Professional Documents
Culture Documents
Oguanobi
Department of Pharmacology and
Therapeutics, Faculty of Medical Sciences,
University of Nigeria Enugu Campus
The Heart
Introduction
Hypertension
Essential Secondary
Environmental
Factors
Cardiovascular system
CNS
Renal system
Retinal damage
Target Organ Damage
Heart
Left ventricular hypertrophy
Coronary artery disease
Myocardial infarcts
Heart failure
Brain
Stroke or transient ischemic attacks
Chronic kidney disease, kidney failure
Retinopathy
Contributing Factors
Obesity
Stress
Lack of exercise
Alcohol intake
Cigarette smoking
Treatment – Why?
Damage to the vascular epithelium, paving the
path for atherosclerosis (IHD, CVA) or
nephropathy due to high intra-glomerular
pressure
Increased load on heart due to high BP can
cause CHF
Hypertension, even asymptomatic needs
treatment
Mean Arterial Pressure
MAP = CO X PVR
myogenic tone
CO = HR X SV vascular
responsivenes
SNS Blood nervous control
volume
Heart
contactility vasoactive
Venous tone metabolites
endothelial factors
circulating hormones
Normal Blood Pressure Regulation
Hydraulic equation:
Blood Pressure = Cardiac output (CO) X
Resistance to passage of blood
through precapillary arterioles (PVR)
Physiologically CO and PVR is
maintained minute to minute by –
arterioles (1) postcapillary venules (2)
and Heart (3)
Kidney is the fourth site – volume of
intravascular fluid
Baroreflex, humoral mechanism and
renin-angiotensin- aldosterone system
regulates the above 4 sites
Local agents like Nitric oxide
In hypertensives – Baroreflex and
renal blood-volume control system –
set at higher level
All antihypertensives act via interfering
with normal mechanisms
Baroreceptor reflex arc
Postural baroreflex:
The Renal response
Long-term blood pressure control – by controlling
blood volume
Reduction in renal pressure - intrarenal redistribution
of pressure and increased absorption of salt and
water
Decreased pressure in renal arterioles and
sympathetic activity – renin production – angiotensin
II production
Angiotensin II:
Causes direct constriction of renal arterioles
Stimulation of aldosterone synthesis – sodium
absorption and increase in intravascular blood volume
How can we treat hypertension
•Secondary hypertension- treat underlying cause
•Essential hypertension- cause not known
•Factors involved- stress, weight, dietary habits, salt retention,
increased angiotensin production, , increased sympathetic tone
•Approaches-
Reduce salt/water content of body
Reduce sympathetic tone
Reduce effects of circulating angiotensin II
Reduce cardiac force of contraction
Dilate peripheral vessels to reduce cardiac filling & consequent
stroke volume
Need for life-style changes:
•Weight loss/control
•Restricted sodium intake
•Increasing aerobic exercise
•Moderating alcohol consumption
These changes in life-style may be sufficient to
control hypertension in early stage I
They also facilitate pharmacological treatment
National Heart Lung Blood Institute
National High Blood Pressure
Education Program
http://www.nhlbi.nih.gov/guidelines/
hypertension/index.htm
New BP Goals
-Adrenoceptor blockers
-Adrenoceptor blockers
•Combined and blockers
•ACE inhibitors
Hydralazine, Minoxidil, Diazoxide,
•ARBs Fenoldopam (arteriolar)
•CCBs Sodium nitroprusside
(arteriolar + venular)
•Vasodilators
Antihypertensive Drugs
Diuretics:
Thiazides: Hydrochlorothiazide, chlorthalidone
High ceiling: Furosemide
K+ sparing: Spironolactone, triamterene and amiloride
MOA: Acts on Kidneys to increase excretion of Na and H2O –
decrease in blood volume – decreased BP
Angiotensin-converting Enzyme (ACE) inhibitors:
Captopril, lisinopril., enalapril, ramipril and fosinopril
MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral
resistance and blood volume
Angiotensin (AT1) blockers:
Losartan, candesartan, valsartan and telmisartan
MOA: Blocks binding of Angiotensin II to its receptors
Antihypertensive Drugs
Centrally acting:
Clonidine, methyldopa
Increased
Blood Vol.
Rise in BP
Vasoconstriction
Kidney
(Adrenal cortex)
RAS – actions of Angiotensin-II.
1. Powerful vasoconstrictor particularly arteriolar – direct action and
release of Adr/NA release
Promotes movement of fluid from vascular to extravascular
More potent vasopressor agent than NA – promotes Na+ and water
reabsorption
It increases myocardial force of contraction (CA++ influx promotion)
and increases heart rate by sympathetic activity, but reflex
bradycardia occurs
Cardiac output is reduced and cardiac work increases
2. Aldosterone secretion stimulation – retention of Na++ in body
3. Vasoconstriction of renal arterioles – rise in IGP – glomerular damage
4. Decreases NO release
5. Decreases Fibrinolysis in blood
6. Induces drinking behaviour and ADH release by acting in CNS –
increase thirst
7. Mitogenic effect – cell proliferation
Angiotensin-II
What are the ill effects on chronic stimulation?
Volume overload and increased t.p.r
Cardiac hypertrophy and remodeling
a) ACE inhibitors
captopril, enalapril, lisinopril
b) Angiotensin II receptor
blockers (ARB)
losartan, valsartan, irbesartan,
Telmisartan, candesartan
ACE inhibitors
Captopril, lisinopril., enalapril, ramipril
and fosinopril etc.
ACE inhibitors in Hypertension
Captopril
Sulfhydryl containing dipeptide and abolishes
pressor action of Angiotensin-I and not
Angiotensin-II and does not block AT
receptors
Pharmacokinetics:
Available only orally, 70% - 75% is absorbed
Partly absorbed and partly excreted
unchanged in urine
Food interferes with its absorption
Half life: 2 Hrs, but action stays for 6-12 Hrs
Captopril – Pharmacological actions
1. In Normal:
Depends on Na+ status – lowers BP marginally on single dose
When Na+ depletion – marked lowering of BP
2. In hypertensive:
Lowers PVR and thereby mean, systolic and diastolic BP
RAS is overactive in 80% of hypertensive cases and contributes
to the maintenance of vascular tone – inhibition causes lowering
of BP
Initially correlates with renin-angiotensin status but chronic
administration is independent of renin activity
Captopril decreases t.p.r on long term – arterioles dilate – fall in
systolic and diastolic BP
No effect on Cardiac output
Postural hypotension is not a problem - reflex sympathetic
stimulation does not occur
Renal blood flow is maintained – greater dilatation of vessels
Captopril – Adverse effects
Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substanceP breakdown in lungs
Hyperkalemia in renal failure patients with K+ sparing diuretics,
NSAID and beta blockers (routine check of K+ level)
Hypotension – sharp fall may occur – 1st dose
Acute renal failure: CHF and bilateral renal artery stenosis
Angioedema: swelling of lips, mouth, nose etc.
Rashes, urticaria etc
Dysgeusia: loss or alteration of taste
Foetopathic: hypoplasia of organs, growth retardation etc
Neutripenia
Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia
ACE inhibitors - Enalapril
•Oxeprenolol
•Pindolol
•Penbutolol
•Acebutolol
Propranolol (Inderal)
Mechanism:
Block cardiac 1 receptors lower CO
Block renal 1 receptors lower renin, lower PVR
Main effects: decrease HR and PVR
Adverse effects: bradycardia, depression, 2
blockade in airways, glucose and lipid
metabolism, vasoconstriction in extremities
Pharmacokinetics: GI, 30-50% metabolized in the
first-pass in liver. T1/2: 3-5 hours, Slow- release
propranolol available
Use: used in stage 1 and 2 HT alone or in
combinations with a diuretic and/or vasodilator
Drug Interactions: verapamil, diltiazem, digitalis
(caution AV Block)
Labetalol (Trandate)
• BP goal: <130/80 mm Hg
Hypertension
• and heart failure with preserved ejection factor (HFpEF)
If symptoms of volume overload, prescribe diuretics
• BP goal: <130 mm Hg
– In adults who have had an MI or ACS, reasonable to continue GDMT beta blockers for
treatment of hypertension beyond 3 years
– In patients with CAD (without HFrEF) and angina who had MI > 3 years previously,
consider beta blockers and/or CCBs
– BP target: <130/80 mm Hg
Whelton PK et al. Hypertension/J Am Coll Cardiol. 2017 [Epub ahead of print].
Antihypertensive Drug Treatment: CKD
Lifestyle Modifications
Not at Goal
Blood Pressure