Pharmacokinetics I

Question 1

Know how to calculate amount of drug in ionized versus unionized form at a given pH

Answer 1

• Determine absolute difference between pKa and pH
• Take antilog of absolute difference Determine what state the drug is in (protonated or unprotonated) Protonated forms dominate at pH below drug pKa
• pH < pKa, drug will be protonated Unprotonated forms dominate at pH above drug pKa
• pH > pKa, drug will be unprotonated See if the question is asking for lipid soluble (neutral form) or aqueous soluble form for a weak acid or a weak base
• Weak acid: lipid soluble = protonated
• Weak base: lipid soluble = unprotonated

Question 2

Know the advantages and disadvantages of different routes of drug administration

Answer 2

When a drug is given orally it has the highest probability to have a first pass effect which involves being metabolized by the gut enterocytes or by the hepatocytes before it is available for systemic circulation.
* notable drugs: morphine, nitroglycerin, lidocaine, HIV protease inhibitors
If a drug is administered any other way - IV, intra muscularly, transdermally, or via rectal route - it has a minimal first pass effect.

Question 3

Know the effects of plasma and/or tissue binding of drugs on volume of distribution

Answer 3

Plasma protein binding: drugs with high plasma protein binding (albumin or alpha-1 acid glycoprotein) often remain in the plasma, thus have a low Vd ​negative acute phase protein: albumin
* decreases with many diseases
* phenytoin, salicylates positive acute phase protein: alpha-1 acid glycoprotein
* increases with inflammation
* quinidine, propranolol
Tissue protein binding: drugs that bind to tissue proteins concentrate in those tissues and have high Vd

Question 4

Know the mechanisms by which drugs cross biological membranes.

Answer 4

Passive diffusion: molecule must be neutral for it to pass via lipid membranes and charged for it to be soluble in aqueous environments
* Protonated (neutral) form of a weak organic acid that passes lipid membranes
* Unprotonated (neutral) form of a weak organic base that passes lipid membranes
Carrier-mediated transport: transporters facilitate movement of molecules into or out of tissues. These have structural selectivity, competition can arise and they can be saturable.
Facilitated diffusion
* Does NOT require energy from ATP - involves movement of a drug DOWN a concentration gradient
* Facilitates passage of polar or charged molecules
Active transport
* Energy dependent carrier mediated transport, coupled to ATP hydrolysis (primary active transport) or co-transport substrate down a gradient (secondary active transport)
* Movement occurs against a concentration gradient
Pinocytosis (endocytosis): cell engulfs extracullular material within membrane vesicles…exceptionally large drugs
* Proteins: Botulinum toxin, monoclonal Ab
* Drug/protein complexes: Vitamin B12/IF, Fe/transferrin complex

Question 5

Know the factors that lead to concentration or exclusion of drugs at sites in the body.

Answer 5

Factors that lead to concentration:	
* gender	
* age	
* body fat	
* edema
Exclusion of drugs at specific sites - typically fluid compartments	
* CSF	
* ocular fluid	
* lymph fluid	
* pleural fluid

Question 6

What organ has the highest normalized blood flow?

Answer 6

kidneyyyyyyyy

Question 7

Understand how drugs appear to distribute into different fluid compartments in the body.

Answer 7

The compartment where a drug appears to distribute is referred to as the “Apparent Volume of Distribution (Vd)”. This really represents relative distribution between plasma and the rest of the body. There are different compartments in the body and each corresponds to a specific site:
* Plasma water: 0.045 +/- 0.04 L/kg
* Extracellular water: 0.2 +/- 0.1 L/kg
* Total body water: 0.6 +/- 0.2 L/kg
* Tissue concentration: > 0.8 L/kg
Vd = amount of drug /C0, where C0 is the extrapolated concentration of drug in plasma at time 0 after equilibrationTake Vd divided by the mass of the person (in kg) to get the normalized value and use the above list to select where the drug appears to distribute.

Question 8

Placental and mammary transfer of drugs.

Answer 8

Placental
* Fetus is most vulnerable to the teratogenic effects of drugs during the first trimester
* Very lipid soluble drugs are most likely to pass through the placental barrier
​Milk
* Drugs enter by passive lipid diffusion Weak organic bases - milk is more acidic than plasma
* Amphetamine, cocaine, opioids
* Tetracyclines - chelate with Ca in milk
* Lipid-soluble drugs due to the high fat content of milk