Cardio-tonic drugs and cardiac glycosides

Question 1

Cardio-tonic drugs
• ————— drugs (also called “cardiotonic drugs”)
• Enhance cardiac function by 4 ways:

Answer 1

Cardio-tonic drugs
• Cardiostimulatory drugs (also called “cardiotonic drugs”)
• Enhance cardiac function by
– increasing heart rate (chronotropy)
– myocardial contractility (inotropy),
– May increase electrical conduction (dromotropy) within the heart and
– augment relaxation (lusitropy).

Question 2

Cardio-tonic drugs
– chronotropy:
– inotropy:
–dromotropy:
– lusitropy:

Answer 2

Cardio-tonic drugs
– chronotropy: increasing heart rate
– inotropy: myocardial contractility
–dromotropy: May increase electrical conduction within the heart
– lusitropy:augment relaxation

Question 3

Cardio-tonic drugs
• The cardiac effects of these drugs make them suitable for
———
———
———

Answer 3

Cardio-tonic drugs
• The cardiac effects of these drugs make them suitable for
– Heart failure
– Cardiogenic shock and
– hypotension.

Question 4

Treatment of Heart Failure
To Improve contractility: Positive inotropes
i)
ii)
iii)

To reduce odema:

To reduce preload & after load:

Answer 4

Treatment of Heart Failure
To Improve contractility: Positive inotropes
i) Cardiac Glycosides
i) B, agonists-* Dobutamine, Dopamine ii) PDE inhibitors-* Amrinone, Milrinone

To reduce odema:
Diuretics - Thiazide & Frusemide

To reduce preload & after load: ACE inhibitors

Question 5

Classes of Cardiostimulatory Drugs
•
•
•
•

Answer 5

Classes of Cardiostimulatory Drugs
• Beta-agonists
• Digitalis compounds
• Phosphodiesterase inhibitors PDEI
• Calcium sensitizers

Question 6

Beta-agonists
• Beta-agonists are sympathomimetic drugs that bind to beta-adrenoceptors located in ————, the ————, and ————.
• β1 receptors induces
– positive ————,
– ——— output of the cardiac muscle, leading to increased heart rate and blood pressure,
– secretion of ——— from the stomach, and
– ——— release from the kidneys.
• β2 receptors
– induces smooth muscle relaxation in the ———, ———, ———, and various ———
– increases ——— and —— contraction.
• β3 receptors
– are mainly located in ———
– It induces the metabolism of ———.

Answer 6

Beta-agonists
• Beta-agonists are sympathomimetic drugs that bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes.
• β1 receptors induces
– positive inotropic,
– chronotropic output of the cardiac muscle, leading to increased heart rate and blood pressure,
– secretion of ghrelin from the stomach, and
– renin release from the kidneys.
• β2 receptors
– induces smooth muscle relaxation in the lungs, gastrointestinal tract, uterus, and various blood vessels
– increases heart rate and heart muscle contraction.
• β3 receptors
– are mainly located in adipose tissue.
– It induces the metabolism of lipids.

Question 7

Beta-1 adrenergic receptor agonists
• β1 agonists: stimulates ——— activity; opening of ——— channel. Causing ——— stimulation;
– used to treat——— ,——— , ———-.
• Selected examples are:
–,
–
– (β1 and β2)
–
– (non-selective)

Answer 7

Beta-1 adrenergic receptor agonists
• β1 agonists: stimulates adenylyl cyclase activity; opening of calcium channel. Causing cardiac stimulation;
– used to treat cardiogenic shock, acute heart failure, bradyarrhythmias.
• Selected examples are:
– Dobutamine,
– Dopamine
– Isoproterenol (β1 and β2)
– Xamoterol
– epinephrine (non-selective)

Question 8

Beta-adrenergic receptor agonist MOA

Answer 8

Mechanism of action:
Acts on B1 -adrenoceptor
Increase cAMP
Activates protein kinase
activates sarcolemmal calcium channel
Increase cardiac contractility

Question 9

Dopamine
MOA at high and low doses

Answer 9

At moderate doses:
Acts on the beta-1 receptor at moderate dose
Increase force of construction
Increase cardiac output

At low dose:
At low dose act on D1 R-renal vasodilatation
Increase renal blood flow
So it’s a drug of choice

At high dose:
Arrhythmia develops

Question 10

Dopamine has a long half life T or F

Answer 10

F

Question 11

Dopamine
Very short half life(———), due to metabolism by —— . So, we have to give via ———-

1-5ugm/kg/min - good —— effect
>5ugm/kg/min - ——- effect —> increase ———

Answer 11

Dopamine
Very short half life(2-3 minutes ), due to metabolism by COMT. So, we have to give in IV infusion

1-5ugm/kg/min - good beta effect
>5ugm/kg/min - alpha 1 effect —> increase peripheral resistance

Question 12

Dobutamine
• Act on beta 1 receptor
• increase ———- without increase in ———
• So, decrease ———.

Answer 12

Dobutamine
• Act on beta 1 receptor
• increase force of contraction without increase in Heart rate
• So, decrease cardiac workload

Question 13

Phosphodiesterase inhibitors PDEI
• These drugs mimic ——— stimulation and increase ———.
• are used clinically for (short/long?)-term treatment of ———
• Examples:

Answer 13

Phosphodiesterase inhibitors PDEI
• These drugs mimic sympathetic stimulation and increase cardiac output.
• are used clinically for short-term treatment of cardiac failure
• Examples
– Amrinone
– Milrinone
– Enoximone.

Question 14

Phosphodiesterase inhibitors
• Mechanism of action

Answer 14

Inhibit enzymes that hydrolyzes cAMP
Increase intracellular cAMP
Activates protein kinase
activates sarcolemmal calcium channel
Increase cardiac contractility

Question 15

Phosphodiesterase inhibitors
MOA in vessels

Answer 15

Phosphodiesterase inhibitors
MOA in vessels
In Vessels
- increase cAMP in arterial and venous smooth muscle
• vasodilatation -> decrease peripheral resistance - > decrease Afterload
• Venodilatation -> venous capacitance > increase venous return -> decrease Preload
(the combination of (+ Ve)chronotropic & mixed arterial &venous dilatation leads to PDEi as inodilator)

Question 16

the combination of (+ Ve)chronotropic & mixed arterial &venous dilatation leads to PDEi as———

Answer 16

inodilator

Question 17

Calcium sensitizing drugs
• Calcium sensitizing drugs represent the newest class of cardiostimulatory drugs.
• These drugs increase the sensitivity of ——— for calcium so that more calcium becomes bound to ———, which enhances contractility.
• At present, these drugs are under clinical investigation for ———, and therefore not yet approved.

Answer 17

Calcium sensitizing drugs
• Calcium sensitizing drugs represent the newest class of cardiostimulatory drugs.
• These drugs increase the sensitivity of troponin-C for calcium so that more calcium becomes bound to troponin-C, which enhances contractility.
• At present, these drugs are under clinical investigation for heart failure, and therefore not yet approved.

Question 18

Cardiac glycosides
• Cardiac glycosides are organic compounds containing a ——— (sugar) that act on the ——— of the cardiac muscle.
• Important class of naturally occurring drugs whose actions include both ——— and ——— effects on the heart.

Answer 18

Cardiac glycosides
• Cardiac glycosides are organic compounds containing a glycoside (sugar) that act on the contractile force of the cardiac muscle.
• Important class of naturally occurring drugs whose actions include both beneficial and toxic effects on the heart.

Question 19

Cardiac glycosides
• Found as ——— metabolites in several plants, but also in some insects, such as the ————.
• From ancient times, humans have used cardiac-glycoside-containing plants and their crude extracts as ———-, ——— or ——— aids, rat poisons, heart tonics, diuretics and emetics.

Answer 19

Cardiac glycosides
• Found as secondary metabolites in several plants, but also in some insects, such as the milkweed butterflies.
• From ancient times, humans have used cardiac-glycoside-containing plants and their crude extracts as arrow coatings, homicidal or suicidal aids, rat poisons, heart tonics, diuretics and emetics.

Question 20

Examples of plants producing cardiac glycosides

Answer 20

• Cardenolide type:
– Digitalis lanata and Digitalis purpurea – digoxin, digitoxin
– Strophanthus – Ouabain g/k/e-strophanthin
– Nerium oleander - oleandrin
– Lily of the Valley (Convallaria majalis)
– Antiaris toxicaria
– Asclepias sp.
– Calotropis gigantea

• Bufadienolide type:
– Drimia maritima
– Kalanchoe daigremontiana and other Kalanchoe species
– daigremontianin and others

Question 21

Digitalis lanata - ——
Digitalis purpurea – ——

Answer 21

Digitalis lanata - digoxin
Digitalis purpurea –digitoxin

Question 22

Strophanthus –

Answer 22

Ouabain

Question 23

Chemistry of cardiac glycosides
• All of the glycosides - of which ——— is the prototype –
• combine a
– ——- nucleus linked to an unsaturated — membered lactone ring at the — position
– and a series of sugars at carbon — of the nucleus.

Answer 23

Chemistry of cardiac glycosides
• All of the glycosides - of which digoxin is the prototype –
• combine a
– steroid nucleus linked to an unsaturated 5
membered lactone ring at the 17 position
– and a series of sugars at carbon 3 of the nucleus.

Question 24

Chemistry of cardiac glycosides
• All of the glycosides - of which digoxin is the prototype –
• combine a
– steroid nucleus linked to an ——- 5
membered ——- ring at the 17 position
– and a series of ——- at carbon 3 of the nucleus.

Answer 24

Chemistry of cardiac glycosides
• All of the glycosides - of which digoxin is the prototype –
• combine a
– steroid nucleus linked to an unsaturated 5
membered lactone ring at the 17 position
– and a series of sugars at carbon 3 of the nucleus.

Question 25

Chemistry of cardiac glycosides • Because they lack an easily ——- group, their solubility is not —— dependent. • Steroid nucleus with lactone ring is essential for ———.

Answer 25

Chemistry of cardiac glycosides • Because they lack an easily ionizable group, their solubility is not pH dependent. • Steroid nucleus with lactone ring is essential for myocardial action.

Question 26

CVS effect of Cardiac Glycosides in Heart Failure include

Answer 26

• Mechanical and Electrical effect • (+ve) inotropic. • (-ve) chronotropic • →Binding to Na pumps in the plasma membrane of central & peripheral nervous system → (-) of symp.

Question 27

CVS effect of Cardiac Glycosides • its positive inotropic action results in, – a. – b. – c. – d. – e.

Answer 27

CVS effect of Cardiac Glycosides • its positive inotropic action results in, – a. increased cardiac output – b. decreased heart size – c. decreased venous pressure – d. decreased circulating blood volume – e. diuresis and relief of oedema

Question 28

Electrical activity of Cardiac Glycosides • • • •

Answer 28

Electrical activity of Cardiac Glycosides • ↓ automaticity of SA node indirectly • ↑ Refractory period of the AV node • ↓Condution Velocity at the AV nodal Tissue • Stimulate vagal Nerve

Question 29

Therapeutic Uses of Digitalis Compounds • Heart Failure – – – – • Arrhythmias – –

Answer 29

Therapeutic Uses of Digitalis Compounds • Heart Failure – ↑ inotropy – ↑ ejection fraction – ↓ preload – ↓ pulmonary congestion/edema • Arrhythmias – ↓ AV nodal conduction (parasympathomimetic effect) – ↓ ventricular rate in atrial flutter and fibrillation

Question 30

Contraindication of Digitalis

Answer 30

Contraindication • Ventricular Tachycardia - because digitalis increase automaticity especially at high doses • Heart block.

Question 31

Mechanisms of action of digitalis

Answer 31

Mechanisms of action • Inhibits the Na+/K+-ATPase, which is responsible for Na+/K+ exchange across the muscle cell membrane;increase [Na+]in; increase [Ca2+]in; increase force of myocardial contraction. • Digoxin and K+ ions compete for a “receptor” (Na+/K+-ATPase) on the external membrane. • So, the effects of digoxin may be dangerously increaseed by hypokalemia, produced, for example, by diuretics.

Question 32

• Digoxin and — ions compete for a “receptor” (Na+/K+-ATPase) on the external membrane. • So, the effects of digoxin may be dangerously increaseed by ———, produced, for example, by ———.

Answer 32

• Digoxin and K+ ions compete for a “receptor” (Na+/K+-ATPase) on the external membrane. • So, the effects of digoxin may be dangerously increaseed by hypokalemia, produced, for example, by diuretics.

Question 33

Cardiac Glycosides • Mechanism of Action:

Answer 33

Cardiac Glycosides •Selective inhibitor of the plasma membrane sodium pump. • Mechanism of Action: -Inhibits Na*/K+ ATPase pump - increase Intracellular Na+concentration -Inhibits Na*/Ca2+ exchangers - decreases Calcium efflux from the cell - increases Intracellular calcium - increases Cardiac Contractility

Question 34

———- is the Selective inhibitor of the plasma membrane sodium pump.

Answer 34

Cardiac glycosides

Question 35

Pharmacokinetics • absorption of digoxin after oral administration ranging from — to —%. • absorption can be retarded by, – a. – b. – c. – d. – e.

Answer 35

Pharmacokinetics • absorption of digoxin after oral administration ranging from 40-90%. • absorption can be retarded by, – a. the presence of food in the GIT – b. delayed gastric emptying – c. malabsorption syndromes – d. antibiotics, such as neomycin – e. steroid binding resins

Question 36

A. Drug: digoxin 1.) Oral Availability: 2.) Half-life (hours): 3.) Elimination: B. Drug: digitoxin 1.) Oral Availability: 2.) Half-life (hours): 3.) Elimination: C. Drug: ouabain 1.) Oral Availability: 2.) Half-life (hours): 3.) Elimination:

Answer 36

A. Drug: digoxin 1.) Oral Availability: 75% 2.) Half-life (hours):40 3.) Elimination:kidneys B. Drug: digitoxin 1.) Oral Availability: >90% 2.) Half-life (hours):160 3.) Elimination:liver C. Drug: ouabain 1.) Oral Availability: 0% 2.) Half-life (hours):20 3.) Elimination:kidneys

Question 37

A.) Digoxin 1.) lipid solubility: 2.) oral bioavailability : 3.) route: 4.) Distribution: 4.) PPD: 5.) Metabolism: 6.) Excretion: 7.) Half life concert: 8.) onset:

Answer 37

A.) Digoxin 1.) lipid solubility: Less than digoxin; OH group- 2 2.) oral bioavailability : 75% 3.) route:oral 4.) Distribution: less 4.) PPD:less 5.) Metabolism: Partly in the liver 6.) Excretion: Mainly by kidney 7.) Half life concert: 36 hours 8.) 15-20 mins

Question 38

A.) Digitoxin 1.) lipid solubility: 2.) oral bioavailability : 3.) route: 4.) Distribution: 4.) PPD: 5.) Metabolism: 6.) Excretion: 7.) Half life concert: 8.) onset:

Answer 38

A.) Digitoxin 1.) lipid solubility: More Lipid soluble; OH group- 1 2.) oral bioavailability : 80-90% 3.) route:oral 4.) Distribution: more 4.) PPD:more 5.) Metabolism: mainly liver 6.) Excretion: by bile & stool 7.) Half life concert: 7 days 8.) onset:25-120min

Question 39

A.) ouabin 1.) lipid solubility: 2.) oral bioavailability : 3.) route: 4.) Distribution: 4.) PPD: 5.) Metabolism: 6.) Excretion: 7.) Half life concert: 8.) onset:

Answer 39

A.) ouabin 1.) lipid solubility: H20 soluble; OH group- 5 2.) oral bioavailability :poor 3.) route:perenteral 4.) Distribution: poor 4.) PPD:negligible 5.) Metabolism: not metabolized 6.) Excretion: unchanged by the kidney 7.) Half life concert:24 hrs 8.) onset:immediate

Question 40

Adverse effects of digitalis can be divided into?

Answer 40

Adverse effect • 1.Extracardiac 2.Cardiac effect

Question 41

Adverse effect of glycosides •1.Extracardiac • On GIT→ • Neurological problems • Due to steroid nucleus - ——— in male Adverse effect • 2.Cardiac effect: • i) • ii)

Answer 41

Adverse effect 1.Extracardiac • On GIT→ Anorexia, nausea,vomiting Fatigue ,weakness, diarrhoea • Neurological problems -Blarring of vision, confusion 􏰀 • Due to steroid nucleus - gynaecomastia in male • 2.Cardiac effect: • i)All type of arrythmia (↑ Automaticity in high dose) • ii) Slowing A-V nodal Conduction- Bradycardia Heart block

Question 42

Drug interaction Pharmacodynamic interaction •——— + ——= ↓ AV Conduction -Heart Block • ———+ ——-= ↓ AV Conduction –Heart Block • ———-+———-= cause K+ loss

Answer 42

Drug interaction Pharmacodynamic interaction • B –blocker + digoxin= ↓ AV Conduction -Heart Block • Verapamil+ digoxin= ↓ AV Conduction –Heart Block • Digitalis+ Diuretics(Thiazide/Frusemide)= cause K+ loss

Question 43

Drug interaction Pharmacodynamic interaction • B –blocker + digoxin= ———&——— • Verapamil+ digoxin= ———-&———— • Digitalis+ Diuretics(Thiazide/Frusemide)= cause ———-

Answer 43

Drug interaction Pharmacodynamic interaction • B –blocker + digoxin= ↓ AV Conduction -Heart Block • Verapamil+ digoxin= ↓ AV Conduction –Heart Block • Digitalis+ Diuretics(Thiazide/Frusemide)= cause K+ loss

Question 44

Drug interaction • Pharmacokinetic interaction • ———+ ——— →↑ plasma digitalis conc. by competing with digoxin for renal excretion →↑conc. of digoxin →toxicity • ———+——— = displace digitalis from tissue binding site→↑conc. of digitalis →↑toxicity

Answer 44

Drug interaction • Pharmacokinetic interaction • Verapamil+ digoxin • Digitalis+Quinidine

Question 45

Drug interaction • Pharmacokinetic interaction • Verapamil+ digoxin→↑ plasma digitalis conc. by competing with digoxin for ———- →↑conc. of digoxin →toxicity • Digitalis+Quinidine= displace ——- from ——- site→↑conc. of digitalis →↑toxicity

Answer 45

Drug interaction • Pharmacokinetic interaction • Verapamil+ digoxin→↑ plasma digitalis conc. by competing with digoxin for renal excretion →↑conc. of digoxin →toxicity • Digitalis+Quinidine= displace digitalis from tissue binding site→↑conc. of digitalis →↑toxicity

Question 46

Toxicity • ——— is earliest symptom • ——— is earliest sign ( if <—b/min, digitalis not given) • Low TI- — to — nmol/L

Answer 46

Toxicity • Anorexia is earliest symptom • Bradycardia is earliest sign ( if <60 b/min, digitalis not given) • Low TI- 1-2.6nmol/L

Question 47

Toxicity • Treatment: Rx is different in 2 different condition • (i) • ii) Monitor — level( if ——- administer K+, IV KCL • (iii) If atrial arrythmia - digoxin not given because it ——— —use —— which decrease ——— but not slow ———- • (iv) If ventricular arrythmia- ——— given, it does not slows AV nodal conduction • (v) If heart block – give ——- to increase —

Answer 47

Toxicity • Treatment: Rx is different in 2 different condition • (i) Stop the drug • ii) Monitor K+ level( if hypokalemia administer K+, IV KCL • (iii) If atrial arrythmia - digoxin not given because it slows AV nodal conduction—use phenytoin which decrease arrythmia but not slow AV nodal contraction. • (iv) If ventricular arrythmia- lignocaine given, it does not slows AV nodal conduction • (v) If heart block – give atropine to increase HR

Question 48

Hypokalemia • And digoxin has higher affinity for the ———— form. • K+ and digitalis, interact in two ways- • First – • Second –

Answer 48

Hypokalemia • And digoxin has higher affinity for the phosphorylated form. • K+ and digitalis, interact in two ways- • First – hypokaelamia causes – increases the myocardial localization of digoxin. – reduction in extracellular K+, – Cause increased phosphorylation of Na pump. • Second – abnormal cardiac automaticity is inhibited by hyperkalemia.

Question 49

• Effect of other electrolytes imbalance on digoxin use – • Causing toxicity – ———-, – ———-

Answer 49

• Effect of other electrolytes imbalance on digoxin use – • Causing toxicity – Hypercalcaemia Ca++, – Hypomagnesaemia Mg++

Question 50

Hypercalcemia • Ca++ facilitates the ——— actions of cardiac glycosides by accelerating the overloading of intracellular Ca++ stores that appears to be responsible for —————-. • Hypercalcemia therefore increases the risk of ———— arrhythmia.

Answer 50

Hypercalcemia • Ca++ facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular • Ca++ stores that appears to be responsible for digitalis-induced abnormal automaticity. • Hypercalcemia therefore increases the risk of digitalis induced arrhythmia.

Question 51

Hypomagnesaemia • Decreased Mg++ concentration does not enhance toxicities of cardiac glycosides. T or F

Answer 51

F Hypomagnesaemia • Decreased Mg++ concentration enhances toxicities of cardiac glycosides.

Question 52

Toxicity – Use of Antidote • If patient still refractory to treatment – • Antidotes to digoxin – ————- or – —————(also called ——-) given to remove excess digoxin from the body.

Answer 52

Toxicity – Use of Antidote • If patient still refractory to treatment – • Antidotes to digoxin – monoclonal antibody (Fab fraction) or – digoxin binding specific antibody (digibind) given to remove excess digoxin from the body.