i want 25 multiple choice questions with their model answer below each question that covers different aspects of the following information: 1V) Excretion
Removal of a drug from the body may occur via a number of routes, the most important being through the kidney into the urine. Other routes include: the GIT, skin glands, and the lungs.
Clearance: Clearance of drugs is the process through which a drug or its metabolites can be eliminated from the body.
A) Renal:
1- Non-volatile drugs and metabolites are excreted in the urine.
2- Renal excretion is the result of glomerular filtration and active tubular secretion & reabsorption.
3- Passive Glomerular filtration for water soluble non-bound drugs with M.W. < 500 daltons e.g. Mannitol.
4- Active Tubular Excretion (Saturable & Site for competition & Drug Interaction):
o Weak acid drugs e.g. Penicillin o Weak base drugs e.g. Digoxin
i
T o
5- Changes in urinary pH—> Affect excretion of weak Acid & Base drugs: a) Alkalinization of urine (by giving Na or K Acetate, Bicarbonate or Citrate) -1 Renal excretion of weak acid drugs e.g. aspirin = lon Trapping.
b) Acidification of Urine (by giving NH4Cl or ascorbic acid “Vit C”) —T Renal excretion of weak Base drugs e.g. Ephedrine = lon Trapping
6- The clearance of some drugs depends mainly on renal excretion (Little metabolism) e.g. Atenolol, — Caution in Renal patients.
or no B) The Lungs — Gases (CO2) & Volatile Liquids (Halothane which is used in anesthesia).
C) The Alimentary Tract: 1-_Saliva (pH = 8): lodide. 2- Stomach— Morphine. 3- Bile: some drugs may be secreted in the bile by a mechanism similar to that of renal tubular drug secretion. Such drugs reach the intestines in the bile and can have one or more of the following fates: - Be excreted in large intestine or - Be absorbed again from the small intestines and so undergo enterohepatic
circulation. e.g., Rifampicin. - Some anti-microbials are excreted in bile in an active form e.g. Ampicillin — Useful
in treatment of Cholecystitis & Typhoid carrier. 4- Large Intestine: Either via the bile or unabsorbed oral drugs.
12D) Skin Glands:
1- Sweat-> Vit B-1, Hg, As (arsenic) & Rifampicin results in red discoloration of sweat.
2- Milk
a- Most of drugs administered to lactating women are detectable in breast milk.
b- pH of milk (7) is more acidic than plasma (7.4) — lon trapping for basic drugs.
c- Milk is rich in fat — Retention of lipid soluble drugs.
d- May affect suckling baby e.g. purgatives
Fundamental Principles of Pharmacokinetics
To treat a certain disease, we need to maintain a steady state concentration (Css) or
constant drug level.
« To maintain a steady state concentration (Css) the dose regimen must be designed to
replace the medication at approximately the rate with which it is eliminated (rate of drug
administration = rate of drug elimination).
¢ The most accurate way to do this is with a constant intravenous infusion, but an attempt
to maintain an approximate steady state can be reached with repeated doses.
¢ Elimination processes may be first or zero order kinetics.
A) First-Order (Linear) Kinetics:
1-
Kinetics
of
drug
(ADME)
PROPORTIONAL to its concentration.
B) Zero-Order (Saturation) Kinetics:
are | 1- Limited capacity of drug’s kinetics due to
SATURATION of involved enzyme &/or
2- Fixed FRACTION (%) of the drug is | carrier = Rate of kinetics is Fixed and NOT
eliminated per unit time.
proportional to drug concgmration
3- LINEAR drug disappearance curve.
4- CONSTANT t12.
5- AUC is PROPORTIONAL to
concentration.
drug
2- Fixed AMOUNT of the,i drug_is eliminated |_
per unit hme
|3- NON-LINEkRmd pfieafienee—euwe—-
4-
ti2 increases with mcrease ki drug
6- Repeated intake of the drug at regular | concentration.
intervals—> Css within 4 — 5 t1/2.
5- AUC is NOT proportional to the drug
7- Examples:
concentration.
- Most drugs obey first order kinetics | 6- If the rate of intake of a drug exceeds its
when given in therapeutic doses.
rate of elimination, this leads to accumulation
-
Small
Phenytoin.
doses.
of
aspirin
and | of the drug leading to toxicity.
Toxicity.7- Examples: L.D. of aspirin and
phenytoin.
13Clearance is expressed as the volume of body fluid from which drug is
removed in unit time
Clearance Cl = Kerx Vo=
(0.693/t1/2) x Va
- Kol is the rate constant of elimination or the percentage of drug eliminated per unit
time (usually per hour) and it = 0.693/t12
-Va=A (mg)/C (mg/ml)
where A = Amount in mg, C = Initial concentration of drug in plasma mg / ml.
- ty2 = Plasma half-life of the drug.
Plasma Half Life (t %):
1- Time needed for the plasma drug concentration to decrease to one half. .
2- Itis affected by clearance and volume of distribution (Vd).
3- For some drugs, the biological t1/2 exceeds the plasma t1/2. This happens if the effect of
the drug persists even after the drug disappears from plasma (Hit and Run). An example is
reserpine which inhibit granular uptake of noradrenaline by irriversible inhibition of vesicular
enzymes and so re-synthesis of new enzymes is needed.
-4- Repeated administration of a drug (that follows first order kinetic elimination) at regular
intervals will lead to achievement of a platuae (Steady State) plasma concentration Css
within 4-5 t1/2s.
2
‘Steady State
Attained atter approximately four haif-times
- Time 1o steady
independent of dosage
‘TIME (multiples of elimination half-time)
5- Most of the drug (> 95%) disappears from the body within 4-5 t12 after stopping its intake:
ti2
t2
100% —> 50%—>
(4 50%)
L 75%)
t2
ti2
25% —> 125%—>
(4 87.5%)
(19375%)
tiz
625%—>
3125%
(4 96.875%)
6- The t %2 is useful to determine the frequency & route of drug administration.
14Loading dose: 1- The initial dose of the drug which can raise its plasma level to the target concentration.
2- Used to reach Css very rapidly as in emergency e.g digoxin in acute heart failure.
3- Loading dose = Va4 x desired concentration . 4- Unexpected toxicity can occur.
Repeated self-administered doses '15 30
Maintenance dose: 1- The dose needed to replace the drugs eliminated since the preceding dose, to maintain steady state (Css).
Time (minutes)
2- The maintenance dose= Cl x Css X Tm Cl = Clearance
Css =steady state concentration Tr= dose interval
3- The smaller the dose interval, the smaller the maintenance dose. 4- If the drug is taken by infusion, dose interval (T = ONE unit of time = 1.
Infusion rate (mg/min) = clearance (ml/min) x Css (mg/ml