflow.
It inhibits renin release and plasma renin activity.
Therapeutic uses:
1-Moderate to severe hypertension.
2-Prophylaxis of migraine.
3-In opiate withdrawal to decrease symptoms of sympathetic overactivity.
4-As a sedative to reduce anxiety in preanesthetic medication.
Side effects:
Sedation and dry mouth (xerostomia).
Severe hypertension can occur with overdoses due
to stimulation of α1 receptors as a result of loss of
selectivity.
Sudden withdrawal can lead to hypertensive crisis
(treated by combined α & β blockers), so it must be
stopped gradually.
Salt and water retention.
Guanfacin: it has a mechanism of action and
side effects similar to clonidine.
Serotonin receptor blockers: Ketanserine
Mechanism:
It blocks vascular α1 receptors and platelet 5-HT2
receptors → VD and ↓ platelet aggregation.
Uses:
Treatment of hypertension.
Treatment of peripheral vascular disease.
Thrombophlebitis and pulmonary embolism.
Side effects: dizziness and fatigue.
Dopamine (D1) receptors agonists: Fenoldopam
Mechanism:
It stimulates D1 receptors in peripheral arteries leading to VD
and diuresis.
Uses: it is given by continuous i.v. infusion
1-Treatment of hypertensive emergencies.
2-Treatment of post-operative hypertension.
Side effects:
Hypotension and reflex tachycardia
Increase IOP so it should be avoided in patients with glaucoma.
LOOP DIURETICS (High-Ceiling Diuretics)
Loop diuretics include: furosemide, bumetanide, ,,,,,
Pharmacokinetics
They are rapidly absorbed from GIT and can be given i.v.
General characteristics
1-Efficacy:
are the most potent diuretics.
They are effective at low GFR even below 10 ml/minute.
2-Onset:
They have rapid onset of action, ½ - 1 hour after oral
administration and 5-10 min. following i.v. injection.
3-Duration: They have short duration of action up to 4
hours.
Mechanism of action
A.Renal mechanism:
1-Diuretic : see renal pharmacology………………..
2-The loop diuretic furosemide produces stimulation of
cyclooxygenase activity resulting in increased synthesis of
vasodilator prosta-glandins PGE2 and PGI2. These
prostaglandins may contribute to furosemide increased
glomerular filtration and promoting water and sodium
excretion.
B. Extra-renal mechanism:
Furosemide has actions on the vascular system (venodilator
action) that occur before its diuretic and is mediated by PGs.
These effects produces changes in renal blood flow and a
reduction in LV filling pressure.
Uses
1-Acute pulmonary edema.
2-All types of Na+ salt and water retention including
edema, ascites and pleural effusion especially
severe cases.
3-Hypertensive emergencies (by i.v. route) and in
some cases of renal hypertension.
4-Oliguria due to acute renal failure.
5-Hyperkalemia; they can significantly enhance
urinary K+excretion.
6-Drug poisoning to produce forced diuresis and
enhance renal excretion of the offending drug.
Side Effects
Hypokalaemia metabolic alkalosis:
Hypomagnesaemia:
Hyovolaemia and hyponatraemia:
Hyperuricaemic:
Ototoxicity (more with ethacrynic acid):
It is common with impaired renal functions and in patients receiving other
ototoxic drugs such as aminoglycoside antibiotics.
Glucose intolerance (hyperglycemia):
this is due to inhibition of insulin release from B cells of pancreas (by opening
K+ channels) and/or diminishes peripheral glucose utilization.
This is less common than with thiazides.
Hypersensitivity and idiosyncrasy:
allergic reactions in the form of skin rash, oesinophilia or allergic interstitial
nephritis occur with furosemide and are usually reversible.
Hyperlipidemia:
increase LDL & TG and decrease HDL.
Interactions
1-The diuretic induced K+ deficiency increases the sensitivity of
myocardium to digitalis.
2-Glucocorticoid treatment produces additive decrease in serum
potassium level.
4-Ethacrynic potentiates ototoxicity of aminoglycosides.
5-Furosemide potentates nephrotoxicity of cephalosporins.
6-Non-steroidal anti-inflammatory drugs which are potent
inhibitors of prostaglandin synthesis, reduce the diuretic
effects of furosemide because these effects may be mediated
through furosemide induced increase in synthesis of PGE2 and
PGI2.
7-Organic acid such as probenicid and indomethacin which are
secreted by the active organic acid secretory system in the
PCT could inhibit tubular secretion of loop diuretic
competitively and thus prevent them to reach their site of
action and reduce their diuretic activity.
THIAZIDES
e.g. chlorothiazide and hydrochlorothiazide
Widely used diuretics because they are effective orally
and have moderate diuretic efficacy (prevents
reabsorption of about 10% of Na+ in the filtrate).
Pharmacokinetics
Thiazides are well absorbed one hour after oral
administration.
They are widely distributed in the body and can cross the
placenta
Thiazides are excreted by the renal organic acid secretory
system at the PCT.
General Characteristics
Site: They act principally at proximal part of DCT.
Efficacy: They have moderate diuretic efficacy
(prevents reabsorption of about 10% of Na+ in the
filtrate. They should be avoided in renal
impairment.
Onset: They act within one hour after oral
administration.
Mechanism of Action:
• See renal pharmacology(urine block)
Pharmacological Effects
1-They increase renal excretion of Na+ and Cl- accompanied with water.
2-They increase K+ excretion.
3-They may decrease uric acid excretion leading to hyperuricaemia.
4-They decrease renal blood flow through a direct action on renal vasculature.
7-Antihypertensive effect (zhe mechanism of antihypertensive action is):
*Decrease
peripheral vascular resistance due to
vasodilator action possibly through:
A- Direct V.D
B- Decreased vascular receptor sensitivity to
vasopressor agents (adrenaline, angiotensin...) by
decreasing Na+ content in the cells of vascular wall.
C- Increase synthesis of the vasodilator PGs.
*Decreased cardiac output due to decrease blood volume
by the diuretic action
Uses
Essential hypertension:
they may be used alone as initial monotherapy or as a
part of combined antihypertensive regimen.
They are used in treatment of edema and ascites (i.e.
all types of Na+ and H2O retention) due to mild or
moderate congestive heart failure, hepatic disease
and renal disease.
Side Effects
Hypokalaemia metabolic alkalosis.
Hypovolaemia and hyponatraemia.
Hypotension
Hyperuricaemia.
Hyperglycaemia: produced by the same mechanisms mentioned
with loop diuretics.
Hyperlipidaemia: thiazides increase serum cholesterol,
triglycerides and LDL. This is possibly due to decreased insulin
activity or release.
Hypersensitivity: hypersensitivity reactions are related to
sulfonamide moiety and there is cross sensitivity with other
sulfonamides.
Deterioration of patients with hepatic or renal failure.
Other side effects: parethesia, drowsiness, fatigability and
impotence are dose-related side effects.
POTASSIUM - SPARING DIURETICS
Aldosterone antagonists: Spironolactore and
eplerenone.
Direct Na+- channel inhibitors: Triamterene and
amiloride.
General Characteristics
Site: Distal part of DCT or cortical part of collecting
ducts.
Efficacy: weak since the fraction of filtered Na load
reabsorbed at thus site is only 2-5% of the filtered
Na+ load.
Mechanism of action
1-Block of aldosterone receptors (spironolactone
&eplerenone):
2-Direct inhibition of Na+ transport though specific
Na+ channels in late part of the DCT and the
collecting tubules. e.g. triamterene and amiloride.
Uses of K+ Sparing Diuretics
1-Commonly given with loop acting or thiazide
diuretics to balance the excessive K+ loss and to
limit the incidence of metabolic alkalosis that
occurs at the same setting during use of loop
acting or thiazide diuretic.
2-Cases of hyperaldosteronism either primary
(Conn's syndrome) or secondary (CHF, hepatic
cirrhosis, nephrotic syndrome) especially
spironolactone.
3-Refractory edema (with potent diuretics to
potentate their diuretic action).
Side Effects of K+ Sparing Diuretics
1-It may cause hyperkalemia due to decrease k+ secretion. This occurs
especially in patients on high K+ intake or in patients with severe renal
insufficiency or in-patient treated with other drugs that cause potassiumsparing effect e.g. beta-blockers, non-steroidal anti-inflammatory drugs,
angiotensin converting enzyme inhibitors or angiotensin receptor
blockers.
2-Hyperchloraemic metabolic acidosis.
3-Nausea, abdominal pain, drowsiness and mental confusion.
4-Spironolactone, lead to gynecomastia and impotence in males and
menstrual disordersin females.
Contraindications of K+ Sparing Diuretics
In presence of hyperkalemia
In combination with other K+ sparing drugs or with K+ supplements.
In-patient with chronic renal insufficiency.
Drug interactions
Administration with ACE inhibitors and other agents causing hyperkalemia or
potassium supplements may cause hyperkalemia.
►Indications of diuretics in hypertension:
1-Thiazides are given as initial therapy in most cases
of essential hypertension.
2-Loop diuretics are given in hypertensive
emergencies.
3-Hypertension associated with salt and water
retention: e.g.
Congestive heart failure (CHF).
Chronic renal failure (give loop diuretics).
Liver cirrhosis (give spironolactone).
Primary hyperaldosteronism (give spironolactone).