T2 - Drug Distribution and Metabolism E2 Flashcards
What is the purpose of drug disposition?
Lowers its concentration in the plasma
Describe drug disposition
- Drug distribution
- Drug elimination → Drug metabolism and drug excretion
What is drug distribution?
The reversible mass transfer process of a drug from one location to another within the body
Where are drug mass transferred?
Drugs moves from vascular to the extravascular space that occurs through the endothelial lining of blood capillaries
What factor does the rate of drug distribution strongly depend on?
The features of the capillary bed under consideration
What are steps of drug distribution?
- The transport of drug by blood to different tissues
- The transport of the drug from blood into the tissue across the cell membrane
How is the rate of blood flow compensate for its irregularity in the body?
Blood flow to a particular tissues determines the rate and extent of drug distribution to the particular tissue
What are the mechanisms of drug transfer in comparison to drug absorption?
Similar movements across endothelia and cell membranes such as passive diffusion and carrier mediated active transport
What influences drug distribution?
Reversible binding to:
Plasma proteins and tissue elements
What is the difference between plasma protein and tissue element reversible binding events?
Plasma proteins limit drug distribution outside the vascular system
Tissue elements promote drug distribution outside the vascular system
What is the key concept of drug distribution?
Only free, unbound drug molecules can efficiently cross endothelia and thus engage in the pseudo-equilibrium of distribution
Depict the image of drugs progression in the body
Depict the factors that influence drug distribution
Depict the movement of unionized and ionized drugs throughout the body
What is volume of distribution (Vd)?
The theoretical body fluid volume required to dissolve the amount of drug in the body (A) to give the observed (measured) drug concentration in plasma
What is the quantitative definition of Vd?
Vd = amount of drug in body (A)/ measured concentration of the drug in plasma (C)
What is the volume distribution of a drug from an IV bolus?
The amount of drug in body is equal to the injected dose, then [plasma] can be calculated of the drug during this time
What is the irreversible loss of the drug in the body?
Drug elimination
What processes of ADME lead to drug elimination?
Drug metabolism and excretion
What is drug metabolism?
The enzymatic conversion of one chemical form into another
What is the pro and con of lipid solubility?
Lipid solubility is effective for absorption, however, reduces drug excretion
Compare how water-soluble and and lipid soluble drugs are eliminated?
W: undergo excretion
L: undergo renal tubule reabsorption
What are the drug metabolism pathways?
Phase 1 and 2
What are the reactions of Phase 1 metabolism?
- Oxidation (CYPs, Alcohol dehydrase)
- Hydrolysis (esterases)
- Reduction
What are the reactions of Phase 2 metabolism?
- Conjugation (Glucouronic acid UGT)
- Acetylation (NAT)
- Methylation (TPMP)
- Sulfate
What are the drug metabolizing organs?
- Hepatic
- Extrahepatic
What are the extrahepatic organs that metabolize drug?
- Intestine
- Kidneys
- Biliary
- Lung
- Placenta
- Skin
What are the outcomes of drug metabolism?
- Renders pharmacologically active drug to inactive metabolites
- Occasionally yields pharmacologically active metabolites
- Rarely leads to toxic metabolites
- Pharmacologically inactive (prodrugs) are rendered active
What are examples of drug metabolisms yielding pharmacologically active metabolites?
- Amitryptyline to Nortriptyline
- Imipramine to Desipramine
- Codeine to Morphine
What are examples of drug metabolisms that can lead to toxic metabolites?
Paracetamol to N-acetyl-p-benzoquinone imine (NAPQI)
What are examples of drug metabolisms that activates prodrugs?
- Pivampicillin to Ampicillin
- Enalapril to Enalaprilat
- Phenacetin to Paracetamol
What are the factors that affect drug metabolism?
- Drug-drug interactions (enzyme induction and inhibition)
- Physiologic and pathologic factors (Age, sex, enzyme genetics, liver disease, diet, pregnancy)
Describe the mechanism of the inhibitor and how it slows down metabolism?
Inhibitor → Rapid direct inhibition of CYP450 isoenzymes → Decrease metabolism of target drug and increase in toxicity
Describe the mechanism of the inducers and how it increases metabolism?
Inducer → slow synthesis or degradation of CYP450 isoenzymes → Increased metabolism of target drug and increased excretion
