Pharmacokinetics

Question 1

Determinants of absorption

Answer 1

• Drugs are found as acid & bases that ionize in solution
• Uncharged species readily crosses membrane = absorbed
• Absorption of Acid or Base depends on the local PH enviroment
• Acidic PH = acids protonated = Uncharged
• Acidic PH = Bases protanted = charged
• Alkalinization of urine = excretion of acidic substances (aspirin)

Question 2

Determinants of distrubution

Answer 2

• Binding of drugs to plasma proteins will INCREASE volume BUT NOT active
• Bound drug = volume of distrubtion
• Drugs compete for SAME protein - displacement = alter conc of ACTIVE drug
• Binding below 80-90% not relevant BUT above 95% ALWAYS relevant
• BBB VERY selective barrier for CNS
• In severe meningitis it can breakdown allowing for PENICILLIN to infiltrate @ high dose = treatment

Question 3

Time course & plasma conc for drug

Answer 3

• Rate of drug elimination is NOT constant depends on conc of drug
• Higer conc = Faster elimination
• dC/dt = -K (x) C
• t 1/2 = 0.63/k
• Takes 3-4 1/2 lives to eliminate 90% of drug
• Zero order kinetics = drug is eliminated regardless of conc (alcohol)
• Batemann function combines invasion & elimination
• Slow absorption = long duration in body BUT max plasma conc will NOT be high
• Fast absorption = faster duration BUT max plasma conc HIGH
• Anaesthesia low conc = Fast absorption
• Anti-epileptic drugs = high conc = slow absorption

Question 4

Bateman Single & Multi

Answer 4

• Semilog plot of plasma conc over time = Straight line (ONE comparment model)
• Multicomp:
• Drug will distribute into chief & peripheral comp
• Great drop in conc in chief = drug eliminated into periphery
• Peripheral comp will REPLENISH cheif during elimination
• RESULT: 2 (1/2) lives
• 1. short steep - Distrubution
• 2. longer and LESS steep -Terminal
• _3 comp = 2 peripheral comp _
• Factors = rate of distribution & capacity in each comp
• 3 (1/2) lives = alpha, beta, gamma
• Last half life always terminal - 1/2 lives become longer as you move down

Question 5

Example of Multicompartment

Answer 5

• _Thiopental (Injectable anesthetic) _
• Fast shallow comp in brain
• Slow deep comp in Fatty tissue & muscle
• Fast distrubution to brain BUT Pt wakes up after 15 min despite little drug elimination
• DUE to plasma conc & Brain (chief) will distrubute to fatty tissue/muscle (peripheral)
• Fast comp = Brain, kidneys, liver, lung
• Slow comp = fatty tissues & bone (muscle)
• Compartment properties = substrate specific (healthy brain are slow comp for penicillin)

Question 6

Area under the curve

Answer 6

• Not DEPENDENT on absorption speed
• Physical dimensions of AUC = Plasma conc (x) time
• Determine bioavailability measure AUC for an IV route 100% & measure AUC after oral admin (70%)
• BA is important for dosage conversion w/different forms of application (different formulations of same drug)
• Lower BA = HIGHER variation in absorb
• HIGHER BA = more stable drug absorb
• Lower BA is **unsuitable for oral dosing **
• Ex. Nitro 0% oral

Question 7

AVD (apparent volume distrubution)

Answer 7

• Total distrubution of DRUG calculated if APPLIED dose & initial plasma conc are KNOWN
• AVD measured by Liters per meter squared (L per m2 of body surface)=related to drug metab
• Determine Avd from plasma curve take semilog plot & located position of Beta-elimination = solve line back to 0 hour
• 0 hour = initial plasma conc
• Drug evenly distrubuted between compartments AVD = **real volume of distrubution **
• 3L distrubutes plasma only
• 15L distrubutes in ECF
• 50L distrubutes into Total body fluid space
• Greater than 50 accumulation in tissue or percipitates out
• Ex Doxorubicin = Anti leukemia drug 650 L/m2 needed to be distrubuted THROUGHOUT

Question 8

Solving for Clearance

Answer 8

• If you have clearance = Calculate amount of drug if you have plasma conc
• Clearance is additive via diff routes = TOTAL clearance (Cl kidney + Cl Liver + Cl gall bladder…)
• _Clearance = AVD (x) k _
• k= 0.693 is half life

Question 9

Drug dosing

Answer 9

• Consider target plasma lvls
• therapeutic margin (TD50 / ED50)
• Bioavail (except IV)
• AVD
• Clearance or 1/2 life
• Loading Dose:
• Drugs w/very long 1/2 life = long time b4 reach equilibrium
• Loading is given to SHORTEN time interval to reach equilibrium
• Increased risk of toxic peak levels
• Drugs with low therapeutic index NOT used
• given in SLOW doses - prevent high peak lvls

Question 10

Maintenance levels

Answer 10

• Aim to maintain steady state level plasma conc = repetitive dosing or constant infusion
• Repetitive dosing = NEW equilibrium levels reach after 4-6 1/2 lives
• Infusion = drug is delivered to plasma @ constant rate - drug elimination increases w/INCREASE in plasma lvls
• BUT stay constant when speed of infusion=drug elimination
• **Drugs w/short 1/2 lives work best **

Question 11

Formulas for BA

Answer 11

• PC (plasma conc) = Dose / AVD (apparent volume of distrubution)
• CL = AVD (x) 0.693 1/2 life
• Maint dose = PC (x) CL (which can be additive)

Question 12

Oscillation in plasma conc

Answer 12

• _Related to multiple dosing _
• Minimal & max conc kept w/in therapuetic range
• Reduce chance of oscillation DECREASE dose interval & use drugs w/LONG 1/2 life
• Sustained release prep
• Continous infusion NO peaks/valleys Is OPTIMUM for eliminating oscillating conc