Post on 22-Nov-2014
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