Lecture 1 Pharmacology

Za
Dr Noor Al-Hasani (2020-2021)

Drugs affecting the Cardiovascular system

(Antihypertensive--Part-1)
Hypertension (HT) occurs when systolic blood pressure exceeds 130 mm Hg or
diastolic blood pressure exceeds 80 mm Hg on at least two occasions. The mean
arterial pressure can be calculated from the following equation:

Mean arterial pressure = Cardiac output (CO) X Peripheral resistance (PR)

According to the above equation a decrease in either CO or PR will decrease blood

pressure. Conversely, any increase in blood pressures can be traced back to something
can increase one of these two variables.
HT is also an important risk factor in the development of chronic kidney disease, heart
failure and stroke specifically when the patient is asymptomatic. The incidence of
morbidity and mortality significantly decreases when HT is diagnosed early and is
properly treated.
HT is classified into four categories for the purpose of treatment management as
demonstrated in table 1.

Table 1: Classification of blood pressure.

ETIOLOGY OF HYPERTENSION
Although HT may occur secondary to other disease processes, more than 90% of
patients have essential HT (HT with no identifiable cause).
The main suggested causes for HT are:
1- Family history of HT
2- The prevalence of HT increases with age but decreases with education and income
level.
3- Ethnicity
4- The prevalence of HT increases in persons with diabetes, obesity, or disability
status

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 Lecture 1 Pharmacology
Za
Dr Noor Al-Hasani (2020-2021)

5- In addition, environmental factors, such as a stressful lifestyle, high dietary intake

of sodium, and smoking, may further predispose an individual to HT.
MECHANISMS FOR CONTROLLINGBLOOD PRESSURE
As mentioned above, arterial blood pressure is directly proportional to cardiac output
and peripheral vascular resistance. Cardiac output and peripheral resistance, in turn,
are controlled mainly by two overlapping control mechanisms: the baroreflexes and
the renin–angiotensin–aldosterone system (RAAS). So, most antihypertensive drugs
lower blood pressure by reducing cardiac output and/or decreasing peripheral
resistance.
A- Baroreceptors and the sympathetic nervous system
Baroreflexes act by changing the activity of the sympathetic nervous system.
Therefore, they are responsible for the rapid, moment-to-moment regulation of blood
pressure. A fall in blood pressure causes pressure-sensitive neurons to send fewer
impulses to cardiovascular centres in the spinal cord. This prompts a reflex response
of increased sympathetic and decreased parasympathetic output to the heart and
vasculature, resulting in vasoconstriction and increased cardiac output. These changes
result in a compensatory rise in blood pressure (figure 1).
B- Renin–angiotensin–aldosterone system
The kidney provides long-term control of blood pressure by altering the blood volume.
Baroreceptors in the kidney respond to reduced arterial pressure (and to sympathetic
stimulation of β1-adrenoceptors) by releasing the enzyme renin (figure 1). Low sodium
intake and greater sodium loss also increase renin release. Renin converts
angiotensinogen to angiotensin I, which is converted in turn to angiotensin II, in the
presence of angiotensin-converting enzyme (ACE). Angiotensin II is a potent
circulating vasoconstrictor, constricting both arterioles and veins, resulting in an
increase in blood pressure. Angiotensin II exerts a preferential vasoconstrictor action
on the efferent arterioles of the renal glomerulus. Furthermore, angiotensin II
stimulates aldosterone secretion, leading to increased renal sodium reabsorption and
increased blood volume, which contribute to a further increase in blood pressure.
These effects of angiotensin II are mediated by stimulation of angiotensin II type 1
(AT1) receptors.

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 Lecture 1 Pharmacology
Za
Dr Noor Al-Hasani (2020-2021)

Figure 1: Response of the autonomic nervous system and the renin–angiotensin–aldosterone system
to a decrease in blood pressure.
TREATMENT STRATEGIES
 The blood pressure goal when treating HT is a systolic blood pressure of less than
130 mm Hg and a diastolic blood pressure of less than 80 mm Hg. Mild HT can
sometimes be controlled with monotherapy, but most patients require more
than one drug to achieve blood pressure control.
 Current recommendations are to initiate therapy with a thiazide diuretic, ACE
inhibitor, angiotensin receptor blocker (ARB), or calcium channel blocker. If blood
pressure is inadequately controlled, a second drug should be added.
 The selection of the 2nd drug is based on minimising the adverse effects of the
combined regimen and achieving goal blood pressure.
 Patients with systolic blood pressure greater than 20 mm Hg above goal or
diastolic blood pressure more than 10 mm Hg above goal should be started on two
antihypertensives simultaneously.
 HT treatment plan can be (or should be) individualised. In addition, the blood
pressure goals may also be individualised based on concurrent disease states. For
instance, in patients with diabetes, some experts recommend a blood pressure
goal of less than 140/90 mm Hg.
TYPES OF ANTIHYPERTENSIVE DRUGS:
1- DIURETICS
There are 3 classes of diuretics, which are:
a- Thiazide diuretics
b- Loop diuretics
c- Potassium-sparing diuretics

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 Lecture 1 Pharmacology
Za
Dr Noor Al-Hasani (2020-2021)

Regardless of class, the initial mechanism of action of diuretics is based upon

decreasing blood volume leading to decrease in blood pressure.
Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke,
myocardial infarction, and heart failure. Routine serum electrolyte monitoring should
be done for all patients receiving diuretics.

a- Thiazide diuretics:
Thiazide diuretics, such as hydrochlorothiazide and chlorthalidone can be used as
initial drug therapy for HT unless there are compelling reasons to choose another
agent.
Mechanism of action:
Thiazide diuretics lower blood pressure initially by increasing sodium and water
excretion. This causes a decrease in extracellular volume, resulting in a decrease in
cardiac output and renal blood flow (figure 2). With long-term treatment, plasma
volume approaches a normal value, but a hypotensive effect persists that is related to
a decrease in peripheral resistance.

Figure 2: Actions of thiazide diuretics.

Therapeutic uses:
Thiazides are useful in combination therapy with a variety of other antihypertensive
agents. With the exception of metolazone, thiazide diuretics are not effective in
patients with inadequate kidney function (estimated glomerular filtration rate less
than 30 mL/min/m2). Loop diuretics may be required in these patients.

Adverse effects:
Thiazide diuretics can induce hypokalaemia, hyperuricemia and, to a lesser extent,
hyperglycaemia in some patients. Thiazides increase serum uric acid by decreasing the
amount of acid excreted through competition in the organic acid secretory system.
Being insoluble, uric acid deposits in the joints and may precipitate a gouty attack in
predisposed individuals. Therefore, thiazides should be used with caution in patients
with gout or high levels of uric acid.

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 Lecture 1 Pharmacology
Za
Dr Noor Al-Hasani (2020-2021)

b- Loop diuretics (LD)

The loop diuretics (such as furosemide) act by blocking sodium and chloride
reabsorption in the kidneys, even in patients with poor renal function or those who
have not responded to thiazide diuretics. LD cause decreased renal vascular resistance
and increased renal blood flow.
In comparison to thiazides diuretics:
Like thiazides, LD can cause hypokalaemia. However, unlike thiazides, LD increase the
Ca2+ content of urine, whereas thiazide diuretics decrease it. These agents are rarely
used alone to treat HT, but they are commonly used to manage symptoms of heart
failure and oedema.
In addition, LD can cause hyperuricemia as Loop diuretics compete with uric acid for
the renal secretory systems, thus blocking its secretion and, in turn, may cause or
exacerbate gouty attacks.
 Ototoxicity : Reversible or permanent hearing loss may occur with loop diuretics,
particularly when infused intravenously at fast rates, at high doses, or when used
in conjunction with other ototoxic drugs (for example, aminoglycoside antibiotics)

c- Potassium-sparing diuretics (PSD)

PSD (such as amiloride and spironolactone (aldosterone receptor antagonists) reduce
potassium loss in the urine. Aldosterone antagonists (spironolactone) have the
additional benefit of diminishing the cardiac remodelling that occurs in heart failure.
Potassium-sparing diuretics are sometimes used in combination with loop diuretics
and thiazides to reduce the amount of potassium loss induced by these diuretics.

2- β-ADRENOCEPTOR–BLOCKING AGENTS (β-BLOCKER (BB))

β-Blockers are a treatment option for hypertensive patients with concomitant heart
disease or heart failure. A summary of BB mechanism of action is demonstrated in
figure 3. The nonselective β-blockers, such as propranolol and nadolol, are
contraindicated in patients with asthma due to their blockade of β2-mediated
bronchodilation. β-Blockers should be used cautiously in the treatment of patients
with acute heart failure or peripheral vascular disease.

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 Lecture 1 Pharmacology
Za
Dr Noor Al-Hasani (2020-2021)

Figure 3: Actions of β-adrenoceptor–blocking agents.

Therapeutic uses
The primary therapeutic benefits of β-blockers are seen in hypertensive patients with
concomitant heart disease, such as previous myocardial infarction, angina pectoris,
and chronic heart failure. Conditions that discourage the use of β-blockers include
reversible bronchospastic disease such as asthma. Oral β-blockers may take several
weeks to develop their full effects. Esmolol, metoprolol, and propranolol are available
in intravenous formulations.
Adverse effects
Common effects: The β-blockers may cause bradycardia, hypotension, and CNS side
effects such as fatigue, lethargy, and insomnia. The β-blockers may decrease libido
and cause erectile dysfunction, which can severely reduce patient compliance.
Alterations in serum lipid patterns: Non-cardioselective β-blockers may disturb lipid
metabolism, decreasing high-density lipoprotein cholesterol and increasing
triglycerides.
Drug withdrawal: Abrupt withdrawal may induce angina, myocardial infarction, and
even sudden death in patients with ischemic heart disease. Therefore, these drugs
must be tapered over a few weeks in patients with HT and ischemic heart disease.

References:
1- Katzung, B.G., 2018. Basic and clinical pharmacology. Mc Graw Hill.
2- Whalen, K., 2019. Lippincott illustrated reviews: pharmacology. Lippincott Williams & Wilkins.