Circulation
PCTH 300 and 305
2018-19
Blood pressure
Cardiac output
Blood
volume
Venous tone
Heart rate &
Contractility
Total peripheral resistance
(TPR)
Constriction and/or reduced
lumen diameter of arterioles
Blood pressure = Cardiac output x Total peripheral resistance (TPR);TPR = BP/CO
Cardiac output = Volume of blood pumped out per minute
Arterioles (smallest diameter arteries): primary site of resistance to BF
Established hypertension is associated with normal CO, but ↑TPR and/or ↑large
artery stiffness, together with defective baroreceptor and blood volume regulation.
Systolic blood pressure (SBP)
Pulse pressure
Diastolic blood pressure (DBP)
Hypertension: ↑SBP (>140 mmHg ), ↑DBP (>90 mmHg) or ↑SBP/DBP (>140/>90) :
1. ↑SBP only (due to ↑stiffness of large arteries) – Isolated systolic hypertension
2. ↑DBP only (due to narrowing of arterioles) – Isolated diastolic hypertension
3. ↑SBP/DBP (a combination of 1 and 2) – Systolic-diastolic hypertension
Essential hypertension (>80% of hypertension): unknown cause
Secondary hypertension: secondary to a medical condition – e.g, pheochromocytoma,
renovascular hypertension (narrowing of renal arteries), aldosteronism (↑aldosterone causing
Na+ retention/↑blood volume), gestational hypertension, pulmonary hypertension.
Isolated systolic hypertension: prominent in people > 50 years old.
Isolated diastolic hypertension: prominent in adults < 40 years old.
Williams B et al. http://211.144.68.84:9998/91keshi/Public/File/36/371-9631/pdf/1-s2.0-S0140673608608041-main.pdf
Management of blood pressure (BP)
BP management target depends on age, is dependent on the community
(European or N Am), and may be variable from one year to the next.
General treatment BP targets:
Aged >60 years: <150/90 mmHg (BP too low can reduce cardiac
perfusion).
Aged <60 years: <140/90 mmHg.
Patients with diabetes, heart failure, chronic kidney disease: <130/90
mmHg.
Hypertension: general information
• About 90% of North Americans develop hypertension, but
only ≈60% of hypertensive patients are treated.
• Only one-third of treated hypertensive patients have effective
control of blood pressure (<140/90 mmHg).
• Hypertension is usually asymptomatic.
• Severe hypertension is associated with:  mortality,
atherosclerosis, kidney damage, left ventricular (LV) failure,
myocardial infarction (MI), stroke.
Non-pharmacological management of hypertension
1. Weight loss for overweight individuals
2. Physical activity
3. Low sodium diet
4. No smoking
5. Reduce alcohol intake (<2 drinks/day for men, <1 drink per
day for women)
First-line antihypertensive drugs
1. Thiazide diuretics (e.g., chlorthalidone, hydrochlorothiazide,
indapamide)
2. Angiotensin converting enzyme inhibitors (ACEI, e.g., captopril)
3. Angiotensin receptor blocker (ARB, e.g., losartan)
4. Ca2+ channel blocker (CCB, e.g., amlodipine , nifedipine, verapamil)
Not reach BP goal with 1 drug: add 2nd or 3rd drug from above list.
Not reach BP goal with 2-3 drugs from the list: use other classes (see later).
ACEI and ARB are not to be used concurrently.
Note: The 2018 European guideline suggests use of two pills to initiate
treatment for most hypertensive patients.
Add on drug
-Blockers (propranolol, atenolol)
-Blockers (prazosin)
2-Adrenoceptor agonists (-methyldopa)
Vasodilators (hydralazine)
Unease on Industry's Role in Hypertension Debate (by S. Saul)
New York Times (May 20, 2006)
• Three pharmaceutical companies (Merck, Novartis, Sankyo) donated
$700,000 to the Am. Hypert. Soc. that used most of the money on dinner
lectures to brief doctors on the latest news and expanded concept of high
blood pressure (pre-hypertension).
• About 65 million Americans have high blood pressure (>140/90 mmHg)
under the current definition. But another 59 million are on the borderline
(pre-hypertensive). Redefining hypertension could make drugs a
standard treatment for patients with SBP of 120-139, and DBP of 80-89
mmHg.
• Six of the 7 doctors who wrote the new definition have served as
consultants/speakers for pharmaceutical companies that make
antihypertensive drugs. The 7th is a consultant/stockholder in a company
that markets a diagnostic method to measure damage to blood vessels.
Note: the 2018 US guideline suggests again targeting BP to <130/80
mmHg.
Thiazide diuretics (hydrochlorothiazide, chlorthalidone)
↑ Renal Na+ excretion (diuresis) →  total body sodium, blood volume and CO
initially.
After a few weeks, TPR is decreased due to:
 vascular [Na+ ]i leads to [Ca2+ ]i
 [Na]i enhances Na influx and Ca efflux via the Na-Ca antiporter → [Ca 2+]i
→  vascular stiffness/reactivity.
Risk of heart attacks, stroke, heart failure and death (ALLHAT Trial).
Used alone: limited efficacy ( BP by 10 mmHg).
Side effects: Reflex  HR, hyponatremia, hypokalemia (due to ↑aldosterone);
 serum lipid (cholesterol and LDL), insulin resistance.
Blockers of renin-angiotensin system
1. Angiotensin converting enzyme inhibitors (ACEI, e.g., captopril):
 Formation of ANG II, aldosterone.
 Activity of sympathetic nervous system.
 Bradykinin (vasodilator).
Side effects: cough, angioedema, hyperkalemia.
Avoid use in pregnancy: may cause fetal malformation.
2. Angiotensin (AT1) receptor Blocker (ARB, e.g., losartan):
Blocks effect of ANG II on AT1 receptors.
Similar effects as ACEI (but does not increase bradykinin → does
not induce coughing; less angioedema).
3. Renin inhibitor (aliskiren):
Similar efficacy as ACE inhibitor and angiotensin antagonist.
Benefit as an add-on drug is uncertain.
Note: avoid use of 2 or more angiotensin blockers.
Ca2+-channel blockers
↓ Ca2+ influx into vascular smooth muscle/cardiac cells.
Cardiac selective: verapamil
Vascular selective: nifedipine, amlodipine
High dose of short-acting nifedipine: risk of heart attack.
Side effects: AV block, heart failure,
HR ( with nifedipine; ↓ with verapamil)
-Adrenoceptor antagonists
 Activities of sympathetic nervous and renin-angiotensin systems
 HR and cardiac contractility.
 Myocardial infarction, stroke, death.
Non-selective -blockers: propranolol, labetalol (3:1 for :1-block)
Selective 1-blocker: atenolol, metoprolol.
Side effects:
1-Block: fatigue, myocardial depression, heart block, exercise
tolerance,
2-Block: peripheral circulation and bronchospasm.
β-adrenoceptor blockers and pulmonary function
β-blockers are often given to patients with both cardiovascular disease
and chronic obstructive pulmonary disease (COPD with ↑airway
resistance). |
Study: Does cardioselective β-blockers affect lung function?
Results: Even β1-Blockers reduce expiratory functions (forced
expiratory volume and forced vital capacity). Non-cardioselective β-
blockers, however, cause greater impairment of expiratory functions.
British Journal of Clinical Pharmacology, 77: 190–200, 2014
-Adrenoceptor antagonists (prazosin, doxazosin)
Block noradrenaline-induced vasoconstriction.
Side effects: reflex HR; orthostatic hypotension and syncope;
edema; sedation/depression.
Inferior to chlorthalidone as a 1st line agent (ALLHAT trial):
 incidence of CHF, stroke, angina and MI (despite:  insulin
resistance,  LDL-cholesterol and  HDL-cholesterol).
Use: primarily in men with concurrent hypertension and benign
prostatic hyperplasia.
Antihypertensive and Lipid Lowering Treatment to
Prevent Heart Attack (ALLHAT) Trial
A randomized, double-blind trial involving >40,000 patients
within 8 years. The goal was to lower BP to <140/90 mmHg.
Assess effects of 4 antihypertensive drugs on cardiovascular
complications in high risk adults with essential hypertension:
Chlorthalidone (diuretic)
Doxazosin (-blocker)
Amlodipine (Ca2+ channel blocker)
Lisinopril (ACE inhibitor)
Diuretic was superior to -blocker, Ca2+ antagonist or ACE
inhibitor in reducing some cardiovascular disease risks.
Note: the drugs were compared with each other, not with placebo.
Centrally acting (2-adrenoceptor agonist):
Clonidine, -methyl dopa
Both drugs decrease sympathetic nerve activity (SNA) via activation of
CNS 2-adrenoceptors.
-Methyl dopa is converted to -methyl norepinephrine (2adrenoceptor agonist).
Clonidine also stimulates CNS imidazoline I1 receptors that  SNA.
Side effects: sedation, fatigue, dry mouth, HR, rebound hypertension
with sudden discontinuation of therapy (need gradual withdrawal of
drug along with administration of another medication).
Vasodilators
Dilates only arterioles (not capacitance vessels).
↑ Sympathetic nerve activity: ↑HR (reflex) – may provoke angina.
↑ Renin-angiotensin-aldosterone: Fluid retention (peripheral edema).
Therefore, it is often given along with a diuretic and β-blocker.
Minoxidil: hyperpolarizes vascular smooth muscle cells by opening K+
channels. Causes hypertrichosis (i.e., excessive hair growth;
Rogaine)
Hydralazine: multiple mechanism of action (opens K+ channels?
release NO? Ca2+ release from SR?)
Blood pressure regulation &
Management of hypertensive
emergencies
Hypertensive urgencies (not required)
SBP >180 or DBP >120 mmHg; no end-organ damage
Due to inadequate treatment or non-adherence of treatment
Oral antihypertensive drug therapy to gradually lower BP to
160/100 mmHg within 24-48 h
Hypertensive emergencies
Occurrence: <1% of hypertensive patients
Rapid increase in SBP/DBP to >180/130 mmHg with signs of acute
end-organ damage.
If untreated promptly, can lead to:
- Brain hemorrhage (stroke); encephalopathy (neural deficit due to
loss of autoregulation → ↑ flow, vascular leakage, edema)
- LV failure/pulmonary edema/acute MI
- Others: aortic dissection, endothelial damage, intravascular
coagulation, kidneys failure, retina damage
Common causes of hypertensive emergencies
Pheochromocytoma.
Acute renal failure, renovascular disease.
Drugs: Clonidine withdrawal; Use of cocaine,
amphetamine, MAO inhibitors (along with food
containing tyramine).
Pharmacotherapy
Gradual reduction of BP (by  25%) via i.v. infusion of
antihypertensive drugs, followed by oral antihypertensive therapy.
Preferred drugs are fast-acting, rapidly reversible/titratable; e.g.:
- Nitrovasodilators: nitroprusside
- Adrenoceptor antagonist (mixed -/- or -): labetalol
- Dopamine D1 agonist: fenoldopam
- Ca2+ channel blocker: nicardipine, clevidipine
- Ganglionic blockers: trimethaphan (less used)
Nitrovasodilators
Nitroprusside
- Efficacious - dilates arterioles and veins via NO release and
activation of guanylyl cyclase.
- Fast acting: onset (immediate), duration (≈2 min).
-  TPR + venous pooling (orthostatic hypotension) →  BP, 
HR, coronary steal
- Cyanate (CN−)/thiocyanate [SCN]− toxicity when given >3 days.
Sodium nitroprusside
Fenoldopam
Dopamine D1-receptor agonist
- Arteriolar dilatation: especially renal (GFR) and
mesenteric vascular beds,  natriuresis
- Reflex HR
- Venodilation → orthostatic hypotension
- Short acting: onset (5-10 min), duration (30 min)
Dihydropyridine Ca++ channel blocker
Nicardipine - 2nd generation.
Onset (5-10 min), duration (2-4 h).
High vascular selectivity; reflex ↑HR.
Clevidipine (not required) – 3rd generation (approved 2011).
Similar pharmacological actions as nicardipine; but faster
onset (2 - 4 min) and shorter duration (15 min).
Trimethaphan
Ganglionic blocker.
Quaternary amine - does not cross the BBB.
Short acting: onset (1-5 min), duration (10 min).
Side effects: hypotension, orthostatic hypotension,
negatively inotropic, urinary retention, paralytic ileus,
dry mouth, blurred vision.