2. Pharmacokinetics Flashcards
What does pharmacology mean and where does it come from?
What does drug mean?
Pharmacology- study if the changes produced in cling animals by chemical substances
Or
Branch of medicine that deals with the interaction of drugs with the systems and processes of living animals
Derived from Greek word pharmakon meaning magic charm for treating disease
Pharmakon later came to mean remedy or drug
Drug- broadly defined as any chemical agent that affects living processes
Any chemical compound used in the diagnosis, treatment, or prevention of disease or other abnormal conditions
What are the 4 names drugs have?
Brand name- amoxil
Generic name- amoxicillin
Pre-market manufacturer code- BRL-2333
Chemical name- long jibberish
Slide 6 general principles
What is pharmacokinetics?
What is pharmacodynamics?
Pharmacokinetics- the study of the 4 different processes of absorption, distribution, metabolism, and excretion of drugs
(What does body do to drug?)
Pharmacodynamics- the study of the processes of drug-receptor interaction, signal transduction and responses (effects) produced by the drugs
(What does the drug do to the body)
Slides 7-8 General principles
What is an iatrogenic effect?
Adverse effect or complication caused by a physician (resulting from medical treatment or device)
Most cases are unintentional
What are the 2 routes of drug administration and examples of each?
Enteral- drug eventually ends up through digestive tract
Oral, sublingual (under tongue), rectal
Parenteral- a route other than the digestive tract (more expensive, more pain)
Intravenous, intramuscular, subcutaneous (under skin layer), intra-arterial, intrathecal (in subarachnoid space), intraperitoneal
What is drug absorption and the factors affecting it?
Refers to passage of drug from site of admin to general circulation (except drugs applied directly to target tissue)
Intravenous injection is immediately 100% absorbed
Factors:
Non-ionized, small molecules, and lipid-soluble drugs are better absorbed
Ionized and large molecules are poorly or not absorbed. Stomach acid or digestive enzymes can destroy drugs, can be so polar they won’t cross membranes
Slide 14-15 General Principles
What are the 2 examples of organs with gaps between capillary endothelial cells?
Slide 15-16 general principles
Capillary barrier with gaps between endothelial cells or fenestrations- liver sinusoids and kidney glomerular capillaries
What is the pKa?
How are acids and bases absorbed differently?
The pKa of a drug is the pH at with half the drug is ionized
Acid is proton donor
HA=H + A
The protonated form is uncharged and better absorbed
Base is proton acceptor
B+H=HB
The protonated form is charged and not well absorbed
Weak acids and bases only ionize partially
Strong ones ionize fully (dissociate)
Slide 20 general principles
What is ion trapping?
What is example?
At steady state- an acidic drug would accumulate on the more basic side of a membrane and a basic drug on the more acidic side- this is ion trapping
Body has different compartments with different pH so drugs get ionized to different extent in different areas (basic drug gets more ionized if medium is more acidic, vice versa)
Fetal blood and breast milk- more acidic than mothers plasma
Poisoning- urine excretion of drugs can be accelerated by giving opposite solution of drug (basic drug feed acidic solution to excrete quick)
What is first-pass metabolism and the cheese-wine reaction? (They’re the same)
Metabolizing enzymes in the intestinal wall and/or liver destroy drug molecules so very little or no drug reached general circulation
Tyramine is found in wine and cheese and is metabolized by enzymes in GI wall and liver
When patient is taking MAO inhibitor, tyramine is absorbed and reaches circulation where it releases norepinephrine which will cause tachycardia and high blood pressure
What is bioavailability?
What factors affect drug distribution?
The fraction of an orally given drug that reaches circulation
BA= (AUC oral / AUC i.v.) x100
If it is 1, it is fully absorbed
If it is 0, it does not reach circulation
Ionization, capillary permeability, blood flow, and plasma protein binding effect drug distribution after absorption
Brain, liver, kidneys blood flow > skeletal muscle blood flow > fat, skin
What is capillary permeability?
Drugs can leave capillaries regardless of whether they are poorly lipid soluble, charged, or polar
Capillaries are leaky in liver and spleen
Capillary permeability increases when inflammation occurs
Slide 25-26 general principles
What is the significance of the blood brain barrier?
What’s an example?
Brain capillaries have tight junctions
Glucose and amino acids and specific carrier mediated transport systems
Only lipophilic drugs diffuse across brain capillaries (unless active transported across)
Blood brain barrier doesn’t work proper in areas of infection or injury because inflammation occurs which increase capillary permeability
So degree to which drugs penetrate the brain should be known to treat diseases of nervous system
What is the volume of distribution (Vd)?
What do low and high values mean?
Theoretical (or apparent) volume in which the total amount of administered drug should be uniformly distributed to account for its plasma or blood concentration
Vd= dose administered / plasma concentration
High Vd means most of drug is in extravascular compartment (likely for lipid soluble drug)
Low Vd means most of drug is in vascular compartment (drug highly bound to plasma proteins)
Slides 30-31 general principles
What is biotransformation (drug metabolism)?
Where are drug metabolizing enzymes present?
Chemical modification of drugs by enzymes, to make them more polar (less lipid soluble), and therefore readily excretable by the kidneys
Drug metabolizing enzymes are present in: The liver Gastrointestinal wall Lungs Kidneys Skin Blood Brain
What are the two phases of biotransformation (drug metabolism)?
Phase I- functionalization reactions (oxidation, reduction, hydrolytic reactions) makes drug more polar but not always inactive
P450 enzymes are used
Phase II- conjugation (something attached) reactions (conjugation to polar groups; glucuronidation, sulfation, acetylation) most cause drug inactivation
Conjugated drug is excreted rapidly
What are P450 enzymes?
What is the main enzyme in this family?
Monooxygenase (CYP) family of enzymes- main enzymes in phase I drug metabolism
Mainly oxidize drugs
Most cases inactivate drug, but can also produce active metabolites
CYP3A4 is primary enzyme for metabolism of about half of all drugs and is inhibited by many drugs
induction it inhibition of phase I enzymes can cause drug interactions when 2+ drugs are metabolized by same enzyme
Slides 35-37 General principles
What are the factors affecting drug biotransformation (metabolism)?
Enzyme induction and inhibition- drugs and other substances can stimulate or inhibit the expression of some metabolizing enzymes (P450 ones especially)
Enzyme induction- faster metabolism
Enzyme inhibition- slower metabolism
Lipid solubility of drug
First order or zero order rate of metabolism
Blow flow to liver
What are inducers and an example?
Cause expression of more CYP enzymes and faster elimination of substrate drugs (more enzyme=faster elim of drugs)
Lower than expected drug levels can cause treatment failure
Ex:
St. John’s Wart (herbal antidepressant)
What are inhibitors and an example?
What is an example?
Inhibit the activity of CYP enzymes and reduce elimination of substrate drugs
Higher than expected drug levels can cause drug toxicity
Example: Grapefruit juice (stomach acid inhibitor)
What are mutations in drug metabolism enzymes?
CYP Polymorphism- genetic variations in population
Most common P450 polymorphism is of CYP2D6 expression
Codeine is almost ineffective as an analgesic in these patients with CYP2D6 mutation since CYP2D6 metabolizes codeine to morphine
What are prodrugs?
Certain drugs do not reach their site of action because of pharmacokinetic obstacles (drug being destroyed by digestive enzymes)
Their precursors, know as prodrugs, May be useful in such cases
Prodrug is an inactive precursor with favourable pharmacokinetics which is metabolized into the active drug in the body
Proton-pump inhibitors- reduce stomach acid secretion
Levo-dopa- converted to dopamine
What is P-glycoprotein?
Efflux pump
Uses ATP energy to remove compounds (drugs) from inside to outside
Located at luminal surfaces in colon brain kidney tubules etc
Can be expressed or inhibited by drugs- St. John’s wart or verapamil
P-glycoprotein in brain blood barrier protects CNS
What is the medical significance of P-glycoprotein?
Plays a role in drug resistance to cancer chemotherapeutic agents
Over expressed in rumour cells
Pumps out anti cancer drugs
