Week 1: Pharmacokinetics and Drug Distribution

Question 1

Pharmacology

Answer 1

Study of drugs and how they interact with the human body

Science, patient preference, health coverage are involved in the prescription decision (including dose, drug, dosing interval, and route of administration)

Question 2

Chemical classification of drugs

Answer 2

Small molecules (i.e. morphine) - organic chemicals (natural or synthetic)
Molecular weights from 300-900 Da

Peptides (i.e. insulin) - up to tens of amino acids
Small peptidic hormones

Proteins (up to 50% of all new medications; i.e. breast cancer meds)
Enzymes, hormones, antibodies

Oligonucleotides (i.e. mRNA vaccine, lower cholesterol)
Antisense therapeutics
Alter protein expression in the body

Question 3

Drug names

Answer 3

Chemical name: IUPAC nomenclature (i.e. n-acetyl-p-aminophenol)

Generic name: based on National and International standards (i.e. paracetamol, acetaminophen)

Brand name: chosen by drug company or manufacturer (i.e. tylenol)

Usually use generic name

Question 4

Pharmacokinetics

Answer 4

What the body does to the drug

• Quantitative description of drug concentrations in the body over time
• The PK of a drug (as it is administered via a specific route in each patient) determines in part the optimum dose (amount and interval) to be prescribed

Dosage regimen –> Blood concentration

Related to dose
Related to the concentration achieved in the blood or tissues affected
Related to the length of time that a chemical persists in the blood/tissues

Concentration of drugs in the body at the site of action better relates to drug effects than dose

Question 5

Pharmacodynamics

Answer 5

What the drug does to the body

Concentration at site of action –> effects

Question 6

Relationship between PK and PD

Answer 6

Concentration of drug in the blood will correspond to concentration of the drug at the site of action

They will not be EQUAL but the conc of the drug at the site of action will determine the responsiveness

It is not routine to measure the blood conc of drugs during the treatment but there will be a change in the blood concentration of drugs every time you change the dose = changes in response

Question 7

Drug Distribution Process (ADME)

Answer 7

1. Absorption
   Bioavailability: degree of absorption of the drug from the site of the admin to the bloodstream (systemic circulation)
2. Distribution
   Volume of distribution: degree to which a drug accesses the different body tissues outside the blood circulation
3. Metabolism (conversion of drug into another chemical form = metabolites)
   Clearance: efficiency of drug removal by the body (impacted by drug metabolism)
4. Elimination
   Clearance is also affected by elimination (bile, feces)
   Half life: length of time for drug concentration to be reduced by 50% in the body

All ADME processes are dependent on drug movement across membranes

Question 8

PK determinants of a drug

Answer 8

• The drug may be absorbed by GI tract at different rates
• The heart pumps drug through the circ system at defined rates
• Drug enters membranes at specific rates
• Drugs are metabolized at a certain rate
• Drugs inside cells/bloodstream may bind to proteins (Reversible, Different rates for different proteins)

Question 9

Pathways of Membrane Permeation

Answer 9

Passive diffusion: drug must be hydrophobic (lipid-soluble) OR water-soluble if it moves through an aqueous channel or pore
Not common; only for tiny drugs

Facilitated diffusion: drug binds to protein, which undergoes conformational changes

Active transport: uses ATP

Endocytosis: receptor-mediated or fluid pinocytosis (for large drugs)

Question 10

Passive Membrane Diffusion

Answer 10

• Drug is transferred down a conc gradient (i.e. high to low conc)
• Membrane plays a passive role; no energy is required beyond what is necessary to maintain its integrity
• Rate of drug transport is proportional to the conc gradient and follows first-order (linear) kinetics
• Rate of Transport = k x conc where k = first-order constant
• Process is independent of other compounds
• Transport rate is determined by physicochemical properties of the drug (i.e. lipophilicity and degree of drug ionization)

Question 11

Fick’s Law

Answer 11

A drug will favour diffusion if it:

1. Is small (MW < 500 Da)
2. Has good lipophilicity
3. Lacks charge (ionization)

Rate of transport = P x SA x (Chigh - Clow)/X

P=Permeability (size, lipophilicity, ionization)
SA= Surface area
Chigh-Clow=Drug concentration difference
X = membrane thickness

Question 12

Chemical substituents that increase lipophilicity

Answer 12

Alkyl groups

Carbon rings

Aromatic rings

Fluorine
Small halogen to replace hydrogen -> reduce ability of enzymes to metabolize a drug
Adding fluorine increases lipophilicity - but this is not always the case
Fluorine isn’t a common way to increase lipophilicity

Question 13

Chemical substituents that decrease lipophilicity

Answer 13

Nitrogen, oxygen, sulfur
Alcohols
Aldehydes
Amides
Carboxylic acids (charged)
Phosphate (charged)

Question 14

Measuring Lipophilicity

Answer 14

• Observe the water-oil partitioning of a drug
• Fill a separatory funnel with a buffer at pH 7.4 as well as an oil (i.e. octanol; similar to lipid bilayer of cell membranes)
• Add drug to the funnel and shake the flask to mix the liquids and allow them to completely separate
• The drug will favour either the octanol or the water
• Greater PC = greater lipophilicity

Question 15

Partition Coefficient (PC)

Answer 15

PC = [drug]octanol/[drug]buffer

Higher PC = Higher Lipophilicity

Log(P) = Log (PC)

Question 16

pH partition hypothesis (Henderson-Hasselbach Equation)

Answer 16

• Drugs can be in ionized and un-ionized forms in the body
• Rate of passive diffusion is dependent on the conc of the diffusible form of the drug (different from the total drug level)
• Un-ionized form of drug permeates through lipid bilayers better than the ionized form
• The fraction of the drug that is un-ionized is controlled by the pH of the biological fluid and the pKa of the drug’s ionizable groups

For Acids: pH = pKa + log[ionized/unionized]

For Bases: pH = pKa + log[unionized/ionized]

Question 17

Equilibrium in Drug Ionization and Membrane Permeability

Answer 17

Weak Acids:
Deprotonated (A-) form is repelled by the membrane
Protonated (HA) form is able to traverse the membrane

Weak Bases:
Neutral form (B) is able to traverse the membrane
Protonated (BH4) form is unable to pass through the membrane

Question 18

pKa of functional groups

Answer 18

Carboxylic acid - 3 
Aromatic alcohol - 10
Aliphatic alcohol - >14
Aliphatic amine - 11
Aromatic amine - 4.5
Amide - >14

Question 19

pH of tissues

Answer 19

Blood - 7.4
Tissues - 7.4
Stomach - 1.0-3.5
Duodenum - 5-6
Jejunum/ileum - 6-8
Urine - 5-8 (tends to be more acidic)

Question 20

Physiochemical properties of drugs that necessitates carrier-mediated transport

Answer 20

Good hydrophilicity
Ionized
Metabolized to a drug conjugate (“Phase II” metabolites: sulfate, glucuronide or glutathione group added to drug)

Drugs do not always possess these chemical properties when they are substrates of membrane transporters!!!!
Hydrophobic drugs are often substrates of drug transporters despite that they are able to cross membranes by passive diffusion more readily than hydrophilic drugs

Question 21

Drug Absorption

Answer 21

Absorption is the transfer of drug from its site of administration (i.e. inhalation, oral, injection - intravenous, directly into muscle, into eye, rectal, patches) to the bloodstream

The rate and extent of absorption depend on factors in the environment where the drug is absorbed, the drug’s chemical characteristics, and it’s route of administration

Question 22

Most common route of administration

Answer 22

Oral

thus the extent of intestinal drug absorption impacts the dose of many drugs

Question 23

Factors affecting oral drug absorption

Answer 23

Gastrointestinal Tract (GIT)
Small intestine is most important for oral drug absorption due to large SA
pH varies along length from stomach (pH 1-2) to small intestine (pH 3-8)

Physiochemical: lipophilicity, molecular weight, drug ionization, chemical stability

Pharmaceutical: timing of drug release, site of drug release, tablet additives

Physiology: surface area, blood circulation, pH of lumen, gastric emptying time, first-pass effect, intestinal drug transporters

Interactions: co-prescribed drugs, food, diseases

Question 24

Bioavailability (F)

Answer 24

The proportion of drug dose which reaches the systemic circulation in an unaltered form after drug is administered
Bioavailability of a drug is often reported as % of the dose administered

calculated by comparing the area under the blood conc vs. time curves (AUCs) after a single IV bolus and an oral dose of the same size to the same individual

AUC oral / AUC injected x 100

*AUC is the exposure (area under curve)

Question 25

Comparative bioavailability

Answer 25

studies are done where subjects are administered the Brand Name and Generic drugs on separate occasions to the same individuals Blood levels of the drugs are determined IV is not necessary here - no determinations about absolute bioavailability Generic drug must show that it can deliver the same amount of medicinal ingredient at the same rate as the original brand name drug One criteria for “bioequivalence” is that the AUC of the Generic drug is between 80% and 125% of the Brand Name drug

Question 26

First Pass Effect

Answer 26

Drug can be metabolized by the gut and liver during the initial absorption of an oral dose before it reaches the systemic circulation Fraction of the drug moves from intestine to enterocytes Enterocytes have the ability to metabolize drugs This decreases the amount of drugs that enters the circulation Drug drains to liver Hepatocytes also metabolize drugs

Question 27

Drug Distribution

Answer 27

Process by which a drug reversibly leaves the blood-stream and enters the tissue interstitium (extracellular fluid) and then the cells of the tissues Interchange between blood and organs of the body The rate and extent to which a drug distributes from blood to tissues depends on: 1. Blood flow rate to each tissue (differs between tissues) 2. Structure of tissue capillaries (e.g. fenestrations) allows drugs to move more readily from the bloodstream 3. Capillary and tissue membrane permeability of a drug (diffusion and drug transport) - determined by physical/chemical characteristics for passive diffusion or presence of drug transporters in endothelial cells 4. Binding of the drug to plasma proteins and proteins in the tissues - not free-floating in solution.

Question 28

Drug distribution: blood drug levels

Answer 28

Distribution phase: After an IV dose (bolus or rapid dose) of a drug, the blood (serum, plasma) levels decline over time Elimination phase: Shortly after dose is given, drug levels decline rapidly as drug distributes into the tissues (distribution phase) Drug levels then fall less rapidly and the rate of decline in conc is dependent partly on how efficient the body is at eliminating the drug

Question 29

Volume of Distribution (APPARENT)

Answer 29

Given the same dose, when a drug has a large volume of distribution, levels in the blood are lower than a drug that has a small volume of distribution - The volume into which a drug appears to distribute after absorption and the distribution is complete - It does not give any indication of what particular tissues the drug is distributed - use IV dose Vd = amount of drug in body / concentration of drug in blood Vd differs between drugs Vd is different between individuals for the same drug Degree of body fat (and other composition)

Question 30

Physiological Volumes

Answer 30

42L can be divided into intra/extracellular volume 28 for intra 14 for extra 14L of extracellular volume 10 for interstitial 4 for plasma

Question 31

Volume of Distribution of Drugs

Answer 31

- Drugs that accumulate in organs by active transport or specific binding to tissue molecules have a high volume of distribution, which can exceed several times the anatomical body volume - Vd should NOT be identified too closely with a particular anatomical compartment - It is simply a proportionality constant relating drug mass in the body with blood concentration Vd cannot be LESS than plasma volume Vd = plasma volume cannot distribute into tissues Vd can reach very high/limitless values

Question 32

Distribution Movement

Answer 32

Capillary endothelial cells have fenestrations (holes, windows) that allow for drugs to exit the bloodstream to interact with tissues (e.g. liver, kidney, spleen) -In some tissues, capillary endothelial has gaps between cells, allowing for paracellular transport of drugs from blood to tissue (liver) HOWEVER in other organs such as the brain and testes, capillary endothelial cells form tight junctions that prevent paracellular solute movement - Component of blood brain barrier - In these organs, drugs enter tissues from blood stream via transcellular mechanisms - It must pass through the cell membranes of the capillary endothelial layer

Question 33

Plasma Protein Binding

Answer 33

Drugs can bind to plasma proteins (e.g. albumin, α1-acid glycoprotein) -Only drug in solution can readily move from blood to parenchymal cells Plasma protein binding keeps drug in vascular compartment, reducing tissue distribution and decreasing volume of distribution The pharmacological/toxicological activity of a compound is thought to be related to the free (unbound) concentration in the blood Changes in plasma protein binding may have large effects on unbound drug concentrations, drug pharmacokinetics, and response Alters how patients respond to medications