L P 4 Drugs used for Heart Failure-final_٠٩٥٢٢٧ (1).pdf

Pharmacology

1. 1

2. Dr. Ahmed G. Al- Akydy

Pharmacology
ةيودأ ملع
Assoc. Prof.
Pharmacology & Therapeutics
Faculty of Medicine & Health Sciences
Thamar University

3. Drugs Used in Heart Failure

4. Learning Objectives
Upon completion of the lecture , the student will be able to:
1)Identify the common underlying etiologies of HF
2)List characteristics of digoxin in terms of effects on myocardial contractility and
cardiac conduction, indications for use, and principles of therapy.
3)Differentiate therapeutic effects of digoxin in HF and atrial fibrillation.
4)Differentiate digitalizing and maintenance doses of digoxin.
5)Identify therapeutic and excessive serum digoxin levels.
6)Identify individuals at risk for development of digoxin toxicity.
7)Discuss interventions to prevent or minimize digoxin toxicity.
8)Explain the roles of potassium chloride, lidocaine, atropine, and digoxin immune fab
in the management of digoxin toxicity.

5. Drug (s) Action
Diuretics, ACEIs, ARBs, venodilators ↓ preload 1)
ACEIs, ARBs, arteriodilators ↓ afterload 2)
+ve inotropic agents: digitals, β1-agonists, PDE III
inhibitors
↑ contractility 3)
ACEIs, ARBs, β- blockers, aldosterone receptor
antagonists
↓ remodeling of cardiac
muscle & mortality rates
4)
Definition: ―a complex progressive clinical syndrome that can result from any
structural or functional cardiac disorder that impairs the ability of the hear to meet
metabolic needs of the body.
Heart failure (HF)

6. ↓ the number of sacks on the wagon
Diuretics, ACE Inhibitors, venodilators
Limit the donkey‘s speed, thus
saving energy
ß-Blockers
Like the carrot placed in
front of the donkey
+ve inotropic agents

7. Mechanism of action
Cardiac positive inotropes
3)PDE inhibitors
oInamrinone (amrinone)
oMilrinone
1)Cardiac glycosides
oDigoxin
oDigitoxin
2)Sympathomimetic inotropic drugs
oDopamine
oDobutamine
oDopexamine

8. A.Cardiac glycosides (CGs): found in several plants like foxgloves (digitalis lanata
& purpurea) & in toad skin (Bufotoxin).
Chemistry
1)An aglycone (genin)
B.A lactone ring: (essential
for drug activity)
A.A steroid nucleus
Steroid & Sugar parts: determine potency & pharmacokinetic properties
2)Sugar (≥ 1
moieties)

9. Ca
++ ↑Ca
2+
Na
+
K
+
ATP

ADP + Pi

Out

In

Digitalis

Na
+
Na
+
/ Ca
++


exchanger
Voltage – sensitive
L type Ca
2+
channel
Na
+
/K
+
ATPase
Mechanism of action:
1)Positive inotropic effect (in myocardium): A membrane-bound enzyme (called
sodium pump)

↑Na
+
Ca
2+
2)Autonomic effects: inhibit Na+/K+ ATPase → ↑sensitivity of cardiac baroreceptors
→↑ vagal activity → ↓ HR → ↓myocardial O2 demand
3)In renal cells: inhibit Na+/K+ ATPase →↓ renal tubular reabsorption of Na+ → ↓
renin secretion →↓ aldosterone →↓ Na
+
& water retention → diuresis →further ↓
preload.
4)In the A-V node: ↓ conduction velocity → ↑ERP → ↑PR interval → used to treat
AF & other supraventricular arrhythmias.
↑FOC of myocardium ←
RyR2
troponin C

10. Pharmacological actions
A.Cardiac actions:
1)Myocardial contractility:
Digitalis → ↑FOC of the myocardium (high in HF) → complete emptying of the
ventricles during systole → ↑ CO →↓ pulmonary congestion & systemic venous
pressure
↓ diastolic volume →↓ muscle fibre length →↓ myocardium O2 demand
2)Heart rate:
In small doses: digitalis → ↑ vagal & ↓ sympathetic activities on the heart → ↓
HR
In toxic doses: digitalis → ↑sympathetic activity on the heart → ↑ HR
3)Automaticity & excitability:
At therapeutic levels: digitalis → ↑vagal action in atria & A–V node →
↓automaticity & ↑ resting membrane potential → bradycardia & A–V block
At higher levels: digitalis →↑ automaticity in cardiac tissue → atrial &
ventricular arrhythmias.
4)ECG effects:
Depressed ST segment, inverted T wave (‗reversed
tick‘(√), narrow QRS complex, & PR interval
prolongation, ↓ QT interval
B.Extracardiac effects: GI tract, Kidney (diuresis), &
CNS

11. Digoxin
Oral, IV Administration
Rapid (75%), delays by food Absorption
60- 80% (tablets) , 70 -85 (elixir)
Intestinal Eubacterium metabolizes & inactivates digoxin
→ ↓ bioavailability (in 10% of people)
Bioavailability
25% to plasma proteins & proteins of skeletal muscles →
plasma levels of ―free‖ drug variable from person to
person
Protein-bound
Wide (concentrated in the heart (20 times > plasma),
skeletal muscle, liver & kidney
Distribution
+ BBB passing
Rapid (20 min) Onset of action
2- 4 days DOA
Pharmacokinetics

12. Only 5–10% to inactive metabolites Metabolism
Renal: 70%, unchanged
Bile, P-gp, metabolism: 30%
Daily elimination: 35%
Excretion
1.5: in normal renal function → once-a-day dosing
3.5 – 5: in elderly & patients with renal failure → once a
day/alternate day
T½ (day)
Narrow → RFTs, serum Es & ECG should be monitored
during digitalis therapy esp. when changing of renal
function/or suspected toxicity/or after addition/or
subtraction of an interacting drug
Therapeutic index
0.5 - .8 ng/ mL Ideal therapeutic
Concentration
≥ 1.2 ng/ml Toxic concentration

13. Therapeutic uses:
1)Chronic CHF + atrial fibrillation (AF), & atrial flutter (Afl)
2)AF, Afl, other supraventricular tachycardia, EXCEPT, Wolff-Parkinson White
(WPW) syndrome

Side effects (digitalis toxicity):
1)Cardiac effects:
•Ventricular arrhythmias: premature ventricular beat (PVB), ventricular
tachycardia (VT) & ventricular fibrillation (VF).
•Atrial arrhythmias: paroxysmal atrial tachycardia (AT), AF, Afl
•Bradycardia & Partial to complete A–V nodal block
2)Extracardiac effects:
–Fatigue & sleeplessness: early
–GIT effects: anorexia, nausea, vomiting, abdominal pain & diarrhoea, d/t
stimulation of CTZ & an irritation on the gut, mesenteric VC — early
–CNS effects: headache, confusion, disorientation, hallucination, delirium, &
psychosis
–Visual disturbances: halos, photophobia, chromatopsia (red-green/or yellow-
green vision), diplopia, amblyopia, scotoma, d/t retrobulbar neuritis
–Others: skin rash, gynecomastia, galactorrhea — rare

14. Predisposing factors to digitals toxicity:
1)Electrolyte disturbances: Hypokalemia, Hypercalcaemia, Hypomagnesaemia
2)Hypothyroidism: d/t ↓metabolism & renal excretion of digitals
3)Drugs: Quinidine, verapamil & amiodarone, thiazide & loop diuretics
4)Others: hypoxia, renal & hepatic failure, myocarditis, elderly patients & IV
administration
Treatment of digitals toxicity:
1)Discontinue digitals & K -depleting drugs
2)Activated charcoal/or cholestyramine
3)KCI (IV/or orally) to correct hypokalemia
4)Antiarrhythmic drugs
Propranolol: orally/or IV, for supraventricular arrhythmias
Lignocaine (IV): the DOC for ventricular arrhythmias.
Phenytoin: in ventricular arrhythmia with heart block
Atropine (IV)/or temporary pacemaker: for bradycardia/or A–V nodal block
4)Digoxin immune FAB fragments (Digibind, DigiFab)
Given by IVI, bind circulating digitalis & ↑ their renal clearance → reverses
their toxicity within an hour in most cases.
Used only for patients with life-threatening toxicity

15. Contraindications
Relative Absolute
oBradycardia
oSystemic HTN
oPulmonary HTN d/t chronic lung disease
oAcute MI
oRenal failure & older age: digoxin
oHepatic diseases: digitoxin
oCardioversion: d/t fatal arrhythmia
oAV nodal heart block
oHypertrophic obstructive
cardiomyopathy (HOCM)
oWPW syndrome:
oPVT
Drug interactions
1)Pharmacokinetic interactions:
Drugs that ↑ intestinal motility (e.g., metoclopramide) → ↓digitals absorption
Drugs that ↓ intestinal motility(e.g., atropine) →↑ digitals absorption
Antacids, Kaolin, cholestyramine → bind digitals in gut → ↓ absorption.
Amiodarone, quinidine, verapamil, diltiazem, cyclosporine, itraconazole →
displace digoxin from plasma & tissue-binding sites & inhibit its elimination by P-
gp & kidney → ↑its plasma levels →↑ its toxicity
2)Pharmacodynamic interactions
Thiazide/loop diuretics, β-agonists, steroids) → hypokalemia→ ↑digoxin toxicity
β - Blocker/verapamil → additive depressant effect to digoxin on S–A & A–V
nodes → precipitate A–V nodal heart block.

16. B.Sympathomimetic inotropic drugs: dopamine, dobutamine, dopexamine
Used by IVI in acute HF with renal impairment, & in cardiogenic shock.
Side effects: tachycardia, ↑ BP & tolerance on prolonged use (b/c
downregulation of β1-receptors).
1)Dopamine (DA):
oLow doses (<2 mcg/kg/min) → stimulates D1receptors in the renal vasculature
→ VD → improve RBF → improve diuresis
oModerate doses (2- 10 mcg/kg/min) → stimulates β1-receptors on the heart →
+ve inotropic effect
oHigh doses (>10 mcg/kg/min) →stimulates a- receptors in the vasculature → ↑
afterload → exacerbates HF
2)Dobutamine:
•A relatively selective β1 agonist → +ve inotropic action
•T½ : 2 min., but its effect can be observed for several days – months.
•Initiated dose: 2.5- 5 mcg/kg/min, gradually titrated to 20 mcg/kg/min based on
clinical response
3)Dopexamine: stimulates β2 receptors in heart with a lesser effect on peripheral
D1 & D2 → + ve inotropic effect & ↑renal perfusion

17. C.Phosphodiesterase (PDE) inhibitors/or inodilators (Milrinone Enoximone,
Inamrinone):
Selectively inhibit PDE-3 in heart & smooth muscles of BVs & bronchi → ↑
cAMP →↑ intracellular Ca
2+
in myocardial cells → +ve inotropic &
chronotropic effects in the heart
Has VD actions →↓ preload & afterload
Used only IVI for short-term treatment of acute HF/or severe exacerbation of
chronic HF, d/t long –term use → ↑ mortality.
Adverse effects:
oNausea, vomiting, arrhythmias (both)
oThrombocytopenia & hepatotoxicity (less/no with milrinone).
D.Myofilament calcium sensitizers (Levosimendan, Pimobendan)
o↑ sensitivity of myocardial troponin C to Ca2+, & inhibit PDE-3 → ↑cardiac
contractility
oOpens ATP-dependent K+ channels in vascular smooth muscle cells →↓preload
& afterload.
oUsed as IV, for the short--term treatment of acutely decompensated HF →
Improves symptoms, but not survival rate.

18. E.Other drugs
1)Vasodilators
ISDN/hydralazine
Nesiritide
oA recombinant brain natriuretic peptide (BNP), given by continuous IVI.
oActivates GC→↑ cGMP → VD →↓ preload & afterload
oAlso suppresses RAS & SNS → ↑ water & Na excretion
oImproves symptoms of refractory CHF for short- term
ARNI (sacubitril +valsartan)
oSacubitril: an orally prodrug, inhibit neprilysin enzyme →↓ degradation of
endogenous ANP, BNP → VD, natriuresis & diuresis.
oUsed (+ valsartan) in advanced HFrEF (↓ the incidence of death, ↓ in
hospitalization & acute decompensation)
2)Ivabradine
3)Antidiabetic drugs
SGLT2 Inhibitors (empagliflozin, canagliflozin): inhibit renal tubular glucose
reabsorption →↓ BG & diuresis →↓ preload → used primarily in type 2 DM, & also
↓ hospitalization for patients with HFrEF
GLP-1 agonist (liraglutide): ↓hospitalization of patients with HF
4)Tolvaptan: an orally active vasopressin V2 receptor antagonist, ↓ water retention &
hyponatraemia in patients with ‗inappropriate ADH secretion syndrome, & in those
with advanced CHF(useful for short- term).