Transcript 7&8-Hypertension

TREATMENT OF HYPERTENSION
Profs.
Abdulqader Alhaider; Azza El-Medany
Department of Pharmacology
College of Medicine
OBJECTIVES
• At the end of lectures , the students should :
• Identify factors that control blood pressure
• Identify the pharmacologic classes of drugs
used in treatment of hypertension
• Know examples of each class.
OBJECTIVES ( continue)
• Describe the mechanism of action ,
therapeutic uses & common adverse effects of
each class of drugs including :
• Adrenoceptor blocking drugs ( β & α
blocking drugs )
• Diuretics
• Calcium channel blocking drugs
• Vasodilators
OBJECTIVES ( cont.)
• Converting enzyme inhibitors
• Angiotensin receptor blockers.
• Describe the advantages of ARBs over ACEI
FACTORS IN BLOOD PRESSURE CONTROL
Hypertension
Blood pressure is determined by :
1- Blood volume
2- Cardiac output ( rate & contractility )
3- Peripheral resistance
i
Hypertension
• Is a major risk factor for cerebrovascular
disease, heart failure, renal insufficiency
and myocardial infarction.
It is often asymptomatic until organ damages
reaches a critical point.
Antihypertensive therapy
• Initially consists of lifestyle changes , such as
weight reduction , smoking cessation,
reduction of salt, saturated fat, , excessive
alcohol intake , and increased exercise
before drug therapy. Is initiated .
Indications for Drug Therapy
 Sustained blood pressure elevations > 140/
90 mmHg.
 when minimally elevated blood pressure is
associated with other cardiovascular risk
factors (smoking, diabetes, obesity,
hyperlipidemia, genetic predisposition).
When end organs are affected by
hypertension (heart, kidney , brain).
Drug Management of Hypertension







Diuretics
Cardio inhibitory drugs
Beta- blockers
Calcium –channel blockers
Centrally acting sympatholytic
Vasodilators (a1-antagosits; Hydralazine)
Drugs acting on renin-angiotensin
aldosterone system
Diuretics:
- e.g. Thiazides ( hydrochlorothiazide)
Indapamide (NatrilexR)
► cause more sodium loss than water loss
decrease volume of blood
decrease cardiac output
lower blood pressure.
Also, Diuretics decrease SVR via decreasing the
sodium
►diuretics may be adequate in
mild to moderate hypertension
• Note1: Diuretics are the drugs of choice
for most hypertensive patients either
alone or in combination
• Note 2: Black people, elderly and obese
patients respond better for diuretics
because they are salt-sensitive.
B. Potassium-sparing diuretics
Amiloride as well as spironolactone reduce
potassium loss in the urine. Spironolactone
has the additional benefit of diminishing the
cardiac remodeling that occurs in heart
failure.
Cardio inhibitory Drugs
β- Adrenoceptor –Blocking Agents
• β- adrenoceptor blocking agents can be used
in mild to moderate hypertension.
• In severe cases used in combination with
other drugs.
Nadolol (non cardio selective)
Bisoprolol , Atenolol, metoprolol ( cardio
selective)
Labetalol , carvidalol ( α – and β adrenergic
Beta-Adrenoceptor –Blocking Agents
• They lower blood pressure by :
Decreasing cardiac output.
Decreasing renin release (very
important effect and more related to the
clinical response)
α1-adrenoceptor blockers
• Prazocin , Terazocin
• Added to β- blockers for treatment of
hypertension of pheochromocytoma
Due to the postural hypotension α1-adrenoceptor
blockers are not commonly used for Rx of
HTN
CALCIUM CHANNEL BLOCKERS
• Classification

Dihydropyridine group (Nifedipine,
Nicardipine , Amlodipine (AmlorR) is
more selective as vasodilator than a
cardiac depressant. This group is used
for treatment of hypertension
 Verapamil is more effective as cardiac
depressant , therefore it is not used as
antihypertensive agent .
 Diltiazem .Used mainly for angina
❏
Mechanism of Action: (Arterial)
Block the influx of calcium through L-type calcium
channels resulting in:
1- Peripheral vasodilatation (at arteries)
2- Decrease cardiac contractility & heart rate??
Both effects lower blood pressure
Pharmacokinetics:
❏ given orally and intravenous injection
❏ well
absorbed from G.I.T
❏ verapamil and nifedipine
are highly bound to
plasma protiens ( more than 90%)
while diltiazem is less ( 70-80%)
(Cont’d):
❏ onset
of action --- within 1-3 min --- after i.v.
30 min – 2 h --- after oral dose
❏ verapamil & diltiazem have
active metabolites,
nifedipine does not
❏
sustained-release preparations of Nifedipine can
permit once-daily dosing.
Clinical uses
• Treatment of chronic hypertension with
oral preparation (Nifedipine; Amlodipine)
• Nifedipine used for Raynoids phenomena
• Nicardipine can be given by I.V. route &
used in hypertensive emergency
ADVERSE EFFECTS
Verapamil
Diltiazem
Nifedipine
Headache , Flushing ,
Hypotension
Headache, Flushing,
Hypotension
Headache , Flushing,
Hypotension
Peripheral edema
(ankle edema)
Peripheral edema
(ankle edema)
Peripheral edema
(ankle edema)
Cardiac depression, A-V
block , bradycardia
Cardiac depression , A-V
block , bradycardia
Reflex Tachycardia
Constipation
Centrally acting sympatholytic drugs
e.g. Clonidine direct
α2-agonist
Reduce sympathetic outflow to the
heart thereby decreasing cardiac
output (by decreasing heart rate &
contractility ).
Reduced sympathetic output to the
vasculature, decreases sympathetic
vascular tone , which causes
vasodilation & reduced systemic
vascular resistance, which decreases
arterial pressure.
α methyl dopa
indirect
• α 2 agonist is converted to methyl
norepinephrine centrally to diminish the
adrenergic outflow from the C.N.S. This
lead to reduced total peripheral
resistance, and a decreased blood
pressure.
• Safely used in hypertensive pregnant
women
Side effects of centrally acting
sympatholyics
•
•
•
•
•
•
Depression
Dry mouth, nasal mucosa
Bradycardia
Impotence
Postural hypotension
Fluid retention & edema with chronic use
• Sudden withdrawal of clonidine can lead to
rebound hypertension
VASODILATORS
Compensatory Response to Vasodilators
Vasodilators
Hydralazin
e
Site of
action
Mechanism
of action
Route of
admin.
Diazoxide
Na
nitropruside
Arteriodilator
Arteriodilator
Arterio &
venodilator
Direct
Opening of
potassium channels
in smooth muscle
membranes by
minoxidil sulfate
( active metabolite )
Opening of
potassium
channels
Release of nitric
oxide ( NO)
Oral
Oral
Rapid
intravenous
Intravenous
infusion
Arteriodilator
Minoxidil
Continue
Vasodilators
Hydralazine
1.Moderate severe
hypertension.
CHF
Minoxidil
1.severe
hypertension
Diazoxide
1.Hypertensive
emergency
( in the past )
Therapeutic
uses
2.Hypertensive
pregnant
woman
2.correction of
baldness
2.Treatment of
hypoglycemia due to
insulinoma
Na
nitropruside
1.Hpertensive
emergency
Continue
Vasodilators
Hydralazine
Minoxidil
Diazoxide
Hypotension, reflex tachycardia, palpitation, angina,
salt and water retention ( edema)
Na nitropruside
Severe
hypotension
Adverse effects
Specific adverse lupus
erythematosus
effects
like syndrome
Hypertrichosis.
Inhibit insulin
release from β
cells of the
pancreas
causing
hyperglycemia
Contraindicated
in females
Contraindicated
in diabetic
1.Methemoglobin
during infusion
2. Cyanide
toxicity
3. Thiocyanate
toxicity
Give reason : Why β-blockers &
diuretics are added to
vasodilators for treatment of
hypertension?
te
A vasoconstrictor peptide
Synthesis Precursor is Angiotensinogen; a plasma a-globulin synthesized in the liver.
Endothelium, brain &
Other Proteolytic Enzymes
Chymase
Endoperoxidase
AT2
AT1
Secreted by renal juxtaglomerular apparatus
 Renal SN activation
Blood Pressure
Renal Blood flow by
b2 agonists & PGI2
Mechanism of action of Angiotensin-converting enzyme inhibitors (ACEI)
Angiotensin I
(inactive)
ACE
inhibitors
Bradykinin
(active vasodilator)
angiotensinconverting
enzyme
Angiotensin II
(active vasoconstrictor)
Inactive metabolites
Mechanism of action:
Converting enzyme inhibitors lower blood pressure by reducing
angiotensin II, and also by increasing vasodilator peptides
such as bradykinin.
Dilatation of arteriol  reduction of peripheral vascular
resistance (afterload )
Increase of Na+ and decrease of K+ excretion in kidney by inhibition
Aldosterone secretion
reduction of sympathetic activity
(use is not associated with reflex tachycardia
despite causing arterioral and venous dilatation)
Reduce the arteriolar and left ventricular remodelling that are
believed to be important in the pathogenesis of human essential
hypertension and post-infarction state
Pharmacokinetics
• Captopril, Lisonopril; Enalapril and Ramipril;
Fisonopril .
• All are rapidly absorbed from GIT after oral
administration.
• Food reduce their bioavailability.
• Enalapril , ramipril are prodrugs, converted to the
active metabolite in the liver
• Have a long half-life & given once daily except
Captopril
• Enalaprilat is the active metabolite of enalapril
given by i.v. route in hypertensive emergency.
Phrmacokinetics
• Captopril is not a prodrug
• Has a short half-life & given twice /day
• All ACEI are distributed to all tissues except
CNS.
Clinical uses
 Treatment of hypertension

Treatment of heart failure
Diabetic nephropathy . How do they work?
ADVERSE EFFECTS:
Acute renal failure, especially in patients
with bilateral renal artery stenosis
 Hyperkalemia How?
(Cont’d):

Persistent cough Why?

Angioneurotic edema (swelling in the
nose , throat, tongue, larynx)
(Cont’d):
( cough & edema due to bradykinin)
 severe hypotension in hypovolemic
patients (due to diuretics, salt restriction or
gastrointestinal fluid loss)
(Cont’d):
Taste loss
 Skin rash, fever
( taste loss. is due to a sulfhydryl group in the
molecule of captopril ).
Contraindications
• During the second and third trimesters of
pregnancy due to the risk of : fetal
hypotension, anuria, renal failure &
malformations .
• Bilateral renal artery stenosis or stenosis of a
renal artery with solitary kidney. How?
Drug interactions
• With potassium-sparing diuretics (e.g:
Spirinolactone)
• NSAIDs impair their hypotensive effects
by blocking bradykinin-mediated
vasodilatation.
BLOCKERS OF AT1 RECEPTOR
losartan, valosartan, irbesartan
- competitively inhibit angiotensin II at its AT1
receptor site
most of the effects of angiotensin II - including
vasoconstriction
and aldosterone release - are mediated by the AT1 receptor
they influence RAS more effective because of selective
blockade
(angiotensin II synthesis in tissue is not completely dependent
only on renin release, but could be promote by serinprotease 
angiotensinogen
renin
angiotensin I
chymase
CAGE
ACE
angiotensin II
nonrenin proteases
cathepsin
t-PA
Continue
They have no effect on bradykinin system
causing neither: cough, wheezing nor
angioedema
Losartan, valsartan , irbesartan
Adverse effects
• As ACEI except cough, wheezing, and
angioedema.
• Same contraindications as ACEI.
Drug Combination for
Hypertension
• Hydrochlorothiazide (12.5 mg+ Valsartan
• (60 or 80 mg) (Co-DiovanR)
• Hydrochlorothiazide (12.5 mg + Losartan
(50 or 100 mg)
• Hydrochlorothiazide (12.5 mg + Lisinopril
(10 or 20 mg)
Drugs for treatment of
hypertensive crisis
• Labetalol
• Hydralazine (in pregnancy)
• Sodium nitroprusside (2nd line)
General characters of good drug for Crisis:
• Fast & short acting
• Given by IV
Precaution in management of
hypertensive emergencies
Avoid using short-acting nifedipine because of
the risk of rapid, unpredictable hypotension &
the possibility of precipitating ischemic events
Drugs used for management of
hypertension in pregnancy
•
•
•
•
Methyldopa ( the preferred first line )
Labetalol
Hydralazine
Diuretics??
THANK YOU
Any Questions 0505281200