Pharmacokenetics

Question 1

Therapeutic window

Answer 1

between MEC (Min Effect Conc) and MTC (Min Tox Conc)

Question 2

Absorption

Answer 2

The process of the drug entering the bloodstream

Question 3

Distribution (and factors)

Answer 3

Dispersion of drug throughout tissues in the body (permeability, blood perfusion, plasma protein binding)

Question 4

Metabolism

Answer 4

The conversion of a drug into other molecules to increase excretion

Question 5

Excretion

Answer 5

removal of drug in body (faeces, urine, sweat, saliva, exhalation) gall bladder (MW > 350), lungs (inhaled + non soluble)

Question 6

Bioavailability (and factors)

Answer 6

F=AUCoral/AUCiv - fraction of drug dose ingested orally that goes to the systematic circulation (enzyme activity, pH, gastric motility)

Question 7

Vd

Answer 7

= A/Cp - volume drug appears to be uniformly distributed at the concentration measured in the plasma.

Question 8

Css

Answer 8

steady state conc - equilibrium (in=out/dose=elimination)

Question 9

Loading dose

Answer 9

target Css x Vd

Question 10

Topical

Answer 10

surface

Question 11

enteral (2)

Answer 11

GI tract (oral, sublingual-dissolved)

Question 12

parenteral (3)

Answer 12

avoid GI (IV bolus - all at once/infusion, IM-intramuscular, subcutanous-underskin)

Question 13

Oral absorption factors

Answer 13

GI motility, disorders, other drugs, illness, blood flow, food, size, ionisation, lipid solubility

Question 14

Phase 1 metabolism

Answer 14

increases water solubility - small changes (oxidation) via CYP450 = target for phase 2

Question 15

Phase 2 metabolism

Answer 15

increases size via conjugation (nutrition/cofactors - niacin NADPH CYP, cysteine GSH, sulphate PAPS)

Question 16

CYP450

Answer 16

mono-oxygenases, NADPH-CYP450 molecule, reactive Oxygen

Question 17

CYP3A4

Answer 17

largest and most common

Question 18

CYP2D6

Answer 18

human polymorphisms = different reactions

Question 19

CYP2E1

Answer 19

smallest

Question 20

Half life

Answer 20

how long it takes to halve conc (exp)

Question 21

Drug response factors

Answer 21

age, ethnicity, pharmacogenetics, enterohepatic circulation, nutrition, intestinal flora, sex, liver and heart disease

Question 22

Phase two metabolism enzymes

Answer 22

Epoxide hydrolase (EH), Sulfotransferase (ST), UDP Glucoronsyl Transferase (UDPGT), Glutathione S-Transferase (GST)

Question 23

Epoxide hydrolase

Answer 23

epoxide plus H2O to diol (highly reactive)

Question 24

Sulfotransferase

Answer 24

sulphation = phenols (low capacity), alcohols, hydroxyamines, cytosolic (liver, gut, kidneys), cofactor-PAPS

Question 25

UDP Glucoronsyl Transferase

Answer 25

glucuronidation = conjugation with endogenous glucuronic acid (UDPGA), liver-sER lumen, attacks diff groups

Question 26

Glutathione S-Transferase

Answer 26

glutathione conjugation = endogenous tripeptide, electrophilic centre, soluble or microsomal, GSH, varies

Question 27

B-glucuronidase

Answer 27

bacteria? hydrolyses glucuronide conjugated drugs - unconjugated = entero-hepatic recycling (bile duct)

Question 28

Ion trapping

Answer 28

alter urine pH to change excretion, pH = pKa +Log(ionised/unionised), pH below pKa = unionised = reabsorbed

Question 29

Metabolic elimination

Answer 29

= 1 - fu (fraction unchanged)

Question 30

Clearance

Answer 30

Cl (L/h) plasma drug conc at steady state (constant, low = high Css)

Question 31

Rate of elimination

Answer 31

Cl x Cp (mg/h)

Question 32

Partition coefficient

Answer 32

p = [L]/[W] soluable, high p = more absorption

Question 33

Rule of 5

Answer 33

M < 500 daltons, octanol-water partition coefficient log P < 5, <5 H bond donors, <10 H bond acceptors

Question 34

BBB

Answer 34

passive transport, size dependant gaps and transporter protein families (efflux proteins eg PGP1) , 98% don’t cross (M<400, < 8-10 H bonds)

Question 35

Penicillin in bioavailability

Answer 35

unstable in the gut = excreted unchanged

Question 36

Tubocurarine in bioavailability

Answer 36

poorly absorbed as it is not lipid soluble

Question 37

Simvastatin in bioavailability

Answer 37

metabolised in gut wall

Question 38

Glyceryl trinitrate GTN in bioavailability

Answer 38

metabolised in intestine/liver = 100% first pass

Question 39

Morphine in bioavailability

Answer 39

50-70% first pass metabolism (some oral bioavailability)

Question 40

Benzodiazepine in metabolism

Answer 40

action effected by hormones, elderly decreases in metabolism

Question 41

Prodrug for active metabolite

Answer 41

L-dopa

Question 42

Drug inactivation example

Answer 42

Alcohol to acetaldehyde to (disulfiram inhibits ALDH) acetic acid

Question 43

Toxic metabolite

Answer 43

Paracetamol can go to four substrates one causes liver cell death (NAPQI)

Question 44

CYP grapefruit inhibits transcription and dextamethasome promotes transcription (cocaine is substrate)

Answer 44

CYP3A4

Question 45

CYP2D6 substrates

Answer 45

CYP fluoxetine inhibits, antidepressants and codeine are substrates

Question 46

CYP ethanol induces via ligand stabilisation, paracetamol is substrate.

Answer 46

CYP2E1

Question 47

Phase 2 metabolism drugs

Answer 47

- Epoxide hydrolase = tobacco smoke (PAH to diol, carcinogenic) - UDP Glucoronsyl Transferase = THC-COOH (CYP2C)

Question 48

Paracetamol metabolites

Answer 48

UDPGT, ST, CYP2E1 -> GST, NAPQI (cell death)

Question 49

Codeine metabolism

Answer 49

glucuronides excreted, heroin and codeine -> morphine -> glucuronidine = bad

Question 50

Ethanol elimination

Answer 50

zero order elimination (saturable)

Question 51

BBB diffusion example

Answer 51

Crizotinib- bad BBB, lorlatinib - good BBB diffusion

Question 52

Renal excretion

Answer 52

A: Glomerular filtration of plasma water + unbound drugs B/C: Active tubular secretion (carrier meditated) D: Tubular reabsorption of nutrients in renal tubule E: Urinary excretion

Question 53

Absorption barriers

Answer 53

Lipid membranes, transporter proteins, enzymes