11. DRUGS ACTING ON THE CARDIOVASCULAR SYSTEM.ppt
LyanneSackey4
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Jul 30, 2024
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About This Presentation
CARDIOVASCULAR PHARMACOLOGY
Slide Content
DRUGS AFFECTING THE
CARDIOVASCULAR
SYSTEM
CARDIOVASCULAR
SYSTEM
Objectives
To Introduce Students to the Pharmacology
of the cardiovascular system
To understand the pharmacology of drugs of
the cardiovascular system.
To relate the pharmacology of the drugs to
drug therapy and toxicity.
7/30/20242
To Introduce Students to the Pharmacology
of the cardiovascular system
To understand the pharmacology of drugs of
the cardiovascular system.
To relate the pharmacology of the drugs to
drug therapy and toxicity.
7/30/20242
Topics to discuss
Anti-arrhythmic drugs
Cardiac glycosides
Drugs for Heart failure
Antiangina drugs
Antihypertensives.
7/30/20243
Anti-arrhythmic drugs
Cardiac glycosides
Drugs for Heart failure
Antiangina drugs
Antihypertensives.
7/30/20243
CARDIAC ARRHYTHMIAS
Brief Introduction
Cardiac conducting system &
Electrophysiological activity
Mechanisms of arrhythmias
Classification of Anti arrhythmic drugs
Pharmacology of anti arrhythmic drugs
7/30/20244
Brief Introduction
Cardiac conducting system &
Electrophysiological activity
Mechanisms of arrhythmias
Classification of Anti arrhythmic drugs
Pharmacology of anti arrhythmic drugs
7/30/20244
Introduction
Arrhythmias :Abnormal cardiac rhythms
One of the commonest problems in
cardiology
Commonly associated with IHD’s (Ischemic
Heart Diseases)
7/30/20245
Arrhythmias :Abnormal cardiac rhythms
One of the commonest problems in
cardiology
Commonly associated with IHD’s (Ischemic
Heart Diseases)
7/30/20245
Causes:
May be due to:
Abnormalities in cardiac impulse conduction.
Arrhythmogenic drugs
Anti arrhythmic drugs themselves
Metabolic disturbances in the body e.g. hypo
and hyperkalaemia, hypoxiaetc.
7/30/20246
May be due to:
Abnormalities in cardiac impulse conduction.
Arrhythmogenic drugs
Anti arrhythmic drugs themselves
Metabolic disturbances in the body e.g. hypo
and hyperkalaemia, hypoxiaetc.
7/30/20246
Electro-physiology of the cardiac
fibres
Cardiac muscles are electrically excitable like
other excitable tissues.
Transient increase in membrane permeability
to Na
+
and/or Ca
2+
(inward currents-in response to
depolarisation),is responsible for the excitability
of the cardiac cells.
Repolarisation as a result of delayed ↑se in
K+ permeability (outward K+ current)
7/30/20247
fibres
Cardiac muscles are electrically excitable like
other excitable tissues.
Transient increase in membrane permeability
to Na
+
and/or Ca
2+
(inward currents-in response to
depolarisation),is responsible for the excitability
of the cardiac cells.
Repolarisation as a result of delayed ↑se in
K+ permeability (outward K+ current)
7/30/20247
Cardiac muscles & Electrophysiology
cont.
The Cardiac muscles divided into three
electro physiologically distinct types of cells.
1)Tissues with spontaneous pacemaker
activity→sinoatrial (SA) & atrioventricular
(AV) nodes
2) Specialised high velocity conducting tissue
–The His-purkinge network.
3) The working atrialand ventricular
muscles.
7/30/20248
cont.
The Cardiac muscles divided into three
electro physiologically distinct types of cells.
1)Tissues with spontaneous pacemaker
activity→sinoatrial (SA) & atrioventricular
(AV) nodes
2) Specialised high velocity conducting tissue
–The His-purkinge network.
3) The working atrialand ventricular
muscles.
7/30/20248
THE CARDIAC CONDUCTING SYSTEM
7/30/20249
7/30/20249
Cardiac muscles &
Electrophysiology cont.
The SA (main pace maker)and AVnodal
cells show diastolic depolarization,
that results in the generation of spontaneous
action potential.
NB: Action potential in these cells is
dependant on slow inward current of Ca
2+
.
7/30/202410
Electrophysiology cont.
The SA (main pace maker)and AVnodal
cells show diastolic depolarization,
that results in the generation of spontaneous
action potential.
NB: Action potential in these cells is
dependant on slow inward current of Ca
2+
.
7/30/202410
Cardiac muscles &
Electrophysiology cont.
Conduction velocity in the AV is slow, leading
tothe pause between atrial and ventricular
contraction
Depolarisation in the HIS-PURKINGE TISSUE,
the ATRIALand VENTRICULAR fibresdepend
on rapid influx of Na
+
ions or rapid inward Na
current.
7/30/202411
Electrophysiology cont.
Conduction velocity in the AV is slow, leading
tothe pause between atrial and ventricular
contraction
Depolarisation in the HIS-PURKINGE TISSUE,
the ATRIALand VENTRICULAR fibresdepend
on rapid influx of Na
+
ions or rapid inward Na
current.
7/30/202411
Cardiac muscles &
Electrophysiology cont.
Action potential and the conduction
velocity is much faster than that in the
nodal fibres.
This allows electrical activation of the
atria or ventricles in a short period of
time, permitting coordinated contraction.
7/30/202412
Electrophysiology cont.
Action potential and the conduction
velocity is much faster than that in the
nodal fibres.
This allows electrical activation of the
atria or ventricles in a short period of
time, permitting coordinated contraction.
7/30/202412
Cardiac muscles &
Electrophysiology cont.
NB: the atrial and ventricular fibres
normally have no automaticity &
that of the His-Prukinge network is
slow
7/30/202413
Electrophysiology cont.
NB: the atrial and ventricular fibres
normally have no automaticity &
that of the His-Prukinge network is
slow
7/30/202413
ORIGIN AND CO-ORDINATION OF THE
HEART BEAT
Heart beat originates at the
S.A. node (Pace maker).
The atrial muscles contracts
followed by a short pause.
(the contraction wave moves downwards
the Bundle and the His purkinge system
to the ventricles).
The ventricles contract and
blood is ejected into the
Arteries (ventricular systole).
The ventricular muscle relaxes,
(DIASTOLE-.a longer pause)before
the next beat occurs
7/30/202414
HEART BEAT
Heart beat originates at the
S.A. node (Pace maker).
The atrial muscles contracts
followed by a short pause.
(the contraction wave moves downwards
the Bundle and the His purkinge system
to the ventricles).
The ventricles contract and
blood is ejected into the
Arteries (ventricular systole).
The ventricular muscle relaxes,
(DIASTOLE-.a longer pause)before
the next beat occurs
7/30/202414
Uniqueness of the cardiac muscles & Its difference
from other excitable tissues
1) Spontaneous intrinsic rhythm generated by
the SAand the AV nodes (specialized/Pace
maker cells).
2) Absence of fast Na
+
current in the nodal
cells (SA & AV)
3) The long duration of action potential and
long refractory period
4) The large influx of Ca
2+
ions during the
plateau of the action potential.
7/30/202415
from other excitable tissues
1) Spontaneous intrinsic rhythm generated by
the SAand the AV nodes (specialized/Pace
maker cells).
2) Absence of fast Na
+
current in the nodal
cells (SA & AV)
3) The long duration of action potential and
long refractory period
4) The large influx of Ca
2+
ions during the
plateau of the action potential.
7/30/202415
7/30/202416
The wave form of a normal
electrocardiogram (E.C.G).
The p wave → The spread of excitation
from the S.A. node over the atrial muscles
Propagation of the contraction wave down
the BoH [does not produce any detectable
electrical changes, denoted by the P –Q
interval (isoelectric.)]
The QRS complex: The beginning of
ventricular excitation and ventricular
systole.
STVentricular relaxation, and The T-wave
caused by currents generated, as the
ventricles recover from a state of
depolarization.→ a repolarisation wave.
7/30/202417
electrocardiogram (E.C.G).
The p wave → The spread of excitation
from the S.A. node over the atrial muscles
Propagation of the contraction wave down
the BoH [does not produce any detectable
electrical changes, denoted by the P –Q
interval (isoelectric.)]
The QRS complex: The beginning of
ventricular excitation and ventricular
systole.
STVentricular relaxation, and The T-wave
caused by currents generated, as the
ventricles recover from a state of
depolarization.→ a repolarisation wave.
7/30/202417
MECHANISM OF ARRHYTHMIAS
Arrhythmias may arise from
Abnormal automaticity, or from
Disorders of impulse conduction.
Majority of clinically important
arrhythmias depends on/ or results from
disorders of impulse conduction.
7/30/202418
Arrhythmias may arise from
Abnormal automaticity, or from
Disorders of impulse conduction.
Majority of clinically important
arrhythmias depends on/ or results from
disorders of impulse conduction.
7/30/202418
Four (4) basic mechanisms underlie Pathological/
drug induced disturbances of cardiac rhythm:
1)Delayed after depolarization: triggers
ectopic beats.
2)‘Re-entry’ phenomenon: Occurs when
an advancing wave of depolarization finds
one pathway temporarily inexcitable or
refractory due to acute ischaemia, or prior
to ischaemic damage.
7/30/202419
drug induced disturbances of cardiac rhythm:
1)Delayed after depolarization: triggers
ectopic beats.
2)‘Re-entry’ phenomenon: Occurs when
an advancing wave of depolarization finds
one pathway temporarily inexcitable or
refractory due to acute ischaemia, or prior
to ischaemic damage.
7/30/202419
Schematic representation of
re-entry.
7/30/202420
re-entry.
7/30/202420
Continue
3) Abnormal automaticity : This is
encouraged by ↑sedsympathetic
activity. It may also be due to digitalis
toxicity.
4) Heart block:Results from damage to
the AV node or the ventricular
conducting system.
7/30/202421
3) Abnormal automaticity : This is
encouraged by ↑sedsympathetic
activity. It may also be due to digitalis
toxicity.
4) Heart block:Results from damage to
the AV node or the ventricular
conducting system.
7/30/202421
Clinically arrhythmias are
divided according to:
Their site of origin (i.e. supraventricular
or ventricular)
Whether the heart rate is increased
(tachycardia) or decreased
(bradycardia)
7/30/202422
divided according to:
Their site of origin (i.e. supraventricular
or ventricular)
Whether the heart rate is increased
(tachycardia) or decreased
(bradycardia)
7/30/202422
ANTIARRYTHMIC DRUGS
Anti arrhythmic drugs may be categorized according
to their predominant site of action.
some act predominantly on arrhythmias arising
in the ventricles e.g. lignocaine,
Nodal e.g. verapamil
others have effects on both atrial and ventricular
muscles. E.g. disopyramide
7/30/202423
Anti arrhythmic drugs may be categorized according
to their predominant site of action.
some act predominantly on arrhythmias arising
in the ventricles e.g. lignocaine,
Nodal e.g. verapamil
others have effects on both atrial and ventricular
muscles. E.g. disopyramide
7/30/202423
ANTIARRYTHMIC DRUGS cont.
Most commonly used classification is
the Vaughan Williams classification
It Identifies four(4) principal mech. of
action or classesof the anti arrhythmic
drugs.
Limmitation to this classification is that an individual drug
may have actions in more than one category.
7/30/202424
Most commonly used classification is
the Vaughan Williams classification
It Identifies four(4) principal mech. of
action or classesof the anti arrhythmic
drugs.
Limmitation to this classification is that an individual drug
may have actions in more than one category.
7/30/202424
Class 1 Anti-arrhythmic drugs
(membrane stabilising drugs)
Interfere with or block voltage
sensitive sodium channels.
resulting in slowing of conduction,
and
increase in refractory period or
both.
(i.e. a membrane stabilizing effect).
7/30/202425
(membrane stabilising drugs)
Interfere with or block voltage
sensitive sodium channels.
resulting in slowing of conduction,
and
increase in refractory period or
both.
(i.e. a membrane stabilizing effect).
7/30/202425
Note this !!!
The Class 1 drugs cause reduction
in the excitability of the non-nodal
regions of the heart where rapid Na+
current is important for propagation
of action potential.
7/30/202426
The Class 1 drugs cause reduction
in the excitability of the non-nodal
regions of the heart where rapid Na+
current is important for propagation
of action potential.
7/30/202426
Class 1 Anti-arrhythmic drugs
cont.
Class 1 antiarrythmic drugs are further sub-
divided into 1a, 1b, and 1c, According to their
peculiar subsidiary properties.
Class 1a agents
Lengthen action potential duration moderately
cause minor slowing of intra cardiac conduction
and widens the QRS complex in therapeutic
concentrations.
E.g. Quinidine, Procainamide and disopyramide.
7/30/202427
cont.
Class 1 antiarrythmic drugs are further sub-
divided into 1a, 1b, and 1c, According to their
peculiar subsidiary properties.
Class 1a agents
Lengthen action potential duration moderately
cause minor slowing of intra cardiac conduction
and widens the QRS complex in therapeutic
concentrations.
E.g. Quinidine, Procainamide and disopyramide.
7/30/202427
Continue
Class 1b Drugs
shorten action potential duration
no effect on intra cardiac
conductionor the QRS complexin
sinus rhythm.
E.g. Lignocaine,torcainide, Phenytoin,
mexiletine etc.
7/30/202428
Class 1b Drugs
shorten action potential duration
no effect on intra cardiac
conductionor the QRS complexin
sinus rhythm.
E.g. Lignocaine,torcainide, Phenytoin,
mexiletine etc.
7/30/202428
Continue
Class 1c drugs
No effect on action potential duration,
Exerts their most powerful effect by slowing
intra-cardiac conduction, and
Widening the QRS complex.
E.g. Flecainide, Encainide & propafenone
7/30/202429
Class 1c drugs
No effect on action potential duration,
Exerts their most powerful effect by slowing
intra-cardiac conduction, and
Widening the QRS complex.
E.g. Flecainide, Encainide & propafenone
7/30/202429
Propafenone
Propafenonehas minor β-blocking and Ca
2+
antagonist properties.
Used for
prophylaxis of Paroxysmal Atrial Fibrillation &
Sustained Ventricular Tachycardia (SVT).
Supressionof recurrent Sustained Ventricular
Tachycardia (SVT)
7/30/202430
Propafenonehas minor β-blocking and Ca
2+
antagonist properties.
Used for
prophylaxis of Paroxysmal Atrial Fibrillation &
Sustained Ventricular Tachycardia (SVT).
Supressionof recurrent Sustained Ventricular
Tachycardia (SVT)
7/30/202430
Class II (beta-blockers)
These decrease the arrythmogenic effects of
catecholamines e.g. adrenaline,
noradrenaline, etc.
Effect may occur by competitive antagonism
e.g -blockers
Or by non-competitive adrenoceptor
antagonism. e.g.amiodarone
or by inhibition of noradrenaline release at
sympathetic nerve terminals ☛bretylium
7/30/202431
These decrease the arrythmogenic effects of
catecholamines e.g. adrenaline,
noradrenaline, etc.
Effect may occur by competitive antagonism
e.g -blockers
Or by non-competitive adrenoceptor
antagonism. e.g.amiodarone
or by inhibition of noradrenaline release at
sympathetic nerve terminals ☛bretylium
7/30/202431
Class III agents
Activity involve lengthening of cardiac action
potential durationand effective refractory period
without interference with the Na+ inward current.
Some drugs in this group possess additional Class II
effects e.g. bretylium, satolol
Some-class I, II, and IV activity e.g. Amiodarone
Class III drugs could cause prolongation of the QT
interval
(detected clinically on an E.C.G.; especially in pts taking other drugs that
prolongs the QT interval-Terfenadine.)
7/30/202432
Activity involve lengthening of cardiac action
potential durationand effective refractory period
without interference with the Na+ inward current.
Some drugs in this group possess additional Class II
effects e.g. bretylium, satolol
Some-class I, II, and IV activity e.g. Amiodarone
Class III drugs could cause prolongation of the QT
interval
(detected clinically on an E.C.G.; especially in pts taking other drugs that
prolongs the QT interval-Terfenadine.)
7/30/202432
Class IV agents/Others
Slow Ca
2+
channel antagonists/blockers.
Acts by blocking voltage sensitive Ca2+ channels on the heart
cells
Action results in:
slowed conduction in the SA and AV nodes
prolonged refractoriness in the A.V node.
Shorten the plateau phase of the action potential and
reduce the force of contraction
Suppresses premature ectopic beats
They are particularly useful in blocking supra ventricular
tachycardia involving the A.V node.
7/30/202433
Slow Ca
2+
channel antagonists/blockers.
Acts by blocking voltage sensitive Ca2+ channels on the heart
cells
Action results in:
slowed conduction in the SA and AV nodes
prolonged refractoriness in the A.V node.
Shorten the plateau phase of the action potential and
reduce the force of contraction
Suppresses premature ectopic beats
They are particularly useful in blocking supra ventricular
tachycardia involving the A.V node.
7/30/202433
OTHER USEFUL DRUGS AND INORGANIC IONS USEFUL FOR
TREATING ARRHYTHMIAS IN CLINICAL PRACTICE but do not
fit into the Vaughan Williams classification.
DigoxinIncreases vagal stimulation and slows the
heart rate in atrial fibrillation/atrial flutter.
Adenosine nucleotidesFor supraventricular
tachycardia
Atropine,(Muscarinic antagonist) For sinus
bradycardia
Isoprenaline/adrenaline → For heart block.
Ca2+ salts (e.g. CaCl2) For ventricular tachycardia
caused by hyperkalaemia
MgCl
2→ Ventricular fibrillation
Direct current ⇒for emergency treatment of life-
threatening arrhythmias such as heartblock.
also known as electrical cardioversionor pacing.34 7/30/2024
TREATING ARRHYTHMIAS IN CLINICAL PRACTICE but do not
fit into the Vaughan Williams classification.
DigoxinIncreases vagal stimulation and slows the
heart rate in atrial fibrillation/atrial flutter.
Adenosine nucleotidesFor supraventricular
tachycardia
Atropine,(Muscarinic antagonist) For sinus
bradycardia
Isoprenaline/adrenaline → For heart block.
Ca2+ salts (e.g. CaCl2) For ventricular tachycardia
caused by hyperkalaemia
MgCl
2→ Ventricular fibrillation
Direct current ⇒for emergency treatment of life-
threatening arrhythmias such as heartblock.
also known as electrical cardioversionor pacing.34 7/30/2024
QUINIDINE, PROCAINAMIDE &
DISOPYRAMIDE
Quinidine and procainamide are
pharmacologically similar in activity
▬antiarrythmic effects
Quinidine is a D-isomer of quinine
formally used for management of arrhythmias
now rarely used clinically. Because safer and more
effective drugs are now available for management of
arrhythmias.
Used in some countries for management of
severe falciparum malaria.
7/30/202435
DISOPYRAMIDE
Quinidine and procainamide are
pharmacologically similar in activity
▬antiarrythmic effects
Quinidine is a D-isomer of quinine
formally used for management of arrhythmias
now rarely used clinically. Because safer and more
effective drugs are now available for management of
arrhythmias.
Used in some countries for management of
severe falciparum malaria.
7/30/202435
QUINIDINE ctn
Higher concentrations of quininidineare associated
with
decreased myocardial contractility,
peripheral vasodilatation and hypotension.
It could also cause Sino-Atrial block,
progressive QRS and QT prolongation, which may
lead to paroxysmal ventricular tachycardia (PVT).
Other side effects include
nausea, diarrhoea, etc.(G.I.)
cinchonism
thrombocytopenia
and hepatic dysfunction.
7/30/202436
Higher concentrations of quininidineare associated
with
decreased myocardial contractility,
peripheral vasodilatation and hypotension.
It could also cause Sino-Atrial block,
progressive QRS and QT prolongation, which may
lead to paroxysmal ventricular tachycardia (PVT).
Other side effects include
nausea, diarrhoea, etc.(G.I.)
cinchonism
thrombocytopenia
and hepatic dysfunction.
7/30/202436
Drug Interactions
QUINIDINE + DIGOXIN:
QUINIDINE ()DIGOXIN PLASMA LEVELS
QUINIDINE () RENAL CLEARANCE
Similar with Verapamil
7/30/202437
QUINIDINE + DIGOXIN:
QUINIDINE ()DIGOXIN PLASMA LEVELS
QUINIDINE () RENAL CLEARANCE
Similar with Verapamil
7/30/202437
Procainamide/Disopyramide
PROCAINAMIDE
Not very much used because of unpleasant side effects
such as QRS and QT prolongation.
Causes drug-induced lupus erythematosussyndrome
DISOPYRAMIDE
Electrophysiological properties are similar to that
of Quinidine.
Has marked negative ionotropiceffect and
should be avoided in patients with cardiac failure.
38 7/30/2024
PROCAINAMIDE
Not very much used because of unpleasant side effects
such as QRS and QT prolongation.
Causes drug-induced lupus erythematosussyndrome
DISOPYRAMIDE
Electrophysiological properties are similar to that
of Quinidine.
Has marked negative ionotropiceffect and
should be avoided in patients with cardiac failure.
38 7/30/2024
DISOPYRAMIDE ctn
Other side effects are related to its
anticholinergic effect such as urinary retention, blurred
vision and glaucoma.
QTprolongation occurs with increasing plasma
concentrations which may predispose to re-entry arrythmia.
It is contraindicated in patients with Stick Sinus
Syndrome and prostate hypertrophy.
It is used clinically for atrialand ventricular
arrythmiasincluding those resistant to
lignocaine.
7/30/202439
Other side effects are related to its
anticholinergic effect such as urinary retention, blurred
vision and glaucoma.
QTprolongation occurs with increasing plasma
concentrations which may predispose to re-entry arrythmia.
It is contraindicated in patients with Stick Sinus
Syndrome and prostate hypertrophy.
It is used clinically for atrialand ventricular
arrythmiasincluding those resistant to
lignocaine.
7/30/202439
LIGNOCAINE
It is a very important Class I anti arrhythmic agent.
Used clinically to treat and prevent ventricular arrhythmias
following myocardial infarction and surgery in coronary
intensive care units.
(It is also widely used as a local anaesthetic)
It is not effective orally because of extensive first pass
metabolic effect.
It is usually administered by IV infusion
t1/2 is about 2 hrs.
Side effects include drowsiness, disorientation, convulsion etc.
Due to its short t
1/2, plasma concentrations can be adjusted
rapidly by varying the infusion rate
7/30/202440
It is a very important Class I anti arrhythmic agent.
Used clinically to treat and prevent ventricular arrhythmias
following myocardial infarction and surgery in coronary
intensive care units.
(It is also widely used as a local anaesthetic)
It is not effective orally because of extensive first pass
metabolic effect.
It is usually administered by IV infusion
t1/2 is about 2 hrs.
Side effects include drowsiness, disorientation, convulsion etc.
Due to its short t
1/2, plasma concentrations can be adjusted
rapidly by varying the infusion rate
7/30/202440
FLECANIDE & ENCAINIDE
FLECANIDE & ENCAINIDE
These are long acting and effective orally.
Evidence from clinical trials shows that these
drugs increase the incidence of sudden death
associated with ventricular fibrillation after
myocardial infarction
Encainidehas been withdrawn from the market
Flecainideis rarely used except in life
treatheningventricular arrhythmias that does
not respond to any other therapy.
41 7/30/2024
FLECANIDE & ENCAINIDE
These are long acting and effective orally.
Evidence from clinical trials shows that these
drugs increase the incidence of sudden death
associated with ventricular fibrillation after
myocardial infarction
Encainidehas been withdrawn from the market
Flecainideis rarely used except in life
treatheningventricular arrhythmias that does
not respond to any other therapy.
41 7/30/2024
AMIODARONE
It is effective in a wide variety of supraventricular and
ventricular arrhythmias, including those associated with
Wolf-Parkinson-White syndrome.
Main MOA to prolong action potential duration and
effective refractory period in all cardiac tissues.
It suppresses both atrial and ventricular re-entrant
rhythms.
It is also a non-competitive and adrenoceptor
antagonist.
7/30/202442
It is effective in a wide variety of supraventricular and
ventricular arrhythmias, including those associated with
Wolf-Parkinson-White syndrome.
Main MOA to prolong action potential duration and
effective refractory period in all cardiac tissues.
It suppresses both atrial and ventricular re-entrant
rhythms.
It is also a non-competitive and adrenoceptor
antagonist.
7/30/202442
Amiodarone ctn
It has an extremely long t1/2 and accumulates
considerably in muscles and fats.
It has the tendency to accumulate in the body for a
long time.
It is the best tolerated of all the anti arrhythmic drugs
in heart failure.
Side effects include
photosensitive skin rashes,
thyroid abnormalities etc.
7/30/202443
It has an extremely long t1/2 and accumulates
considerably in muscles and fats.
It has the tendency to accumulate in the body for a
long time.
It is the best tolerated of all the anti arrhythmic drugs
in heart failure.
Side effects include
photosensitive skin rashes,
thyroid abnormalities etc.
7/30/202443
Amiodarone ctn
It is capable of causing ‘Torsades de pointes’
a form of ventricular tachycardia.
Due to its accumulating effect in the body,
chronic amiodarone therapy should be used
only in life threatening or severely disabling
arrhythmias or when conventional drugs have
been shown to be ineffective.
7/30/202444
It is capable of causing ‘Torsades de pointes’
a form of ventricular tachycardia.
Due to its accumulating effect in the body,
chronic amiodarone therapy should be used
only in life threatening or severely disabling
arrhythmias or when conventional drugs have
been shown to be ineffective.
7/30/202444
Amiodarone ctn
Drug interactions:
Amiodaronepotentiates the effect of
warfarin
Increases plasma digoxin levels;
Dose reduction may be necessary if
there is the need to use both drugs
together.
7/30/202445
Drug interactions:
Amiodaronepotentiates the effect of
warfarin
Increases plasma digoxin levels;
Dose reduction may be necessary if
there is the need to use both drugs
together.
7/30/202445
VERAPAMIL
It acts by inhibiting slow inward Ca
2+
mediated
current
→decreasing AV conduction and blocking intra-
nodal re-entry circuits.
It is used to terminate and prevent paroxysmal
supraventricular tachycardia (SVT)
and to reduce ventricular rate in patients with atrial
fibrillation, who are not adequately controlled with
digoxin.
It is not effective for ventricular arrhythmias.
7/30/202446
It acts by inhibiting slow inward Ca
2+
mediated
current
→decreasing AV conduction and blocking intra-
nodal re-entry circuits.
It is used to terminate and prevent paroxysmal
supraventricular tachycardia (SVT)
and to reduce ventricular rate in patients with atrial
fibrillation, who are not adequately controlled with
digoxin.
It is not effective for ventricular arrhythmias.
7/30/202446
Verapamil ctn
Systemic bioavailability is about 10-20%.
It could be given orally but could also be given by i.v to
terminate SVT.
The plasma t1/2 is about 6-8 hrs.
The main side effect is precipitating heart failure,
which is caused by inhibition of Ca2+ entry into the
cardiac cells. It has depressant effect on the SA. node
automaticity and A.V nodal conduction,
It is therefore contra-indicated in heart block or sino-
atrial disease.
7/30/202447
Systemic bioavailability is about 10-20%.
It could be given orally but could also be given by i.v to
terminate SVT.
The plasma t1/2 is about 6-8 hrs.
The main side effect is precipitating heart failure,
which is caused by inhibition of Ca2+ entry into the
cardiac cells. It has depressant effect on the SA. node
automaticity and A.V nodal conduction,
It is therefore contra-indicated in heart block or sino-
atrial disease.
7/30/202447
Ca2+ Channel blockers ctn
Due to its severe ionotropic action,
verapamil is contra-indicated in heart failure.
Verapamil and Diltiazem potentiates the
negative effects of digoxin and blockers on
AV nodal conduction.(a potentially serious or
fatal interaction)
Diltiazem is another Ca
2+
channel antagonist.
Has similar antiarrythmic properties to
verapamil.
7/30/202448
Due to its severe ionotropic action,
verapamil is contra-indicated in heart failure.
Verapamil and Diltiazem potentiates the
negative effects of digoxin and blockers on
AV nodal conduction.(a potentially serious or
fatal interaction)
Diltiazem is another Ca
2+
channel antagonist.
Has similar antiarrythmic properties to
verapamil.
7/30/202448
βblockers (VW class II)
The βblockers reduce mortality in patients
recovering from MI
Can be used for prophylaxis against recurrent
tachy-arrhythmias
(e.g. Paroxysmal atrial fibrillation)
Especially when the arrhythmias are provoked
by increased sympathetic activity.
Examples metoprolol, Atenolol, Propranolol, Satolol, Acebutolol,
esmolol, Labetalol etc.
49 7/30/2024
The βblockers reduce mortality in patients
recovering from MI
Can be used for prophylaxis against recurrent
tachy-arrhythmias
(e.g. Paroxysmal atrial fibrillation)
Especially when the arrhythmias are provoked
by increased sympathetic activity.
Examples metoprolol, Atenolol, Propranolol, Satolol, Acebutolol,
esmolol, Labetalol etc.
49 7/30/2024
β blockers (VG class II) cont.
Significant differences b/n the βblockers
Selectivity for various adrenoceptorsrelevant
to CV Disorders (α
1, β
1β
2),
Pharmacokinetics:
lipid solubility properties,
intrinsic sympathomimetic activity, etc
7/30/202450
Significant differences b/n the βblockers
Selectivity for various adrenoceptorsrelevant
to CV Disorders (α
1, β
1β
2),
Pharmacokinetics:
lipid solubility properties,
intrinsic sympathomimetic activity, etc
7/30/202450
CARDIAC GLYCOSIDES
(digitalis)
Discovery accredited to the Scottish doctor
William Withering
Obtained from the leaves of Digitalis spp
(Foxglove).
Have been in clinical use for management of
cardiac failure particularly that associated with atrial
fibrillation.Egs Digitoxin, digoxin and Ouabin.
Digoxin-The most widely used.
7/30/202451
(digitalis)
Discovery accredited to the Scottish doctor
William Withering
Obtained from the leaves of Digitalis spp
(Foxglove).
Have been in clinical use for management of
cardiac failure particularly that associated with atrial
fibrillation.Egs Digitoxin, digoxin and Ouabin.
Digoxin-The most widely used.
7/30/202451
Cardiac effects
Effects on the heart include:
effect on the rate,& rhythm
(anti arrhythmic/arrhythmogenic)
and the force of contraction of the
heart. [+veionotropiceffect]
7/30/202452
Effects on the heart include:
effect on the rate,& rhythm
(anti arrhythmic/arrhythmogenic)
and the force of contraction of the
heart. [+veionotropiceffect]
7/30/202452
Major pharmacological effects on heart
1)Increase the force of myocardial
contractility, This isbeneficial in patients
with heart failure.
2)Decreased ventricular rate byslowing
A.V. conduction due to increased vagal
stimulation.
This effect is diminished on exercise due to
withdrawal of the underlying vagal tone.
7/30/202453
1)Increase the force of myocardial
contractility, This isbeneficial in patients
with heart failure.
2)Decreased ventricular rate byslowing
A.V. conduction due to increased vagal
stimulation.
This effect is diminished on exercise due to
withdrawal of the underlying vagal tone.
7/30/202453
continue
3) Increased ectopic pacemaker
activity or myocardial automaticity
at high concentrations or even at
therapeutic concentrations in the
presence of hypokalaemia
7/30/202454
3) Increased ectopic pacemaker
activity or myocardial automaticity
at high concentrations or even at
therapeutic concentrations in the
presence of hypokalaemia
7/30/202454
CARDIAC GLYCOSIDES -MECH. OF ACTION
This include increased vagal activity and
inhibition of Na
+
/K
+
ATPase activity (Na pump)
Molecular mechanism:
The C glycosides act by ↓singNa
+
transport out
of the cardiac cells by inhibiting Na+/K+ ATPase
activity
This leads to an increase in intracellular Na
+
concentration and an increase in intracellular
Ca
2+
concentration [ by decreasing the activity of
Na+/Ca
2+
exchange}
The High [Ca
2+
] Responsible for the positive ionotropic effect.
7/30/202455
This include increased vagal activity and
inhibition of Na
+
/K
+
ATPase activity (Na pump)
Molecular mechanism:
The C glycosides act by ↓singNa
+
transport out
of the cardiac cells by inhibiting Na+/K+ ATPase
activity
This leads to an increase in intracellular Na
+
concentration and an increase in intracellular
Ca
2+
concentration [ by decreasing the activity of
Na+/Ca
2+
exchange}
The High [Ca
2+
] Responsible for the positive ionotropic effect.
7/30/202455
continue
The anti arrhythmic effect is exerted by
enhancing vagal inhibition of S.A. nodal
automaticity and A.V. node conduction
At high concentrations the cardiac glycosides
↑semyocardial automaticity leading to
arrhythmia, (Due to raised intracellular
calcium ion concentration)
Effect/Toxicity is potentiated by low plasma
potassium concentration (hypokalaemia)
7/30/202456
The anti arrhythmic effect is exerted by
enhancing vagal inhibition of S.A. nodal
automaticity and A.V. node conduction
At high concentrations the cardiac glycosides
↑semyocardial automaticity leading to
arrhythmia, (Due to raised intracellular
calcium ion concentration)
Effect/Toxicity is potentiated by low plasma
potassium concentration (hypokalaemia)
7/30/202456
continue
Increased K+ concentration inhibits the
binding of C glycosides to the Na+/K+
ATPase enzyme
. Low levels of K+ ↑sethe binding of C
glycosidesto Na+/K+ ATPase, leading to
higher build up of Ca
2+
in the cells ,causing
digitalis toxicity.
7/30/202457
Increased K+ concentration inhibits the
binding of C glycosides to the Na+/K+
ATPase enzyme
. Low levels of K+ ↑sethe binding of C
glycosidesto Na+/K+ ATPase, leading to
higher build up of Ca
2+
in the cells ,causing
digitalis toxicity.
7/30/202457
Clinical uses
For control of ventricular rate in atrial
fibrillation.
Also for improving pump fxn in pts with heart
failure (maximum benefit ifassociated with
atrial fibrillation).
Evidence have shown that digoxin improves
cardiac performance in heart failure patients
with atrial fibrillation (life saving)
7/30/202458
For control of ventricular rate in atrial
fibrillation.
Also for improving pump fxn in pts with heart
failure (maximum benefit ifassociated with
atrial fibrillation).
Evidence have shown that digoxin improves
cardiac performance in heart failure patients
with atrial fibrillation (life saving)
7/30/202458
Actual role of digoxin in HF
Digoxin may be added to treatment
of chronic heart failure in patients
who are still symptomatic despite
optimal use of diuretics and A.C.E.
inhibitors.
7/30/202459
Digoxin may be added to treatment
of chronic heart failure in patients
who are still symptomatic despite
optimal use of diuretics and A.C.E.
inhibitors.
7/30/202459
Administration/Side effects
Usually administered orally or by i.v. injectionfor
rapid digitalization in emergency situations
[caution!!!)
The side effects are determined by the levels of
plasma concentration (dose related) and also by
electrolyte balance.
Hypercalcaemia and hypokalaemia potentiates
digoxin toxicity.
7/30/202460
Usually administered orally or by i.v. injectionfor
rapid digitalization in emergency situations
[caution!!!)
The side effects are determined by the levels of
plasma concentration (dose related) and also by
electrolyte balance.
Hypercalcaemia and hypokalaemia potentiates
digoxin toxicity.
7/30/202460
Non-Cardiac side effects
The common non-cardiac side
effects are:
anorexia, nausea, vomiting
diarrhoea
fatigue, weakness,,
rarely confusion and psychosis
which are central effects.
7/30/202461
The common non-cardiac side
effects are:
anorexia, nausea, vomiting
diarrhoea
fatigue, weakness,,
rarely confusion and psychosis
which are central effects.
7/30/202461
Cardiac side effects
sinus bradycardia,
various degrees of AV block including
complete heart block,
ventricular ectopic beats,
ventricular fibrillation
Atrial and ventricular tachycardia.
7/30/202462
sinus bradycardia,
various degrees of AV block including
complete heart block,
ventricular ectopic beats,
ventricular fibrillation
Atrial and ventricular tachycardia.
7/30/202462
continue
Digoxin has a narrow therapeutic to toxic
ratio,
Determination of the plasma digoxin
concentration may be useful when lack of
efficacy or toxicity is suspected during
therapy
7/30/202463
Digoxin has a narrow therapeutic to toxic
ratio,
Determination of the plasma digoxin
concentration may be useful when lack of
efficacy or toxicity is suspected during
therapy
7/30/202463
Drug interactions
Absorption is ↓sedby drugs that increase
intestinal motility e.g. metoclopramide,
↑sedby drugs that decreases gastro
intestinal motility e.g. propantheline,.
Other clinically important interactions
Drugs that reduce plasma K+ concentration,
e.g. the loop diuretics
Amiodarone, Quinidine &verapamil ↑ses
digoxin toxicity
7/30/202464
Absorption is ↓sedby drugs that increase
intestinal motility e.g. metoclopramide,
↑sedby drugs that decreases gastro
intestinal motility e.g. propantheline,.
Other clinically important interactions
Drugs that reduce plasma K+ concentration,
e.g. the loop diuretics
Amiodarone, Quinidine &verapamil ↑ses
digoxin toxicity
7/30/202464
continue
The elimination t1/2 of digoxin is 2days in
patients with normal renal function,
Prolonged in the elderly and in patients with
renal disease
7/30/202465
The elimination t1/2 of digoxin is 2days in
patients with normal renal function,
Prolonged in the elderly and in patients with
renal disease
7/30/202465
Other Myocardial stimulants
1 AGONISTS
DOPAMINE/DOBUTAMINE
Causes an increase in myocardial cellular
levels of cyclic AMP
increases [ Ca
2+
] concentration ; effect is
1
mediated/stimulation.
Useful for management of acute severe heart
failure accompanied by hypotension and poor
tissue perfusion.
7/30/202466
1 AGONISTS
DOPAMINE/DOBUTAMINE
Causes an increase in myocardial cellular
levels of cyclic AMP
increases [ Ca
2+
] concentration ; effect is
1
mediated/stimulation.
Useful for management of acute severe heart
failure accompanied by hypotension and poor
tissue perfusion.
7/30/202466
continue
They have short-term effects, and their
effects are dose dependent.
Both Dopamine and dobutamine undergoes
rapid clearance from the body leading to a
shorter duration of action.
They are not effective orally and are usually
administered by the IV route.
7/30/202467
They have short-term effects, and their
effects are dose dependent.
Both Dopamine and dobutamine undergoes
rapid clearance from the body leading to a
shorter duration of action.
They are not effective orally and are usually
administered by the IV route.
7/30/202467
Side effects
Mainly tachyarrhythmias due to 1 stimulation,
and when used in excessive doses.
The tachyarrhythmic effect is lesser with
dobutamine compared to dopamine.
Clinically the 1-adrenoceptor agonists are used
to increase cardiac contractility when a rapid
response is needed for a short term as in acute
heart failure.
7/30/202468
Mainly tachyarrhythmias due to 1 stimulation,
and when used in excessive doses.
The tachyarrhythmic effect is lesser with
dobutamine compared to dopamine.
Clinically the 1-adrenoceptor agonists are used
to increase cardiac contractility when a rapid
response is needed for a short term as in acute
heart failure.
7/30/202468
continue
Stimulation of receptors in skeletal
muscle can cause hypokalaemia
(arrhythmogenic).
Read about phosphodiesterase inhibitors
(milrinone, Xamoterol etc) How useful are
these in HF.
Why are they not in use in practice.
7/30/202469
Stimulation of receptors in skeletal
muscle can cause hypokalaemia
(arrhythmogenic).
Read about phosphodiesterase inhibitors
(milrinone, Xamoterol etc) How useful are
these in HF.
Why are they not in use in practice.
7/30/202469
Drugs to be used with care in patients
with Heart failure
Steroids
NSAIDS
Tricyclic anti depressants
Anti arrhythmic drugs
Calcium channel blockers except Amlodipine
and probably felodipine
Carbenoxlone
7/30/202470
with Heart failure
Steroids
NSAIDS
Tricyclic anti depressants
Anti arrhythmic drugs
Calcium channel blockers except Amlodipine
and probably felodipine
Carbenoxlone
7/30/202470
HEART FAILURE
Aprogressive complex clinical syndrome
usually with high mortality rate
HF is X’terised by the presence of a
significant heart disease,
usually with dypnoea, fatigue and fluid
retention.
Congestive HF: A condition in which the body
dissolves in water.
There is decreased C.O & Increased
sympathetic activity
7/30/202471
Aprogressive complex clinical syndrome
usually with high mortality rate
HF is X’terised by the presence of a
significant heart disease,
usually with dypnoea, fatigue and fluid
retention.
Congestive HF: A condition in which the body
dissolves in water.
There is decreased C.O & Increased
sympathetic activity
7/30/202471
continue
HF is defined as:
Inability of the heart to maintain C.O.
sufficient to meet the metabolic needs of the
bodyduring excercise and ultimately at rest
Whilst mentaining a normal filling pressure
7/30/202472
HF is defined as:
Inability of the heart to maintain C.O.
sufficient to meet the metabolic needs of the
bodyduring excercise and ultimately at rest
Whilst mentaining a normal filling pressure
7/30/202472
Pathophysiological
Sequence of CHF
Heart Failure
Inadequate Cardiac Output
() O
2Delivery (rest and/or exercise)
Systemic Vasoconstriction
SAS (NE)) RAAS (A-II)
() Flow to Skin, Gut,
and Renal Circulations
7/30/202473
Sequence of CHF
Heart Failure
Inadequate Cardiac Output
() O
2Delivery (rest and/or exercise)
Systemic Vasoconstriction
SAS (NE)) RAAS (A-II)
() Flow to Skin, Gut,
and Renal Circulations
7/30/202473
Four Determinants of
CO
1) Heart Rate→ Chronotropy
2) Contractility → Inotropy
3) Venous Return → Preload
4) Total Peripheral Resistance→
Afterload
7/30/202474
CO
1) Heart Rate→ Chronotropy
2) Contractility → Inotropy
3) Venous Return → Preload
4) Total Peripheral Resistance→
Afterload
7/30/202474
symptoms suggestive
of heart failure
Exertional breathlesness
Ankle swelling
& evidence of cardiac dysfunction
of sufficient severity that accounts for the symptoms
(by Echo).
7/30/202475
of heart failure
Exertional breathlesness
Ankle swelling
& evidence of cardiac dysfunction
of sufficient severity that accounts for the symptoms
(by Echo).
7/30/202475
Factors
affecting cardiac performance
CARDIAC PERFORMANCE IS INFLUENCED BY:
1)Preload→ Determines ventricular end diastolic pressure and
volume.⇒venous return
2)Afterload▬Ventricular wall tension developed during
ejection⇒Total peripheral resistance
3)Force of myocardial contraction→ Determined by the strength
and intergrity of the muscle cells.
Force of contraction is decreased in
IHD, Hypertension, myocarditis and dilated cardiac myopathy,
Vulvular heart disease
4)Neuroendocrine activation.
7/30/202476
affecting cardiac performance
CARDIAC PERFORMANCE IS INFLUENCED BY:
1)Preload→ Determines ventricular end diastolic pressure and
volume.⇒venous return
2)Afterload▬Ventricular wall tension developed during
ejection⇒Total peripheral resistance
3)Force of myocardial contraction→ Determined by the strength
and intergrity of the muscle cells.
Force of contraction is decreased in
IHD, Hypertension, myocarditis and dilated cardiac myopathy,
Vulvular heart disease
4)Neuroendocrine activation.
7/30/202476
NEUROENDOCRINE
ACTIVATION cont.
In Heart failure:
Plasma concentrations of renin, angiotensen II,
Aldosterone, noradrenaline, ADH etc increases.
Increased sympathetic activity leads to
sympathetically mediated increase in renin
secretion and ↑sesin angiotensen II and
aldosterone levels.
Neuroendocrine activation may be responsible
for many of the characteristic features of heart
failure.
7/30/202477
ACTIVATION cont.
In Heart failure:
Plasma concentrations of renin, angiotensen II,
Aldosterone, noradrenaline, ADH etc increases.
Increased sympathetic activity leads to
sympathetically mediated increase in renin
secretion and ↑sesin angiotensen II and
aldosterone levels.
Neuroendocrine activation may be responsible
for many of the characteristic features of heart
failure.
7/30/202477
NEUROENDOCRINE ACTIVATION cont.
(THE RAAS SYSTEM)
7/30/202478
(THE RAAS SYSTEM)
7/30/202478
Neuroendocrine
activation ctn
Angiotensen II causes:
vasoconstriction,
Na+ retension,
destruction of the cardiac cells
progressive ventricular dilatation (re-
modelling),
stimulation of aldosterone secretion.
7/30/202479
activation ctn
Angiotensen II causes:
vasoconstriction,
Na+ retension,
destruction of the cardiac cells
progressive ventricular dilatation (re-
modelling),
stimulation of aldosterone secretion.
7/30/202479
continue
Aldosterone:
Na+ retension, K+ loss (could cause arrhythmia)
Sympathetic activation:
Vasoconstriction, arrhythmias, Na+ retension
(NB: initially there appears to be an improvement of
cardiac contractility but has adverse effects on
long term cardiac Fxn).
7/30/202480
Aldosterone:
Na+ retension, K+ loss (could cause arrhythmia)
Sympathetic activation:
Vasoconstriction, arrhythmias, Na+ retension
(NB: initially there appears to be an improvement of
cardiac contractility but has adverse effects on
long term cardiac Fxn).
7/30/202480
GOALS OF THERAPY
To improve the quality of life of the patients;
by improving the signs and symptoms
Avoid side effects
Preventing major C.V. events such as:
MI,
stroke,
hypertension
These may be responsiblefor increased
morbidity of heart failure.
7/30/202481
To improve the quality of life of the patients;
by improving the signs and symptoms
Avoid side effects
Preventing major C.V. events such as:
MI,
stroke,
hypertension
These may be responsiblefor increased
morbidity of heart failure.
7/30/202481
continue
Improve cardiac performance
Improve exercise capacity
Reduce arrhythmias (both ventricular and
supraventricular),
Maintain adequate renal function and prevent
electrolyte inbalance
7/30/202482
Improve cardiac performance
Improve exercise capacity
Reduce arrhythmias (both ventricular and
supraventricular),
Maintain adequate renal function and prevent
electrolyte inbalance
7/30/202482
DRUGS USED FOR
TREATING HEART FAILURE
Diuretics⇒Mainly Loop diuretics and thiazides
Neuro endocrine antagonists
e.g. A.C.E.Inhibitors, Ag II antagonist,
Aldosterone antagonists, β-Adrenoceptor
antagonist.
Drugs with positive ionotropic effect
e.g. cardiac glycosides, 1-adrenoceptor
agonists.
Vasodilators e.g. the organic nitrates,
hydrallazine, sodium nitroprusside and
prazocin
7/30/202483
TREATING HEART FAILURE
Diuretics⇒Mainly Loop diuretics and thiazides
Neuro endocrine antagonists
e.g. A.C.E.Inhibitors, Ag II antagonist,
Aldosterone antagonists, β-Adrenoceptor
antagonist.
Drugs with positive ionotropic effect
e.g. cardiac glycosides, 1-adrenoceptor
agonists.
Vasodilators e.g. the organic nitrates,
hydrallazine, sodium nitroprusside and
prazocin
7/30/202483
VASODILATORS
Arteriolar vasodilators
reduce aortic impedance (decrease after
load)
☛enhance cardiac output
useful during episodes of acute heart failure.
Eg includes α
1adrenoceptor antagonist
7/30/202484
Arteriolar vasodilators
reduce aortic impedance (decrease after
load)
☛enhance cardiac output
useful during episodes of acute heart failure.
Eg includes α
1adrenoceptor antagonist
7/30/202484
Venodilators
reduces left ventricular end diastolic pressure
and volume(preload)
reduces pulmonary congestion and
symptoms of breathlessness in acute heart
failure.
Most of the vasodilators have both arteriolar
dilatating and venodilation effects.
E.g. Hydrallazine, Isosorbide dinitrate,
prazocin, Nitroprusside etc.
The use of these drugs for management of heart failure have
has been replaced by A.C.E. inhibitors
7/30/202485
reduces left ventricular end diastolic pressure
and volume(preload)
reduces pulmonary congestion and
symptoms of breathlessness in acute heart
failure.
Most of the vasodilators have both arteriolar
dilatating and venodilation effects.
E.g. Hydrallazine, Isosorbide dinitrate,
prazocin, Nitroprusside etc.
The use of these drugs for management of heart failure have
has been replaced by A.C.E. inhibitors
7/30/202485
A.C.E. INHIBITORS
Role in heart failure
Improve pump function
Reduces arteriolar and venous constriction
Reduce sympathetic stimulation
Reduce diuretic induced renin secretion
Increase renal and skeletal muscle blood
flow.
They do not only improve symptoms, but
reduces mortality in patients with heart failure
7/30/202486
Role in heart failure
Improve pump function
Reduces arteriolar and venous constriction
Reduce sympathetic stimulation
Reduce diuretic induced renin secretion
Increase renal and skeletal muscle blood
flow.
They do not only improve symptoms, but
reduces mortality in patients with heart failure
7/30/202486
MECH. OF ACTION
The Angitensen coverting enzyme
concerts angitensen I to Angiotensen II
degrades bradykinins.
Angiotensen II
is a potent vasoconstrictor,
stimulates aldosterone and anti-diuretic hormone
release,
enhances sympathetic activity,
causes renal sodium retension etc.
7/30/202487
The Angitensen coverting enzyme
concerts angitensen I to Angiotensen II
degrades bradykinins.
Angiotensen II
is a potent vasoconstrictor,
stimulates aldosterone and anti-diuretic hormone
release,
enhances sympathetic activity,
causes renal sodium retension etc.
7/30/202487
continue
Angitensen II also causes direct damage to the
cardiac myocytes (mechstimulates vascular
and myocardial hypertrophy).
Bradykinin
is a powerful vasodilator,
stimulates the production of vasodilator
prostaglandins and NO.
By blocking the formation of Angiotensen II
A.C.E.Inhibitors reduce vascular resistance and
thus improve tissue perfusion.
7/30/202488
Angitensen II also causes direct damage to the
cardiac myocytes (mechstimulates vascular
and myocardial hypertrophy).
Bradykinin
is a powerful vasodilator,
stimulates the production of vasodilator
prostaglandins and NO.
By blocking the formation of Angiotensen II
A.C.E.Inhibitors reduce vascular resistance and
thus improve tissue perfusion.
7/30/202488
continue
A.C.E.I
reduces the secretion of aldosterone
leading to a reduction in Na+ and water
retention.
Produce both arterial(dec. afterload) and venous
dilatation(↓se preload),
The later effect may be mediated through raised levels of
bradykinis in the body.
By reducing aldosterone secretion, A.C.E.I
increases the levels of serum K+
Caution with K+ sparing diuretics.
7/30/202489
A.C.E.I
reduces the secretion of aldosterone
leading to a reduction in Na+ and water
retention.
Produce both arterial(dec. afterload) and venous
dilatation(↓se preload),
The later effect may be mediated through raised levels of
bradykinis in the body.
By reducing aldosterone secretion, A.C.E.I
increases the levels of serum K+
Caution with K+ sparing diuretics.
7/30/202489
SIDE EFFECTS
Profound hypotension after the first dose in patients on
diuretics or hyponatraemic pts.
Others:
renal dysfunction
hyperkalaemia
loss of taste
& cough.
7/30/202490
Profound hypotension after the first dose in patients on
diuretics or hyponatraemic pts.
Others:
renal dysfunction
hyperkalaemia
loss of taste
& cough.
7/30/202490
DRUG INTERACTIONS/KINETICS
Hyperkalaemia→A.C.E.I + K+ sparing diuretics.
A.C.E.I + N.S.A.I.D.S may ppt renal failure
Examples: captopril, enalapril, lisinopril, Ramapril,
Fosinopril
They are all orally active.
Captopril is short acting, t
1/2is about 2hrs.
Drug elimination is reduced in renal failure (accumulation
& enhanced adverse effects).
Enalapril is a prodrug →coverted to the active metabolite
enalaprilaat in vivo, which is longer acting.
Enalapril,Fosinopril and lisinopril usedonce daily for
management of heart failure and hypertension.
Ramapril may be used 2x daily. 7/30/202491
Hyperkalaemia→A.C.E.I + K+ sparing diuretics.
A.C.E.I + N.S.A.I.D.S may ppt renal failure
Examples: captopril, enalapril, lisinopril, Ramapril,
Fosinopril
They are all orally active.
Captopril is short acting, t
1/2is about 2hrs.
Drug elimination is reduced in renal failure (accumulation
& enhanced adverse effects).
Enalapril is a prodrug →coverted to the active metabolite
enalaprilaat in vivo, which is longer acting.
Enalapril,Fosinopril and lisinopril usedonce daily for
management of heart failure and hypertension.
Ramapril may be used 2x daily. 7/30/202491
ANGIOTENSEN II ANTAGONISTS
Beneficial effects on symptoms and
haemodynamics in heart failure, Similar to
that of A.C.E. Inhibitors.
Have the advantage of being free of cough
with A.C.E.Inhibitors.
May be used as an alternative to A.C.E.
Inhibitors
If the troublesome cough cannot be torelated
e.g Losartan, Valsartan, Candesartan
.
7/30/202492
Beneficial effects on symptoms and
haemodynamics in heart failure, Similar to
that of A.C.E. Inhibitors.
Have the advantage of being free of cough
with A.C.E.Inhibitors.
May be used as an alternative to A.C.E.
Inhibitors
If the troublesome cough cannot be torelated
e.g Losartan, Valsartan, Candesartan
.
7/30/202492
SPIRONOLACTONE
Competitively inhibits the effects of aldosterone.
Useful in managing resistant oedema associated
with excess aldosterone including nephritic syndrome,
cirrhosis and heart failure.
Side effects:
Nausea
Gynaecomatsia in men
Menstrual irregularities in women.
Should with caution to other potassium sparing
diuretics and/or A.C.E Inhibitors/angiotensen II
antagonists.
7/30/202493
Competitively inhibits the effects of aldosterone.
Useful in managing resistant oedema associated
with excess aldosterone including nephritic syndrome,
cirrhosis and heart failure.
Side effects:
Nausea
Gynaecomatsia in men
Menstrual irregularities in women.
Should with caution to other potassium sparing
diuretics and/or A.C.E Inhibitors/angiotensen II
antagonists.
7/30/202493
Beta blockers
☛Not all β-Blockers could be used in HF.
Ones found useful in HF are Bisoprolol,
Metoprolol, Carvedilol
Bisoprolol and metoprolol (β1 selective)
Carvedilol (α1, βnon-selective), also has
antioxidant properties
β-Blockers have been found to decrease risk of
hospitalization & mortality in HF Pts.
7/30/202494
☛Not all β-Blockers could be used in HF.
Ones found useful in HF are Bisoprolol,
Metoprolol, Carvedilol
Bisoprolol and metoprolol (β1 selective)
Carvedilol (α1, βnon-selective), also has
antioxidant properties
β-Blockers have been found to decrease risk of
hospitalization & mortality in HF Pts.
7/30/202494
β-Blockers continue….
Evidence from trials :
Carvedilol better than Metoprolol and
Bisoprolol.
The most promising of the beta blockers
have been Carvedilol
7/30/202495
Evidence from trials :
Carvedilol better than Metoprolol and
Bisoprolol.
The most promising of the beta blockers
have been Carvedilol
7/30/202495
Difference b/n carvedilol and Labetalol
Carvedilol & labetalol, both are 1,βnon-
specific.
The ß1:alpha -blocking ratio is greater in
carvedilol than labetalol
Also the duration of ß1 effects is longer for
carvedilol than Labetalol.
Carvedilol has antioxidant properties(protects
against MI)
7/30/202496
Carvedilol & labetalol, both are 1,βnon-
specific.
The ß1:alpha -blocking ratio is greater in
carvedilol than labetalol
Also the duration of ß1 effects is longer for
carvedilol than Labetalol.
Carvedilol has antioxidant properties(protects
against MI)
7/30/202496
CARVEDILOL
Benefits in Heart failure :
Safe in patients with heart failure.
Reduces mortality in all stages of HF
↓progression of the disease
↓recurrent myocardial infarction.
Has been found to be useful as an adjunct to
diuretics, digoxin & A.C.E. Inhibitors for
management of chronic heart failure.
7/30/202497
Benefits in Heart failure :
Safe in patients with heart failure.
Reduces mortality in all stages of HF
↓progression of the disease
↓recurrent myocardial infarction.
Has been found to be useful as an adjunct to
diuretics, digoxin & A.C.E. Inhibitors for
management of chronic heart failure.
7/30/202497
Side effects
Postural hypotension
bradycardia,
fluid retention
Dizziness
Headache
some G.I. disturbances.
Allergic reactionsfacial swelling and/or
difficulty breathing
7/30/202498
Postural hypotension
bradycardia,
fluid retention
Dizziness
Headache
some G.I. disturbances.
Allergic reactionsfacial swelling and/or
difficulty breathing
7/30/202498
Side effects ctn
Diltiazem or verapamil could worsen the adverse
effects of Carvedilol on the heart.
Contra indicated in Asthmatics or pts with
bronchospastic conditions
Pts with Kidney disease or Liver disease
Effects of carvedilol may be increased because
of slower elimination from the body
Contraindicated in pts with perepheral vascular
diseases.
7/30/202499
Diltiazem or verapamil could worsen the adverse
effects of Carvedilol on the heart.
Contra indicated in Asthmatics or pts with
bronchospastic conditions
Pts with Kidney disease or Liver disease
Effects of carvedilol may be increased because
of slower elimination from the body
Contraindicated in pts with perepheral vascular
diseases.
7/30/202499
Drug interactions
☛carvedilol undergoes oxidative metabolism.
the pharmacokinetics of carvedilol may be
affected by induction or inhibition of P450
enzymes.
Rifampicin:decreases the serum levels of
carvedilol by about 70%.
Cimetidine:may increase the levels of
carvedilol.
7/30/2024
10
0
☛carvedilol undergoes oxidative metabolism.
the pharmacokinetics of carvedilol may be
affected by induction or inhibition of P450
enzymes.
Rifampicin:decreases the serum levels of
carvedilol by about 70%.
Cimetidine:may increase the levels of
carvedilol.
7/30/2024
10
0
Interactions continue.
Digoxin + Carvedilol
Trough concentrations of digoxin may be
increase
Caution! pts on potent diuretics/digoxin and
carvedilol.
7/30/2024
10
1
Digoxin + Carvedilol
Trough concentrations of digoxin may be
increase
Caution! pts on potent diuretics/digoxin and
carvedilol.
7/30/2024
10
1
ANGINA
Angina occurs:
when there is an INBALLANCE between O
2
requirementsof the heart cells (myocardial
O
2demand) and O
2available to it
(myocardial O
2supply).
In angina,Coronary blood supplyis insufficient
to meet the myocardial energy requirements.
.
7/30/2024
10
2
Angina occurs:
when there is an INBALLANCE between O
2
requirementsof the heart cells (myocardial
O
2demand) and O
2available to it
(myocardial O
2supply).
In angina,Coronary blood supplyis insufficient
to meet the myocardial energy requirements.
.
7/30/2024
10
2
The three forms of Angina
Stable angina,
Unstable angina
and Variant angina
7/30/2024
10
3
Stable angina,
Unstable angina
and Variant angina
7/30/2024
10
3
ANGINA cont.
STABLE ANGINA
Attacks are provoked by exertion or excitement.
Attack ceases when the increased energy
demand is withdrawn.
The underlying pathology is usually chronic
coronary artery disease.
Treatment could be directed at
Increasing myocardial O
2supply through
vasodilation
or reducing myocardial O
2consumption through
reduced heart rate, decreased myocardial
contractility, decreased preload and decreased
afterload.
7/30/2024
10
4
STABLE ANGINA
Attacks are provoked by exertion or excitement.
Attack ceases when the increased energy
demand is withdrawn.
The underlying pathology is usually chronic
coronary artery disease.
Treatment could be directed at
Increasing myocardial O
2supply through
vasodilation
or reducing myocardial O
2consumption through
reduced heart rate, decreased myocardial
contractility, decreased preload and decreased
afterload.
7/30/2024
10
4
ANGINA cont.
Drugs that reduce heart rate ↑sesthe duration of
diastole( the time when the cardiac cells are supplied
with blood through the coronary circulation)
Variant angina/Atypical angina
occurs when the increase in myocardial O
2
demand is due to spasms of the coronary
arteriesas in coronary artery stenosis
Unstable angina
occurs with lesser exertion or at rest
It is unpredictable, unlike stable angina.
7/30/2024
10
5
Drugs that reduce heart rate ↑sesthe duration of
diastole( the time when the cardiac cells are supplied
with blood through the coronary circulation)
Variant angina/Atypical angina
occurs when the increase in myocardial O
2
demand is due to spasms of the coronary
arteriesas in coronary artery stenosis
Unstable angina
occurs with lesser exertion or at rest
It is unpredictable, unlike stable angina.
7/30/2024
10
5
Unstable angina ctn
Underlying pathology:
Usually rapture of an atheromatous
plaque with thrombus formation in a
coronary artery.
Coronary spasms may be an additional
mechanism.
Unstable angina may lead to MI and/or
sudden death.
7/30/2024
10
6
Underlying pathology:
Usually rapture of an atheromatous
plaque with thrombus formation in a
coronary artery.
Coronary spasms may be an additional
mechanism.
Unstable angina may lead to MI and/or
sudden death.
7/30/2024
10
6
continue
Drugs that are used for treating or
preventing attacks of angina include:
Organic nitrates,
Ca
2+
channel antagonists,
adrenoceptor antagonist
K+ channel activators
7/30/2024
10
7
Drugs that are used for treating or
preventing attacks of angina include:
Organic nitrates,
Ca
2+
channel antagonists,
adrenoceptor antagonist
K+ channel activators
7/30/2024
10
7
ORGANIC NITRATES
E.g Amyl nitrate, glyceryl trinitrate, Isosorbide
mono nitrate (ISM) and ISD
They are powerful vasodilators,
Act by releasing NO.
The mechanism is believed to involve the
activation of protein kinases via GMP
7/30/2024
10
8
E.g Amyl nitrate, glyceryl trinitrate, Isosorbide
mono nitrate (ISM) and ISD
They are powerful vasodilators,
Act by releasing NO.
The mechanism is believed to involve the
activation of protein kinases via GMP
7/30/2024
10
8
Nitrates ctn
Pharmacological effects:
The nitrates cause arteriolar dilatation →
lowers peripheral resistance, ↓ses
myocardial O2 / energy demand.
It also causes venodilatation→decreases
venous return.
Hence reduce end diastolic pressure and
volume.
Net results → Reduces myocardial work
and O
2demand.
7/30/2024
10
9
Pharmacological effects:
The nitrates cause arteriolar dilatation →
lowers peripheral resistance, ↓ses
myocardial O2 / energy demand.
It also causes venodilatation→decreases
venous return.
Hence reduce end diastolic pressure and
volume.
Net results → Reduces myocardial work
and O
2demand.
7/30/2024
10
9
continue
The nitrates relieves coronary arterial
spasms in variant angina
and any vascular spasm occurring in stable
or unstable angina,
Nitrates causes improvement in blood flow
through the coronary vessels and hence
improvement of perfusion to ischaemic
areas.
7/30/2024
11
0
The nitrates relieves coronary arterial
spasms in variant angina
and any vascular spasm occurring in stable
or unstable angina,
Nitrates causes improvement in blood flow
through the coronary vessels and hence
improvement of perfusion to ischaemic
areas.
7/30/2024
11
0
GLYCERYLTRINITRATE (GTNT)
It is a potent, short acting smooth muscle
relaxant with widespread vasodilator
activity.
Extensively metabolized in the liver
Has almost 0% bioavailability when
administered orally.
Usually administered sublingually or as a
transdermally patch or paste
It is also rapidly eliminated from the body
T1/2 of about 2mins.
7/30/2024
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1
It is a potent, short acting smooth muscle
relaxant with widespread vasodilator
activity.
Extensively metabolized in the liver
Has almost 0% bioavailability when
administered orally.
Usually administered sublingually or as a
transdermally patch or paste
It is also rapidly eliminated from the body
T1/2 of about 2mins.
7/30/2024
11
1
continue
GTNT could be used prophylactically before
an individual carries out a task known to
produce angina, such as an exercise.
The daily dose may be individualized
It is determined as that required to control
the symptoms of angina.
GTNT may be used IV with other drugs for
management of unstable angina.
7/30/2024
11
2
GTNT could be used prophylactically before
an individual carries out a task known to
produce angina, such as an exercise.
The daily dose may be individualized
It is determined as that required to control
the symptoms of angina.
GTNT may be used IV with other drugs for
management of unstable angina.
7/30/2024
11
2
continue
Side effects
Dose related ⇒Headache, flushing, postural
dizziness.
postural hypotension, syncope etc.
The symptoms of the adverse effects can be
terminated by swallowing the tablet or
spitting it out.
Patch or paste, ⇒Effect could be terminated
by removing the patch.
7/30/2024
11
3
Side effects
Dose related ⇒Headache, flushing, postural
dizziness.
postural hypotension, syncope etc.
The symptoms of the adverse effects can be
terminated by swallowing the tablet or
spitting it out.
Patch or paste, ⇒Effect could be terminated
by removing the patch.
7/30/2024
11
3
ISD vs ISM
The pharmacological properties of isosorbide
nitrates →similar to that of GTNT,
The isosorbides are effective orally and have a
relatively longer t
1/2. (i.e. t1/2 of ISDN is about 40
mins)
The isosorbides are used in the management
of acute phase of unstable angina.
ISM has a longer t1/2 than dinitrate.
ISM is an active metabolite of ISDN, and has a
longer duration of action.
7/30/2024
11
4
The pharmacological properties of isosorbide
nitrates →similar to that of GTNT,
The isosorbides are effective orally and have a
relatively longer t
1/2. (i.e. t1/2 of ISDN is about 40
mins)
The isosorbides are used in the management
of acute phase of unstable angina.
ISM has a longer t1/2 than dinitrate.
ISM is an active metabolite of ISDN, and has a
longer duration of action.
7/30/2024
11
4
CONTINUE
Prolonged use of the ISD/ISM after several
weeks and at high doses is associated with
loss of efficacy.
This may be due to tolerance (Nitrate
tolerance)
Drug effect could be restored after a short
break of therapy.
Evidence has shown that about 6-8 hrs
nitrate free interval with isosorbide therapy
in 24 hrs, restores the efficacy of the nitrates.
7/30/2024
11
5
Prolonged use of the ISD/ISM after several
weeks and at high doses is associated with
loss of efficacy.
This may be due to tolerance (Nitrate
tolerance)
Drug effect could be restored after a short
break of therapy.
Evidence has shown that about 6-8 hrs
nitrate free interval with isosorbide therapy
in 24 hrs, restores the efficacy of the nitrates.
7/30/2024
11
5
CONTINUE
Isosorbide mono nitrate is given once daily
while the dinitrate may be administered 2 or
3 times with about 6 to 8 hr drug free period
between doses.
It is important to remove the nitrate patches
at night to ensure efficacy during the day
Side effects →Similar to GTNT
7/30/2024
11
6
Isosorbide mono nitrate is given once daily
while the dinitrate may be administered 2 or
3 times with about 6 to 8 hr drug free period
between doses.
It is important to remove the nitrate patches
at night to ensure efficacy during the day
Side effects →Similar to GTNT
7/30/2024
11
6
-ADRENOCEPTOR BLOCKERS
The -blockers reduce myocardial O
2
consumption by:
Reducing heart rate associated with
exercise and anxiety.
Reducing the force of contraction of
the heart Both effects are 1 mediated.
Also improve myocardial perfusion
due to its effect on heart rate.
7/30/2024
11
7
The -blockers reduce myocardial O
2
consumption by:
Reducing heart rate associated with
exercise and anxiety.
Reducing the force of contraction of
the heart Both effects are 1 mediated.
Also improve myocardial perfusion
due to its effect on heart rate.
7/30/2024
11
7
-BLOCKERS ctn
The -blockers reduces the rate of mortality in patients
with myocardial infarction.
It also reduces re-infarction following a previous
myocardial infarction
The 1 selective antagonists e.g Atenolol, metoprolol,
Bisoprolol is preferred over the others. ( both for stable
and unstable)
Other reasons:
They cause fewer respiratory, central or peripheral
vascular side effects, often associated with the non-
selective blockers.
7/30/2024
11
8
The -blockers reduces the rate of mortality in patients
with myocardial infarction.
It also reduces re-infarction following a previous
myocardial infarction
The 1 selective antagonists e.g Atenolol, metoprolol,
Bisoprolol is preferred over the others. ( both for stable
and unstable)
Other reasons:
They cause fewer respiratory, central or peripheral
vascular side effects, often associated with the non-
selective blockers.
7/30/2024
11
8
-BLOCKERS ctn
-blockers could be used prophylactically for
preventing acute attacks of angina.
Rebound worsening of angina occurs when the -
blockers are suddenly with drawn.
Worsening of myocardial infarction, tachycardias etc
have also been reported in patients who withdraw -
blockers suddenly
7/30/2024
11
9
-blockers could be used prophylactically for
preventing acute attacks of angina.
Rebound worsening of angina occurs when the -
blockers are suddenly with drawn.
Worsening of myocardial infarction, tachycardias etc
have also been reported in patients who withdraw -
blockers suddenly
7/30/2024
11
9
ADVERSE EFFECTS OF BETA
BLOCKERS
Bradycardia; AV Block
Peripheral Vascular Disease
Depression
Dreams
Sexual Dysfunction
7/30/2024
12
0
BLOCKERS
Bradycardia; AV Block
Peripheral Vascular Disease
Depression
Dreams
Sexual Dysfunction
7/30/2024
12
0
Examples of β-blockers
Atenolol⇒water soluble cardio selective
Metoprolol⇒Lipid soluble cardio selective
Propranolol⇒Lipid soluble non-selective.
Labetalol⇒ α1 βnon-selective
Carvedilol⇒ α1 βnon-selective
Practolol⇒ β1 selective –very toxic, has been withdrawn from
the market.
Pindolol⇒ Non selective with ISA
satolol⇒ non selective water soluble with ISA
Esmolol⇒Cardio selective with low t
½
Other e.g. Timolol,betaxolol, acebutolol, celiprolol etc.
7/30/2024
12
1
Atenolol⇒water soluble cardio selective
Metoprolol⇒Lipid soluble cardio selective
Propranolol⇒Lipid soluble non-selective.
Labetalol⇒ α1 βnon-selective
Carvedilol⇒ α1 βnon-selective
Practolol⇒ β1 selective –very toxic, has been withdrawn from
the market.
Pindolol⇒ Non selective with ISA
satolol⇒ non selective water soluble with ISA
Esmolol⇒Cardio selective with low t
½
Other e.g. Timolol,betaxolol, acebutolol, celiprolol etc.
7/30/2024
12
1
CA
2+
CHANNEL ANTAGONISTS
Classified into three groups :
1)Dihydropyridines
e.g. Nifedipine, felodipine, amlodipine,
isradipine, nimodipine
2)Phenyl alkyl amines e.g. Verapamil
3)Benzothiazipinee.g. Diltiazem
7/30/2024
12
2
2+
CHANNEL ANTAGONISTS
Classified into three groups :
1)Dihydropyridines
e.g. Nifedipine, felodipine, amlodipine,
isradipine, nimodipine
2)Phenyl alkyl amines e.g. Verapamil
3)Benzothiazipinee.g. Diltiazem
7/30/2024
12
2
CA
2+
CHANNEL ANTAGONISTS
Acts by blocking the opening of voltage-gated Ca
2+
channels on
the heart and the vascular smooth muscles.
Resultant effect is ↓sedtone of the vascular smooth muscles
including the coronary arteries.
↓sedcontractility of the myocardial cells.
Selectivity varies between the heart and the vascular smooth
muscles.
Effect of verapamil is more on the heart (cardio selective),
That of nifedipine and the dihydropyridines are more on the
vessels (arteries more sensitive than veins).
Diltiazem is intermediate (acts both on the heart and the
vessels)
7/30/2024
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3
2+
CHANNEL ANTAGONISTS
Acts by blocking the opening of voltage-gated Ca
2+
channels on
the heart and the vascular smooth muscles.
Resultant effect is ↓sedtone of the vascular smooth muscles
including the coronary arteries.
↓sedcontractility of the myocardial cells.
Selectivity varies between the heart and the vascular smooth
muscles.
Effect of verapamil is more on the heart (cardio selective),
That of nifedipine and the dihydropyridines are more on the
vessels (arteries more sensitive than veins).
Diltiazem is intermediate (acts both on the heart and the
vessels)
7/30/2024
12
3
continue
Verapamil and diltiazem have depressant effect
on S.A and A.V nodal function
leading to slowing of the heart rate and A.V nodal
conduction.
The Ca
2+
channel antagonist may be used in both
stable and unstable angina.
Verapamil or diltiazem could be used as a single
agent for management of stable angina.
The dihydropyridines dilate coronary vessels
and may be useful in patients with variant angina
7/30/2024
12
4
Verapamil and diltiazem have depressant effect
on S.A and A.V nodal function
leading to slowing of the heart rate and A.V nodal
conduction.
The Ca
2+
channel antagonist may be used in both
stable and unstable angina.
Verapamil or diltiazem could be used as a single
agent for management of stable angina.
The dihydropyridines dilate coronary vessels
and may be useful in patients with variant angina
7/30/2024
12
4
Pharmacokinetics/ Side effects
The Ca
2+
antagonist are well absorbed after oral
administration and metabolized in the liver.
They all undergo extensive 1st pass metabolism
Some of their products of metabolism may be active, →
contributing to their pharmacological action.
Side effects
Headache, nausea, flushing and ankle swelling are
observed with nifedipineand related drugs.
Reflex tachycardia is also associated with the use of
nifedipine.
This effect may diminish when nifedipineis used in
combination with -blockers.
7/30/2024
12
5
The Ca
2+
antagonist are well absorbed after oral
administration and metabolized in the liver.
They all undergo extensive 1st pass metabolism
Some of their products of metabolism may be active, →
contributing to their pharmacological action.
Side effects
Headache, nausea, flushing and ankle swelling are
observed with nifedipineand related drugs.
Reflex tachycardia is also associated with the use of
nifedipine.
This effect may diminish when nifedipineis used in
combination with -blockers.
7/30/2024
12
5
continue
Diltiazem and verapamil causes sinus
bradycardia,
Have negative ionotropic effect
Combination may ppt heart failure
They also cause A.V block and must be avoided
if the QRS complex or QT is widened on the ECG
7/30/2024
12
6
Diltiazem and verapamil causes sinus
bradycardia,
Have negative ionotropic effect
Combination may ppt heart failure
They also cause A.V block and must be avoided
if the QRS complex or QT is widened on the ECG
7/30/2024
12
6
K+ CHANNEL ACTIVATORS
Have both arteriolar and veno dilating properties.
The pharmacological activity is similar to that of the
nitrates but less tolerance problem.
Could be used for prophylaxis and treatment of
angina.
It acts by activation of K
+
channels on the vessels
causing vaso dilation.
E.g Nicorandil
7/30/2024
12
7
Have both arteriolar and veno dilating properties.
The pharmacological activity is similar to that of the
nitrates but less tolerance problem.
Could be used for prophylaxis and treatment of
angina.
It acts by activation of K
+
channels on the vessels
causing vaso dilation.
E.g Nicorandil
7/30/2024
12
7
HYPERTENSION
Blood pressure
Is the hydrostatic within the systemic
arteries
required for maintaining perfusion to the
tissues.
It is determined by the TPR and the
cardiac out put
HPT is persistently raised arterial blood
pressure above "normal"
{Systolic -> 140 mmHg and/or Diastolic -
> 90 mm Hg}
7/30/2024
12
8
Blood pressure
Is the hydrostatic within the systemic
arteries
required for maintaining perfusion to the
tissues.
It is determined by the TPR and the
cardiac out put
HPT is persistently raised arterial blood
pressure above "normal"
{Systolic -> 140 mmHg and/or Diastolic -
> 90 mm Hg}
7/30/2024
12
8
HYPERTENSION ctn
HPT is usually asymptomatic and a progressive
disorder,
If not effectively managed or controlled
could develop complications such as Heart
failure, Myocardial Ischaemia, Stroke, renal
failure
For both systolic and diastolic high B.P.
The higher the B.P., the greater the risk of
cardiovascular and other complications
7/30/2024
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9
HPT is usually asymptomatic and a progressive
disorder,
If not effectively managed or controlled
could develop complications such as Heart
failure, Myocardial Ischaemia, Stroke, renal
failure
For both systolic and diastolic high B.P.
The higher the B.P., the greater the risk of
cardiovascular and other complications
7/30/2024
12
9
HYPERTENSION cause
No underlying cause can be identified for about 95% of the
hypertensive cases( Essential HPT).
The cause of HPT may be secondary to some definite
abnormality such as
renal Parenchymal disease
Renovascular disease
steroid secreting tumours of the adrenal cortex
Drugs such as NSAIDS, steroids
Endocrine diseases such as hyperaldosteronism(Conn’s
disease)
Hypercortism(Cushing’s disease)
hyperthyroidism
7/30/2024
13
0
No underlying cause can be identified for about 95% of the
hypertensive cases( Essential HPT).
The cause of HPT may be secondary to some definite
abnormality such as
renal Parenchymal disease
Renovascular disease
steroid secreting tumours of the adrenal cortex
Drugs such as NSAIDS, steroids
Endocrine diseases such as hyperaldosteronism(Conn’s
disease)
Hypercortism(Cushing’s disease)
hyperthyroidism
7/30/2024
13
0
Determinants of Blood Pressure
Blood Pressure = Cardiac Output (x) Total
Peripheral Resistance
Cardiac Output = Heart Rate (x) Stroke
Volume
TPR -reflects relative tone of peripheral
arterioles
7/30/2024
13
1
Blood Pressure = Cardiac Output (x) Total
Peripheral Resistance
Cardiac Output = Heart Rate (x) Stroke
Volume
TPR -reflects relative tone of peripheral
arterioles
7/30/2024
13
1
PHYSIOLOGICAL MECHANISMS
REGULATING B.P
Baroreceptor mechanism
–Pressure sensing areas throughout the CV
system
–Alters autonomic outflow
–Acts minute by minute
Renin-angiotensin system
–Acts long-term (weeks/months)
7/30/2024
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2
REGULATING B.P
Baroreceptor mechanism
–Pressure sensing areas throughout the CV
system
–Alters autonomic outflow
–Acts minute by minute
Renin-angiotensin system
–Acts long-term (weeks/months)
7/30/2024
13
2
Baroreceptor
Reflex ctn
Decreased BP
–Increased sympathetic tone
–Decreased parasympathetic tone
Increased BP
–Decreased sympathetic tone
–Increased parasympathetic tone
7/30/2024
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3
Reflex ctn
Decreased BP
–Increased sympathetic tone
–Decreased parasympathetic tone
Increased BP
–Decreased sympathetic tone
–Increased parasympathetic tone
7/30/2024
13
3
Why reduce blood
pressure in HPTN?
Slow or interrupt progressive
tissue/organ damage
Brain
Eyes
Kidney
Heart
Prolongs life
7/30/2024
13
4
pressure in HPTN?
Slow or interrupt progressive
tissue/organ damage
Brain
Eyes
Kidney
Heart
Prolongs life
7/30/2024
13
4
continue
Direct relationship has been found between
the severity of HPT and ↑sedmorbidity and
mortality from cardiovascular disorders.
Severe HPT associated with renal damage
and vascular damage has high mortality rate
usually from cerebral hemorrhage or renal
failure
7/30/2024
13
5
Direct relationship has been found between
the severity of HPT and ↑sedmorbidity and
mortality from cardiovascular disorders.
Severe HPT associated with renal damage
and vascular damage has high mortality rate
usually from cerebral hemorrhage or renal
failure
7/30/2024
13
5
THE AIM OF THERAPY
To reduce the B.P. and to reduce the risk of
cardiovascular and other complications.
To prevent premature death from cardiovascular
diseases.
Drug therapy should control B.P. without less
adverse effects
Not worsening the quality of life of the individual.
Target of drug therapy is a diastolic B.P. of
90mmHg or less
and systolic B.P. between 130-140mmHg
7/30/2024
13
6
To reduce the B.P. and to reduce the risk of
cardiovascular and other complications.
To prevent premature death from cardiovascular
diseases.
Drug therapy should control B.P. without less
adverse effects
Not worsening the quality of life of the individual.
Target of drug therapy is a diastolic B.P. of
90mmHg or less
and systolic B.P. between 130-140mmHg
7/30/2024
13
6
Drugs used for management of
hypertension includes
Diuretics
β-Adrenoceptor antagonists
Ca
2+
channel antagonists/blockers
A.C.E. Inhibitors
α1 –adrenoceptor antagonists
Other vasodilators such as hydrallazine
Centrally acting drugs.
7/30/2024
13
7
hypertension includes
Diuretics
β-Adrenoceptor antagonists
Ca
2+
channel antagonists/blockers
A.C.E. Inhibitors
α1 –adrenoceptor antagonists
Other vasodilators such as hydrallazine
Centrally acting drugs.
7/30/2024
13
7
DIURETICS
The preferred diuretic is the Thiazide diuretics.
e.g. Bendrofluazide, Hydrochlorthiazide, chlorthalidone,
chlothiazide etc.
Mechanism of action as anti hypertensive is not clear.
The diuretic activity was Initially thought to be the mechanism for
the antihypertensive effect but more potent diuretics like loop
diureticsare not potent antihypertensives.
The B.P. lowering action is believed to depend on alterations to
the contractile response of vascular smooth muscles
Thiazides have direct action on the vascular smooth muscles,
causing vasodilatation.
Compared to loop diuretics, thiazides are less powerful diuretics
but have more potent antihypertensive properties.
7/30/2024
13
8
The preferred diuretic is the Thiazide diuretics.
e.g. Bendrofluazide, Hydrochlorthiazide, chlorthalidone,
chlothiazide etc.
Mechanism of action as anti hypertensive is not clear.
The diuretic activity was Initially thought to be the mechanism for
the antihypertensive effect but more potent diuretics like loop
diureticsare not potent antihypertensives.
The B.P. lowering action is believed to depend on alterations to
the contractile response of vascular smooth muscles
Thiazides have direct action on the vascular smooth muscles,
causing vasodilatation.
Compared to loop diuretics, thiazides are less powerful diuretics
but have more potent antihypertensive properties.
7/30/2024
13
8
DIURETICS ctn
The potent diuretic effect of the loops may
provoke reflex stimulation of the R-A-A-S. that
may counter any fall in Blood pressure.
The antihypertensive effect of thiazides are at
relatively low dosages
There is no additional benefit when the drug is
administered at high doses for blood pressure
control.
The diuretic response may however increase at
higher doses which could lead to hypokalaemia
and other side effects.
7/30/2024
13
9
The potent diuretic effect of the loops may
provoke reflex stimulation of the R-A-A-S. that
may counter any fall in Blood pressure.
The antihypertensive effect of thiazides are at
relatively low dosages
There is no additional benefit when the drug is
administered at high doses for blood pressure
control.
The diuretic response may however increase at
higher doses which could lead to hypokalaemia
and other side effects.
7/30/2024
13
9
Kinetics
Thiazides are well absorbed after oral
administration and widely distributed in the
body.
The antihypertensive effect is long-lasting
and may persist for 24 hours
(used once daily as monotherapy for mild to
moderate HPT)
7/30/2024
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0
Thiazides are well absorbed after oral
administration and widely distributed in the
body.
The antihypertensive effect is long-lasting
and may persist for 24 hours
(used once daily as monotherapy for mild to
moderate HPT)
7/30/2024
14
0
Side effects:
Hyperuricaemia, hyperglycaemia,
hyperlipidaemia and impotence.
Most of the side effects are reversible on withdrawal
of therapy.
Thiazides are widely used and effective
antihypertensive agents for mild to moderate
hypertension.
They may be added to other treatments in severe
hypertension.
7/30/2024
14
1
Hyperuricaemia, hyperglycaemia,
hyperlipidaemia and impotence.
Most of the side effects are reversible on withdrawal
of therapy.
Thiazides are widely used and effective
antihypertensive agents for mild to moderate
hypertension.
They may be added to other treatments in severe
hypertension.
7/30/2024
14
1
continue
Where the hypertension is complicated by
renal failure,it may be necessary to use a
loop diuretic (more potent diuretic)
To avoid cardiac rhythm disturbances with
diuretic-induced hypokalaemia, It may be
necessary to add a K+ sparing diuretic such
as amiloride or triamterene or a potassium
supplement..
7/30/2024
14
2
Where the hypertension is complicated by
renal failure,it may be necessary to use a
loop diuretic (more potent diuretic)
To avoid cardiac rhythm disturbances with
diuretic-induced hypokalaemia, It may be
necessary to add a K+ sparing diuretic such
as amiloride or triamterene or a potassium
supplement..
7/30/2024
14
2
β adrenoceptor
Antagonist
β adrenoceptor stimulation in the heart, the
kidneys and the nervous system
could lead to
an increase C.O.,
↑se in TPR
And an ↑sein aldosterone mediated Na+ and
water retension.
All of these effects could be antagonized with the
use of β blockers to cause a reduction in B.P.
But the principal antihypertensive mechanism is
notclear.
7/30/2024
14
3
Antagonist
β adrenoceptor stimulation in the heart, the
kidneys and the nervous system
could lead to
an increase C.O.,
↑se in TPR
And an ↑sein aldosterone mediated Na+ and
water retension.
All of these effects could be antagonized with the
use of β blockers to cause a reduction in B.P.
But the principal antihypertensive mechanism is
notclear.
7/30/2024
14
3
continue
β blockers vary in the way they are eliminated
from the body.
Lipid soluble β blockers such as propranolol
depend on liver metabolism and clearance from
the body
Water soluble derivative like Atenolol are
eliminated through the kidneys.
Propranolol is extensively metabolized in the
liver and has a short t
1/2
Atenolol has a longer t1/2 and may be
administered once daily.
7/30/2024
14
4
β blockers vary in the way they are eliminated
from the body.
Lipid soluble β blockers such as propranolol
depend on liver metabolism and clearance from
the body
Water soluble derivative like Atenolol are
eliminated through the kidneys.
Propranolol is extensively metabolized in the
liver and has a short t
1/2
Atenolol has a longer t1/2 and may be
administered once daily.
7/30/2024
14
4
Refer previous
slides on other CVD’s
nonselective –both beta receptors
cardioselective -
1>
2
intrinsic sympathomimetic activity (ISA)
cardioselective with ISA
7/30/2024
14
5
slides on other CVD’s
nonselective –both beta receptors
cardioselective -
1>
2
intrinsic sympathomimetic activity (ISA)
cardioselective with ISA
7/30/2024
14
5
Side effects
Bradycardia and impairment of myocardial
contractility
peripheral vasoconstriction with β
2blockade.
Antagonism of β receptors in the CNS is
associated with reduced sympathetic outflow,
this may cause
a sence of malaise, vivid dreams, night mares,
hallucinations, sexual dysfunction,& sedation.
The central effects are common with highly lipid
soluble β blockers such as propranolol.
7/30/2024
14
6
Bradycardia and impairment of myocardial
contractility
peripheral vasoconstriction with β
2blockade.
Antagonism of β receptors in the CNS is
associated with reduced sympathetic outflow,
this may cause
a sence of malaise, vivid dreams, night mares,
hallucinations, sexual dysfunction,& sedation.
The central effects are common with highly lipid
soluble β blockers such as propranolol.
7/30/2024
14
6
Other side effects
bronchospasm (β2-mediated),
Tiredness and fatiue.
(Nb β2-stimulation of skeletal muscle is associated with
increased muscle activity so blockade will lead to tiredness and
fatigue especially during exercise)
β blockers could mask the signs of hypoglycaemia
Must be used with care in diabetics
may increase plasma TG’s and decrease HDL
Ppt heart failre??
AV Block
Peripheral Vascular Disease(C.I)
7/30/2024
14
7
bronchospasm (β2-mediated),
Tiredness and fatiue.
(Nb β2-stimulation of skeletal muscle is associated with
increased muscle activity so blockade will lead to tiredness and
fatigue especially during exercise)
β blockers could mask the signs of hypoglycaemia
Must be used with care in diabetics
may increase plasma TG’s and decrease HDL
Ppt heart failre??
AV Block
Peripheral Vascular Disease(C.I)
7/30/2024
14
7
continue
Sudden withdrawal may be associated with nervousness,
tachycardia, ppt HTN or MI
β blockers with additional α1 blocking effects
e.g. labetalol and carvedilol could be used for
hypertension.
For management of hypertension and other cardiovascular
diseases,
selective β1 blockers that can be administered once daily
has the advantage over the others.
E.g. Atenolol, Bisoprolol
β blockers with additional α1 adrenoceptor blocking
effects such as labetalol preferred over non-selective β
blockers for HPT .
7/30/2024
14
8
Sudden withdrawal may be associated with nervousness,
tachycardia, ppt HTN or MI
β blockers with additional α1 blocking effects
e.g. labetalol and carvedilol could be used for
hypertension.
For management of hypertension and other cardiovascular
diseases,
selective β1 blockers that can be administered once daily
has the advantage over the others.
E.g. Atenolol, Bisoprolol
β blockers with additional α1 adrenoceptor blocking
effects such as labetalol preferred over non-selective β
blockers for HPT .
7/30/2024
14
8
Ca2+ Channel
Antagonists
All are effective antihypertensive agents but the
dihydropyridines are the most commonly used
( because of their peripheral vasodilating effect).
The longer acting dihydropyridines are preffered (They lack –ve
cardiac effects and are suitability for once daily administration).
But if a Ca
2+
Antagonists is needed for management of a
hypertensive with angina, verapamil or diltiazem may be
preferred
7/30/2024
14
9
Antagonists
All are effective antihypertensive agents but the
dihydropyridines are the most commonly used
( because of their peripheral vasodilating effect).
The longer acting dihydropyridines are preffered (They lack –ve
cardiac effects and are suitability for once daily administration).
But if a Ca
2+
Antagonists is needed for management of a
hypertensive with angina, verapamil or diltiazem may be
preferred
7/30/2024
14
9
A.C.E.Inhibitors
Some hypertensive patients have HIGH renin
activity(caucasians)
respond well to beta blockers
respond well to angiotensin blockers
Some have LOW renin activity
respond poorly to beta blockers
respond poorly to angiotensin blockers
7/30/2024
15
0
Some hypertensive patients have HIGH renin
activity(caucasians)
respond well to beta blockers
respond well to angiotensin blockers
Some have LOW renin activity
respond poorly to beta blockers
respond poorly to angiotensin blockers
7/30/2024
15
0
A.C.E.I mech. of action.
angiotensin II is a very potent vasoconstrictor
angiotensin II releases aldosterone
aldosterone enhances Na
+
and H
2O retention
and K
+
loss from the kidney
BV and BP increase as a result of salt &
water retention + vasoconstricttion by AGII
7/30/2024
15
1
angiotensin II is a very potent vasoconstrictor
angiotensin II releases aldosterone
aldosterone enhances Na
+
and H
2O retention
and K
+
loss from the kidney
BV and BP increase as a result of salt &
water retention + vasoconstricttion by AGII
7/30/2024
15
1
A.C.E.Inhibitors
Reduce circulating levels of Angiotensen II in the body (a potent
vasoconstrictor).
A.C.E.I reduces aldosterone production
decreases Na+ retention,
reduces sympathetic activity facilitated by Angiotensen II both
centrally and peripherally.
Unlike other vasodilators, A.C.E.Inhibitors does not provoke
reflex tachycardia.(absence of cardiostimulation →safe in patients with
ischemia)
Dose-response relationship for B.P. reduction is linearinitially
but a plateau could be reached within the therapeutic dosage
range, where further increases in doses do not increase the
antihypertensive effect.
7/30/2024
15
2
Reduce circulating levels of Angiotensen II in the body (a potent
vasoconstrictor).
A.C.E.I reduces aldosterone production
decreases Na+ retention,
reduces sympathetic activity facilitated by Angiotensen II both
centrally and peripherally.
Unlike other vasodilators, A.C.E.Inhibitors does not provoke
reflex tachycardia.(absence of cardiostimulation →safe in patients with
ischemia)
Dose-response relationship for B.P. reduction is linearinitially
but a plateau could be reached within the therapeutic dosage
range, where further increases in doses do not increase the
antihypertensive effect.
7/30/2024
15
2
Side effects
:
Profound hypotension (much higher in patients with Na+
or volume depletion).
▬The need for dosage adjustment when used
together with diuretics.
Others,
skin rashes,
neutropenia and renal damage.
Reversible renal failure ppted in patients with
renovascular disease.
Dry non-productive/dry irritant cough.
7/30/2024
15
3
:
Profound hypotension (much higher in patients with Na+
or volume depletion).
▬The need for dosage adjustment when used
together with diuretics.
Others,
skin rashes,
neutropenia and renal damage.
Reversible renal failure ppted in patients with
renovascular disease.
Dry non-productive/dry irritant cough.
7/30/2024
15
3
continue
A.C.E.I. contra-indicated absolutely in 2
nd
and 3
rd
trimester of pregnancy.
Fetal hypotension
Fetal renal failure
Fetal malformation/death
A.C.E.I combines well with thiazides or Ca
2+
channel blockers for management of
hypertension.
7/30/2024
15
4
A.C.E.I. contra-indicated absolutely in 2
nd
and 3
rd
trimester of pregnancy.
Fetal hypotension
Fetal renal failure
Fetal malformation/death
A.C.E.I combines well with thiazides or Ca
2+
channel blockers for management of
hypertension.
7/30/2024
15
4
A.C.E.I ctn
K+ supplements and K+ sparing diuretics should
be used with caution with A.C.E.Inhibitorsb’cosof
the risk of hyperkalaemia, especially in patients with pre-existing
renal impairment.
The use of NSAIDS could compromise the
antihypertensive effect of A.C.E.I>
Examples:
Captopril, Enalapril, Lysinopril, Fosinopril,
Quinapril and Ramapril.
7/30/2024
15
5
K+ supplements and K+ sparing diuretics should
be used with caution with A.C.E.Inhibitorsb’cosof
the risk of hyperkalaemia, especially in patients with pre-existing
renal impairment.
The use of NSAIDS could compromise the
antihypertensive effect of A.C.E.I>
Examples:
Captopril, Enalapril, Lysinopril, Fosinopril,
Quinapril and Ramapril.
7/30/2024
15
5
AG II RECEPTOR ANTAGONIST
Ag II receptor antagonists could also be used
for hypertension.
Blocks AG type 1 receptors
No effect on bradykininmetabolism
Contraindicated in pregnancy.
E.g.
Losartan
Valsaltan
7/30/2024
15
6
Ag II receptor antagonists could also be used
for hypertension.
Blocks AG type 1 receptors
No effect on bradykininmetabolism
Contraindicated in pregnancy.
E.g.
Losartan
Valsaltan
7/30/2024
15
6
α1 Adrenoceptor antagonists
These have vasodilating effect on vascular
smooth muscles. E.g. Prazocin, Indoramin,
Terazocin and doxazocin.
Terazocin and Doxazosin are longer acting and
well tolerated. They are used once daily.
Labetalol combines α1 –adrenoceptor and
nonspecific β-Adrenoceptor blocking effect for
hypertension.
Other vasodilators that are used for management
of hypertensive emergencies include Sodium
nitroprusside, minoxidil and hydrallazine.
7/30/2024
15
7
These have vasodilating effect on vascular
smooth muscles. E.g. Prazocin, Indoramin,
Terazocin and doxazocin.
Terazocin and Doxazosin are longer acting and
well tolerated. They are used once daily.
Labetalol combines α1 –adrenoceptor and
nonspecific β-Adrenoceptor blocking effect for
hypertension.
Other vasodilators that are used for management
of hypertensive emergencies include Sodium
nitroprusside, minoxidil and hydrallazine.
7/30/2024
15
7
CENTRALLY ACTING
ANTIHYPERTENSIVES (CAAHPT)
Drugs acting on α
2receptors in the brain
stem reduce sympathetic out flow and
eventually, reduces B.P.
These drugs are associated with central side
effects.
e.g. Clonidine and methyldopa.
7/30/2024
15
8
ANTIHYPERTENSIVES (CAAHPT)
Drugs acting on α
2receptors in the brain
stem reduce sympathetic out flow and
eventually, reduces B.P.
These drugs are associated with central side
effects.
e.g. Clonidine and methyldopa.
7/30/2024
15
8
CLONIDINE
α2 adrenoceptoragonist
Causes
sedation,
drowsiness,
dry mouth
and interference with sexual function in men.
Abrupt cessation with the use of clonidine give rise
to a rebound hypertensive effect.
7/30/2024
15
9
α2 adrenoceptoragonist
Causes
sedation,
drowsiness,
dry mouth
and interference with sexual function in men.
Abrupt cessation with the use of clonidine give rise
to a rebound hypertensive effect.
7/30/2024
15
9
α-Methyldopa
Acts through its active metabolite, methylnoradrenaline.
Mechanism is similar to that of Clonidine.
The side effect profile of CAAHPT central effect,limits
their use.
Methyldopa is very useful in the management of
hypertension in pregnancy.
Apart from the side effects listed for clonidine,
methyldopa is associated with immunological side effect
including hepatitis and pyrexia.
Could also cause haemolytic anaemia
7/30/2024
16
0
Acts through its active metabolite, methylnoradrenaline.
Mechanism is similar to that of Clonidine.
The side effect profile of CAAHPT central effect,limits
their use.
Methyldopa is very useful in the management of
hypertension in pregnancy.
Apart from the side effects listed for clonidine,
methyldopa is associated with immunological side effect
including hepatitis and pyrexia.
Could also cause haemolytic anaemia
7/30/2024
16
0
RESERPINE
Reserpine is an alkaloids obtained from
Rawoulfia spps.
originally used in psychiatry
Is known to lower BP
It acts by:
Inhibiting the transport of dopamineand NEinto
the storage granule
Causes depletionof neuronal stores of
Catecholaminesboth centrally and peripherally.
Major central side effect →depression
7/30/2024
16
1
Reserpine is an alkaloids obtained from
Rawoulfia spps.
originally used in psychiatry
Is known to lower BP
It acts by:
Inhibiting the transport of dopamineand NEinto
the storage granule
Causes depletionof neuronal stores of
Catecholaminesboth centrally and peripherally.
Major central side effect →depression
7/30/2024
16
1
END
7/30/2024
16
2
THANK
YOU
7/30/2024
16
2
THANK
YOU
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