Pharmacology is the study of the interaction of chemicals with living

systems.

- Human Pharmacology

▪ Neuropharmacology

▪ Behavioral Pharmacology

▪ Cardiovascular Pharmacology

▪ Molecular Pharmacology

▪ Clinical Pharmacology

▪ Chemotherapy

▪ Biochemical Pharmacology
 Pharmacokinetics

Drug absorption, distribution, metabolism &

Excretion

Involves permeation across cell membranes

which depends on

▪ drug solubility (especially in lipid)

▪ concentration gradient
▪ surface area and vascularity
 Pharmacokinetics

Ionization
▪ Weak acids or bases exist in either nonionized or
ionized in equilibrium depend on pH and pKa pH at
which the molecule is at which 50% ionized and 50%
nonionized

▪ Only
nonionized (uncharged) drugs form cross
biomembranes
 Ａｃｉｄｉｃ　ｍ Ｂａｓｉｃ　ｍｅ
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ｐＨ＜ｐＫａ ｐＨ＞ｐＫａ
Ｗｅａｋ R-COOH RCOO- + H+

Acid (across membranes)

Weak RNH3+ RNH2 + H+
(across membranes)
base
% Ionization is determined by
Henderson-Hasseibalch eqn.
Weak
pH - pKa = log [ionized]
[nonionized]
Acids
Weak
pH - pKa = log [nonionized]
Bases [ionized]
Degree of ionization and Clearance versus pH Deviation from pKa

Weak

Renal Clearance of Drug

% nonionized forms
80 base

60

40

Weak
20 acid

-2 -1 0 +1 +2
pH - pKa
 Table 1-1. Percent Drug Ionized as a Function of pH

pH-pKa -2 -1 0 +1 +2

Weak Base 99 90 50 10 1

%nonionized 1 10 50 90 99
Example

Morphine is a weak base (pKa= 8.0). What %

will be ionized in the urine at a pH of 6.07

pH – pKa = -2

From the table, 1% of morphine is in nonionized form, so

99% is ionized
 Ionization Increases Renal Clearance of Drugs

•Only free, unbound drug is filtered

•Both ionized and nonionized forms are filtered
•Only nonionized forms undergo secretion and reabsorption
•Ionized forms of drugs are “trapped” in the filtrate
 Ionization and Renal elimination

Acidification of urine

▪ Increases ionization of weak bases

Increases Renal elimination

Alkalinization of urine

▪ Increases ionization of weak acids

Increases Renal elimination
Modes of Drug Transport Across Membranes

Mechanism Energy carrier Direction Saturable

Required

Passive No No Down No
diffusion gradient

Not passive No Yes Down Yes

diffusion gradient

Active Yes Yes Agaisnt Yes

diffusion gradient
 Absorption

•Drug entry into the systemic circulation from site of

administration
•Determinants are those for drug permeation
•Intravascular administration (IV) does not involve
absorption
•With extravascular administration (eg. PO, IM, SC,
inhalation) less than 100% of a dose may reach the
sytemic circulation, due to variations in bioavailability
 Plot of Plasma Drug Concentration and Time

Cmax
Plasma Drug Concentration

rptio
n minimum effective
concentration
Abso

elim
inati
on

lag tmax Time

Duration of action
Onset of activity
 Plasma Drug Concentration and Time

•Cmax , maximal drug level obtained

•Tmax , time at which Cmax occurs
•Lag time, time to appearance in blood
•Onset, time to reaching MEC
•Duration, time above MEC
•Time to peak, time to Cmax
 Bioavaibility

Plasma Drug Concentration Cmax Intravascular dose

Cmax /extravascular dose

Time

Fraction of dose reaching systemic circulation

AUCPO
F = AUC
IV

IV doses have 100% bioavailability, F=1

 Bioavailibility

Extent of absorption (f)

After oral administration, a drug may be incompletely

absorbed, due to lack of absorption from the gut.
Example: only 70% of a dose of digitoxin reaches the
systemic circulation

First-Pass Effect

Oral absorption into portal circulation can result in rapid liver metabolism
*may decrease bioavailability* first pass effect.
 Bioavailability

Effect of first-pass hepatic elimination on bioavailibility is expressed

as extraction ratio (ER):
Clliver
ER =
Q

Q: hepatic blood flow, normally about 90 L/h in a person weighing 70 kg

Bioavailability (F) = f x (1-ER)

Example: morphine is completely absorbed with f=1, but ER= 0.67. Thus F=
33%
 Distribution

•Depends on drug solubility and binding to plasma proteins

•Equilibrium between bound and free drug molecules
•Only unbound drug (free fraction) exerts pharmacological effects

Free DRUG + PROTEIN ↔ DRUG-PROTEIN

Complex
 Distribution

Comparison for plasma protein binding sites may

increase drug fraction, possibly enhancing effects of
drug displaced

Example

Anticoagulant effects of wafarin increased by

displacement from plasma albumin by sulfonamides
 Special Barriers to Distribution

Placental

•Most drugs cross the placental barrier, but fetal blood level
usually lower than material

Blood Brain

- Permeable to lipid-soluble or very small drug molecules

 Special Barriers to Distribution

Redistribution

Lipid-soluble drugs redistribute into fat tissues prior to

elimination-repeated doses cause saturation-may prolong
duration of action
 Apparent Volume of Distribution (Vd)

Correlates drug dose with resultant plasma levels

V = Dose/C0 where Co= [plasma] at zero time

 Apparent Volume of Distribution (Vd)

•The higher the Vd, the lower the plasma concentration

and vice versa
•Vd is low when a high % of drug is bound to plasma
proteins
•Can only calculate Vd using dose if one knows Co
 Biotransformation
(Drug Metabolism)

▪ Conversion of drug molecules to more water – soluble metabolites

that are more readily excreted.
▪ Results in formation of compounds with less pharmacologic activity
that determines the elemination rate.
▪ Metabolism may result in formation of active metabolites
▪ Pro-drugs have no activity until they undergo metabolite activation
 Drug Metabolism

Phase I
Modification of the drug molecule via oxidation, reduction, and
hydrolytic reactions

Phase II

Conjugation with endogenous compounds via the activity of

transferases