Download Therapy of hypertension

Therapy of hypertension
By
Dr. Mohamed Abd Almoneim Attia
Calcium channel blockers (CCBs)
These are drugs that block voltage-gated Ca2+ channels.
Classification of CCBs according to therapeutic effect:
CCB with mainly cardiac effects: verapamil, diltiazem.
CCB with mainly vascular effects: nifedipine, amlodipine, isradipine.
CCB with mainly tissue protection: flunarizin, cinnarizine
N.B : Voltage-dependent Ca2+ channels: they are of 3 main types:
L-type (Large in conductance or Long lasting).
T-type (Transient in duration).
N-type (Neuronal in distribution).
L-type channel is the dominant type in cardiac and vascular sm ms.
They open in response to cell depolarization and could be blocked by calcium
channel blockers.
Calcium channel blockers block the L-type more than other types.
Pharmacokinetics:
Oral absorption is nearly complete.
Plasma protein binding is 70-98% .......
Metabolism: verapamil and diltiazem are
metabolized into active metabolites.
In older patients and in patients with liver
cirrhosis the dose should be decreased.
Pharmacological effects:
Heart:
–ve inotropic effect
A-V conduction
HR
Blood vessels:
Coronary and arterial
dilatation
BP
Nifedipine
Diltiazem
Verapamil
↑ (reflex)
++
↓↓
↓
+++
↓↓↓
↓↓
+++
↓↓↓
++
↓
+
↓
Other effects:
1-Smooth muscles: they relax bronchial, GIT, and
uterine smooth ms.
2-Platelets: they ↓ platelet aggregation.
3-Insulin release: verapamil ↓ insulin release (in
high dose).
4-CNS: they ↓ seizure (convulsions) activity.
Therapeutic uses:
A. Cardio-selective CCBs (verapamil and diltiazem):
1-Ischemic heart disease: see IHD
They ↓ myocardial contractility and myocardial O2 demand.
They ↓ coronary vascular resistance and increase coronary
blood flow.
They dilate epicardial coronary vessels.
They improve myocardial relaxation and ↓ myocardial cell
necrosis.
N.B.
Although nifedipine is coronary dilator, it has some
disadvantages in angina:
It may cause hypotension and reflex tachycardia.
It may cause “steal phenomenon” .
2-Cardiac arrhythmias: supraventricular tachycardia
(SVT):
Because they ↓ SAN activity and slow A-V
conduction.
N.B.
Nifedipine is contraindicated because it cause
hypotension and reflex tachycardia.
3-Hypertrophic obstructive cardiomyopathy (IHSS):
In hypertrophic obstructive cardiomyopathy, the wall of
the left ventricle and interventricular septum is much
thickened leading to narrowing of the aortic outlet and
obstruction of blood flow. This obstruction is increased
by increasing contractility while decreasing
contractility leads to decrease resistance to blood flow
through the aortic outlet.
N.B.
Nifedipine is contraindicated because it produces
reflex tachycardia → worsening of the outflow
obstruction.
4-Arterial hypertension:
They cause VD due to ↓ Ca2+ influx in the vascular sm ms.
They ↓ myocardial contractility and COP.
They ↓ platelet aggregation.
B. Vasculo-selective CCBs (Nifedipine and amlodipine):
1-Arterial hypertension.
2-Senile cerebral ischemia (nimodipine).
3-Peripheral vascular disease: to improve peripheral
microcirculation.
4-Chronic renal failure: to minimize renal ischemia.
5-Re-perfusion injury: to minimize tissue damage.
6-Prophylaxis of migraine: by unknown mechanism.
Adverse effects:
1-Verapamil and diltiazem:
*Bradycardia and heart block.
*Worsening of CHF (due to their –ve inotropic
effect).
*↓ insulin release and worsening of DM.
*Constipation and reversible hepatotoxicity.
*Ankle edema (less common than with nifedipine).
2-Nifedipine:
*Hypotension and reflex tachycardia.
*Steal phenomenon and aggravation of angina.
*Gingival hyperplasia.
*Ankle edema (due to VD).
How to treat ankle edema if occurred from CCBs?
Minimize sodium intake.
Avoid prolonged standing.
Mild diuretics.
Stop CCBs if the above measures failed.
Contraindications and precautions:
1-Verapamil:
Heart failure.
Bradycardia, heart block, or sick sinus syndrome (SSS).
With β-blockers: because both β-blockers and verapamil
have –ve inotropic and chronotropic effects, this will
cause severe cardiac depression (nifedipine is the
drug of choice if β-blockers are used with CCBs
because it doesn't cause bradycardia).
With digitalis: because digitalis also ↓ A-V conduction
and HR.
2-Nifedipine:
Severe heart failure.
Hypotension.
Hypertrophic obstructive cardiomyopathy (IHSS)
Unstable angina (for fear of reflex tachycardia and
steal phenomenon).
RENNIN ANGIOTENSIN ALDESTERON SYSTEM
• RENIN: It is a proteolytic enzyme secreted by the
kidney into the blood stream.Stimuli that increase
renin secretion: Sodium depletion, diuretics,
hypotension, hemorrhage, upright posture,
dehydration, constriction of renal artery, heart
failure and Cirrhosis
Actions of Angiotensins
• Angiotensin I (precursor of angiotensin II): It has no
pharmacological action.
• Angiotensin II: It acts on two receptors; AT1 and AT2 receptors
(1) Its action on AT1 receptor produces the following:
CVS:
• Arteriolar constriction leading to increased systolic and diastolic
blood pressure (40 times as active as norepinephrine).
• Angiotensin II produces positive inotropic and chronotropic effects
which are primarily due to central and peripheral sympathetic
stimulation.
Endocrine:
• Increase secretion and synthesis of aldosterone which causes Na
and water retension.
• Facilitate catecholamine synthesis and release.
• Increase pituitary vasopressin and ACTH.
Renal:
• Suppress renin release
• V.C of renal efferent arterioles, increases proximal
tubular Na+ reabsorption
C.N.S
• Increase H2O intake and vasopressin secretion.
• Stimulate central sympathetic discharge.
(2)Its action on AT2 receptor produces the following:
• Antiproliferation.
• Apoptosis (normal cell death).
• Vasodilatation and increase local bradykinin.
Stimulators of renin-Ang system:
Renal ischemia of any cause.
Hypovolemia and hypotension.
β1 agonists.
Vasodilators.
Inhibitors of the renin-Ang system:
Inhibitors of renin release: β-blockers, α-methyldopa,
clonidine.
Inhibitors of plasma renin activity: aliskrine.
Inhibitors of Ang-2 formation: angiotensin-converting
enzyme inhibitors (ACEIs)(pril)
Blockers of AT receptors: saralasin, losartan, valsartan
Angiotensin-converting enzyme inhibitors (ACEIs):
Classification:
A-SH-Containing:
Captopril
Zofinopril
The sulfhydryl group (-SH) present in captopril may be
responsible for the immunological side effects e.g.
angioedema, taste changes, skin rash, leukopenia
B-Non SH-Containing:
Enalapril
Fosinopril
Lisinopril
Benazepril
Mechanism of action: They inhibit Ang-converting
enzyme (ACE) leading to:
Inhibition of Ang-2 formation in the heart, blood
vessels, and tissues.
Prevent degradation of bradykinin which is a potent
VD.
Inhibition of aldosterone release.
ACEIs have direct VD action to both arteries and
veins.
Pharmacological effects:
CVS:
1-They ↓ BP mainly by decreasing peripheral resistance but no
reflex tachycardia or changes in the COP can occur due to:
Resetting of baroreceptors downwards.
Venodilatation
Enhanced parasympathetic activity.
2-They ↑ COP only in congestive heart failure (not in normal
conditions) due to reduction of systemic BP and peripheral
VD.
3-They ↓ the left ventricular mass and wall thickening after
myocardial infarction because they prevent myocyte cell
proliferation and collagen synthesis (i.e. prevent cardiac
remodeling).
4-They maintain cerebral and coronary blood flow.
Kidney:
They ↓ proteinuria in mild renal impairment and
diabetic patients.
They ↑ RBF.
Cell growth and proliferation:
They ↓ cell apoptosis
They ↓ cell proliferation and collagen synthesis.
Therapeutic uses:
1-Hypertension:
2-Congestive heart failure (CHF):
To ↓ arterial BP → ↓ afterload.
To ↓ aldosterone → ↓ Na and H2O retention → ↓ preload.
To prevent myocardial hypertrophy and degeneration.
3-Post-infarction ventricular remodeling:
To ↓ mass and wall thickness of the left ventricle through:
↓ arterial BP.
↓ myocyte cell proliferation and collagen synthesis.
↓ apoptosis.
4-Diabetic nephropathy and microalbuminuria:
To ↓ apoptosis, cell proliferation, and collagen synthesis.
5-Possible other uses:
Insulin resistance
- Atherosclerosis - Rheumatoid arthritis
Side effects: CAPTOPRIL
C Cough and bronchospasm: inhibition of ACE leads to accumulation of bradykinin, which
cause bronchial irritation and constriction.
Prevention: by administration of NSAIDs (e.g. aspirin) to ↓ bradykinin synthesis
A
Angioedema (edema of the face and throat): due to accumulation of bradykinin or due to
autoimmune reaction. It may be fatal.
P
:Proteinuria in patients with compromised renal function.
T Taste changes: temporary loss of taste (ageusia and dysgeusia).
O Orthostatic (First dose) hypotension: especially in sodium depleted patients.
Prevention: the first dose must be small and at bedtime then increase gradually.
P
Pregnancy: teratogenesis (fetal pulmonary hypoplasia and growth retardation)
R
skin Rash
I
Increased K+ (hyperkalemia).
L
Leukopenia (neutropenia): especially in patients with impaired renal function.
Contraindications:
1-Hypotension.
2-Severe renal failure (serum creatinine > 3 mg/dl).
3-Bilateral renal artery stenosis or stenosis in a solitary kidney.
In these conditions, the use of ACEIs is dangerous because they ↓
Ang-2 → ↓ VC of the efferent arterioles → ↓ GFR → aggravation
of renal failure in both kidneys.
4-Pregnancy and lactation: they may cause fetal pulmonary
hypoplasia and growth retardation.
5-Hyperkalemia.
6-Neutropenia or thrombocytopenia.
7-Severe anemia: as they may cause bone marrow depression.
8-Immune problems: e.g. autoimmune diseases and with
immunosuppressive drugs.
Precautions:
1-Initial dose should be small and at bedtime to
avoid 1st dose hypotension.
2-Frequent monitoring of kidney functions (serum
creatinine) one week after treatment and then
every 3 months.
3-Frequent monitoring of serum K+.
4-Avoid use with K+ sparing diuretics to avoid severe
hyperkalemia.
5-Mention other contraindications…….
Angiotensin II receptor blockers (ARBs)
(Losartan, valsartan, candesartan, eprosartan,
telmisartan)
They selectively block AT1 receptors.
They have no effect on bradykinin metabolism.
They have the potential for more complete inhibition of
Ang-2 action compared with ACE inhibitors because
there are non-ACE enzymes (cathepsin and chymase)
that can convert Ang-1 into Ang-2.
The adverse effects and contraindications are similar to
those described for ACE inhibitors but cough and
angioedema are less common than with ACE
inhibitors.
Vasodilators
Classification
1-Arterio-dilators: e.g. nifedipine, hydralazine, minoxidil, diazoxide.
They directly dilate arteries and reduce blood pressure (↓
afterload) so they are used in systemic hypertension and
congestive heart failure.
2-Venodilators: e.g. nitrates.
They dilate veins (↓ preload) so they are used in acute pulmonary
edema.
3-Mixed dilators: sodium nitroprusside, prazosin, ACEIs,
trimetaphan.
They are used in congestive heart failure because they ↓ preload
and afterload.
General considerations:
They usually cause reflex sympathetic stimulation
(e.g. reflex tachycardia and ↑ plasma renin) so they
can be combined with beta-blockers.
They usually cause salt and water retention so they
should be combined with diuretics.
They don't cause CNS side effects or orthostatic
hypotension.
They preserve renal and cerebral blood flow.
Hydralazine
Mechanism: direct vasodilator for small arteries and
arterioles.
Therapeutic uses:
Severe systemic hypertension.
Primary pulmonary hypertension.
Hypertension in pregnancy (2nd choice after α-methyldopa).
Side effects:
Hypotension and reflex tachycardia.
Salt and water retention.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Systemic lupus erythematosis (SLE)-like syndrome in slow
acetylators.
Minoxidil
Mechanism: direct arteriolodilator by opening K+ channels →
hyperpolarization → relaxation of the vascular sm ms.
Therapeutic uses:
Severe hypertension in combination therapy.
Hypertension in (renal) patients.
Topical minoxidil is used to stimulate hair growth in male baldness.
Side effects:
Hypotension and reflex tachycardia.
Salt and water retention.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Hypertrichosis= hirsutism (undesirable hair growth in the face and body).
Diazoxide
Mechanism: direct arteriolodilator by opening K+
channels → hyperpolarization → relaxation of the
vascular sm ms.
Therapeutic uses:
Hypertensive emergencies e.g. hypertensive
encephalopathy. (rapid i.v. injection to avoid rapid
and extensive binding with plasma proteins).
Hypoglycemia due to hyperinsulinism to decrease
insulin secretion from the pancreatic β-cells through
opening of its K+ channels.
Side effects:
Hypotension and reflex tachycardia.
Salt and water retention.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Hyperglycemia due to inhibition of insulin release.
Hyperuricemia.
Sodium nitroprusside
Mechanism: It liberates nitric oxide (NO) → ↑ cGMP →
↓ Ca2+ entry in the vascular sm ms → dilatation of
both arteries and veins.
It is rapidly metabolized in RBCs into cyanide then to
thiocyanate before excretion.
Therapeutic uses:
Hypertensive encephalopathy: It must be given by i.v.
infusion .
Congestive heart failure: to ↓ both preload
(venodilatation) and afterload (arteriolodilatation).
Side effects:
Hypotension and reflex tachycardia.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Prolonged therapy can lead to cyanide toxicity (death can
occur from metabolic acidosis and arrhythmia) or
thiocyanate toxicity (delirium and psychosis).
►Precautions:
Avoid exposure to light because the drug is sensitive to light.
Stop infusion gradually to avoid rebound hypertension.
Too much infusion may lead to cyanide toxicity.
In liver disease cyanide ions are not converted into thiocyanate
and become more toxic.
Hypertensive emergencies:
Defined as diastolic blood pressure more than 130
mmHg associated with progressive end organ
damage e.g papilledema , hypertensive
encephalopathy, pulmonary edema or acute renal
failure.
The patient should be hospitalized for rapid but
(careful and controlled) reduction of blood
pressure.
Avoid excessive rapid lowering of blood pressure
since it can result in stroke or myocardial
infarction.
Management of hypertensive emergencies
They include: hypertensive encephalopathy, acute left ventricular failure, cerebral
stroke, and aortic dissection.
Management:
Hospitalization
Rapid reduction of BP in hours not in minutes by one or more of the following drugs:
Sublingual drugs: nifedipine and captopril
Parenteral drugs:
Furosemide i.v.
Hydralazine i.v. slowly .
Diazoxide (rapid i.v. injection).
Sodium nitroprusside 5 μg/kg/min i.v. infusion.
Nitroglycerine i.v. infusion.
Nifedipine i.v. slowly .
Beta-blockers (propranolol) 1-2 mg i.v. slowly.
α-methyldopa i.v.
Investigations:
A)Basic studies for all cases:
1-Renal function tests: (urine examination-serum createnineblood urea).
2-Plasm electrolyte level :
*As a base line before diuretics therapy.
*As screen for mineralocorticoids induced hypertension.
3-Blood glucose:
*As a base line before diuretics therapy.
* To diagnose other conditions associated with increased
blood glucose + hypertension as pheocromocytoma…..etc
4-Serum uric acid:
*As a base line before diuretics therapy.
*As a risk factor for hypertension ……….(metabolic syndrome).
5-Serum cholesterol:
*As a base line before diuretics therapy.
*As a risk factor for hypertension
……….(metabolic syndrome).
6-Measurment of plasma rennin:
7-ECG: to assess LVH and cardiac status.
B) To detect secondary cause in selected cases:
*Pheocromocytoma (sweating,
palpitation,headache…..)
*renal arteriography in renal artery stenosis
(abdominal bruit)
C) To detect occurrence of complications:
*Fundus examination.
*Renal function tests.
*ECG- CXR- angiography.
*EEG
Choice of drugs in therapy of hypertension:
A) Mild or moderate hypertension:
1-Start with a single drug (monotherapy) using
one of the following: (A-B-C-D). Here D refers
to thiazide type diuretics.
Choice of first line therapy should be based on
(type of patient and presence of concomitant
diseases ).
However, the preferred drug for initial therapy of
mild or moderate hypertension are thiazide
diuretics or beta blockers which shown to reduce
cardiovascular morbidity and mortality in large
clinical trials.
2) The started drug should be started at a low dose
to avoid side effects. If blood pressure remains
uncontrolled, the dose is increased.
3) If blood pressure is not controlled either change
to a single drug of a different group or ADD a
second drug with a different site of action e.g
(thiazide +BB) or (thiazide +ACEI).
4) If hypertension is not controlled by the (two
drug regimen), ADD a third drug e.g thiazide
+BB+ vasodilator (ACEI or CCB or hydralazine or
prazocin).
B-Severe hypertension:
Start by (triple therapy) using a combination of 3
drugs e.g thiazide +B B +vasodilator??????
N.B:
In patients with renal impairment, thiazides are
contraindicated so, loop diuretics as frusemide
are recommended.
Beta blockers can be replaced with a central α2
agonist as (clonidine and α methyl dopa) if
beta blockers are contraindicted.
C-Hypertension resistant to triple therapy:
Patients resistant to triple therapy described
above may respond to:
Minoxidil + beta blocker + loop diuretics
(frusemide).
ACEI + loop diuretics (frusemide) +CCB.
Causes of failure of treatment of hypertension:
1-Non compliance with drug therapy.
2- Inadequate drug dosage.
3- Incorrect choice of drug e.g thiazide in advanced
renal insufficiency.
4-Excess salt intake.
5-Concomitant use of antagonistic drugs e.g NSAIDs
,cold remedies, oral contraceptives ….etc
6-Failue to recognize the cause of hypertension e.g
pheochromocytoma or renal artery stenosis.
Choice of antihypertensive drugs in special
situations:
Clinical situation
Preferred drug
Hypertension in pregnancy
Methyl dopa,hydralazine,labetalol α
and nifedipine
Hypertension and diabetes
Methyl dopaαACEI ,
Hypertension and bronchial asthma
CCB
Hypertension and renal failure
,CCB
Methyl dopa, Loop αclonidine,
diuretics (frusemide)
Hypertension and heart failure
Diuretics and ACEI
Case I
A 47 old male presents to your office for a yearly
checkup. He smokes 40 cigarette/day, and
examination detect wheezy chest and
bronchospasm. His blood pressure is 175/105
mm Hg. (measured more than once). His
fundoscopic examination is normal.
1-Mention the stage of hypertension in this case?
2-Mention the investigations of a patient with
hypertension ?
3-What is the goal of hypertension therapy ?
4-What are the most common drug classes in
therapy of hypertension now ?
5-What are other drug classes used for treatment of
hypertension ?
Can you start with thiazide in this case ?
6-What is the mechanism of action of the thiazide in this
case ?
7-Mention the adverse effects of the thiazide ?
8-After 2 weeks of therapy the patient bl.pr. became
150/95 do you recommend adding a new drug ?
9- What, and why?
10-What is the mechanism of action of this drug As
antihypertensive ?
11-What is the possible side effects in this patient ?
12-If the patient develop bradycardia ( 60 beats/min ) ,
how to deal with ?
Case II
A male patient is presented to you by moderate
degree of hypertension and chronic renal
impairment ( serum creatinine 4 mg /dl ).
• Can you give diuretic in this case ? what and why
?
• Can you give ACE inhibitors in this case? When?
and Why?
• What are other safe drugs used for treatment of
hypertension in presence renal insufficiency?
• Mention antihypertensive drug/s contraindicated
in treatment of hypertension with renal failure?
Case III
A 35 old obese pregnant lady with moderate
degree of hypertension and What is your
advice as regard to diet in this case?
• What is /are the antihypertensive drugs/s of
choice?
• Mention mechanism of action of methyldopa
as antihypertensive?
• What are antihypertensive drugs absolutely
contraindicated in pregnancy and why?
Case IV
A 45 old diabetic female presented in your office
with headache and dizziness, her blood pressure
170/100 and fasting blood glucose level 130
mg/dl and postprandial blood glucose 160 mg/
dl , she is controlled by glimpride drug .
• Mention antihypertensive drug/s used in this
case?
• What are antihypertensive drugs contraindicated
in this case? Why?
Case V
If you are faced with a male patient with
hypertension and left sided congestive heart
failure, what are the antihypertensive of
choice in this case and what is/are the drug/s
contraindicated and why?
Case VI
Patient with hypertension and elevated
cholesterol and triglyceride
• What are antihypertensives that can be used ?
• What are antihypertensives that are
contraindicated ?
Case VII
How can you treat a patient in a state of
hypertensive emergency?
Case :
A 56 year old obese male lawyer was found to have a blood pressure of
180/110mmHg during routine checkup, otherwise he was clinically free.
The same BP was noted on three subsequent visits. He smoked at least 30
cigarettes a day for 20 years. How would you proceed to manage this
case?
Case :
A 58 year old professor complained of headache. His blood pressure was
found to be 220/115 mmHg and there was no evidence of cardiac failure
or renal impairment.
How would you treat this patient?
Case:
A 47 year old man presented with a history of attacks of chest pain provoked
by exertion and relieved by rest. Exercise stress test was performed and
the patient was diagnosed as (exertional angina pectoris) .How would you
proceed to manage this man taking in consideration that his blood
pressure was 170/100 mmHg and that he is a heavy smoker?