PHARMACOKINETICS

1. Bioavailability is defined as … … … … … … … … … … It is affected by … … … … … … … … … …

2. Do you expect a digoxin tablet synthesized by 2

different pharmaceutical companies to have similar effects? Why?

3. Can the patient opens an enteric coated capsule &

dissolves its content before intake? Why?

4. A hypertensive patient was instructed to take

captopril before meal to be fully effective. Why?

5. Why subcutaneous injection of morphine may not

be effective in case of shock?

6. A surgeon gives patient repeated injections of a

local anesthetic to drain an abscess. However, the local anesthetic fails to act. Explain

7. Oral administration is usually preferred to

sublingual administration since the latter has lower bioavailability 2ry to … … … … … … … … … … However, sublingual may be preferred in some cases because of … … … … … … … … & … … … … … … … …

8. What is the mechanism of action of

thiazides diuretics?

9. What is first pass metabolism? Give examples

10. Which routes of administration can escape

hepatic first pass effect

11. Bioavailability of IV drugs = … … … … … … …

… … …

12. Oral bioavailability is calculated by the

equation: … … … … … …

13. Define the volume of distribution (Vd)

14. The smallest Vd = … … … … … … … … … …

while the largest Vd may reach up to … … … … … … … … … …

15. What is the significance of Vd?

16. Tricyclic antidepressants (TCA) poisoning

can not be treated with hemodialysis because … … … … … … … … … …

17. What are the factors which affect Vd ?

18. What is the significance of plasma protein

binding?

19. Why highly protein bound drugs have low

Vd?

20. Why plasma protein binding interaction

occurs between warfarin & aspirin & not between diazepam & propranolol?

21. Why chloroquine is effective in hepatic

amoebiasis but not in intestinal amoebiasis?

22. What is the significance of lipophilicity?

23. Give examples for drugs which can cross the

blood brain barrier easily

24. Why physostigmine affects CNS while

neostigmine can not?

25. Why penicillin is used in treatment of

meningitis although it can not cross blood brain barrier well?

26. Give examples for drugs which can cross the

placental barrier easily. What is the clinical significance

27. Tetracyclines are contraindicated in

pregnancy because a) they can cross … … … … … … … … … … and b) they chelate … … … … … … … … … …

28. Lipid soluble drugs are eliminated by … … …

… … … … … … … while hydrophilic drugs are eliminated by … … … … … … … …

29. The aim of hepatic metabolism is … … … …

… … … … … … The metabolites are usually… … … … … … … … … … but they may be … … … … … … … …, … … … … … … … … , or … … … … … … … …

30. What are the types of hepatic metabolism?

31. The most important enzyme system of

hepatic metabolism is … … … … … … … … … … because … … … … … … … … … …

32. Why oxidation –rather than conjugation- is

more commonly involved in drug metabolism?

33. What is the pharmacological significance of

enzyme induction? Give examples

34. Give examples for enzyme inhibition

35. What are the factors that affect renal

excretion?

36. How can the pH of urine affect excretion of

drugs?

37. Why plasma protein bound drugs are not

eliminated by the kidney?

38. Give examples for drugs to be avoided during

lactation

39. Enumerate kinetic orders of elimination

40. First order kinetics is … … … … … … … … … … while zero order kinetics is … … … … … … … … … …

41. What is the meaning of saturation kinetics?

42. What are the differences first and zero order

kinetics?

43. Why zero order kinetic drugs are more toxic

than first order kinetics?

44. Css is … … … … … … … … … … It can be

reached after … … … … … … … … … … However, you can reach Css immediately by giving … … … … … … … … … …

45. The kinetic order of glomerular filtration is

usually … … … … … while that of metabolism by conjugation is usually … … … … …

46. Define half life (t½). What are the factors

affecting it?

47. What is the significance of elimination half

life?

48. Why the best dose interval ≈ t½?

49. How can you adjust the dose regimen of

drugs eliminated by the kidney in patients with renal impairment?

50. What is meant by systemic clearance & organ

clearance?

51. Why changes in hepatic blood flow markedly

affect the elimination of propranolol but not warfarin?

52. What are the factors affecting systemic

clearance (CLs)?

53. What is the significance of calculating CLs?

54. Define extraction ratio (ER)?

55. What is the relation between Vd, t½ & CLs

56. Enumerate types of drug-drug interactions.

Give examples

Bioavailability is defined as the fraction of the dose

which reaches the systemic circulation. It is affected by:

1. Factors which affect absorption e.g.

• dosage forms factors (synthesis technique & exipients added to the formulation)

• drug factors (molecular weight, solubility coefficient, pKa)

• patient factors (the rate of gastric emptying, GIT transit time, surface area available for absorption, presence of GI disease)

• GIT contents and their pH (secretions; food; other drugs)

2. Factors which affect first-pass metabolism e.g. portal blood flow and hepatic enzyme activity

No, because the exipients added by one company may be

different from another company. In fact the cardiac glycoside digoxin as well as the antiepileptic phenytoin are 2 famous drugs that were recorded to induce toxicity on changes of the dosage formulation.

No, because the enteric coat protects the drug from

gastric HCl. Proton pump inhibitors (used for peptic ulcer) are famous examples. However, they may be taken with excess alkaline fluid to protect them if the enteric coat is to be broken.

Captopril is one of the angiotensin converting enzyme

inhibitors. The bioavailability of most members of this group is seriously impaired by food.

Because in presence of shock, there is nearly no blood

supply to the subcutaneous tissue as most of the blood is diverted to the important organs morphine will not be absorbed after SC injection. IVI is advised in case of shock.

Local anesthetics are weak bases and accordingly, they

are ionized at the acidic pH of pus they will not be able to cross the cell membranes since ionized drugs are hydrophilic

Oral administration is usually preferred to sublingual

administration since the latter has lower bioavailability 2ry to limited extent of absorption (small surface area of sublingual mucosa). However, sublingual may be preferred in some cases because of rapid rate of absorption & no first pass metabolism

Diclofenac sodium or potassium are famous NSAIDs,

however, they has short duration of action due to rapid elimination. The resinate form of diclofenac retards the absorption of the drug prolonged duration of action

First pass metabolism is pre-systemic metabolism

(metabolism of the drug before it reaches the systemic circulation) e.g. • Hepatic first-metabolism e.g. propranolol,

nitroglycerin, morphine • Intestinal first pass metabolism e.g. tyramine,

estrogens • Pulmonary first pass metabolism e.g.

isoprenaline, nicotine

• Sublingual & parenteral routes completely

escape hepatic first pass effect • Rectal route partially escapes hepatic first pass

effect since the blood supply from the upper rectum passes to the portal circulation (inferior mesenteric blood vessels) while that of the lower rectum passes to the systemic circulation (pudendal blood vessels)

Bioavailability of IV drugs = 100% since the entire

dose reached the systemic circulation

Oral bioavailability (F) is calculated by the equation:

F= AUC after oral administration/ AUC after IV administration

It the constant that relates the amount of drug in the body

to its plasma or blood concentration: Vd = Dose/ Concentration

The smallest Vd = blood volume (in case all the

drug remains in the blood) while the largest Vd may reach up to infinity (in case all the drug passes to the tissues i.e. the concentration = 0)

• High Vd drugs are cumulative drugs e.g. dioxin

• High Vd drugs are not amenable to dialysis e.g.

TCA • Estimation of the loading dose (LD= Vd * Css/

Bioavailability)

Tricyclic antidepressants (TCA) poisoning can not be

treated with hemodialysis because the Vd of TCA > 300 L; this implies that most of the drug escapes to the tissue it is impossible to get rid of it by hemodialysis. In fact, suicide with TCA is very difficult to treat and almost ends fatally.

• Blood flow • Plasma Proteins Binding • Tissue Binding • Lipophilicity (pH, PKa)

• It may facilitate drug absorption

• It decreases Vd • It protects from renal excretion (bound drug cannot

be filtered) & probably from hepatic metabolism as well

• The bound drug is inactive but provides a reservoir that releases the free active drug

• Significant drugs interaction may occur between at the acidic site of albumin between highly bound drugs

Because protein-bond drugs can not pass across cell

membranes (e.g. can not enter CNS or to inside the cells) remain in the circulation

Because the acidic binding site (which binds warfarin and

aspirin) has limited binding capacity while the basic binding site (which binds diazepam and propranolol) has high binding capacity.

Because chloroquine is concentrated in the hepatocytes

• Lipophilicity facilitates drug absorption

• Lipophilicity increases Vd, (lipophilic drugs can

penetrate into most tissues e.g. CNS & placenta or enter the cells).

• Lipophilicity enhances hepatic elimination (lipophilic drugs can enter the hepatocytes)

• Lipophilicity reduces renal excretion (due to enhanced tubular re-absorption)

General anesthetics, antidepressants, antipsychotics,

opioids, levodopa

Because physostigmine is 3ry amine (non ionizable, lipid

soluble) can cross the blood brain barrier while neostigmine is 4ry ammonium compound (ionizable, water soluble) can not cross the blood brain barrier

Because in meningitis, the permeability of the blood brain

barrier is increased

Morphine asphyxia neonatorum Warfarin fatal hemorrhage & malformation Sulphonylurea group of drugs neonatal hypoglycemia Methimazole fetal goiter and hypothyroidism Glucocorticoids used for treatment of respiratory

distress syndrome

Tetracyclines are contraindicated in pregnancy

because a) they can cross the placenta and b) they chelate calcium of bone & teeth

Lipid soluble drugs are eliminated by hepatic

metabolism (can enter the hepatocytes easily) while hydrophilic drugs are eliminated by renal excretion (are not reabsorbed after filtration)

The aim of hepatic metabolism is to convert lipid

soluble drugs into water soluble metabolites. The metabolites are usually pharmacologically inactive but they may be more active, equally active or more toxic than the parent drug

Phase I reactions e.g. oxidation, reduction, hydrolysis Phase II reactions (conjugation) e.g. acetylation,

glucuronidation

The most important enzyme system of hepatic

metabolism is microsomal cytochrome P450 oxidase because it has many isozymes each is specific for certain chemical structure e.g. CYP 3A4, CYP 2C19 …etc. The metabolism by CYP 450 oxidase is non-restricted. In addition it is liable for enzyme induction when needed. However, it is also liable to enzyme inhibition

Because oxidation does not require synthesis of any

additional substances (non-synthetic reactions) while conjugation requires synthesis of the substance to be conjugated (synthetic reactions)

• Adaptation for pharmacological pollution e.g.

nicotine in smokers • Explains tolerance to some drugs e.g.

phenobarbitone • May result in drug interactions e.g. rifampicin can

increase elimination of warfarin and phenytoin can increase the metabolism of estrogen in oral contraceptive

• It may be used for therapy e.g. phenobabitone is used to induce the metabolism of bilirubin in neonatal jaundice

Chloramphenicol, cimetidine, ciprofloxacin, erythromycin,

Ketoconazole

Glomerular filtration rate: determines the rate of drug

filtration Plasma protein binding: prevents drug filtration pKa of the drug & pH of urine: determines the rate of

drug reabsorption

If the urine pH is acidic ionization of basic drugs with

high pKa e.g. amphetamine while If the urine pH is alkaline ionization of acidic drugs with high pKa e.g. phenobarbitone

Ionized drugs are not reabsorbed by the tubular & thus excreted in urine

Because albumin (as well as the drugs bound to it) can not

pass through the glomerular pores

• Some antibiotics e.g. chloramphenicol ( grey baby

syndrome), sulfonamides ( kernicterus), tetracycline ( bone & teeth deformities)

• CNS depressants e.g. opioids, sedative hypnotics, alcohol fetal respiratory depression

• Some laxatives e.g. senna, cascara ( fetal diarrhea)

• Corticosteroids ( fetal growth retardation) • Bromocryptine & estrogen ( suppress lactation)

First order kinetics Zero order kinetics Saturation kinetics

First order kinetics is the kinetics in which the rate

of elimination ∝ concentration (i.e. a constant fraction of drug is eliminated per unit time) while zero order kinetics is the kinetics in which the rate of elimination is constant (i.e. a constant amount of drug is eliminated per unit time)

It is the kinetics in which the drug follows first order

kinetic at low dose but follows zero order kinetics at high doses e.g. phenytoin, salicylates, theophylline.

It is called saturation kinetics because the eliminating enzyme is saturated with the drug at low concentration. Accordingly, modest increase in the dose can result in non-predictable increase in the blood level

First order kinetics Zero order Kinetics

The rate of elimination ∝ concentration

The rate of elimination is constant

Exponential concentration-time curve

Linear concentration-time curve

It has a constant t½. No constant half life

Repeated dosing steady state concentration (Css) which is ∝

dose Time to reach the Css ≈ 4-5 t½

Repeated dosing no Css; but overshot in drug

concentration

Modest changes in dose or bioavailability do not cause

toxicity

Modest changes in dose or bioavailability can lead to

toxicity.

Examples: Most drugs are eliminated by this method

Examples: ethanol

Because repeated dosing overshot in the blood

concentration

Css is the concentration achieved by repeated

dosing when the rate of elimination = the rate of administration of the drug. It can be reached after 4-5 t½. However, you can reach Css immediately by giving a loading dose

The kinetic order of glomerular filtration is usually

first order kinetic while that of metabolism by conjugation is usually saturation kinetics

It is the time required to reduce the plasma concentration

of drug to half the initial concentration It is affected by:

• The state of the eliminating organs i.e. liver & kidney functions

• The delivery of the drug to the eliminating organs e.g. i. drugs with very high Vd are accumulated in

the tissues & escape from elimination. ii. Plasma protein binding limits renal filtration

as well as penetration of the drug into the hepatocytes

• It is an index of drug elimination • It determines the dosage interval; the best is to

give the drug every t½ • It indicates the time required to attain steady state

concentration: ≈3-4 t½

• If τ = t½ body stores twice the dose (for most

drugs, this is an accepted choice) • If τ < t½ more drug accumulation occurs. • If τ > t½ decrease in drug concentration occurs

between doses.

The dose is adjusted according to the glomerular filtration

rate which can be estimated by creatinine clearance. We can either: • Decrease the dose (the best) • Increase the dose interval (may lead to

fluctuation in blood levels of the drug)

Systemic clearance is the volume of a fluid cleared from

the drug per unit time. (= sum of individual organs clearance)

Organ clearance is the volume of blood cleared by the organ in unit time (= organ blood flow * extraction ratio)

Because propranolol has high extraction ratio (i.e. the liver

can extract the excess amount delivered to when the hepatic blood flow in increased) while warfarin has low extraction ratio (i.e. the liver can extract no more drug if the hepatic blood flow is increased)

They are the same as those affecting the elimination t½

Estimation of the maintenance dose; maintenance dose =

CLs * Css /Bioavailability

Extraction ratio is the fraction of the drug eliminated by

the liver ER= Hepatic blood flow * (CA-CV)/CA

Where CA=arterial concentration & CV= venous concentration

t½=0.693 * Vd/Cls

Where 0.693 = Ln 2 (the natural logarithm of 2)

A) Pharmaceutical interaction: interactions that

occur outside the body e.g. adding penicillin to streptomycin in the same syringe

B) Pharmacokinetic interactions: interactions that affect the action of the drug 2ry to changing its blood level: a. Absorption: e.g. metoclopramide enhances

absorption of aspirin b. Distribution e.g. aspirin displaces warfarin from

plasma proteins c. Metabolism e.g. phenytoin enhances estrogen

metabolism d. Excretion e.g. probenicid inhibits penicillin

excretion C) Pharmacodynamic interactions: interactions that

affect the action of the drug without changing its blood level: a. Synergism: e.g. antihistaminic drugs enhances

sedatives action b. Antagonism: e.g. aspirin reduces the diuretic

action of loop agents