2. Pharmacokinetics

Question 1

What does pharmacology mean and where does it come from?

What does drug mean?

Answer 1

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

Question 2

What are the 4 names drugs have?

Answer 2

Brand name- amoxil
Generic name- amoxicillin
Pre-market manufacturer code- BRL-2333
Chemical name- long jibberish

Slide 6 general principles

Question 3

What is pharmacokinetics?

What is pharmacodynamics?

Answer 3

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

Question 4

What is an iatrogenic effect?

Answer 4

Adverse effect or complication caused by a physician (resulting from medical treatment or device)

Most cases are unintentional

Question 5

What are the 2 routes of drug administration and examples of each?

Answer 5

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

Question 6

What is drug absorption and the factors affecting it?

Answer 6

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

Question 7

What are the 2 examples of organs with gaps between capillary endothelial cells?

Answer 7

Slide 15-16 general principles
Capillary barrier with gaps between endothelial cells or fenestrations- liver sinusoids and kidney glomerular capillaries

Question 8

What is the pKa?

How are acids and bases absorbed differently?

Answer 8

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

Question 9

What is ion trapping?

What is example?

Answer 9

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)

Question 10

What is first-pass metabolism and the cheese-wine reaction? (They’re the same)

Answer 10

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

Question 11

What is bioavailability?

What factors affect drug distribution?

Answer 11

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

Question 12

What is capillary permeability?

Answer 12

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

Question 13

What is the significance of the blood brain barrier?

What’s an example?

Answer 13

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

Question 14

What is the volume of distribution (Vd)?

What do low and high values mean?

Answer 14

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

Question 15

What is biotransformation (drug metabolism)?

Where are drug metabolizing enzymes present?

Answer 15

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

Question 16

What are the two phases of biotransformation (drug metabolism)?

Answer 16

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

Question 17

What are P450 enzymes?

What is the main enzyme in this family?

Answer 17

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

Question 18

What are the factors affecting drug biotransformation (metabolism)?

Answer 18

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

Question 19

What are inducers and an example?

Answer 19

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)

Question 20

What are inhibitors and an example?

What is an example?

Answer 20

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)

Question 21

What are mutations in drug metabolism enzymes?

Answer 21

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

Question 22

What are prodrugs?

Answer 22

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

Question 23

What is P-glycoprotein?

Answer 23

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

Question 24

What is the medical significance of P-glycoprotein?

Answer 24

Plays a role in drug resistance to cancer chemotherapeutic agents
Over expressed in rumour cells

Pumps out anti cancer drugs

Question 25

What is enterohepatic recirculation?

Answer 25

Slide 52-54 general principles

Compound is conjugated in the liver, excreted in the bile, deconjugated in the intestine, and is reabsorbed into the circulation

Prolongs the duration of action (half-life) of a drug- recycling prolongs half life of drug

If we disrupt this cycle the drugs excretion will be faster

Ex: oral contraceptive fails when antibiotic is taken

Question 26

What are the factors affecting drug excretion?

Answer 26

Lipid solubility of drug
First order or zero order rate of metabolism
Blood flow to kidney (GFR)
Maturation if metabolizing enzymes
Diseases of the liver and the kidney
Competition for transport systems in renal tubules 
pH of blood and urine
Plasma protein binding

Question 27

What is clearance?

What is it’s unit?

Answer 27

Clearance is the volume of blood from which a drug is irreversibly removes per unit time
Unit: mL/min (/kg)

Clearance values are used to calculate maintenance dose of a drug (the dose that will allow us to maintain a steady-state concentration of a drug in the plasma, figure out when to re up the drug)

Rate of administration (maintenance dose)= rate of elimination
Maintenance dose= Cp (steady state plasma conc.) x Cl (clearance)

Question 28

What are the processes which determine the net removal of a drug by the kidney?

Answer 28

Slide 57 general principles
Renal clearance
Only free drug can be filtered at the glomerulus in kidney (protein bound drug cannot)
Some drugs that are strong acids or strong bases are secreted mainly in proximal tubule
Unless drug is very polar, some of it will be reabsorbed

Net removal=filtered + secreted - reabsorbed

Question 29

What is first order rate of elimination?

Answer 29

A constant fraction of drug is eliminated per unit of time
Rate of elimination is proportional to plasma concentration
Blood concentration declines in an exponential fashion over time

Slide 59 general principles

Question 30

What is zero order rate of elimination?

Answer 30

A constant amount (not reaction) of drug is eliminated per unit time (ex: 10g/hour) because that is maximum rate of elimination when the pathway for elimination is SATURATED

Question 31

What is half-life?

Answer 31

Half-life is the time required for the blood (or plasma) concentration of a drug to be reduced by 50%
Applies to drugs that are eliminated by first order rate of elimination

Question 32

What is the relationship between half-life and steady state concentrations?

Answer 32

If a fixed dose of a drug is given repeatedly at fixed intervals. It takes about 5 half-lives for that drug to achieve steady state concentrations in the plasma

Ex: if the half life of a drug is 20 hours, then it will reach a steady state concentration (where elimination rate = administration rate) after 5 x 20= 100 hours

Slide 62 general principles