Exam 2 - Medchem 753, Stevens Inotropics Flashcards
What effects are seen during cardiac failure?
Inability of heart to pump blood effectively - Force of contraction of Cardiac Muscle - dec CO; dec BP; Dec Renal Q Edema in legs/Lungs Renal failure
What is the action of all positive Inotropes?
They affect the availability of intracellular Ca or inc sensitivity of contractile proteins
What is the basic action of cardiac steroids?
inhibit the Na/K ATPase
What is the basic action of Phospodiesterase inhibitors?
Block cAMP degradation
- inc [cAMP]; activating cAMP dependent protein kinases
- stimulate Ca influx through VG channels,
- inc release and reaccumulation of CA in SR
What is the basic action of Ca2+ sensitivity stimulants
Inc the effect of existing Ca2+ levels
What is the basic action of B-adrenergic agonists?
Leads to inc cAMP production, more forceful contractions due to inc calcium presence
How are cardiac steroids different from other average steroids?
They are characterized by their 5B, 14B stereochemistry, which results in a curved, or convexely shaped molecule
What are the 2 different groups of cardiac steroids?
- Cardenolides
2. Bufadienolides
Cardenolides
- Origin
- Chemical structure
- Plant Origin
2. C-17R group is an alpha-B-unsaturated butyrolactone
Bufadienolides
- Origin
- Chemical structure
- Found in Toad Skin
2. C-17R group is a Pyrrone Ring
Most cardiac sterols naturally occur as ______ and have approximately ______ sugars attached where?
Glycosides
1-4 sugars
3B-OH of steroid
Digitalis Purpurea
Flox Glove (purple), it is the commercial source of digitoxin
Digitalis lanata
Woolly foxglove (white) commercial source of digoxin
in 1785, Digitalis leaves were used to treat several things including swelling. What were some remarkable side effects of the drug?
Yellow Vision
Nausea
What kept most physicians from using digitalis preparations until the 1900s?
Narrow therapeutic index
What site difference between digitoxigenin, Digoxigenin and Gitoxigenin makes the large pharmacological difference in their chemistry?
12-OH (Digoxin)
12-H (Digitoxin)
16-OH (gitoxigenin); pharmaceutically irrevelevant
What is the main cardiac glycoside found in Digitalis Lanata leaves?
Lanatoside C
How is Digoxin extracted from Digitalis leaves?
Lantoside C is treated w/ Bglucosidase, to form acetyldigoxin, which is then treated with NaOH and neutrialized with Ch3COOH to become digoxin
Inhibition of Na/K-ATPase has what effect on calcium levels?
Increased intracellular Na levels –> increased release of Ca from intracellular stores
Why is simultaneous treatment of Lasix and Digoxin dangerous?
Lasix lowers extracellular K levels, which increases phosphorylation and eventually the binding affinity of Digoxin
What is the result of coadministration of Digoxin and Erythromycin?
Erythromycin kills microbes that would otherwise help metabolize orally available digoxin, increasing the amount of Digoxin available.
What neuro-hormonal effect does Digoxin have in CHF patients?
Inc Parasympathetic (vagal activation) and decreased sympathetic activity
What is the preferred cardiac glycoside for CHF?
Digoxin
What is the metabolism for Digoxin?
minimal (80% unchanged) Hepatic Metabolism by:
- Hydrolysis
- Sulfation
- Glucuronidation
What result would be seen from Quinidine coadminstration with Digoxin?
Increased plasma levels of Digoxin
What result would be seen with coadminstration of Verapamil and Digoxin
Increased absorption of Digoxin
Verapamil inhibits intestinal pgp efflux of digoxin
What result would be seen with coadministration of Rifampin and Digoxin
Decreased absorption of Digoxin
Rifampin induces intestinal pgp efflux expression
What would the results of coadministration of Bile Acid binding resins such as Cholestryamine and Digoxin be?
Decreased Digoxin Absorption
What is the plasma protein binding, onset, and 1/2 life for Digoxin?
PPB - 30%
Onset - 15-30min
T1/2 - 1-2 days
What is the plasma protein binding, onset and 1/2 life for digitoxin?
PPB - ~95%
onset - 05-2hrs
T1/2 - 4-7 days
What are the primary problems and side effects of Cardiac Glycosides?
Narrow Therapeutic WIndow
SE: Loss of appetite, blurred vision, GI distress, potentially proarrhythmmic (Afib, Vtach, MI)
How would you treat acute toxicity of Digoxin?
Digibind (digoxin immune Fab)
What are the disappointing results of most PDE inhibitors?
Inc Mortality rates
Inc Incidence of arrhythmias
Causes tachycardia
Loss of positive inotropic effect w/ chronic use
When are PDE3 inhibitors used for CHF?
Acute CHF
Why was amrinone renamed in the year 2000?
Was confused with Amiodarone, which led to some fatal medication errors
What is the difference in naming between PDE3 inhibitors and PDE5 inhibitors?
PDE3 - ends in ‘one’
PDE5 - ends in ‘fil’
Inamrinone
- Class, indication
- Metabolism/T1/2
- SE
- Formulations
- PDE3 inhibitor, Acute CHF
- 3-4hrs, mainly excreted unchanged in urine
- Thrombocytopenia (10%)
- Short term IV
Milrinone
- Class, Indication
- Metabolism/T1/2
- SE
- Formulation
- PDE3 inhibitor, Acute CHF
- 30-60min, Mainly excreted unchanged in urine
- Fewer side effects than Inamrinone
- Lactate for IV
MoA for Ca sensitizing agents
Increase contractility by binding the N-terminus of troponin C and stabilizing the Ca-bound conformation.
Activation of ATP-regulated K channels and cause vasodilation in vascular smooth muscle.
Levosimendan
- Class/Indication
- Formulations
- Calcium sensitizing agent, CHF
2. IV formulation for Acute CHF
B-adrenergic agent for treatment of CHF
Dobutamine
Dobutamine Racemate actions results in what overall effect?
In vasculature, A1 agonist negated by A1-antagonist (no vasodilation)
Overall: B1 effect: increased stroke volume and little increase in HR.
Dobutamine Administration and Availbility
T1/2 ~2min
Only active
Rapid first pass COMT
(Wrap IV bags in aluminum to prevent oxidation to ortho-quinone)
