Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
31 Cards in this Set
- Front
- Back
|
Where is Digoxin Metabolized?
|
SI (GIT) and Liver
|
|
|
Digoxin is eliminated by?
|
Kidneys
|
|
|
How does Quinidine affect digoxin concentration?
|
Quinidine will INCREASE level of digoxin
-Quinidine is an inhibitor of PgP in kidneys, increases serum levels of digoxin by decreasing elimination |
|
|
How does Rifampin affect digoxin concentration?
|
Rifampin will DECREASE level of Digoxin.
-Rifampin is an inducer of PgP in SI, decreases serum levels of digoxin - It displaces Digoxin from the tissues (remember it is a narrow therapeutic index drug) |
|
|
How do antibiotics affect digoxin concentration?
|
Antibiotics will INCREASE level of Digoxin.
-Antibiotics kill bacteria which contain K+ = ↓ K+ = ↑ Digoxin |
|
|
How does K+ affect digoxin concentration?
|
DECREASED K+ (hypokalemia) will INCREASE Digoxin in blood (because it increases distribution of Digoxin)
(K+ and Digoxin both bind to the Na/K ATPase ↑ K+ = ↓ Volume of Distribution ****↓ K+ = ↑ VD Which in turn causes Digoxin Toxicity***** |
|
|
How does Verapamil affect digoxin concentration?
|
Verapamil inhibits PGP in SI, so it INCREASES concentration of Digoxin
|
|
|
What are the 5 possible metabolized products of Digoxin and their enzymes?
|
1. Digoxigenin and 3-keto-digoxigeninn
In SI via sugar hydrolysis (breaking off sugar) -This is NOT as active as Digoxin -Can act as a Hapten( illicits an immune response/allergic reaction to digoxin) 2. Digitoxigenin -In Liver via dehydroxylation (-OH) -this leads to 3.Polar Metabolites via the liver that are eliminated via the Kidney. 4. Reduced Lactone Derivatives -In 10% of population, the Digoxin becomes Inactive Digoxin via reduction of the lactone group. |
|
|
What is Digoxin a substrate of?
|
PGP/MDR1 efflux transporters
|
|
|
What 4 factors is the Distribution of Digoxin dependent on ?
|
a) Age
(ex: old = ↓ muscle = ↓ VD = ↓ Digoxin) b) Thyroid function -affects skeletal muscle function c) Skeletal Muscle activity (↑ exersizing = ↑ binding of Digoxin to skeletal muscle = ↑ VD = ↑ Digoxin level d) Potassium levels ↓ K+ = ↑ VD= ↑ Digoxin level |
|
|
What 3 factors affect Absorption of Digoxin?
|
1. Orally absorbed
2. PGP inhibitors affect absorption (ex: verapamil increases concentration of digoxin cuz its not being metabolized as fast) 3. Oral bioavailability depends on the dosage form used - Enteric coated tablet prevents the hydrolysis of Digoxin in the stomach, which increases the bioavailability of the drug |
|
|
What 2 things affect distribution of Digoxin?
|
1.Bound to skeletal muscle (~50% of the dose)
-Binds to ATPase in skeletal muscle 2. Bound to Plasma Protein (20-30%) 2. Quinidine displaces digoxin from protein binding sites - Quinidine= ↑ VD = ↑ Digoxin |
|
|
What are the 3 components of Digoxin?
|
1. Sugar
2. Steroid 3. Lactone Need ALL 3 components to be ACTIVE |
|
|
What is the function of lactone in Digoxin?
|
1. The unsaturated 17-lactone crucial for receptor binding
2. Saturation of the lactone ring dramatically reduced the biological activity -if reduced (loses double bond), then it won't bind to receptor) Lactones by themselves, when not attached to the steroid skeleton, are NOT ACTIVE |
|
|
What is the function of Steroid in Digoxin?
|
Steroid skeleton is essential for activity
-it's not soluble |
|
|
What is the function of Sugar in Digoxin?
|
The sugar INCREASES hydrophilicity, which inceases solubility, which increases distribution.
-It possesses NO biological activity. |
|
|
How do the (Non-Glycosides) Phosphodiesterase Inhibitors work? (Inamrinone, Milrinone)
|
PDE3Is= cAMP= ↑Ca++= ↑ cardiac muscle contraction and vasodilation of vascular smooth muscle
|
|
|
What is the difference between Inamrinone and Milrinone?
|
MILRINONE is MORE POTENT than Inamrinone because it is MORE SELECTIVE for PDE3
Milrinone has Less thrombocytopenia and gastric side-effects as compared to Inamrinone both Excreted primarily in urine both IV Milrinone (weak base) has a Chemical interaction with Furosemide (weak acid) in IV -forms a insoluble salt precipitate. (Inamrinone does NOT have that interaction) |
|
|
Which drug can cause a sulfa allergy?
|
Dobutamine (B1-agonist)
-Sodium metabislfite is used to prevent oxidation which improves the chemical stability of dobutamine but contains sulfa and can cause a bisulfite allergy) |
|
|
Which drug can cause a hapten related allergy?
|
Digoxin
due to the metabolite Digoxigenin |
|
|
Dopamine
Enzymes metabolized by? Route of administration? Duration of Action? |
1. Catecholamine
2. Rapidly metabolized by COMT and MAO 3. SHORT duration of action 4. NO ORAL activity (breaks down quickly) |
|
|
Dobutamine
Which isomers and receptors does it affect? Enzymes metabolized by? Duration of Action? Degradation by and where on molecule? ADR? Route of Administration? |
Arylalkyl derivative of dopamine
S(-) isomer α1 & β1 agonist R(+) isomer α 1 antagonist Rapidly metabolized by COMT and MAO Short duration of action Undergoes degradation by oxidation at catacholamine site, 2 -OHs) Sodium metabisulfite is used as an anti-oxidant and can cause a sulfa allergy No oral activity (IV only) |
|
|
What are organic nitrates and how do they work?
|
Esters of simple organic alcohols or polyols with nitric acid
Mimic the actions of endogenous NO by releasing NO or forming NO within tissues |
|
|
1. What makes organic nitrates volatile?
2. What are the Disadvantages of organic nitrates? 3. What are the Advantages of organic nitrates? |
1. Composed of one nitrite and three nitrates
****Small lipophilic ester character makes them volatile 2.- Volatility is an important concern in drug formulation because of the potential loss of the active principle from the dosage form -Moisture should be avoided during storage to minimize the hydrolysis of the ester bond -Possess explosive properties 3. -Rapidly absorbed -Very efficient in emergency treatment of anginal episodes |
|
|
What is REQUIRED in the conversion of organic nitrates (RONO2) to nitrous oxide (NO, active vasodilator)?
|
R'-SH
CYSTEINE or THIOL donors are required -Thiol source is in the cell naturally. This breaks down the RONO2 into NO (what you want) + R'S |
|
|
Nitroglycerin
-Absorption -Metabolism -Onset of Action -Route of Administration |
Onset and duration of action depends on the dosage form
-IV, sublingual are fastest - Oral, ointment, patch are slower Undergoes extensive rapid HEPATIC (glutathione reductase) and NON-HEPATIC metabolism (blood vessel walls) Orally absorbed -can use all routes of admin Absorbed through skin -this has a fast onset -patch and buccal route minimizes first pass effect but Does NOT completely bypass first pass |
|
|
What happens in the inactivation pathway of Nitroglycerin?
ex: enzyme responsible, where it happens, the product |
-Glutathione nitroreductase is the enzyme
-In Liver -The product is the nitroglycerin LOSING -(OH) |
|
|
What is the ACTIVATION pathway of Nitroglycerin?
|
CYSTEINE (HS-) is required for activation (NO)
Nitroglycerin + Cysteine (HS) → Intermediate →NO (active) + Dimer (eliminated) |
|
|
What is the difference between the two organic nitrates Isosorbide dinitrate and Isosorbide 5-mononitrate?
|
***Iso 5-mononitrate stays in the body longer because it is resistant to hydrolysis due to the location of the - group being BELOW the plane (it's protected from hydrolysis)
Isosorbide dinitrate has shorter duration of action because the -ONO2 group is ABOVE the plane. ISO Dinitrate is Metabolized primarily in the LIVER by glutathione-nitrate reductase into more potent vasodilator product ISO 5-Mononitrate Denitration of the parent drug yields 5-isosorbide mononitrate The 5-ISO Mononitrate is MORE POTENT and has LONGER DURATION OF ACTION than parent (plane location of ONO2) |
|
|
Molsidomine
and lindosimine (Nitric Oxide Donor) -These are therapeutic alternatives to organic nitrates |
Molsidomine (non-active), a sydnone imine derivatice, is oral NO donor
Metabolized by LIVER esterases (SLOWLY) to its active metabolite: LINSIDOMINE It has a SLOWER ONSET and LONGER duration of action than conventional nitrates because of the relatively slow rate of conversion to linsidomine Molsidomine is light sensitive, hence infusion bags and tubing during administration should be protected Do not require cysteine or thiol donors for conversion into NO Molsidomine and lindosimine are therapeutic alternatives to traditional organic nitrates ADR: Superoxide, during the release of NO, is a major concern limiting its therapeutic potential in the treatment of angina |
|
|
Nicorandil
(Coronary Vasodilator) |
Nicorandil is a nicotinamide-nitrate ester
Dual mechanism of action Hybrid of organic nitrates and potassium channel activators (This produces the MAJOR EFFECT) Pharmacological properties differ from organic nitrates. (extra: K+ channel agonists dilate the arteries only (↓ afterload) and Organic nitrates dilate the veins only (↓ preload) So (↓ afterload and ↓ preload) |
