Pharmacokinetics Flashcards
Pharmacokinetics
concerned w/ the relationship between the dose and concentration of the drug.
What are pharmacokinetics determined by?
Drug absorption, distribution, metabolism (biotransformation), and elimination.
Drug absorption
what can interfere w/ the absorption of drugs (food, pH, etc.)
Drug distribution
The passage of drug from the blood (circulation) to the tissues and organs of the body.
Drug metabolism (biotransformation)
Enzyme-catalyzed convertion of drugs to their metabolites; most metabolism occurs in the liver, some occurs in the kidney, GI, and lungs.
Drug elimination/excretion
elimination of drug from the body
Bound drug
drug bound to a protein (usually albumin)
Free drug
Drug not bound to a protein (will be the only thing that works since it is the only thing that can be absorbed and excreted); can cause adverse effects and toxicity.
Drug absorption
the passage of a drug from its site of administration into the circulation
What are factors that influence rate of absorption
Passage across membrane (process of absorption)
Site of administration
Food (oral administration)
Effects of pH
Drugs administered orally vs. parenteral (IV, SQ)
greater barrier to absorption
Passive diffusion
*most drugs are absorbed by this process; High concentration to low concentration.
Lipid diffusion
(Passive diffusion) facilicated by degree of lipid solubility.
Aqueous membrane
(Passive diffusion) most drugs are too large to be absorbed (penetrate aqueous channels)
Active transport
Mediated process of moving particles across a biological membrane against a concentration gradient. *uses ATP
Facilitated diffusion
process of diffusion, a form of passive transport facilitated by transport proteins; no energy required.
What is an example of facilitated diffusion?
Glucose is transported into muscle cells by glucose transporter protein (GLUT4)
Why might facilitated diffusion be needed?
Larger molecules are transported by transmembrane carrier proteins.
Efflux pump
Transport drugs from enterocytes into the intestinal lumen from hepatocytes into bile for elimination.
Where is P-glycoprotein (P-gp) found?
Cancer cells, gut, kidney, and blood-brain barrier.
Uptake transporter
Transport drugs into cell, enhancing absorption.
What is an example of an uptake transporter?
organic anion transporting peptide (OATP)
What can inhibit OATP?
Fruit juices (grapefruit, orange, apple) and other drugs.
What is the effect of inhibiting OATP?
Inhibiting OATP can decrease plasma levels of drugs that are transported by OATP leading to lower efficacy.
What do nonioinized/uncharged substances act like?
Act like nonpolar, lipid-soluble compound that can readily pass across body membranes.
What do ionized/charged substances act like?
Act like polar, less-soluble compound that has greater difficulty passing across body membranes (less drug absorbed).
When are weak acids better absorbed?
When the pH is acidic.
When are weak bases better absorbed?
When the pH is basic or alkaline.
How can organ flow (cardiac output) affect distribution of a drug?
- Drugs are rapidly distributed to highly perfused tissues (brain, liver, heart, kidney)
- Drugs are distributed slowly to less highly perfused tissues (skeletal muscle) and even more slowly to those w/ the lowest blood flow (skin and adipose tissue)
Albumin
binding site for many drugs
Why do drugs dissociate from albumin?
To maintain equilibrium between free drug and bound drug.
How can a drug be displaced from albumin?
By other drugs that have a higher affinity for albumin.
What is the effect of a drug being displaced from albumin?
- Causes temporary increase in concentration and pharmacologic effect.
- This effect is usually short lived, however because the increased free drug concentration will accelerate metabolism and excretion.
How can molecular size affect drug distribution?
Extremely large molecule sare confined to plasma.
How can lipid solubility affect drug distribution?
Major factor affecting the exten of drug into the CNS. Blood-brain-barrier restricts polar and ionized molecules so the more lipid soluble a drug, the more it’s going to penetrate the BBB and affect the CNS.
What is volume of distribution? (Vd)
A theoretical volume of fluid; relates the concentration of drug in the body to the concentration of the drug in the plasma.
How is volume of distribution useful?
It is useful to calculate the amount of drug needed to achieve a desired plasma concentration.
What does low Vd mean?
Indicates the drug’s distribution is restricted to plasma fluid or extracellular fluid.
What is Vd equivalent to?
Total body water
What does large Vd mean?
Indicates a drug is concentrated intracellular, with a resulting low concentration (ion trapping).
What does the rate of distribution from blood into various tissues depend on?
Perfusion of the tissue and the ease the drug can pass through lipid membranes of the cell.
What can the rate of distribution determine?
The onset or duration of drug effect.
What is the primary purpose of metabolism (biotransformation)?
To inactivate and detoxify drugs and xenobiotics that can harm the body.
- Drug metabolistes are more water soluble and are more readily excreted.
- Drug metabolites can be either active or inactive.
Prodrugs
Inactive drugs that are metabolized to active drugs; they are better absorbed than its metabolite (drug is inactive before metabolism.
Active drug
Drug takes effect directly; metabolized to active metabolites.
First-pass metabolism
drugs extensively metabolized as they pass through the liver the first time.
- Drugs absorbed from the GI reach the liver (by hepatic portal vein) before entering the systemic circulation
What routes of administration minimize the effect of first-pass metabolism?
sublingual and transdermal routes
What is an effect of first time metabolism?
Extensively converted to inactive metabolites and have low bioavailability (amount of drug that reaches the systemic circulation)
What is Phase I of drug metabolism?
Oxidative, hydrolytic, and reductive
Phase I of drug metabolism
- Generally results in loss of pharmacologic activity (inative metabolite) although may result in retention of action (active metabolites)
- Primarily located in the liver
- Other organs such as the GI tract has metabolic capacity.
What is Phase II of drug metabolism?
Conjugation
- acetylation
- GLUCORONIDE FORMATION
- sulfation
Phase II of drug metabolism
conjugation involves enzymes which serve to conjugate various drugs to form water soluble etabolites that are mostly inactive and excreted.
How do many drugs alter metabolism?
By inhibiting or inducing CYP 450 enzymes resulting in drug interactions.
What are the most important organs for drug exretion?
kidneys
How are most drugs excreted?
As parent compound or metabolite in urine.
What are other minor routes of excretion?
saliva, sweat, feces, biliary
Drug clearance
volume of blood from which a drug is removed per unit of time
Total clearance is calculated by…
adding the renal clearance, heaptic clearance, and other organs involved in clearance.
Elimination half life T1/2
time required to eliminate half of the amount of a drug in the body to reduce the plasma level by 50%
First-order kinetics
rate of elimination is proportional to the plasma drug concentration. (the majority of drugs exhibit first-order clearance)
- constant fraction of drug is eliminated per unit of time
- predictable dose response
Zero-order kinetics
the rate of drug elimination is constant and independent of plasma; capacity-limited elmination clearance will vary depending on the conentration of drug that is achieved.
Other characteristics of zero-order kinetics
- nonlinear
- drug elimination pathway becomes saturated if the dose becomes high enough.
- clinical significance is that smalle changes in doses result in disproportionate increase in plasma drug concentrations.
Bioavailability
fraction of the administered drug that reaches the systemic circulation as intact drug.
What are some factors that affect bioavailability (oral)?
- rate and extent of disintegration and dissolution (how well a drug is absorbed)
- food and gastric acid
- GI and liver enzymes, first-pass
- P-glycoprotein
- OATP
Plasma drug concentration curve
plots the concentration over time; after a single dose, plasma concentration increases as drug is absorbed, reaches a peak, and then declines.
What would happen if food were to decrease the rate but not extent of absorption (plasma drug concentration curve)?
maximal plasma drug concentration Cpmax is less and tmax will increase.
Steady-state
the point when a drug equillibrium between the blood and tissues has be established such that the dose administered each day equals the amount metabolized and excreted each day.
amount of drug injested/day = amount of drug excreted/day
How long does it take to reach a steady state?
4 to 5 half-lives of the drug
What factors affect steady-state concentration?
- Dose
- Dosing interval (frequency)
- Bioavailability (oral)
- Clearance of half-life
What is the equasion for steady state?
dosing interval X excretion
Loading Dose
to rapidly establish a therapeutic plasma drug concentration; larger than the maintenance dose; usually administered as a singel dose but can be divided into fractions that are given over several hours.
How is the loading dose calculated?
By multiplying volume of distribution by the desired plasma concentration.
Loading dose = Vd X Cp
What is the most common conjugation reaction? What are other conjugation reactions?
Glucoronide formation; acetylation and sulfation are other conjugaion reactions
What are some important enzymes that genetic polymorphism affects?
CYP2C9
CYP2C19
CYP2D6
Polymorphism
causes consequences in drug response and toxicity (if someone metabolises a drug very quickly, there may be a therapeutic failure
CYP2D6
metabolizes 25-30% of meications.
- Beta-blockers
- antiarrhythmics
- antidepressants
- antipsychotics
Poor-metabolizers (PM) CYP2D6
poor metabolizers of 2D6 have a reduced ability to metabolize prodrug substrates to their active metabolite.
- may result in thereapeutic failure (codeine converted to morphine)
- durgs metabolized by 2D6 experience adverse effects due to elevated plasma levels.
Extensive-metabolizer (EM) CYP2D6
thereapeutic failures (TCAs); exhibit adverse effects w/ prodrugs (codeine)
CYP2C19 w/ different populations
asian heritage metabolize most CYP2C19 substrates at a slower rate than caucasians.
PM - CYP2C19
- increased plasma concentrations of proton pump inhibitors: omeparazole (Prilosec)
- May have therapeutic failure: clopidogrel (Plavix)
EM - CYP2C19
require larger doses
CYP2C9
anticoagulant WARFARIN is metabolized by 2C9; poor metabolizers are at high risk of bleeding complications and require lower doses.
Drugs handled by the kidney undergo the process of:
- Glomerular filtration
- Tubular secretion
- Passive tubular reabsorption (acid-base; pH)
- Excretion = sum of the amount filtered and excreted - amount reabsorbed
Effects of Protein binding
drugs highly bound to plasma protein (albumin) will have low filtration rate; only the free drug will be filtered
active tubular secretion is not affected by plasma protein (albumin) binding
Effects of Lipid solubility
the more lipid soluble a drug is, the more passive reabsorption occurs across renal tubular and into the circulation
(why the body makes things more polar so they can be excreted)
Enterohepatic cycling
drugs (MW greater than 300) and conjugated drug metabolites are excreted in the bile
bile empties into intestine, fraction of drug may be reabsrobed into the circulation and eventually return to the liver.
reduces elimination and prolongs half-life and duration of action
intestinal bacteria facilitate this process
Drug clearance
the volume of blood from which a drug is removed per unit of time
Total clearance
renal clearance + hepatic clearance + other organs involved in clearance
What are some examples of a prodrug?
enalapril (Vasotec)
codeine - has to be converted to morphine before it works
