Chapter 4: Pharmacokinetics Flashcards
Pharmacokinetics
the study of drug movement throughout the body.
4 basic pharmacokinetic processes
- absorption
- distribution
- metabolism
- excretion
Absorption
Movement of a drug from site of administration to the bloodstream
Distribution
Movement of a drug through the bloodstream, across the interstitial spaces, and into cells
Metabolism (biotransformation)
Inactivation of drugs
usually takes place in the liver and catalyzed by the cytochrome P450 system of enzymes.
Excretion
Movement of drugs out of the body
elimination
metabolism plus excretion
phospholipids
the basic membrane structure consisting of a double layer of molecules (lipids)
3 ways drugs cross cell membranes
1) channels or pores
2) a transport system
3) direct penetration. (Most common)
channels or pores
- Very narrow
- Very few drugs use this method (ions)
transport system
- Carriers that move drugs from one side of the membrane to the other
- Some require energy
- All are selective
- P-glycoprotein is one that exists on many cells:
P-Glycoprotein
A transporter that can pump certain drugs out of epithelial cells back into the intestinal lumen. Exist in: 1. Liver – drugs into bile 2. Kidney – drugs into urine 3. Placenta – drugs into maternal blood 4. Brain – drugs into bloodstream
direct penetration
- Method for most drugs
- Dissolve in phospholipid membrane to move through
- Molecules must be lipid soluble
Polar molecules
Molecules with no net electrical charge, but have uneven distribution of electrons.
Positive and negative charges on opposite sides of the molecule.
Large polar molecules will not dissolve in non-polar substances
Ions
Molecules that have a net electrical charge (+ or -). Unable to cross membranes unless very small.
- Quaternary ammonium compounds
- pH-dependent ionization
Quaternary ammonium compounds
Carry a positive charge at all times
Because of the charge, these compounds are unable to cross most membranes.
pH-Dependent Ionization
Compounds that become ionized depending upon the pH of the environment (acids and bases)
Acids tend to give up hydrogen in alkaline environment
Bases tend to accept hydrogen in acidic environment
ionization
the process of an acid giving up a proton or a base accepting a proton
Ion Trapping (pH Partitioning)
pH may differ on two sides of a membrane
Drugs will accumulate on the side of a membrane favoring their ionization
Acidic drugs will accumulate on alkaline side; alkaline drugs will accumulate on the acidic side
Absorption
Movement from site of administration to blood.
Enhanced by: rapid dissolve, high lipid solubility, large surface area, and high blood flow.
Embolism
blood vessel blockage at a site distant from the point of administration
Oral absorption
Can be from the stomach, the intestine, or both
Oral Barriers
1) the layer of epithelial cells that lines the GI tract.
2) the capillary wall
what happens to drugs following their absorption from the GI tract
Must pass through the liver (via the portal blood), enter the inferior vena cava then reach general circulation. Some drugs undergo extensive hepatic metabolism.
bioavailability
The quantity of a drug available in the body after it is administered.
100% is recorded when drugs are administered IV.
Many drugs administered by mouth go through first-pass metabolism therefore, less than 100%.
Enteric-Coated
Material designed to dissolve in the small intestine but not the stomach.
1) to protect drugs from acid and pepsin in the stomach
2) to protect the stomach from drugs that can cause gastric discomfort
Sustained-Release
Capsules filled with tiny spheres that contain the actual drug; the individual spheres have coatings that dissolve at variable rates.
Distribution
the movement of drugs throughout the body
Exiting the Vascular System
Drugs in the vascular system pass between cells rather than through them, movement into the interstitial space is not impeded.
Blood-Brain Barrier (BBB)
There are tight junctions between cells of the capillary walls in the CNS that prevent drug passage. Only drugs that are lipid soluble or have a transport system can cross the BBB.
Placental Drug Transfer
Lipid-soluble, nonionized compounds readily pass from maternal blood into fetus blood. In contrast, ionized, highly polar, or protein bound compounds are largely excluded—as are drugs that are substrates for P-glycoprotein.
Protein Binding
Drugs can form reversible bonds with plasma albumin. While bound, drug molecules cannot leave the vascular system
Hepatic Drug-Metabolizing Enzymes
Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, also known as cytochrome P450, a key component of this enzyme system.
cytochrome P450 (CYP450)
3 of the 12 families called CYP1, CYP2, and CYP3 metabolize drugs.
Some are CYP450 (inducers)
Some reduce CYP450 activity (inhibitors)
6 consequences of drug metabolism
- Accelerated renal excretion
- Drug inactivation
- Increased therapeutic action
- Activation of “prodrugs”
- Increased toxicity
- Decreased toxicity
Accelerated Renal Drug Excretion
MOST IMPORTANT
Kidney cannot excrete drugs that are very lipid soluble
Metabolism can convert drugs into water-soluble forms
prodrug
compound that is pharmacologically inactive as administered and then undergoes conversion to its active form via metabolism
Special Considerations in Drug Metabolism
Age Induction Inhibition First-Pass Effect Nutritional Status Competition Between Drugs
Induction
Process of stimulating enzyme synthesis
Inhibition
Decrease rates of enzyme synthesis
First-Pass Effect
Drugs administered through the enteral or rectal routes undergo first-pass metabolism in the liver.
Sublingual, intravenous, and intramuscular routes bypasses the first-pass metabolism, and bioavailability is high.
A higher drug dose will be needed if an oral formulation is prescribed.
Enterohepatic Recirculation
A drug is transported from the liver into the duodenum (via the bile duct) and then back to the liver (via the portal blood)
Excretion
the removal of drugs from the body
Renal Drug Excretion Steps
1) glomerular filtration
2) passive tubular reabsorption
3) active tubular secretion
Glomerular Filtration
Renal excretion begins at the glomerulus of the kidney tubule surrounded by Bowman’s capsule.
Small pores perforate the wall and as blood flows, fluids, small molecules, and drugs are forced through the pores into the urine.
Large molecules and drugs bound to albumin cannot be filtered out.
Minimum Effective Concentration (MEC)
The plasma drug level below which there is no therapeutic effect.
Toxic Concentration
The plasma drug level at which toxic effects are identified.
Therapeutic Range
The range of doses between MEC and toxic concentration
Wide range = more safe (acetaminophen)
Narrow range = less safe (lithium, digoxin)
Plateau
The time at which dosing equals drug elimination between doses.
When the same dose is delivered repeatedly, it typically takes 4 half lives to reach plateau
IV administration advantages
rapid onset
precise control over the amount of drug
suitability for use with large volumes
suitability for irritant drugs
IV administration disadvantages
high cost difficult inconvenience danger because of irreversibility potential for fluid overload infection embolism
IM & Subcutaneous administration advantages
suitability for insoluble and slow release
IM & Subcutaneous administration disadvantages
inconvenience
potential for discomfort
Oral administration advantages
easy
convenient
economic
safe
Oral administration disadvantages
high variability, possible inactivation by stomach acid digestive enzymes
Oral medication
Exercise decreases blood flow to the stomach
Stress can slow gastric emptying time
A high-fat meal slows gastric emptying time.
Hunger and fasting delay drug absorption
Food can stimulate the production of gastric acid.
Protein Bound Drugs
When two protein-bound drugs are given, they compete for sites, causing more free drug to be released. Possible drug toxicity can result.
Breast Milk
Lipid-soluble drugs may be expressed, but water-soluble, ionic, protein-bound drugs will not.
Elderly patients
have less gastric acidity, which causes slow absorption of drugs in the stomach
NOT lipid soluble molecules
Ions
Polar molecules
IV Barriers
None
IM Barriers
capillary wall
Cytochrome (CYP450) Inducers
Increase the activity of CYP450
Increase metabolism of drugs
Drug levels will fall
Dosages need to be increased
Cytochrome (CYP450) Inhibitors
Decrease the activity of CYP450
Decreased metabolism of drugs
Drug levels rise
Dosages need to be reduced
Activation of “prodrugs”
Administered drug is inactive (pro-drug)
Metabolism converts pro-drug into active form
Passive tubular reabsorption
Blood vessels leaving glomerulus run close to renal tubules.
Lipid soluble drugs are reabsorbed into blood.
Non-lipid soluble drugs remain in renal tubule.
Lipid soluble drugs that are metabolized into polar molecules cannot be reabsorbed.
Active tubular secretion
Active transport pumps remove drugs from blood into tubules.
Tubules contain pumps for organic acids and organic bases.
P-glycoprotein also pumps drugs
Factors that influence excretion
- pH
- Competition for active tubular transport
- Age
Competition for active tubular transport
- Multiple drugs competing for use of the same active transport mechanism slows excretion.
- Toxic levels of drugs can occur.
Peak concentration
highest level – usually measured within 1 hour AFTER administration
Trough concentration
lowest level – usually measured within 30 minutes BEFORE administration
Loading dose
Large initial dose followed by smaller maintenance doses.
Usually done for medications with very long half life.
Reduces time to plateau.
Decline of drug levels
When dosing is discontinued, 94% of the drug will be eliminated after 4 half-lives
