ANTIHYPERTENSIVE
DRUGS
Pharmacology
– Hypertension
1.
DRUGS USED IN THE TREATMENT OF HYPERTENSION
A.
TWO MAJOR DETERMINANTS OF BLOOD PRESSURE
Blood pressure depends mainly on:
1. Cardiac Output (CO)
2. Total Peripheral Resistance (TPR)
Basic
relationship
BP ≈ CO × TPR
Cardiac output:
CO = Heart Rate × Stroke Volume
Therefore, blood pressure can be reduced by:
- Decreasing cardiac output
- Decreasing total peripheral
resistance
- Decreasing blood volume
- Reducing sympathetic activity
- Inhibiting the
renin–angiotensin–aldosterone system (RAAS)
B.
SYSTOLIC AND DIASTOLIC BLOOD PRESSURE
Systolic
Blood Pressure (SBP)
Systolic BP is the maximum arterial pressure
during ventricular systole.
It is influenced substantially by:
- Cardiac output
- Stroke volume
- Ventricular contractility
Diastolic
Blood Pressure (DBP)
Diastolic BP is the lowest arterial pressure
during ventricular diastole.
It is strongly influenced by:
- Total peripheral resistance
- Arteriolar tone
Exam
point
Cardiac output → major determinant of systolic BP
Total peripheral resistance → major determinant
of diastolic BP
NON-PHARMACOLOGICAL
MANAGEMENT OF HYPERTENSION
Important lifestyle measures include:
- Regular physical exercise
- Reduction of dietary sodium
intake
- Weight reduction when
overweight/obese
- Smoking cessation
- Limiting alcohol intake
- Stress reduction and relaxation
techniques
- Healthy diet rich in fruits and
vegetables
- Adequate dietary potassium when
appropriate
Management of other cardiovascular risk factors,
including abnormal lipid levels, is also important because hypertension and
dyslipidemia both contribute to cardiovascular disease and atherosclerosis.
2.
REGULATION OF BLOOD PRESSURE AND PHARMACOLOGICAL MANAGEMENT
CARDIAC
OUTPUT
CO = HR × SV
Stroke volume is influenced by:
- Contractility
- Preload
- Afterload
CONTRACTILITY
Contractility is the force with which the ventricular
myocardium contracts.
↑ Contractility → ↑ Stroke volume → ↑ Cardiac
output → ↑ BP
↓ Contractility → ↓ Stroke volume → ↓ Cardiac
output → ↓ BP
PRELOAD
Preload is the ventricular filling/stretch at the
end of diastole and is related to end-diastolic volume.
Preload is influenced by:
- Venous return
- Venomotor tone
- Total blood volume
- Duration of diastole
Venomotor
tone
Venoconstriction → ↑ venous return → ↑ preload →
↑ stroke volume → ↑ CO
Venodilation → ↓ venous return → ↓ preload → ↓
stroke volume → ↓ CO
Blood
volume
↑ Blood volume → ↑ venous return → ↑ preload → ↑
stroke volume → ↑ CO
↓ Blood volume → ↓ venous return → ↓ preload → ↓
stroke volume → ↓ CO
Heart
rate and diastolic filling
A very high heart rate shortens diastolic filling time.
↑ HR → ↓ diastolic filling time → ↓ ventricular
filling
Therefore, reduction in preload generally decreases:
Preload → Stroke volume → Cardiac output → BP
AFTERLOAD
Afterload is the resistance against which the
ventricle must pump.
For the left ventricle, systemic vascular
resistance/arterial pressure is an important component of afterload.
↑ TPR → ↑ afterload
↓ TPR → ↓ afterload
The interaction between:
Preload + Afterload + Contractility
determines:
Stroke volume → Cardiac output → Blood pressure
KIDNEYS
AND BLOOD PRESSURE
The kidneys play a major role in long-term BP regulation
by controlling:
- Sodium balance
- Water balance
- Blood volume
- Renin release
The juxtaglomerular apparatus (JGA)
releases renin in response to appropriate stimuli, including reduced renal
perfusion and sympathetic β₁ stimulation.
CENTRAL
NERVOUS SYSTEM CONTROL
The medullary cardiovascular/vasomotor centers regulate
autonomic activity.
Sympathetic stimulation affects:
- Heart
- Arterioles
- Veins
- Juxtaglomerular apparatus
The baroreceptor reflex, particularly
from receptors in the carotid sinus and aortic arch, helps regulate sympathetic
and parasympathetic outflow.
3.
α₂-ADRENERGIC RECEPTORS AND CENTRALLY ACTING ANTIHYPERTENSIVES
α₂
RECEPTORS
α₂-adrenergic receptors are present presynaptically and
in the central nervous system.
They act as an autoregulatory inhibitory
mechanism.
Normal
mechanism
Norepinephrine is released from a sympathetic nerve
terminal.
↓
Norepinephrine stimulates presynaptic α₂
receptors
↓
Further norepinephrine release is inhibited
↓
Reduced sympathetic neurotransmission
Therefore:
α₂ receptor = “brake” on sympathetic activity
CENTRALLY
ACTING ANTIHYPERTENSIVE DRUGS
Examples:
- Clonidine
- Methyldopa
- Guanfacine
- Guanabenz
These drugs reduce sympathetic outflow from the CNS.
CLONIDINE
Clonidine is a centrally acting sympatholytic drug.
Mechanism
Clonidine
↓
Stimulates central α₂ receptors
↓
↓ Sympathetic outflow
↓
↓ Heart rate
↓ Contractility
↓ Peripheral vascular tone
↓ Renin release
↓
↓ Blood pressure
Thus clonidine can reduce both systolic and diastolic BP.
METHYLDOPA
Methyldopa is a prodrug that is converted to α-methylnorepinephrine,
which acts centrally as an α₂-adrenergic agonist.
Catecholamine
synthesis
Tyrosine
↓
Tyrosine hydroxylase
↓
DOPA
↓
DOPA decarboxylase
↓
Dopamine
↓
Dopamine β-hydroxylase
↓
Norepinephrine
Methyldopa enters this pathway and ultimately produces:
α-methylnorepinephrine
↓
Central α₂ receptor stimulation
↓
↓ Sympathetic outflow
↓
↓ HR + ↓ contractility + ↓ vascular tone
↓
↓ BP
EFFECTS
OF CENTRALLY ACTING SYMPATHOLYTICS
↓ Sympathetic activity
↓
- ↓ Heart rate
- ↓ Contractility
- ↓ Peripheral vascular
resistance
- ↓ Renin release
↓
↓ Blood pressure
4.
SYMPATHETIC NERVE-ENDINGS AND THEIR BLOCKERS
Postganglionic sympathetic nerve endings release norepinephrine
(NE).
NOREPINEPHRINE
SYNTHESIS
Tyrosine
→ Tyrosine hydroxylase
→ DOPA
→ DOPA decarboxylase
→ Dopamine
→ Dopamine β-hydroxylase
→ Norepinephrine
Norepinephrine is stored in synaptic vesicles.
An action potential causes:
Ca²⁺ influx → Vesicle fusion → NE release
NE then acts on adrenergic receptors on target tissues.
After release, NE is mainly terminated by neuronal
reuptake (NET) and subsequent metabolism.
DRUGS
THAT INTERFERE WITH SYMPATHETIC NERVE FUNCTION
Important drugs:
- Guanethidine
- Reserpine
- Metyrosine
GUANETHIDINE
Guanethidine is taken up into sympathetic nerve endings
by the norepinephrine transporter.
↓
It becomes concentrated in the nerve terminal and
interferes with neurotransmitter storage/release.
↓
↓ Norepinephrine release
↓
↓ Sympathetic activity
RESERPINE
Reserpine inhibits the vesicular monoamine transporter (VMAT).
↓
Dopamine cannot be effectively stored in synaptic
vesicles.
↓
Dopamine and other monoamines are metabolized by MAO.
↓
Depletion of catecholamines
↓
↓ Sympathetic activity
Reserpine also depletes central monoamines and can cause
important CNS adverse effects, including depression.
METYROSINE
Metyrosine inhibits:
Tyrosine hydroxylase
↓
Blocks the first and rate-limiting step in catecholamine
synthesis.
↓
↓ DOPA
↓
↓ Dopamine
↓
↓ Norepinephrine
↓
↓ Sympathetic activity
Metyrosine is mainly used to reduce catecholamine
synthesis in conditions such as pheochromocytoma, rather than
as routine hypertension therapy.
5.
ADRENERGIC RECEPTOR BLOCKERS
Important adrenergic receptors:
α₁
Mainly present on vascular smooth muscle.
α₁ stimulation → vasoconstriction
β₁
Present mainly in:
- Heart
- JGA
β₁ stimulation → ↑ HR + ↑ contractility + ↑ renin
β₂
Present in many tissues including vascular smooth muscle.
β₂ stimulation → vasodilation
α₁-ADRENERGIC
BLOCKERS
Examples:
- Prazosin
- Doxazosin
- Terazosin
They block vascular α₁ receptors.
Mechanism
α₁ blockade
↓
Arterial dilation + venodilation
↓
↓ TPR + ↓ venous return
↓
↓ Afterload + ↓ Preload
↓
↓ Cardiac output/vascular resistance
↓
↓ BP
NON-SELECTIVE
α BLOCKERS
Examples:
- Phentolamine
- Phenoxybenzamine
They block:
α₁ + α₂ receptors
Blocking α₂ removes presynaptic inhibition of NE release.
↓
↑ NE release
↓
NE can stimulate β₁ receptors in the heart
↓
Reflex tachycardia
This is one reason selective α₁ blockade is
pharmacologically different from non-selective α blockade.
ORTHOSTATIC
HYPOTENSION
Normally, on standing:
↓ Venous return
↓
Baroreceptor reflex
↓
↑ Sympathetic activity
↓
α₁-mediated venoconstriction
↓
Maintains venous return and BP
With α₁ blockade:
Standing
↓
Venous constriction is impaired
↓
Blood pools in lower extremities
↓
↓ Venous return
↓
↓ Cardiac output
↓
Orthostatic hypotension
Symptoms may include:
- Dizziness
- Light-headedness
- Fainting
6.
BETA BLOCKERS
Examples:
Non-selective
- Propranolol
β₁-selective
- Atenolol
- Metoprolol
- Bisoprolol
β₁
RECEPTORS
β₁ receptors are present in:
- SA node
- AV node
- Myocardium
- Juxtaglomerular apparatus
Cardiac
mechanism
β₁ blockade
↓
↓ Heart rate
↓ AV conduction
↓ Contractility
↓
↓ Stroke volume
↓
↓ Cardiac output
↓
↓ BP
Renal
mechanism
β₁ blockade at JGA
↓
↓ Renin release
↓
↓ Angiotensin II
↓
↓ Aldosterone
↓
↓ Sodium and water retention
↓
↓ Blood pressure
OVERALL
BETA-BLOCKER EFFECT
β₁ blockade
→ ↓ HR
→ ↓ Contractility
→ ↓ Cardiac output
→ ↓ Renin
→ ↓ Angiotensin II
→ ↓ Aldosterone
→ ↓ Blood volume
↓
↓ BP
NON-SELECTIVE
β BLOCKERS
Non-selective β blockers also block β₂ receptors.
β₂ blockade may cause:
- Bronchoconstriction
- Reduced peripheral vasodilation
- Exercise intolerance
- Fatigue
Therefore, non-selective β blockers require caution in
susceptible patients, particularly those with bronchospastic disease.
7.
DIRECTLY ACTING VASODILATORS
Examples:
- Hydralazine
- Minoxidil
- Sodium nitroprusside
These drugs directly relax vascular smooth muscle.
HYDRALAZINE
Hydralazine is predominantly an arteriolar
vasodilator.
↓
↓ Arteriolar resistance
↓
↓ TPR
↓
↓ BP
However:
↓ BP
↓
Baroreceptor-mediated sympathetic activation
↓
↑ HR + ↑ contractility
↓
Reflex tachycardia
It can also activate RAAS, promoting sodium and water
retention.
Therefore, hydralazine is often combined with:
Beta blocker + Diuretic
HYDRALAZINE
– ADVERSE EFFECTS
- Headache
- Flushing
- Reflex tachycardia
- Palpitations
- Fluid retention
- Orthostatic symptoms
- Lupus-like syndrome
Hydralazine-induced lupus-like syndrome is associated
with factors such as:
- Higher doses
- Prolonged therapy
- Slow acetylator phenotype
- Female sex
MINOXIDIL
Minoxidil is a potent arterial vasodilator.
Mechanism
Opens ATP-sensitive K⁺ channels
↓
K⁺ efflux
↓
Hyperpolarization of vascular smooth muscle
↓
Reduced Ca²⁺-dependent contraction
↓
Vasodilation
↓
↓ TPR
↓
↓ BP
Important
adverse effect
Hypertrichosis
Other adverse effects:
- Reflex tachycardia
- Fluid retention
- Headache
- Flushing
- Hypotension
Because of marked reflex sympathetic activation and fluid
retention, systemic minoxidil is generally used with:
β blocker + Diuretic
NITRIC
OXIDE AND cGMP
Nitric oxide (NO)
↓
Activates soluble guanylyl cyclase
↓
GTP → cGMP
↓
Activation of protein kinase G and reduction in
smooth-muscle contractile signaling
↓
↓ Intracellular Ca²⁺/reduced myosin light-chain
phosphorylation
↓
Smooth muscle relaxation
↓
Vasodilation
SODIUM
NITROPRUSSIDE
Sodium nitroprusside is a very potent, rapidly acting arterial
and venous vasodilator.
It releases NO.
↓
↑ Guanylyl cyclase activity
↓
↑ cGMP
↓
Vascular smooth-muscle relaxation
↓
Arterial + venous dilation
↓
↓ TPR + ↓ venous return
↓
Rapid reduction in BP
It is administered by continuous IV infusion
and has an extremely rapid onset and offset.
Important adverse effects include:
- Hypotension
- Cyanide/thiocyanate toxicity
with prolonged or excessive exposure
The solution is light-sensitive and requires appropriate
protection from light.
8.
CALCIUM CHANNEL BLOCKERS
Calcium channel blockers inhibit L-type calcium
channels.
They reduce calcium influx into:
- Cardiac muscle
- Vascular smooth muscle
Main
effects
↓ Ca²⁺ entry
↓
↓ Contractility and/or vascular smooth-muscle contraction
↓
↓ BP
TYPES
Verapamil
Primarily cardiac effects:
- ↓ Heart rate
- ↓ AV conduction
- ↓ Contractility
Diltiazem
Intermediate cardiac and vascular effects.
Dihydropyridines
Examples:
- Nifedipine
- Amlodipine
- Nicardipine
Predominantly cause:
Arteriolar vasodilation
9.
RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM
RAAS
PATHWAY
Kidney
↓
Renin
↓
Angiotensinogen — from liver
↓
Angiotensin I
↓
ACE
↓
Angiotensin II
Angiotensin II is a powerful vasoconstrictor and promotes
sodium and water retention.
ACTIONS
OF ANGIOTENSIN II
Angiotensin II acts mainly through AT₁ receptors.
1.
Arteries
AT₁ stimulation
↓
Arterial vasoconstriction
↓
↑ TPR
↓
↑ BP
2.
Veins
Venoconstriction
↓
↑ Venous return
↓
↑ Preload
↓
↑ Cardiac output
3.
Adrenal cortex
Stimulates aldosterone secretion
↓
↑ Sodium reabsorption
↓
↑ Water retention
↓
↑ Blood volume
↓
↑ BP
4.
CNS
Promotes:
- Thirst
- ADH-related water retention
- Sympathetic activity
5.
Heart and vessels
Chronic RAAS activation contributes to:
- Hypertrophy
- Fibrosis
- Pathological cardiovascular
remodeling
ACE
INHIBITORS
Examples:
- Captopril
- Enalapril
- Lisinopril
- Ramipril
Mechanism
ACE inhibition
↓
↓ Angiotensin I → Angiotensin II conversion
↓
↓ Angiotensin II
↓
↓ Vasoconstriction
↓ Aldosterone
↓ Sympathetic facilitation
↓
↓ BP
ACE also normally degrades bradykinin.
Therefore:
ACE inhibition → ↑ Bradykinin
↓
Additional vasodilatory effect
ACE
INHIBITOR ADVERSE EFFECTS
Important:
- Dry cough
- Angioedema
- Hyperkalemia
- Hypotension
- Increased serum creatinine in
susceptible patients
ACE inhibitors are contraindicated during
pregnancy because of fetal toxicity.
ACE
INHIBITORS IN DIABETIC KIDNEY DISEASE
Reduction of angiotensin II-mediated efferent arteriolar
constriction can reduce intraglomerular pressure.
This can provide renal protection in appropriate patients
with albuminuric chronic kidney disease.
ANGIOTENSIN
II RECEPTOR BLOCKERS (ARBs)
Examples:
- Losartan
- Valsartan
- Candesartan
- Telmisartan
Mechanism
ARBs block AT₁ receptors.
↓
↓ Arterial vasoconstriction
↓ Venoconstriction
↓ Aldosterone secretion
↓ Sodium/water retention
↓
↓ BP
Unlike ACE inhibitors, ARBs do not directly
inhibit bradykinin degradation, so cough is less common.
ARBs are also contraindicated during pregnancy.
ACE
INHIBITOR VS ARB
ACE
inhibitor
ACE blockade
↓
↓ Angiotensin II
↑ Bradykinin
↓
Vasodilation
ARB
AT₁ receptor blockade
↓
Blocks effects of Angiotensin II
↓
Vasodilation + ↓ aldosterone
10.
DIURETICS IN HYPERTENSION
Diuretics increase renal sodium and water excretion.
Initial
effect
↑ Sodium excretion
↓
↑ Water excretion
↓
↓ Blood volume
↓
↓ Venous return
↓
↓ Cardiac output
↓
↓ BP
With chronic therapy, the reduction in BP is maintained
largely through reduction in vascular resistance.
THIAZIDE/THIAZIDE-LIKE
DIURETICS
Examples:
- Hydrochlorothiazide
- Chlorthalidone
- Indapamide
These are important drugs for long-term hypertension
treatment.
COMPENSATORY
MECHANISMS
Antihypertensive therapy can activate compensatory
mechanisms.
Example:
Hydralazine
↓
↓ TPR
↓
↓ BP
↓
Baroreceptor reflex
↓
↑ Sympathetic activity
↓
↑ HR + ↑ Contractility
↓
Reflex tachycardia
Therefore:
Hydralazine + β blocker
can reduce reflex cardiac stimulation.
Another mechanism:
↓ BP
↓
↓ Renal perfusion
↓
↑ Renin
↓
↑ Angiotensin II
↓
↑ Aldosterone
↓
↑ Sodium + water retention
↓
↑ Blood volume
↓
Counteracts BP reduction
Therefore:
Vasodilator + Diuretic
can help control fluid retention.
RATIONAL
DRUG COMBINATION
Combining antihypertensive drugs can:
- Target different mechanisms
- Improve BP control
- Reduce compensatory responses
- Allow lower doses of individual
drugs
- Reduce dose-related adverse
effects
Examples:
Hydralazine + β blocker + diuretic
ACE inhibitor/ARB + thiazide-type diuretic
ACE inhibitor/ARB + CCB
11.
CLINICAL CHOICE OF ANTIHYPERTENSIVE DRUGS
Treatment should be individualized according to:
- Age
- Cardiovascular risk
- Kidney function
- Diabetes
- Heart failure
- Coronary disease
- Other comorbidities
- Drug tolerability
- Contraindications
Common first-line drug classes include:
- Thiazide-type/thiazide-like
diuretics
- ACE inhibitors or ARBs
- Calcium channel blockers
β blockers are particularly useful when there is a
compelling indication such as:
- Angina
- Previous myocardial infarction
- Certain tachyarrhythmias
- Selected heart failure patients
CENTRALLY
ACTING SYMPATHOLYTICS
Examples:
- Clonidine
- Methyldopa
- Guanfacine
Mechanism
Central α₂ stimulation
↓
↓ Sympathetic outflow
↓
↓ HR
↓ Contractility
↓ Vascular tone
↓
↓ BP
They are generally not preferred as routine first-line
therapy because of adverse effects and the availability of better-tolerated
alternatives.
BETA-BLOCKER
WITHDRAWAL
Long-term β-blocker therapy should generally not
be stopped abruptly.
Abrupt withdrawal may produce:
- Rebound tachycardia
- Increased BP
- Angina
- Ischemic events in susceptible
patients
Therefore:
Gradual dose reduction/tapering is generally
recommended.
12.
ADVERSE EFFECTS OF CENTRALLY ACTING SYMPATHOLYTICS
Sedation
Central sympatholytic drugs may cause:
- Drowsiness
- Sedation
- Fatigue
because central sympathetic activity contributes to
alertness and arousal.
Dry
mouth
Reduced autonomic activity can decrease salivary
secretion.
↓
Dry mouth / xerostomia
Other possible effects:
- Dizziness
- Orthostatic symptoms
REBOUND
HYPERTENSION
Abrupt withdrawal of centrally acting sympatholytic
drugs, particularly clonidine, can cause:
Rebound sympathetic activity
↓
Marked increase in BP
↓
Rebound hypertension
Therefore:
Avoid abrupt discontinuation.
METHYLDOPA
– IMPORTANT ADVERSE EFFECTS
Important adverse effects include:
- Sedation
- Hepatotoxicity/hepatitis
- Positive direct Coombs test
- Hemolytic anemia
The Coombs test can detect antibodies associated with
immune-mediated hemolysis.
13.
α₁ BLOCKERS – ADVERSE EFFECTS
α₁ blockers:
Arterial dilation + Venodilation
↓
↓ TPR + ↓ Venous return
↓
↓ BP
Important adverse effects:
- Orthostatic hypotension
- Dizziness
- Headache
- Nasal congestion
- Weakness
- Ejaculatory dysfunction
The characteristic early orthostatic effect is sometimes
called the “first-dose phenomenon,” particularly with
prazosin.
REFLEX
MECHANISMS WITH VASODILATORS
Vasodilation
↓
↓ BP
↓
Baroreceptor reflex
↓
↑ Sympathetic activity
↓
↑ HR + ↑ Contractility
↓
Reflex tachycardia
Vasodilation may also activate:
RAAS
↓
↑ Sodium + water retention
↓
↑ Blood volume
↓
Counteracts antihypertensive effect.
Therefore, combination therapy may be required depending
on the drug.
α
BLOCKERS AND LIPIDS
α₁ blockers generally have a relatively neutral effect on
lipid metabolism compared with some older antihypertensive therapies.
14.
HYPERTENSIVE EMERGENCY
IMPORTANT
CONCEPT
A hypertensive emergency is characterized by severely
elevated BP with acute target-organ damage.
Possible acute target-organ damage includes:
- Hypertensive encephalopathy
- Acute heart failure/pulmonary
edema
- Acute coronary syndrome
- Aortic dissection
- Acute kidney injury
- Retinal injury
The numerical BP level alone does not define
hypertensive emergency.
MANAGEMENT
PRINCIPLE
BP should generally be lowered:
Rapidly but in a controlled manner
—not abruptly to normal levels.
Excessively rapid reduction can cause:
- Cerebral ischemia
- Myocardial ischemia
- Renal hypoperfusion
because organs may have adapted to chronically elevated
BP.
In many hypertensive emergencies, the initial goal is
approximately:
Reduce MAP by no more than about 20–25% during
the first hour
followed by more gradual reduction, depending on the
clinical condition.
Aortic dissection is an important exception
requiring more rapid and specific BP/heart-rate control.
SODIUM
NITROPRUSSIDE
Sodium nitroprusside is a potent, short-acting IV
vasodilator.
Mechanism
Sodium nitroprusside
↓
NO release
↓
↑ Guanylyl cyclase
↓
↑ cGMP
↓
Vascular smooth-muscle relaxation
↓
Arterial + venous dilation
↓
↓ TPR + ↓ venous return
↓
↓ BP
Important
characteristics
- IV continuous infusion
- Very rapid onset
- Very short duration
- Easily titrated
- Requires close BP monitoring
- Light sensitive
Important
toxicity
Metabolism can produce cyanide.
Therefore, prolonged/high-dose administration may cause:
Cyanide toxicity
OTHER
IV DRUGS USED IN HYPERTENSIVE EMERGENCIES
Depending on the clinical situation:
Labetalol
α₁ + β blocker
→ decreases vascular resistance
→ prevents excessive reflex tachycardia
Nicardipine
IV dihydropyridine calcium-channel blocker
→ arterial vasodilation
Clevidipine
Very short-acting IV dihydropyridine CCB
→ arterial vasodilation
Fenoldopam
D₁ receptor agonist
→ vasodilation and natriuresis
Phentolamine
α-adrenergic blocker
→ useful particularly in catecholamine-mediated
hypertensive crises
15.
AORTIC DISSECTION
Aortic dissection occurs when a tear in the aortic intima
allows blood to enter the aortic wall and create a false lumen.
It is a medical emergency.
The major therapeutic principle is to reduce:
- Heart rate
- Contractility
- Blood pressure
- Aortic wall stress
WHY
BETA BLOCKER IS IMPORTANT
Giving a vasodilator alone can produce:
Vasodilation
↓
↓ BP
↓
Baroreceptor reflex
↓
↑ Sympathetic activity
↓
↑ HR + ↑ Contractility
↓
↑ Shear stress on the aorta
This may be undesirable in acute aortic dissection.
Therefore:
First
control cardiac stimulation
IV β blocker
↓
↓ HR
↓ Contractility
↓
↓ Aortic shear stress
Then, if BP remains elevated:
Add an IV vasodilator
such as nicardipine or another appropriate agent.
AORTIC
DISSECTION – SIMPLE FLOW
Aortic dissection
↓
Need to reduce aortic wall stress
↓
β blocker
↓
↓ HR + ↓ Contractility
↓
↓ Shear stress
If BP remains high:
↓
IV vasodilator
↓
↓ BP
↓
Controlled reduction of aortic wall stress
MASTER
CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS
1.
DIURETICS
- Thiazide/thiazide-like
diuretics
- Loop diuretics
- Potassium-sparing diuretics
- Mineralocorticoid receptor
antagonists
Main effect: ↓ Na⁺/water → ↓ volume → ↓ BP
2.
SYMPATHOLYTIC DRUGS
A.
Centrally acting
- Clonidine
- Methyldopa
- Guanfacine
α₂ stimulation → ↓ sympathetic outflow
B.
Adrenergic neuron blockers
- Reserpine
- Guanethidine
- Guanadrel
↓ NE availability/release
C.
α₁ blockers
- Prazosin
- Doxazosin
- Terazosin
α₁ blockade → vasodilation
D.
β blockers
- Propranolol
- Atenolol
- Metoprolol
- Bisoprolol
β₁ blockade → ↓ HR + ↓ contractility + ↓ renin
E.
α + β blockers
- Labetalol
- Carvedilol
3.
VASODILATORS
Arteriolar
- Hydralazine
- Minoxidil
Arterial
+ venous
- Sodium nitroprusside
4.
CALCIUM CHANNEL BLOCKERS
Non-dihydropyridines
- Verapamil
- Diltiazem
Dihydropyridines
- Nifedipine
- Amlodipine
- Nicardipine
- Clevidipine
5.
RAAS INHIBITORS
ACE
inhibitors
- Captopril
- Enalapril
- Lisinopril
- Ramipril
ARBs
- Losartan
- Valsartan
- Candesartan
- Telmisartan
Other
RAAS-related drugs
- Mineralocorticoid receptor
antagonists
- Direct renin inhibitor:
aliskiren
END-POINTS
OF ANTIHYPERTENSIVE THERAPY
Almost all antihypertensive drugs ultimately work by
reducing one or more of:
1. Cardiac output
2. Total peripheral resistance
3. Blood volume
4. Sympathetic activity
5. RAAS activity
ULTRA-SHORT
EXAM REVISION
BP
BP ≈ CO × TPR
CO
CO = HR × SV
Stroke
volume
SV depends on preload + afterload + contractility
α₁
stimulation
Vasoconstriction → ↑ TPR → ↑ BP
α₁
blockade
Vasodilation → ↓ TPR → ↓ BP
β₁
stimulation
↑ HR + ↑ Contractility + ↑ Renin
β₁
blockade
↓ HR + ↓ Contractility + ↓ Renin → ↓ BP
α₂
stimulation
↓ NE release → ↓ sympathetic outflow → ↓ BP
Angiotensin
II
Vasoconstriction + ↑ aldosterone + ↑ sympathetic
activity → ↑ BP
ACE
inhibitor
↓ Ang II + ↑ bradykinin → vasodilation → ↓ BP
ARB
AT₁ blockade → ↓ Ang II effects → ↓ BP
Diuretic
↑ Na⁺/water excretion → ↓ volume → ↓ BP
CCB
↓ L-type Ca²⁺ entry → vasodilation ± ↓ cardiac
activity → ↓ BP
Hydralazine
Arteriolar dilation → ↓ TPR → reflex tachycardia
Minoxidil
K⁺ channel opening → hyperpolarization →
vasodilation
Nitroprusside
NO → ↑ cGMP → arterial + venous dilation
Aortic
dissection
β blocker first → control HR/contractility → then
vasodilator if needed
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