chemistry of glycosides

1. TREATMENT OF
CONGESTIVE HEART
FAILURE (CHF)
DIGITALIS GLYCOSIDES AND
OTHER POSITIVE INOTROPIC
AGENTS

2. Common Diseases
Contributing to CHF
- Cardiomyopathy
 Hypertension
 Myocardial ischemia & infarction
 Cardiac valve disease
 Coronary artery disease

3. CliniCal Features oF
CHF
 Reduced force of
cardiac contraction
 Reduced cardiac
output
 Reduced tissue
perfusion
 Oedema (congestion)
 Increased peripheral
vascular resistance

4. Congestive Heart Failure
events

5. CARDIOTONIC DRUGS
Cardiac Glycosides
 Mechanism of the beneficial positive
inotropic pharmacodynamic effect
 The principal beneficial effect of digitalis in
CHF is the increase in cardiac contractility
(+ve inotropism) leading to the following:
o inCreased CardiaC output
o deCreased CardiaC size
o deCreased venous pressure and blood
volume
o diuresis and relieF oF edema

6. Molecular mechanism of the +ve
inotropic effect
 Inhibition of the Na+
-K+
- pump (Na+
-K+
-ATPase) on the
cardiac myocyes sarcolemma
 A gradual increase in intracellular Na+
([Na+
]i) and a
gradual small fall in [K+
]i
 An inhibitory effect on the non-enzymatic Na+
- Ca2+
-
exchanger, which exchanges extracellular Na+
for
intracellular Ca2+
 The net effect is the increase in intracellular Ca2+
[Ca2+
]I
 The increased [Ca2+
]I stimulates more Ca2+
ions to influx
via voltage gated Ca2+
channels and increase the
storage of Ca2+
into sarcoplasmic reticulum available for
release upon arrival of an action potential

7. Sodium pump inhibition by cardiac
glycosides
 The mechanism by which the cardiac glycosides
induce a positive inotropic effect in cardiac muscle is
based on the specificity of these drugs for Na+
K+
-
ATPase (the “sodium pump”)
Digoxin

8. The direction & magnitude of Na+
& Ca2+
transport during depolarized myocyte
(systole)
 The exchanger may
briefly run in reverse
during cell
depolarization when
the electrical gradient
across the plasma
membrane is
transiently reversed
 The capacity of the
exchanger to extrude
Ca2+
from the cell
depends critically on
the intracellular Na+
concentrations

9. Baroreceptor Dysfunction
 Baroreceptor
dysfunction may account
for increased
sympathetic & reduced
parasympathetic
nervous system activity
in most patients with
congestive heart failure

10. Pharmacological Actions
of Digitalis Glycosides
 Inotropism. Digitalis exerts positive inotropic effect
both in the normal and failing heart via inhibition of
Na+
-K+
-ATPase at cardiac sarcolemma.
Cardiac output (CO)
 Digitalis increases the
stroke volume and hence
the CO
 No increase in oxygen
Consumption
 Decreased EDV

11. Heart rate
 Cardiac glycosides slow the accelerated heart rate in
CHF via two mechanisms:
 A direct extravagal effect & an indirect vagal effect
leading to:
• Slowing of SA nodal firing rate
• Slowing of the AV conduction and prolongation of the
refractory period of the AV node
 The indirect vagal tends to increase the vagal tone to
the heart through:
• Enhancement of the sensitivity of the SA node to vagal
stimulation resulting in diminished firing rate.
• Stimulation of the vagal central nuclei

12. Myocardial
Automaticity/Conductivit
y
 SA nodal firing rate and AV conduction are slowed
down by the direct and indirect mechanisms
 Prolongation of the effective refractory period of
the A-V node
 At high doses, automaticity is enhanced as
result of the gradual loss of the intracellular K+

13. Venous Pressure
 Venous pressure is increased in CHF
 Digitalis reduces venous pressure as a result of
improved circulation and tissue perfusion
produced by the enhanced myocardial
contractility (decreased blood volume)
 This in turn relieves congestion
 Ventricular end-diastolic volume (VEDV) is
reduced

14. Diuresis
 Digitalis causes relief of CHF-induced edema
 This depends on the improved CO that increases
renal blood flow & consequently glomerular
filtration rate is increased
 This results in down-regulation of the renin-
angiotensin-aldosterone (RAA) system that is
stimulated in CHF
 Hence, the edema (pulmonary and peripheral)
is improved in response to digitalis as a result of
the inhibition of the RAA-induced water and salt
retention

15. Therapeutic Uses of
Digitalis Glycosides
 Treatment of congestive heart failure
which does not respond optimally to
diuretics or ACEI.
 Treatment of atrial fibrillation and flutter
by slowing SA nodal firing rate as well as
AV conduction preventing the occurrence
of the life-threatening ventricular
arrhythmias

16. Adverse Effects of
Digitalis Glycosides
Ventricular Arrhythmias
 With increasing cardiac glycoside concentrations, free
intracellular [Ca2+
]I reaches toxic levels
 This high [Ca2+
]I concentration saturates the sarcoplasmic
reticulum sequestration mechanisms resulting in
oscillations in [Ca2+
]I levels due to Ca2+
-induced [Ca2+
]I
release leading to membrane potential oscillations
(oscillatory after potentials)
 Arrhythmias resulting from oscillatory after potentials
include single and multiple ventricular premature beats
and tachy-arrhythmias

17. Adverse Effects of
Digitalis Glycosides
CNS side-effects
 Stimulation of the vagal
centre and chemoreceptor
trigger zone (CTZ) results
in nausea, vomiting,
diarrhea & anorexia
 Other CNS effects include
blurred vision, headache,
dizziness, fatigue, and
hallucinations
Gynecomastia
 Gynecomastia may
occur in men either due
to peripheral esterogenic
actions of cardiac
glycosides or
hypothalamic stimulation

18. TreaTmenT of DigiTalis
ToxiciTy
 Digitalis should be immediately withdrawn, toxicity
symptoms may persist for some time due to slow elimination
 K+
Supplementation, Digitalis treatment usually results in
myocardial K+
loss
 Hence, intravenous administration of K+
salts usually
produces immediate relief, since K+
loss is the probable
cause of dysrhythmias
 K+
supplementation would raise the extracellular K+
decreasing the slope of phase-4 depolarization and
diminishing increased automaticity
 However K+
supplementation may lead to complete A-V
block in cases of depresses automaticity or decreased
conduction (contraindicated with digitalis-induced second-
and third-degree heart block)
 Lidocaine or phenytoin is effective against K+
digitalis-
induced dysryhthmias

19. Digoxin-specific Fab
fragments
 Digoxin-specific Fab fragments are used safely for
the treatment of the life-threatening cardiac glycosides-
induced arrhythmias and heart block
 Digoxin-specific Fab fragments are produced by
purification of antibodies raised in sheep by
immunization against digoxin
 The crude antiserum from sheep is fractionated to
separate the IgG fraction, which is cleaved into Fab
and Fc fragments by papain digestion
 The Fab fragments are not antigenic and with no
complement binding
 They are excreted fairly rapidly excreted by the kidney
as a digoxin-bound complex

20. Selective ß1- Adrenergic
Agonists
 Dobutamine (and dopamine), at doses equal to or less
than 5 µg/kg/min, has a selective ß1- adrenergic agonistic
activity
 Beneficial effects in emergency treatment of acute CHF
include the following:
o 1- Increased cardiac output as a result of enhanced
contractility without appreciably altering the heart rate.
o 2- Reduction of mean arterial blood pressure.
o 3- Lowering of the total peripheral vascular resistance and
consequently decreasing the afterload
o 4- Reduction of ventricular filling pressure
o MOLECULAR MECHANISM OF INOTROPIC EFFECT OF
DOBUTAMINE?

21. PhosPhoDiesTerase iii (PD-
iii) inhibiTors
 Inhibition of myocardial phosphodiesterase III
(PD-III), the enzyme responsible for c.AMP
degradation, results in +ve inotropism via
c.AMP-PKC cascade in a similar way to the
selective ß1- adrenergic agonists
 Agents in this class include: Amrinone, and
milrinone
 PD-III inhibitors are suitable only for acute CHF
because they can induce life-threatening
arrhythmias on chronic use

22. OTHER DRUGS OF USE IN CHF
WITHOUT INOTROPIC EFFECT
Diuretics
 Diuretics cardiac preload by inhibiting sodium
and water retention
 Cardiac pumping improves with the consequent
reduction in venous pressure relieving edema
 Thiazide (e.g., hydrochlothiazide) and loop
diuretics (e.g., frusemide) are routinely used in
combination with digitalis
 Potassium-sparing diuretics can be concurrently
used to correct hypokalemia
o Spironolactone+Digitalis+ACEI clinical trials:
improved survival?

23. Angiotensin Converting
Enzyme Inhibitors
(ACEIs)
Captopril, ACEIs

24. LOCATION FUNCTION
Kidney
Glomerulus Mesangial cell contraction
Proximal tubule Increased reabsorption of sodium
Juxtaglomerular apparatus Decreased renin secretion
Heart Inotropic effect and release of growth factors with
ensuing stimulation of cardiac myocyte
hypertrophy and increased extracellular matrix
production
Blood vessels Vasconstriction with an increase in afterload as
well as local release of growth factors
Adrenal gland Aldosterone and catecholamine release
Brain Vasopressin release, stimulation of thirst;
autonomic activity and cardiovascular reflexes
Sympathetic nervous system Increased sympathetic outflow
Angiotensin II Type-1 Receptor Antagonists (ARBs)
Physiologic functions of AT1 receptors according to their location

25. Effect of ACEIs on
Bradykinin

26. Angiotensin Converting
Enzyme Inhibitors
(ACEIs)
 the use of ACEIs produces the following actions:
 1. Reduced sympathetic nervous system tone
 2. Increased vasodilator tone of vascular smooth muscle
and hence total vascular resistance falls promptly via:
• Decreased circulating AngII
• Increased bradykinin
• Decreased catecholamines
 3. Reduced sodium and water retention as a result of the
reduced AngII-induced reduced aldosterone secretion
 Ultimately both preload and afterload are reduced
 Clinical trials showed that the use of ACEIs in CHF has
significantly reduced morbidity and mortality

27. Adverse Effects of ACEIs
 1. Postural hypotension
 2. Hyperkalemia
 3. Renal insufficiency
 4. Persistent dry cough
 5. ACEIs are contraindicated in pregnancy
 ACEIs include agents like: captopril, enalapril,
lisinopril and many others

28. AT-1 Receptor Blockers
(ARBs)
 Agents include: losartan and valsartan
 They are recently approved for treatment of CHF
 They have the same beneficial effect of ACEIs
 They don’t cause cough

29. AT-1 Receptor Blockers
(ARBs)
 ARBs have the same side-effects like ACEIs except
they don’t cause cough

30. Nitrovasodilators
 Sodium nitroprusside i.v. infusion is used at a
dose of 0.1-0.2 µg/kg/min only in acute CHF
to lower preload and afterload
 Nitrates can be used as well to decrease
preload