1. PHARMACOLOGY INTRODUCTION
Lecture Two

2. Factors Affecting Drug Absorption
Transport
active vs. passive pH
Physical factors
Blood flow
Total surface area
Contact time
Expression of P- glycoprotein
ATP
ADP
+ Pi A-
BH+

3. Factors Affecting Drug Absorption
Duodenum
Stomach
Ascending colon
Descending colon
Jejunum
Ileum
Small intestine
Transverse
colon
Rectum
pH of GIT fluids
Blood = 7.4
pH =
Variations exist due to:
health - fasting < pH to 1.2
disease - ulcers, gastric cancer
food - fats inhibit gastric acid
other drugs - antacids, anticholinergics
pH = 5 - 7
pH = 8

4. Effect of pH on drug absorption
Most drugs are either weak acids or weak bases.
Acidic drugs (HA) release a H + causing a charged anion (A-) to form:
HA H A–
( Protonated ) ( nonprotonted )

5. Effect of pH on drug absorption
Weak bases (BH +) can also release a H+; however, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B).
BH B H +
( Protonated ) ( nonprotonted )

7. Henderson - Hassalbach theory of dissociation
Drug dissociation constant and lipid solubility
Henderson - Hassalbach theory of dissociation
pH = pKa + [ nonprotonated species]
[ protonated species]
Weak acidic drugs
pH = pKa + [A–]
[HA]
where, [A-] = molar concentration of
the salt of the acid
[HA] = molar concentration of
the weak acid
Weak basic drugs
pH = pKa + [ B ]
[BH+]
where, [BH+] = molar concentration of
the salt of the base
[B] = molar concentration of
the weak base

8. Mechanism of Action
Inflammation: extracellular acidosis = decreased LA effect

9. Physical factors blood flow: surface area: contact time:
Expression of P-glycoprotein
Most absorption occurs
in intestine due to:
large area
carrier density

10. Physical factors
Expression of P-glycoprotein

11. lamina propria
lining epithelium
basement membrane
capillary

12. An Important Concept: BIOAVAILABIITY
Defention:
Fraction of a drug that reaches systemic circulation after a particular route of admin’n
Affected by:
1st pass metabolism (eg: Lidocaine, propranolol)
Solubility
Instability (eg: Penicillin G, insulin)
Nature of the formulation
Bioavilability = AUC oral * 100
AUC injected
Injected Dose
Serum Concentration
Oral Dose
Time

13. Bioavailability
1st pass metabolism

14. What Happens After Drug Administration?
Drug at site
of administration
1. Absorption
Drug in plasma
2. Distribution
Drug/metabolites
in tissues
3. Metabolism
4. Elimination
Drug/metabolites
in urine, feces, bile

15. 2- Distribution
Drug distribution : is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.

16. What Factors Affect Distribution?
Endothelial cells
in liver capillary
Blood flow
brain vs. fat
Capillary permeability
differences in capillary structure.
drug structure
Binding to proteins
role of albumin
Endothelial cells
in brain capillary
Glial cell

17. Blood tissue barriers

18. Volume of Drug Distribution (Vd)
Drugs may distribute into any or all of the following compartments:
Plasma
Interstitial Fluid
Intracellular Fluid
Plasma
(4 litres)
Interstitial Fluid
(10 litres)
Intracellular Fluid
(28 litres)
Vd = D/C0

19. Arggh! I can’t fit through these
So What?
Most drugs distribute into several compartments; however …
Some drugs distribute into only one or two compartments
Eg: Aminoglycoside antibiotics
Streptomycin
Gentamycin
Arggh! I can’t fit through these
darn fenestrations!

20. More “So What?” Time Serum Concentration
It takes time for a drug to distribute in the body
Drug distribution is affected by elimination
1.5
Drug is not eliminated
Serum Concentration
1.0
Elimination Phase
0.5
Distribution Phase
Drug is eliminated
Time

21. Albumin Affects Distribution
Drugs bind differentially to albumin
2 drug classifications:
Class I: dose less than available binding sites (eg: most drugs)
Class II: dose greater than binding sites (eg: sulfonamide)
The problem:
one drug may out-compete the other
Drug X
Sulfonamide

22. 3- Drug Metabolism (we’re still talking about Pharmacokinetics)

23. Drug Metabolism First pass
metabolism of drugs may occur as they cross the intestine or transit the liver
eg: nitroglycerin
Other drugs may be destroyed before absorption
eg: penicillin
Such reactions decrease delivery to the target tissues

24. First Pass Metabolism Occurs Primarily in the Liver and Gut

25. Drug Metabolism (cont’d)
Two Phases: I and II
Phase I: conversion of the lipophilic compounds
Phase II: conjugation
Phase I involves the cytochrome P-450 system
Ultimate effect is to facilitate elimination
Phase I
Oxidation
Reduction
Hydrolysis
Activation/Inactivation
Phase II
Glucuronidation
Conjugation Products

26. Drug Metabolism (cont’d)
Phase I reaction – (oxidation, reduction, hydrolysis)
Generally, the parent drug is oxidized or reduced to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH)
The more polar the drug, the more likely excretion will occur
This reaction takes place in the smooth (no ribosomes) endoplasmic reticulum in liver cells (hepatocytes)

27. Drug Metabolism (cont’d)
Phase I reaction
The smooth microsomes are relatively rich in enzymes responsible for oxidative drug metabolism
Important class of enzymes – mixed function oxidases (MFOs)
The activity of these enzymes requires a reducing agent, NADPH and molecular oxygen (O2)

28. Drug Metabolism (cont’d)

29. An Example of Phase I and II Biotransformation:
CH3CON- H
-OC2H5
Phenacetin
PHASE I
Paracetamol
CH3CON- H
-OH
PHASE II OH
Glucuronic Acid
Conjugate
CH3CON- H
-O- HO
-OH O
COOH

30. An Example of Drug Metabolism

31. Cytochrome P450 Is a family of isoenzymes
Drugs bind to this enzyme and are oxidized or reduced
Can be found in the GI epithelium, lung and kidney
Cyp3A4 alone is responsible for more than 60% of the clinically prescribed drugs metabolized by the liver

32. Cytochrome P450 enzyme induction
Stimulation of hepatic drug metabolism by some drugs
Enzyme inducers stimulate their own metabolism and also accelerate metabolism of other drugs
Ex of inducers: phenobarbital, rifampin, phenytoin, carbamazepine, griseofulvin, cigarette smoking

33. Cytochrome P450 enzyme inhibition
Some drugs may decrease the activity of hepatic drug-metabolizing enzymes
Could lead to increase levels of active drug in the body
Ex of inhibitors: alcohol, allopurinol, grapefruit juice, cimetidine, amiodarone, ciprofloxacin, clarithromycin, erythromycin, fluoxetine, isoniazid, metronidazole, verapamil, omeprazole, oral contraceptives

34. Cytochrome P450 enzyme inhibition
Two different mechanisms examples:
Cimetidine binds tightly to Cyp450 and through competitive inhibition reduces metabolism of other drugs
Erythromycin is metabolized at Cyp3A, its metabolite forms complex with enzyme and renders it catalytically inactive

35. 3. Metabolism (biotransformation) Phase II reaction
This involves coupling the drug or it’s polar metabolite with an endogenous substrate (glucuronic acid, sulfate, glycine, or amino acids)
The endogenous substrates originate in the diet, so nutrition plays a critical role in the regulation of drug conjugation

37. Enterohepatic recirculation
some drugs, or their metabolites, which are concentrated in the bile then excreted into the intestines, can be reabsorbed into the bloodstream from the lower GI tract

38. Biotransformation in the fetus or neonate
These individuals are very vulnerable to the toxic effects of drugs
Their liver and metabolizing enzymes are under-developed
They also have poorly developed blood brain barrier
Can get hyperbilirubinemia which leads to encephalopathy
Have poorly developed kidneys which can alter excretion and cause jaundice

39. Biotransformation in the elderly
Hepatic enzymes and other organs deteriorate over time
Variations in drug metabolism:
Generally, men metabolize faster than women (ex: alcohol)
Diseases can affect drug metabolism (ex: hepatitis, cardiac (↓ blood flow to the liver), pulmonary disease)
Genetic differences
Ex: Slow acetylators (autosomal recessive trait mostly found in Europeans living in the high northern latitudes and in 50% of blacks and whites in the US)

40. 4- Drug Elimination (Excretion)
Elimination of unchanged drug or metabolite from the body – terminating its activity
Most important route is the kidney
May also involve bile, intestine, lung, breast milk exhaled air, sweat, saliva, and tears.
What clinical scenarios may affect drug elimination?

42. Elimination of a drug is usually linked to renal filtration, secretion and reabsorption.

43. Mechanisms of Renal elimination of a drug
Three mechanisms for renal excretion:
Glomerular filtration – passive diffusion
Small nonionic drugs pass more readily. Drugs bound to plasma proteins do not
Tubular secretion - drugs which specifically bind to carriers are transported (ex: penicillin)
Tubular reabsorption – Small nonionic drugs pass more readily (ex:diuretics)

44. Pharmacokinetics 4- Excretion
Clearance
The measure of the ability of the body to eliminate the drug
The rate of elimination is directly proportionate to drug concentration
CL = rate of elimination/concentration of drug in biologic fluid
CLsystemic = CLrenal + CLliver + CLother
Other = lungs or other sites of metabolism
Half-life (t1/2)
The time required for the plasma concentration of a drug to be reduced by 50%
4 half-lives must elapse after starting a drug dosing regimen before full effects will be seen
> 90% steady state concentration

45. Food for Thought
What conditions might affect renal function (and therefore drug elimination)?
What other organ systems are involved in drug clearance?

46. Are We Having Fun Yet?