Transcript Antihistamines and Allergic Emergencies

Pharmacokinetics
-- part 1 -W.M. Tom
Department of Pharmacology
University of Hong Kong
Pharmacokinetics
-- refers to the action of the body on the drug,
including:
• absorption
• distribution
• elimination -- metabolism & excretion
Drug Disposition
Drug Absorption
Peroral administration (P.O. route)
• swallowing
• commonly known as “oral administration”
• most convenient and economic method of
systemic drug delivery
• dosage forms,
e.g. tablets, capsules, syrups, etc.
Drug absorption
Solids are not absorbed!
Dissolution is
usually the rate
limiting step!
Drug Absorption
Peroral administration (P.O. route)
• drug release  formulation
(e.g. tablets)
e.g. particle size, surface area,
excipients (inert substances)
DISINTEGRATION (solid )

DISSOLUTION (solution)

ABSORPTION

SYSTEMIC CIRCULATION (% bioavailability)
Drug absorption
stomach (pH 1~3)
in favour of weak acid
absorption
duodenum (pH 5~7)
in favour of weak base
absorption
ileum (pH 7~8)
in favour of weak base
absorption
Diffusion Across Membrane
(pH < pKa ) HA
Weak
Acid
(pH > pKa )
A-
(pH > pKa ) B
Weak
Base
(pH < pKa ) BH+
Drug Absorption
• Factors affecting drug absorption by enteral
routes
1. Drug dissolution
-- depends on drug formulation of oral preparations
2. pH environment in GI tract
-- unionized form efficiently absorbed
3. Lipid solubility of the drug
-- nonpolar form easily absorbed
Drug Absorption
• Factors affecting drug absorption by enteral
routes
4. Effects of food
-- in general delays drug absorption
5. First pass effect
-- absorption of a drug into the portal circulation
-- drug metabolized by liver before it reaches the
systemic circulation
First-pass effect
mouth
esophagus
stomach
small intestine
colon
rectum
First - Pass Effect
Drug Absorption
• Parenteral routes
1. intravenous injection (IV)
-- directly into a vein
-- 100% bioavailability
2. intramuscular injection (IM)
-- into a muscle
-- depends on blood supply
Drug Absorption
• Parenteral routes
3. subcutaneous injection (SC)
-- under the skin
-- intended for slow absorption
4. others
-- inhalation
-- sublingual
-- topical
-- transdermal, etc.
Absorption, distribution, metabolism and excretion
Drug Distribution
• Drug transfer to various tissues
-- depends on drug lipophilicity and blood flow
• Drug barriers
-- e.g. blood-brain barrier, placenta
• Drug binding to plasma proteins
-- bound drugs are pharmacologically inactive
-- unbound drugs are free to distribute to target tissues
-- different drugs may compete for binding to plasma
proteins and displace each other from binding sites
LOCUS OF ACTION
“RECEPTORS”
Bound
Free
ABSORPTION
TISSUE
RESERVOIRS
Free
Bound
Free Drug
SYSTEMIC
Bound Drug CIRCULATION
BIOTRANSFORMATION
EXCRETION
Saturation of Protein Binding Sites
Drug displacement from
protein binding sites
Plasma Protein Binding
consequence of drug displacement
• an increase in free drug concentration of
the displaced drug
 an increase in drug effect
(be cautious when using a drug of low T.I.)
• a decrease in the duration of action of the
displaced drug because more free drugs
are available for elimination
Drug Metabolism
• modification of the chemical structure by enzyme
systems in the body
-- e.g. cytochrome P450 in liver
• these chemical reactions produce water-soluble
metabolites which are more readily excreted by
the kidneys
-- phase I reaction, e.g. oxidation
-- phase II (conjugation) reaction, e.g. glucuronidation
• drug metabolism activity can be influenced by a
variety of drugs
The two phases of drug metabolism
The two phases of drug metabolism
Proportion of drugs metabolized by the
major phase I and phase II enzymes
Drug Metabolism
• enzyme induction
-- results in faster rate of metabolism
-- e.g. in heavy cigarette smokers, alcoholics
• enzyme inhibition
-- results in slower rate of metabolism
-- e.g. taking another drug which uses the same enzyme
for metabolism
• biological variations in drug metabolism
-- e.g. genetics, disease states, age, etc.
Drug Excretion
• in urine
-- by glomerular filtration and renal tubular secretion
-- polar water-soluble metabolites readily excreted while
nonpolar forms reabsorbed back to circulation
• in bile and feces
• other routes
-- e.g. in sweat, milk and other body fluids
-- volatile gases by exhalation
Renal excretion of drugs
-- lipid-soluble and un-ionized drugs are passively reabsorbed
through the nephron
-- active secretion of organic acids and bases occurs only in the
proximal tubular segment
-- in distal tubular segments, the secretion of H+ favours
reabsorption of weak acids (less ionized) and excretion
of weak bases (more ionized)
Part 1 ended
Pharmacokinetics
-- part 2 -W.M. Tom
Department of Pharmacology
University of Hong Kong
Dosage
Plasma
Concen.
Pharmacokinetic
Toxicokinetics
Site
of
Action
Effects
Pharmacodynamics
Toxicodynamics
Time course of action of a single oral dose
Time of onset = T1 - T0
Time to peak effect = T2 - T0
Duration of action = T3 - T1
MEC = minimum effective
concentration
Time course of drug action
• time of onset
-- the time taken for the drug to produce a response
• time to peak effect
-- the time taken for the drug to reach its highest blood
concentration
• duration of action
-- the time during which the drug produces a response
• elimination half-life ( t 1/2 )
-- the time taken to reduce the drug concentration in the
blood by 50%
One Compartment IV Bolus
Pharmacokinetic Model
Assumptions
• drug is mixed instantaneously in blood
• drug in the blood is in rapid equilibrium with drug
in the extravascular tissues
• drug elimination follows first order kinetics
One Compartment IV Bolus
Pharmacokinetic Model
• rate of concentration change at each time point:
dCp
——— = – k • Cp
dt
…. (1)
Cp : plasma drug concnetration
k : elimination rate constant
One Compartment IV Bolus
Pharmacokinetic Model
Ct = C0 • e – k • t
………. (2)
Ct : plasma concentration at time t
C0 : plasma concentration at time 0
One Compartment IV Bolus
Pharmacokinetic Model
k• t
log Ct = log C0 – ————— ………. (3)
2.303
Ct : plasma concentration at time t
C0 : plasma concentration at time 0
One Compartment IV Bolus
Pharmacokinetic Model
Apparent volume of distribution (Vd )
• apparent volume that the drug is distributed into
• not a physiological volume
X
Vd = ———————————— = ——
drug conc. In plasma
Cp
amount of drug in the body
DOSE
or
Vd = —————
C0
………………. (4)
One Compartment IV Bolus
Pharmacokinetic Model
DOSE
Vd = —————
C0
………………. (4)
substitute (4) to (3), I.e. Ct = C0 • e – k • t
DOSE
Ct = ————— • e – k • t
Vd
………. (5)
One Compartment IV Bolus
Pharmacokinetic Model
Half-Life of Elimination ( t 1/2 )
• time taken for the plasma concentration to fall to
half its original value
t 1/2
0.693
= —————
k
………………. (6)
One-compartment pharmacokinetics (single dose, IV)
Cp = plasma drug concentration
k el = elimination constant
C0 = plasma concentration at time zero
elimination half-life t 1/2 = t 2 - t 1
One Compartment IV Bolus
Pharmacokinetic Model
Drug clearance ( CL )
• a measure of he efficiency with which a drug is
removed from the body
• k
CL = ———————— = —————————
Cp
Cp
rate of elimination
= Vd • k
amount of drug
………………. (7)
CL total = CL kidney + CL liver + CL others
One Compartment IV Bolus
Pharmacokinetic Model
Bioavailability ( F )
• measures the extent of absorption of a given
drug, usually expressed as fraction of the
administered dose
• intravenous injection, by definition, has a
bioavailability of 100%
AUC • CL
F = ——————————————
….. (8)
DOSE
AUC : area under the conc.-time curve
Bioavailability
Plasma
concentration
140
(AUC)o
(AUC)iv
i.v. route
120
100
80
oral route
60
40
20
0
0
2
4
Time (hours)
6
8
10
Multiple IV Bolus Dose Administration
• drug accumulation occurs when repeated doses
are given before the drug is completely eliminated
• repeated drug administration at dose intervals (t )
will give a steady state with the plasma
concentration fluctuating between a maximum
(Cmax) and a minimum (Cmin ) value
Plateau principle
Css = steady state concentration
Cmax = maximum Css
Cmin = minimum Css
MEC = minimum effective
concentration
MTC = minimum toxic
concentration
therapeutic range = MTC - MEC
Time course of drug action
• plateau principle
-- repeated drug administration at fixed dosage
intervals will produce a plateau concentration
of drug in the blood (I.e. steady state)
• steady state
-- a state at which the rate of drug administration is
equal to the rate of elimination
• therapeutic range
-- the range between the minimum effective
concentration (MEC) and the minimum toxic
concentration (MTC) of a drug
Effect of dosage intervals on drug concentration
curve 1 -- dosage interval too short; curve 2 -- too long; curve 3 -- ideal
Blood levels of drugs with intermittent dosage
a typical oral dosage four times a day on a schedule of 10-2-6-10 or 9-1-5-9
Time course of drug action
• loading dose
-- a large dose given to achieve therapeutic
concentration rapidly
• maintenance dose
-- a dose given to maintain the drug concentration at
steady state
Combined Infusion and Bolus Administration
• to achieve a therapeutic concentration more
quickly is to give a loading dose by rapid IV
injection and then start the slower
maintenance infusion
Loading dose = Css  Vd
........... (9)
Maintenance dose = CL  Cp  t ………. (10)
Multi-compartment
Pharmacokinetic Model
• the drug appears to distribute between 2 or
more compartments
• the drug is not instantaneously equilibrated in
various tissues
• rapidly perfused tissues often belong to the
central compartment
• slowly perfused tissues belong to the
peripheral compartment
Two-compartment pharmacokinetics (single dose, IV)
central compartment (rapid)
t 1/2 
peripheral compartment (slow) t 1/2 
Part 2 ended