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

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

▪ Only nonionized (uncharged) drugs form cross biomembranes

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

　　　　　　　　　　　　

　　　　　　　　　　　　　　　　　

Ａｃｉｄｉｃ　ｍｅｄｉａ ｐＨ＜ｐＫａ

Ｂａｓｉｃ　ｍｅｄｉａ ｐＨ＞ｐＫａ

Ｗｅａｋ R-COOH

Acid (across membranes)

RCOO- + H+

Weak RNH3+

base RNH2 + H+

(across membranes)

% Ionization is determined by Henderson-Hasseibalch eqn.Weak pH - pKa = log [ionized] [nonionized]AcidsWeak

pH - pKa = log [nonionized]

Bases [ionized]

Degree of ionization and Clearance versus pH Deviation from pKa

Weak base

Weak acid20

40

60

80%

non

ioni

zed

form

sR

enal Clearance of D

rug

-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

•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 Increases Renal Clearance of Drugs

Ionization and Renal elimination

Acidification of urine

▪ Increases ionization of weak bases Increases Renal elimination

Alkalinization of urine

▪ Increases ionization of weak acidsIncreases Renal elimination

Modes of Drug Transport Across Membranes

Mechanism Energy Required

carrier Direction Saturable

Passive diffusion

No No Down gradient

No

Not passive diffusion

No Yes Down gradient

Yes

Active diffusion

Yes Yes Agaisnt gradient

Yes

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

Pla

sma

Dru

g C

once

ntra

tion

Timetmax

Cmax

lag

Abso

rptio

n minimum effective concentration

elimination

Duration of actionOnset 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

Pla

sma

Dru

g C

once

ntra

tion

Time

Cmax Intravascular dose

Cmax/extravascular dose

Fraction of dose reaching systemic circulation

IV doses have 100% bioavailability, F=1

AUCPOF = AUCIV

Oral absorption into portal circulation can result in rapid liver metabolism

*may decrease bioavailability* first pass effect.

Extent of absorption (f)

Bioavailibility

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

Bioavailability

Effect of first-pass hepatic elimination on bioavailibility is expressed as extraction ratio (ER):

ER =Clliver

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

•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

Placental

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