Genetic Variations In Human Populations

Question 1

Pharmacokinetics is concerned with ____, ____, ____, and ____ of the drug

Pharamcodynamics is concerned with _____ of the drug, and it’s _____ with _____ ____.

Drug tolerance requires ____ dosage for therapeutic affect
Drug sensitivit/intolerance indicates a ____ dosage for therapeutic affect.

Answer 1

Pharmacokinetics is concerned with EXCRETION, METABOLISM, TRANSPORTATION and ABSORPTION of the drug

Pharamcodynamics is concerned with ACTIVITY of the drug, and it’s INTERACTION with DOWNSTREAM TARGETS.

Drug tolerance requires HIGHER dosage for therapeutic affect
Drug sensitivit/intolerance indicates a LOWER dosage for therapeutic affect.

Question 2

A genomic appraoch to pharamacogenetics uses ____ to assess the impact of an ensemble of _____ on the impact of drug therapy.

Answer 2

A genomic appraoch to pharamacogenetics uses GWAS to assess the impact of an ensemble of SNPs on the impact of drug therapy.

Question 3

Equation for INR

Answer 3

Time for observed clotting/Time for normal clotting

Question 4

What are the CYP (_____-___) family of enzymes?

• ____ containing proteins expresses primarily in the liver
• resposnsible for ____ and ____ both endogenous and xenobiotic compounds.
• can ____ drugs. Example: ____ converts codeine–>_____. Making codeine a _____.
• accept ___ from donors such as _____ to catalyze different reactions, most importantly the addition of ____ to carbon, N, or S atoms.
• phase I of drug metabolism– addition of __ group to the molecule, which improves _____
• phase II of drug metabolism– functionalization of __ group by a ___ or ___ group, further increasing drug ____, allowing it to be ____.

A single CYP can interact with _____ drugs.

Answer 4

What are the CYP (CYTOCHROME P450) family of enzymes?

• HEME containing proteins expresses primarily in the liver
• resposnsible for DETOXIFYING and EXPORTING both endogenous and xenobiotic compounds.
• can ACTIVATE drugs. Example: CYP2D6 converts codeine–>MORPHINE. Making codeine a PRODRUG.
• accept ELECTRONS from donors such as NADPH to catalyze different reactions, most importantly the addition of OXYGEN to carbon, N, or S atoms.
• phase I of drug metabolism– addition of OH group to the molecule, which improves SOLUBILITY
• phase II of drug metabolism– functionalization of OH group by a SUGAR or ACETYL group, further increasing drug SOLUBILITY, allowing it to be EXCRETED.

A single CYP can interact with MANY drugs.

Question 5

Example of Tylenol drug toxicity:

_____ is the major CYP that metabolizes tylenol to hepatotoxic intermediate (______)

Answer 5

Example of Tylenol drug toxicity:

CYP3A4 is the major CYP that metabolizes tylenol to hepatotoxic intermediate (B-QUINONE IMINE)

Question 6

Warfarin= _____

It’s used to prevent _____, ____ in case of heart valve ____, recurrent ____, ____, ____.

It’s MOA: impairs ___ of _____ dependent clotting factors.
-inhibits _____, which is a key enzyme in _____ recycling, which is necessary for ________.

It ____ ____ with ______ binding to the enzyme.

Answer 6

Warfarin= COUMADIN

It’s used to prevent THROMBOSIS, EMBOLISM in case of heart valve PROSTHESIS, recurrent STROKE, DVT, PE.

It’s MOA: impairs SYNTHESIS of VITAMIN K dependent clotting factors.
-inhibits VITAMIN K EPOXIDE REDUCTASE (VKORC1), which is a key enzyme in REDUCED VITAMIN K recycling, which is necessary for GAMMA GLUTAMYL CARBOXYLATION OF COAGULATION FACTORS.

It DIRECTLY COMPETES with VITAMIN K binding to the enzyme.

Question 7

If looking at [plasma] graph, this is how you can manipulate it:

Change in pharmacodynamics affects _______.

Change in pharmacokinetics affects ____________.

Answer 7

If looking at [plasma] graph, this is how you can manipulate it:

Change in pharmacodynamics affects THERAPEUTIC WINDOW.

Change in pharmacokinetics affects TIME-DEPENDENT PROFILE OF [DRUG].

Question 8

Gamma glutamyl carboxylase takes ____ residues within ______ _____ and _____ them by adding carboxylate, in order to promote ______. If you inhibit recycling of ______, you inhibit recycling of this enzyme, and in doing so, slows down ______.

Answer 8

Gamma glutamyl carboxylase takes GLUTAMATE residues within COAGULATION FACTORS and ACTIVATES them by adding carboxylate, in order to promote THROMBOSIS. If you inhibit recycling of REDUCED VITAMIN K, you inhibit recycling of this enzyme, and in doing so, slows down THROMBOGENESIS.

Question 9

Codeine intoxication associated with ultra-rapid ______ metabolism.

Gene duplication of ____ allele. This enzyme ____ codeine, so it converts rapidly to _____.

Answer 9

Codeine intoxication associated with ultra-rapid CYP2D6 metabolism.

Gene duplication of CYP2D6 allele. This enzyme ACTIVATES codeine, so it converts rapidly to MORPHINE.