Unit Ⅰ

Principles of Drug Therapy

Contents

 Chapter 1 Pharmacokinetics

 Chapter 2 Drug-Receptor Interactions and

Pharmacodynamics
Chapter 1
Pharmacokinetics
 Pharmacokinetics
 Overview
 Movement of drugs in the body
 Routes of drug administration
 Absorption of drugs
 Drug distribution
 Drug clearance through metabolism
 Drug clearance by the kidney
 Clearance by other routes
 Design and optimization of dosage regimen
Ⅰ. Overview
Why do we need to know PK?
Optimize drug therapy to obtain a predictable response!

1. Drug of choice
2. How much
3. How often
4. For how long

The dose makes medicine

–Paracelsus 1538
 Therapeutic Goal is to:

Achieve drug concentrations…

at the site of action (target tissue)…
that are sufficiently high enough…
to produce the intended effect…
without producing adverse drug reactions
 Drug Administration

Pharmacokinetics
Absorption

Drug in Tissues Drug Concentration Drug

of Distribution in Systemic Metabolism or
Circulation Excreted

Distribution Elimination
Drug Concentration at
Site of Action

Pharmacodynamics
Pharmacologic Effect

Clinical Response

Toxicity Efficacy
physiological disposition of drugs

 absorption
 distribution
 metabolism (biotransformation)
 elimination
 100
Drug at absorption site
80
% of dose

60
Metabolites
Drug in body
40

Excreted drug
20

Time
Ⅱ . Movement of drugs in the body
 Passive diffusion
 Driving force: the concentration gradient across
membrane
 Direction: from a region of higher concentration
to a lower one
 No carriers, not saturable, low structural
specificity
 Vast majority of drugs gain access to the body
by this mechanism
 Water-soluble drugs: through an aqueous
channel or pore
 Lipid-soluble drugs: solubility in the membrane
 Facilitated diffusion
 Driving force: specialized transmembrane
carrier proteins, conformational changes
 Direction: from a region of higher
concentration to a lower one
 Does not need energy, can be saturated
 Compounds may compete for the same
carrier---inhibition
 Active transport
 Driving force: specific carrier proteins
 Direction: from a region of lower
concentration to a higher one
 Energy-dependent
 Saturation kinetics for the carrier
 Selective
 May be competitively inhibited by other
co-transported substances
 Endocytosis and exocytosis
 For drugs of exceptionally large size
 Endocytosis: engulfment of a drug molecule
by the cell membrane and transport into the
cell by pinching off the drug-filled vesicle.
Eg. Absorption of VitB12
 Exocytosis: be used by cells to secrete many
substances by a similar vesicle formation
process. Eg. Release of neurotransmitters
Classification of membrane transport mechanisms
 Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation
 A very large percentage of the drugs in use are weak acids or weak
bases
 A drug of weak acid is best defined as a neutral molecule that can
reversibly dissociate into an anion and a proton

 A drug of weak base can be defined as a neutral molecule that can

form a cation by combining with a proton
 Ionization of Weak Acids and Weak Bases; The
Henderson-Hasselbalch Equation
pKa
 the ionization constant
 the pH at which the concentrations of the ionized and nonionized
forms are equal (half the drug is in its ionized form)
 A measure of the strength of the interaction of a compound with
a proton
 Lower pKa indicates more acidic drug, higher pKa indicates
more basic drug
Ionization of Weak Acids and Weak Bases; The Henderson-
Hasselbalch Equation

 If the pKa of the drug and the pH of the medium are known, the fraction of molecules in
the ionized state can be predicted by means of the Henderson-Hasselbalch equation
 the pH of the medium determines the fraction of molecules charged (ionized) versus
uncharged (nonionized)
 the lower the pH relative to the pKa, the greater
 will be the fraction of drug in the protonated form. Because the
 uncharged form is the more lipid-soluble, more of a weak acid will
 be in the lipid-soluble form at acid pH, whereas more of a basic
 drug will be in the lipid-soluble form at alkaline pH
Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation
Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation
 Be clinically important when it is necessary to estimate or alter
the partition of drugs between compartments of differing pH
 If a patient takes an overdose of a weak acid drug, the
excretion of this drug is faster in alkaline urine
 Excretion of a weak base is faster in acidic urine
 Other body fluids in which pH differences from blood pH may
cause trapping or reabsorption are the contents of the stomach
(normal pH 1.9–3) and small intestine (pH 7.5–8), breast milk
(pH 6.4–7.6), aqueous humor (pH 6.4–7.5), and vaginal and
prostatic secretions (pH 3.5–7)
Ⅱ . Routes of drug administration
 Routes of drug administration
 Enteral---Oral
 Sublingual
 Parenteral----Intravenous (IV),
Intramuscular (IM), Subcutaneous (SC)
 Other---Oral inhalation, Nasal inhalation,
Intrathecal /Intraventricular, Topical,
Transdermal, Rectal.

The route of administration is determined primarily by:

Properties of the drug

 Routes of Drug Administration
common abbreviations…

po = per os = oral
iv = intravenous = into the vein
im = intramuscular = into the muscle
sc = subcutaneous = between the skin and muscle
ip = intraperitoneal = within the peritoneal cavity
icv = intracerebroventricular =
directly into the ventricle of the brain
Oral ingestion
Major site: intestine

 Longer transit time = 3 hours

 Larger surface area of villus
 Abundant blood flow
 pH 5-8 good for most of drugs
 Advantages of oral administration

 Most common
 Convenient, be easily self-administered
 Safest
with a low risk of systemic infections
toxicities and overdose may be overcome by antidotes
 Economical
Disadvantages of oral administration
 Limited absorption of some drugs
 Slower rate of absorption
 Food may affect absorption
 Patient must be responsive
 Drugs may be metabolized before systemic absorption
 Oral preparations
--- Enteric-coated preparations

 With chemical envelope that resists the action of enzymes in

the stomach but dissolves in the upper intestine
 Be useful for drugs that are acid unstable: omeprazole
irritant to the stomach: aspirin
 Oral preparations
--- Extended-release preparations
 With special coatings or ingredients that control how fast
the drug is released from the pill into the body
 Merits: having a longer duration of action, then improve
patient compliance
may maintain concentration within an acceptable
therapeutic range over a long period of time
 Especially good for drugs with short half-lives: morphine
 Sublingual---advantages

 Under patient’s tongue

 Quick absorption through blood vessels and cause

immediate pharmacological effects
 Convenient administration
 Bypass of harsh GI environment
 Avoid fire-pass elimination
 Low incidence of infection
 Sublingual---disadvantages

 Patient must be alert

 Limited to certain types of drugs: lipid solubility, drug dose
 Medications administered
 Nitroglycerine tablets
 Nitroglycerine spray
 Parenteral---applications

 Used for drugs that are poorly absorbed from the GI tract: heparin
unstable in the GI tract: insulin
 For treatment of unconscious patients
 Under circumstances that require a rapid onset of action
 Parenteral---advantages

 With highest bioavailability

 Being not subject to first-pass metabolism or harsh GI
environments
 Provides the most control over the actual dose of drug
delivered to the body
 Parenteral---disadvantages

 The administrations are irreversible

 May cause pain, fear, local tissue damage, and infections

 Intravenous (IV)---advantages

 Can have immediate effects

 Ideal if dosed in large volumes
 Suitable for irritating substances and complex mixtures
 Dosage titration permissible
 Ideal for high-molecular-weight proteins and peptide drugs
 Intravenous (IV)---disadvantages

 Unsuitable for oily or poorly absorbed substances

 Bolus injection may result in adverse effects
 Most substances must be slowly injected
 Strict aseptic techniques needed
 Once access, can not be recalled by strategies
 Some unfavorable drug reactions
Intramuscular (IM)---absorption pattern

 Depends on drug diluents

Aqueous solution: prompt
Depot preparations: slow and sustained
 Intramuscular (IM)--- advantages

 Suitable if drug volume is moderate

 Suitable for oily vehicles and certain irritating substances
 Preferable to intravenous if patient must self administer
 Intramuscular (IM)--- disadvantages

 Affects certain lab tests (creatine kinase)

 Can be painful
 Can cause intramuscular hemorrhage
 Subcutaneous (SC)---absorption pattern

 Depends on drug diluents

Aqueous solution: prompt
Depot preparations: slow and sustained
 Somewhat slower than IV injection
 Sometimes in combination with local vasoconstrictor like
epinephrine
 Also be useful in solids such as a signal rod containing
contraceptive, and in programmable mechanical pumps like insulin
 Subcutaneous (SC)--- advantages

 Minimizes the risks of hemolysis or thrombosis associated

with IV injection
 Provides constant, slow, sustained effects
 Suitable for slow-release drugs
 Ideal for some poorly soluble suspensions
Subcutaneous (SC)--- disadvantages

 Pain or necrosis if drug is irritating

 Unsuitable for drugs administered in large volumes
 Oral inhalation--- advantages
 Highly available area of absorption (alveolus area = 100-200m2;
pulmonary capillary area = 80 m2
 Absorption is rapid; can have immediate effects
 Ideal for gases and those that can be dispersed in an aerosol
 Rapidly and directly reach desired site of action; effective for
patients with respiratory problems
 Localized effects to target lungs: lower doses used compared to
that with oral or parental administration
 Fewer systemic side effects
Oral inhalation--- disadvantages

 Most addictive route (drug can enter the brain

quickly)

 Patient may have difficulty regulating dose

 Some patients may have difficulty using inhalers

 Intrathecal / intraventricular

 Drugs are introduced directly into the cerebrospinal fluid

 Bypass of the BBBs

 With local and rapid effect

 Transdermal---absorption pattern

 Slow and sustained

 The rate of absorption varies according to:
① the physical characteristics of the skin at the
site of application
② the lipid solubility of the drug
 Suitable for sustained delivery of drugs: nitroglycerin
 Transdermal--- advantages

 Achieve systemic effects

 Bypasses the first-pass effect
 Convenient and painless
 Ideal for drugs that are lipophilic, thus requiring prolonged
administration
 Ideal for drugs that are quickly eliminated from the body
Transdermal--- disadvantages

 Some patients are allergic to patches, which can cause

irritation
 Drugs must be highly lipophilic
 May cause delayed delivery of drug to pharmacological
site of action
 Limited to drugs that can be taken in small daily doses
 Rectal--- advantages

 Partially bypasses first-pass effect

 Bypasses destruction by stomach acid or intestinal enzymes
 Ideal if drug causes vomiting
 Ideal in patients who are vomiting, or comatose
Rectal--- disadvantages

 Absorption is often erratic and incomplete

 Drugs may irritate the rectal mucosa
 Not a well-accepted route
Ⅲ . Absorption of drugs
 What is Absorption

 The transfer of a drug from its site of administration

to the blood stream via one of several mechanisms

drug

Bloodstream
drug
The rate and efficiency of absorption
depends on

 The environment where the drug is absorbed

 The drug`s chemical characteristics
 The route of administration
Factors influencing absorption

 Effect of PH on drug absorption

 Blood flow to the absorption site

 Total surface area available for absorption

 Contact time at the absorption surface

 Expression of P-glycoprotein
 Effect of PH on drug absorption
 Uncharged drug passes through
membranes easily
 Concentrations of a drug at the
absorption site is determined by
the relative concentration of charged
and uncharged form
 The ratio between the two forms is
determined by the pH at the site of
absorption and by the pKa of the drug
pKa Effect of PH on drug absorption
 the ionization constant
 A measure of the strength of the interaction of a compound with
a proton
 Lower pKa indicates more acidic drug, higher pKa indicates
more basic drug
A real live, actual clinical question...

Aspirin
Aspirin isis an
an acidic
acidic drug.
drug. In
In the
the stomach
stomach will
will itit exist
exist
mostly
mostly in
in ionized
ionized or
or non-ionized
non-ionized form?
form?

NON-IONIZED
Why?
Why?
How will this affect aspirin absorption?

Lipid Bilayer

Ionized
Ionizedform
form
(charged)
(charged)
A-

Ionized
Ionizedform
form
(uncharged)
(uncharged)
HA HA
Moral of the story...

Acidic drugs are best absorbed from acidic

environments

Basic
Basic drugs
drugs are
are best
best absorbed
absorbed from
from
basic
basic environments
environments
 So...

To  absorption
To absorption ofof an
an acidic
acidic drug…
drug…
acidify
acidify the
the environment
environment

To  absorption
To absorption ofof an
an acidic
acidic drug…
drug…
alkalinize
alkalinize the
the environment...
environment...

Question:
How to deal with patients of diazepam overdose
 Blood flow to the absorption site
 Blood flow to the intestine is much greater than
to the stomach
 Total surface area available for absorption

 Oral cavity 0.5-l.0 m2

 Stomach 0.1-0.2 m2
 Small intestine 100 m2
 Large intestine 0.04-0.07 m2
 Rectum 0.02 m2
 Contact time at the absorption surface
 Drug can not be well absorbed if it moves
through the GI tract very quickly. Eg. Severe
diarrhea, parasympathetic input
 Anything that delays the transport of the drug
from the stomach to the intestine delays the rate
of absorption of drug. Eg. Sympathetic input,
anticholinergics, food
 Expression of P-glycoprotein
 A multidrug transmembrane transporter protein
responsible for transporting various molecules across cell
membrane
 Main distribution and function
In the liver: transporting drugs into bile for elimination
In kidneys: pumping drugs into urine for excretion
In the placenta: transporting drugs back into maternal
blood, thereby reducing fetal exposure to drugs
In the intestines: transporting drugs into the intestinal
lumen and reducing drug absorption into the blood
In the brain capillaries: pumping drugs back into blood,
limiting drug access to the brain
C. Bioavailability

 Determination of bioavailability
 Factors that influence bioavailability
 Bioequivalence and therapeutic equivalence
 What is bioavailability
 Bioavailability is the fraction of unchanged drug
that reaches the systemic circulation following
administration by any route
 Determining bioavailability is important for
calculating drug dosages for non-intravenous
routes of administration
 Determination of bioavailability
 Plot plasma concentration of the drug
versus time
 Measure the AUC of drug
 Calculate the ratio of AUC for oral
administration to AUC for IV injection with
equivalent dose
 Factors that influence bioavailability
 a. Administration route
 b. First-pass elimination
 c. Solubility of the drug
 d. Chemical and physical instability
 e. Nature of the drug formulation
Routes of administration and bioavailability
 First pass elimination
• Before drug reaches the systemic circulation, the drug can be
metabolized in the liver or gut wall, or excreted to the bile by the liver
• The amount of drugs that gains access to the systemic circulation is
decreased
• May limit the efficacy of many drugs when taken orally

Site of action

Intestine wall

Portal vein
Stool Metabolism

GI → hepatic portal vein → liver → vena cava

the first pass effect can be avoided by…
doses of sufficient quantities
sublingual
transdermal
im
sc
iv
rectum
inhalation
 Factors that influence bioavailability

 b. Solubility of the drug

a well-absorbed drug should be largely hydrophobic,
yet has some solubility in aqueous solutions
 c. Chemical instability
Penicillin G, insulin
 d. Nature of the drug formulation
particle size, salt form, crystal polymorphism, enteric
coatings, presence of excipients
 Bioequivalence

 Two related drug preparations are bioequivalent if they

show comparable bioavailability and similar times to
achieve blood concentrations
 Therapeutic equivalence

 Two similar drug products are therapeutically equal if

they are pharmaceutically equivalent with similar
clinical and safety profiles
Ⅳ. Drug distribution
 2 ． Distribution
The process by which a drug reversibly leaves the
blood stream and enters the interstitium
(extracellular fluid) and then the cells of the tissues

drug
Bloodstream

cell

drug
For a drug administered IV
 The distribution phase: a drug rapidly
dispersed from the circulation and enters
the tissues
 The elimination phase: drug in the plasma
is in equilibrium with drug in the tissues
Factors that affect drug distribution

Blood flow of organs

Capillary permeability in various tissues
Binding of drugs to plasma proteins and tissues
Volume of distribution
 Factors that affect drug distribution
Blood flow of organs

 Results from the unequal distribution of cardiac output

to various organs
 Organs with higher blood flow: brain, liver and kidney
 Organs with lower blood flow: skeletal muscles, adipose
tissue, skin, viscera
 Eg. thiopental
Factors that affect drug distribution
Capillary permeability in various tissues

 Be determined by capillary structure and chemical

nature of the drug
 Capillary structure depends on the fraction of the
basement membrane that is exposed by slit junctions
between endothelial cells
 In the liver and spleen: large part of basement
membrane is exposed due to large, discontinuous
capillaries through which large plasma proteins can
pass
Factors that affect drug distribution
Capillary permeability in various tissues

 In the brain: the capillary structure is continuous,

no slit junction, but tight junction
 Blood brain barrier (BBB)

 These drugs may enter the brain:

carrier-mediated transport
lipid-soluble drugs: dissolve in the membrane of
ECs and penetrate into the CNS
 Ionized or polar drugs usually fail to enter the CNS
Binding of drugs to plasma proteins
KD Reversible equilibrium
D＋P

DP
 Saturable
[DP] [D]  DP: Non-permeable, a drug reservoir
[PT] KD +[D]  Nonspecific & competitive

Plasma proteins
1. Albumin: Weak acids
2. alpha-acid glycoprotein: Weak bases

Effects of plasma protein binding

3. Free fraction: active, excreted, metabolized
4. the more binding, the less active drug
5. the more binding, the less excreted and
metabolized: “longer half-life”
 Drug interaction of plasma protein binding

Drug A: 1000 molecules

+
Drug B w/ 94% bound
99.9% bound 90.0% bound

1 molecules free 100 molecules free

100-fold increase in free pharmacologically active

concentration at site of action.

Effective TOXIC
 Factors that affect drug distribution
Binding of drugs to tissue proteins

 Numerous drugs accumulate in tissues as a result of:

Binding of drugs to lipids, proteins or nucleic acids
Active transport into tissues

 The tissue reservoir may:

Serve as a major source of the drug and prolong its action
Cause local drug toxicity
 Factors that affect drug distribution
Volume of distribution
 The apparent volume of distribution, Vd, can be thought of as the
fluid volume that is required to contain the entire drug in the body at
the same concentration measured in the plasma
 Volume in which drug appears to distribute
 Vd = Amount of drug in the body (known)/C0 (known)
 Vd has no physiologic or physical basis
 Applications of Vd
1. to compare the distribution of a drug with the volumes
of the water compartments in the body
plasma 4 L
extracellular volume
─ Plasma compartment: for a drug with large molecule
weight or binding extensively to plasma proteins, it
distributes in a volume of about 4L of body fluid, eg,
antibiotics
Intercellular 10 L ─ Extracellular fluid: for a drug with low MW but is
hydrophilic: it distributes in a volume of about 14L of
body fluid, eg, gentamicin
─ Total body water: for a drug with low MW and is
Intracellular 28 L hydrophobic: it distributes in a volume of about 42L of
Relative size of various distribution
body fluid, eg, ethnaol
volumes within a 70-kg individual
 Applications of Vd

plasma 4 L extracellular volume

2. Estimate of how well the drug is distributed

─ Value < 0.071 L/ (70kg) indicates the drug is
mainly in the circulatory system.
Intercellular 10 L
─ For a drug that has a very large molecular
weight or binds extensively to plasma proteins

Intracellular 28 L
Relative size of various distribution
volumes within a 70-kg individual
 Applications of Vd

plasma 4 L extracellular volume

2. Estimate of how well the drug is distributed.

─ Values > 50 L/ (70kg) indicates the drug has
accumulated in specific tissues
Intercellular 10 L
─ e.g. digoxin 5mg0.78 ng/ml Vd = 641L,
mainly in lipid tissue and muscle including
cardiac muscle

Intracellular 28 L
Relative size of various distribution
volumes within a 70-kg individual
 Applications of Vd

 Vd is useful pharmacokinetic parameter for calculating a

drug`s loading dose
Vd = Dose / C0
 Variation of Vd

 The apparent volume of distribution reflects a balance between

binding to tissues and binding to plasma proteins
 Changes in either tissue or plasma binding can change the Vd

 Older people have a relative decrease in skeletal muscle mass and

tend to have a smaller Vd of digoxin
 Variation of Vd

 The volume of distribution may be overestimated in obese patients

if based on body weight and the drug does not enter fatty tissues
well, eg. Digoxin
 Abnormal accumulation of fluid—edema, ascites, pleural effusion
—can markedly increase the volume of distribution of drugs such
as gentamicin that are hydrophilic and have small Vd
 Effect of Vd on drug half-life

Blood flow, the fraction of drug in plasma → amount

of drug delivered to organs of elimination → drug
elimination → half-life of drug
1. If the Vd for a drug is large, most of the drug is in
the extraplasmic space and is unavailable to
excretory organs

2. Any factors that increase Vd can lead to increase in

the half-life and extend the duration of action of the
drug
Ⅴ. Drug clearance through metabolism
 Overview
 Three major elimination routes
hepatic metabolism
elimination in bile
elimination in urine
 The elimination processes cause the plasma
concentration of a drug to decrease exponentially
 Metabolism leads to products with increased polarity,
allowing drugs to be eliminated
 Clearance (CL)

 Clearance estimates the amount of drug cleared from the

body per unit of time
 Measure of the ability of the body to eliminate the drug
 Total CL is a composite estimate reflecting all
mechanisms of drug elimination
 Calculation of CL
CL = 0.693 × Vd / t1/2
 Kinetics of metabolism

First order kinetics:

• The rate of drug metabolism and
elimination is directly proportional Zero order

to the concentration of free drug

Plasma concentration
• A constant fraction of drug is First order

eliminated per unit time

Zero order
• Most drugs are eliminated
according to first-order kinetics First order

Time
 Kinetics of metabolism
Zero order kinetics :
• Doses are very large, enzyme is
saturated by a high-drug
Zero order
concentration, the rate of
metabolism remains constant

Plasma concentration
over time First order

• Same quantity of drug is

eliminated per unit time Zero order

• The rate of elimination is

First order
constant and does not depend
on the drug concentration
 First order and zero order kinetics
Comparison
 First Order Elimination
 [drug] decreases
exponentially with time
 Rate of elimination is
proportional to [drug]
 Plot of log [drug] vs. time
is linear
 t 1/2 is constant regardless
of [drug]
 Zero Order Elimination
 [drug] decreases linearly with
time
 Rate of elimination is constant,
independent of [drug]
 Plot of ln[drug] vs. time is linear
 No true t 1/2
Mixed elimination kinetics
Low concentration (<10mg/L): First order
High concentration (>10mg/L): Zero order
─ Saturation of metabolizing enzyme
 Reactions of drug metabolism
 Enzymatic alteration of a drug molecule

Sites of metabolism
 Most drugs are biotransformed in the liver
 It can occur in renal tissue, lungs, blood
plasma, and intestinal mucosa

 Lipid-soluble agents must first be metabolized into

more polar (hydrophilic) substances in the liver
 Phases of metabolism
Oxidation Drug
reductions Conjugation
hydrolyses (Glucuronidation, etc
Phase
(Cytochrome I
P450) Phase II
Drug may be activated,
Conjugation
unchanged, or most often, Stable adducts Usually inactivated
Metabolites
inactivated
Polar species No-polar species

Renal elimination
(Urine) Billary elimination
(Stool)
 Role of drug metabolism

 Lipid soluble, uncharged drug may diffuse out

of the tubular lumen when the drug
concentration in the filtrate becomes higher than
that in the perivascular space
 Drugs are modified in the liver into more polar
or ionized substances, which can not back-
diffuse out of the kidney lumen, then minimize
the reabsorption
 Cytochrome P50 superfamily
• The primary oxidative enzyme
CYP1B1 CYP2A6 system within the liver
CYP1A1/2 CYP2B6 • Important for the metabolism of
Non-CYP enzymes CYP2C8 many endogenous compounds and
for the biotransformation of
CYP2C9 exogenous substances
• A superfamily of heme-containing
isozymes that are located in most
cells but are primarily found in the
CYP2C19 liver and GI tract
• An individual drug may be substrate
CYP3A4/5/7 CYP 2D6 for more than one isozyme
• CYP3A4/5 (36%), CYP2D6 (19%),
CYP2E1 CYP2C8/9 (16%), CYP1A2 (11%)
 Genetic determined enzyme activity
Phenylbutazone
Antipyrine
Aspirin
Dicumarol
Amobarbital
Sodium salicylate
Lithium
Diphenylhydantoin
Diabetes mellitus EO
Coronary artery disease
Essential hypertension
MI (males)
Breast cancer
Diabetes mellitus LO
•0% •10% •20% •30% •40% •50% •60% •70% •80% •90% •100%

Genes Environment
 Genetic variability

• Considerable genetic variability among individuals and racial

groups
• The variations may alter a drug`s efficacy and the risk of
adverse events
• E.g. CYP2D6 mutations result in very low capacities to
metabolize substrates → individuals obtain no benefit from
codeine
• E.g. People who are poor CYP2C19 metabolizers have a higher
incidence of cardiovascular events when taking clopidogrel
 Enzyme inducers
How to induce the enzyme?
• Stabilizing the enzymes
• Inducing the expression of the
genes encoding the enzyme
No inducer

Clazolimine concentration
Consequences of Induction

（ µg/g tissue ）
phenobarbitone
 Increase drug metabolism
 Decrease drug plasma concentration
 Decrease drug activity if the metabolite is inactive
benzo-pyrene
 Increase drug activity if the metabolite is active
 Decrease therapeutic drug effects Time （ hr ）

In rats
 Enzyme inhibitors
How to inhibit the enzyme?
• Competition for the same isozyme
• Inhibition of the activity of the enzyme
• Natural substances, e.g. grapefruit and its juice

Consequences of Inhibition
 Increase in the plasma concentration of parent drug
 Reduction in metabolite concentration
 Exaggerated and prolonged pharmacological effects
 Increased likelihood of drug-induced toxicity
 An important source of drug interactions that lead to serious
adverse events
More important CYP inhibitors: Erythromycin, ketoconazole, ritonavir
 Enzyme inducer/ inhibitors---drug interactions

An important source of drug interactions

May lead to changed effects or serious adverse events

• Rifampin (inducer) + ritonavir

• Omeprazole (inhibitor) + warfarin

Ⅵ. Drug clearance by the kidney
 Elimination of drugs from the body

Routes of excretion
Kidney (most important)
Biliary tract and the feces
Others: expired air, sweat, saliva, tears and breast milk
 Renal elimination of a drug
Three processes
Glomerular filtration
Drugs enter the kidney through glomerular capillary plexus
Free drugs flow through the capillary slit into glomerular filtrate
Active tubular secretion
By energy-requiring active transport system in proximal tubule
Low specificity, competition between drugs
Passive tubular reabsorption
 Renal elimination of a drug
Three processes
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
• Lipid-soluble, uncharged drug may diffuse out of the nephric
lumen of distal convoluted tubule, back into the systemic
circulation
• Changing pH of the urine, increase the ionized form of the drug
in the lumen, minimize the amount of back-diffusion, and finally
increase the clearance of undesirable drug
•Weak acids can be eliminated by alkalinization of the urine
•Weak bases can be eliminated by acidification of the urine
Ⅶ . Clearance by other routes
 Other routes of drug clearance
 Via intestine
The feces are primarily involved in elimination of unabsorbed orally ingested
drugs or drugs that are secreted directly into the intestine or in bile
 Via the lungs
Lungs are primarily involved in the elimination of anesthetic gases
 Via milk in nursing mothers
be relevant as potential source of undesirable side effects to the infant
 Via sweat, saliva, tears, hair and skin
only to a small extent
 Total body clearance

 The total body clearance, CLtotal is the sum of the

clearances from the various drug-metabolizing and drug-
eliminating organs
 CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother
where CLhepatic + CLrenal are typically the most important

Q: Which kind of drug can be given to patients with renal

failure?
 Enterohepatic circulation

Biliary excretion Liver

&
Enterohepatic Bile duct
recycling
Gut
Portal vein

Feces excretion
Clinical situations resulting in changes in drug half-life

The half-life of a drug may be increased by:

 Diminished renal plasma flow or hepatic blood flow
eg. in cardiogenic shock, heart failure, hemorrhage
 Decreased ability to extract drug from plasma Adjustment
in dosage is
eg. in renal diseases required!
 Decreased metabolism
eg. in hepatic insufficiency, combined use with CYP450 inhibitors
Clinical situations resulting in changes in drug half-life

The half-life of a drug may be decreased by:

 increased hepatic blood flow

 Decreased protein binding

Adjustment
in dosage is
 Increased metabolism
required!
 Biological Half-life (t 1/2)

 Amount of time to eliminate 1/2 of total drug amount

 Shorter t1/2 may need more frequent doses
 Hepatic disease may increase t1/2
A drug has a half life of 10 seconds. You give
a patient a dose of 6mg. After 30 seconds how
much of the drug remains?

Time
Time Amount
Amount

00sec
sec 66mg
mg

10
10sec
sec 33mg
mg

20
20sec
sec 1.5
1.5mg
mg

30
30sec
sec 0.75
0.75mg
mg
 Half-life, T1/2
 Time it takes for drug concentrations to decrease by one half
First order elimination: Zero order elimination:
t1/2 =0.693/Ke t1/2 = 0.5  C0/k
 `Constant rate of Elimination  `Rate of elimination
irrespective of plasma proportional to plasma
concentration concentration.
 `t1/2 is constant regardless  `t1/2 is dependent on drug
of drug amount amount

Plasma Concentration
Plasma Concentration

Slope
= -Ke/2.303

t1/2 t1/2 t1/2 t1/2 t1/2

Time （ h Time （ h
Ⅷ . Design and optimization of dosage
regimen
 1. Single dose

Absorption = elimination

iv
10
Plasma aspirin concentration (mg/L)

Cmax
6 orally
4

Tmax
Area under curve (AUC)
0
0 20 40 60 80 100 120 ngh/mL
1-3 h for most of drugs
Time (min)
 Section 2
Basic concept of pharmacokinetics
A. Time-concentration curve
Minimum toxic concentration

Concentration of drug in plsma Cmax

Peak time TCmin
Peak concentration

distribution phase

Safety range
Absorption and

Balance phase

threshold dose
Minimum effective concentration

Elimination phase
Tpeak
Duration Time
Latent period Residual period
 2. Multiple dose
Constant repeated administration of drugs
To produce a Css > MEC and < MTC
4-5 half-life, 90% of steady-state concentration is
reached in 3.3 half-lives

Css-max < MTC

Css-min > MEC

Drug accumulation and elimination
90%
87.5% 94% 97%

3.3
 Loading dose
Utilized when a therapeutic level is desired quickly
and an initial larger dose is administered followed by
substantially smaller maintenance doses (may
increase risk of toxicity and adverse effects).
Log Concentration

Time Time
 4. Bioavailability

Absolute Bioavailability
 The fraction of the dose of a drug
(F) that enters the general
circulatory system,
F = (AUCev x Div)/(AUCiv x Dev)
ev: extravascular

Relative Bioavailability
 Compurgation of two different drugs or different dosage
forms of same drug
F = (AUCtest x Dstand)/(AUCstand x Dtest)
 Relative Bioavailability
Oral administration of digoxin 0.5mg
Pharmaceutical Co. A

Pharmaceutical Co. B
 2) Bioavailability

 fraction of an administered drug that

reaches the systemic circulation

 for IV, Bioavailability = 1.0

 Fomulation A
Concentration of drug in plsma

Minimum toxic concentration

Fomulation B

Minimumeffective
Minimum toxic concentration
concentration

Formulation C

Time
Pharmacokinetics

 Time course of drug absorption, distribution, metabolism, excretion

How
Howthe
thedrug
drug
comes
comesand
andgoes.
goes.
Pharmacokinetic Processes

“LADME” is key
Liberation
Liberation Metabolism
Metabolism

Absorption
Absorption Excretion
Excretion

Distribution
Distribution
Liberation

 Applies to drugs given orally

 Components
 Release of drug from pill, tablet, capsule
 Dissolving of active drug in GI fluids

Ex:
Ex:Enteric
Entericcoated
coated
aspirin
aspirinslows
slowsabsorption
absorptioninin
stomach
stomachvs vsnon-coated
non-coated
Absorption

 Movement from administration site into circulation

Factors Affecting Liberation/Absorption

 Patient
Formulation
factors
factors
 Tablet
Absorbing
disintegration
surface
 Blood
Inert ingredient
flow / solvent effects
 Solubility
Environmental pH
 Disease
Drug pHstates
 Interactions
Concentrationwith food, other drugs
 Membranes and Absorption

Lipid Bilayer
Hydrophilic
Hydrophilic
Heads
Heads Hydrophobic
Hydrophobic
Tails
Tails
Small, H2O, urea, CO2,
uncharged Swoosh!
O2, N2

Large, Glucose DENIED!

uncharged Sucrose
Small
charged H+, Na+, K+,
ions Ca2+, Cl-, DENIED!
HCO3-
LaChatlier’s Principle

a.k.a.
a.k.a.Mass
MassAction
Action
AAreaction
reactionatatequilibrium
equilibrium
responds
respondstotostress
stressininaa
way
waytotobest
bestreturn
returntoto
equilibrium
equilibrium
System
System
atat
Equilibrium
Equilibrium

4 Na+ + 4 Cl_ 4 NaCl

 Administration Routes

 Intravenous
 Fastest, Most dangerous
 Endotracheal
 Lidocaine, atropine, narcan, epinephrine
 Inhalation
 Bronchodilators via nebulizers
 Transmucosal
 Rectal or sublingual
Administration Routes

 Intramuscular
 Depends on perfusion quality
 Subcutaneous
 Depends on perfusion quality
 Oral
 Slow, unpredictable
 Little prehospital use
 Ionization

Acids
Acids Release/Donate
Release/DonateHH+
+

Ionized
Ionized
HA H+ + A- form
form

Bases
Bases Bind/Accept
Bind/AcceptHH+
+

H+ + B- HB
Non-
Non-
ionized
ionized
form
form
Environmental pH and Ionization

IfIfwe
weputputan
anacidic
acidicdrug
drugininan
anenvironment
environmentwith
withaalot
lotof
ofHH + (low
+
(lowpH)
pH)what
what
will
willthis
thisequilibrium
equilibriumdo?
do?

HA H+ + A-
HA
HA
HA
HA

System
H +
+from
Non-ionized
System
H atatacid
from
Non-ionized Equilibrium
form
acidenvironment
formpredominates!
Equilibrium
environment
predominates!
Distribution

 Rate of perfusion
 Plasma protein (albumin) binding
 Accumulation in tissues
 Ability to cross membranes
 Blood-brain barrier
 Placental barrier
Plasma Protein Binding

warfarin
warfarin(Coumadin)
(Coumadin)isishighly
highlyprotein
proteinbound
bound(99%).
(99%).Aspirin
Aspirinbinds
bindstotothe
the
same
samesite
siteon
onserum
serumproteins
proteinsas
asdoes
doesCoumadin.
Coumadin.IfIfaapatient
patienton
onCoumadin
Coumadinalso also
takes
takesaspirin,
aspirin,what
whatwill
willhappen?
happen?

The available Coumadin

1) will increase.
1)Why?
Why?
2)
2)Why
Whydodowe
wecare?
care?
Blood-Brain Barrier

The
Theblood
bloodbrain
brainbarrier
barrierconsists
consistsof
ofcell
celltightly
tightlypacked
packedaround
aroundthe
the
capillaries
capillariesof
ofthe
theCNS.
CNS.What
Whatcharacteristics
characteristicsmust
mustaadrug
drugpossess
possesstoto
easily
easilycross
crossthis
thisbarrier?
barrier?

Non-protein bound, non-ionized, and highly lipid soluble

Why?
Why?
Metabolism (Biotransformation)

 Two effects
 Transformation to less active metabolite
 Enhancement of solubility
 Liver = primary site
 Liver disease
 Slows metabolism
 Prolongs effects
Hepatic ‘First-Pass’ Metabolism

 Affects orally administered drugs

 Metabolism of drug by liver before drug reaches systemic circulation
 Drug absorbed into portal circulation, must pass through liver to reach systemic circulation
 May reduce availability of drug
 Elimination

 Kidneys = primary site

 Mechanisms dependent upon:
 Passive glomerular filtration
 Active tubular transport

 Partial reabsorption
 Hemodialysis
 Renal disease
 Slows excretion
 Prolongs effects
Active Tubular Transport

Probenecid
Probenecidisismoved
movedinto
intothe
theurine
urineby
bythe
thesame
sametransport
transportpump
pumpthat
thatmoves
moves
many
manyantibiotics.
antibiotics.Why
Whyisisprobenecid
probenecidsometimes
sometimesgiven
givenas
asan
anadjunct
adjuncttoto
antibiotic
antibiotictherapy?
therapy?

It competes with the antibiotic at the pump and slows

its excretion.
 Urine pH and Elimination

AApatient
patienthas
hasoverdosed
overdosedononphenobartital.
phenobartital.Phenobarbital
Phenobarbitalisisan
anacid.
acid.IfIfwe
we
‘alkalinalize’
‘alkalinalize’the
theurine
urineby
bygiving
givingbicarbonate
bicarbonatewhat
whatwill
willhappen
happentotothethe
phenobarbital
phenobarbitalmolecules
moleculesasasthey
theyare
arefiltered
filteredthrough
throughthe
therenal
renaltubules?
tubules?

They will ionize...

How will this affect phenobarbital
reabsorption by the kidney?

Non-ionized Ionized

HA H+ + A-

Decreased
Decreasedreabsorption
reabsorption

Increased
Increasedelimination
elimination
 Drug Actions – Drug Interactions
 Drug actions
 How drugs produce changes within the body
 Drug effect
 Changes that take place in the body as a result of drug action
 Slowing down or speeding up processes
 Destroying certain cells or parts of cells
 Replacing substances that the body lacks or fails to produce
 Drug Actions – Drug Interactions
 Desired effect
 Effect of drug in the body that was intended
 Side effect
 Additional effect on the body by the drug that was not part of the goal for that medication
 Not usually severe enough to warrant discontinuing the medication
 Drug Actions – Drug Interactions
 Adverse reaction
 One in which the body reacts to a drug in an unexpected way that may endanger a
patient’s health and safety
 Contraindication
 Any special symptom or circumstance that indicates that the use of a particular drug or
procedure is dangerous, not advised, or has not been proven safe for administration
 Drug Actions – Drug Interactions
 Local effect
 Response to a medication that is confined to a specific part of the body
 Systemic effect
 Generalized or widespread response to a drug by the body because it is absorbed into the
bloodstream
 Drug Actions – Drug Interactions
 Cumulation
 Occurs when a drug is not completely excreted from the body before another dose is
given
 Drug starts to accumulate in the body tissues when repeated doses are given
 Toxic effects may occur
 Drug Actions – Drug Interactions
 Idiosyncracy
 An unusual, inappropriate response to a drug or to the usual effective dose of a drug
 Anaphylactic Shock = severe idiosyncratic reaction
 Acute respiratory distress, hypotension, edema, tachycardia, cool pale skin, cyanosis, and
possible convulsions shortly after administration of the medication
 Drug Actions – Drug Interactions
 Potentiation
 Occurs when two drugs administered together produce a more powerful response than the
sum of their individual effects
 Tolerance
 Resistance to effect of a drug
 A characteristic of drug addiction
Pharmacokinetics: Absorption

 The rate at which a drug leaves its site of administration, and the extent to
which absorption occurs.
 Bioavailability
 Bioequivalent
Pharmacology
 Routes of medications:
 PO (by mouth)
 IV (intravenous)
 IM (intramuscularly)
 SQ (subcutaneous)
 SL (sub-lingual)
 IO (intraosseous)
 Inhalation
Pharmacology
 Forms
 Solution
 Topical
 Tablet
 Capsule
 Suspension
 Transdermal
 Inhalation
Pharmacokinetics: Absorption
Factors That Affect Absorption

 Administration route of the drug

 Food or fluids administered with the drug
 Dosage formulation
 Status of the absorptive surface
 Rate of blood flow to the small intestine
 Acidity of the stomach
 Status of GI motility
Pharmacokinetics: Absorption

Routes
 A drug’s route of administration affects the rate
and extent of absorption of that drug.
 Enteral
 Parenteral
 Topical
 Pharmacokinetics: Absorption

Enteral Route
 Drug is absorbed into the systemic circulation
through the oral or gastric mucosa, the small intestine, or
rectum.
 Oral
 Sublingual
 Buccal
 Rectal
First-Pass Effect

The metabolism of a drug and its passage

from the liver into the circulation.
 A drug given via the oral route may be extensively
metabolized by the liver before reaching the systemic
circulation (high first-pass effect).
 The same drug—given IV—bypasses the liver, preventing
the first-pass effect from taking place, and more drug
reaches the circulation.
Instructors may want to use
EIC Image #4:

First-Pass Effect
First-Pass Effect

 Routes that bypass the liver:

 Sublingual Transdermal
 Buccal Vaginal
 Rectal* Intramuscular
 Intravenous Subcutaneous
 Intranasal Inhalation
*Rectal route undergoes a higher degree of first-pass effects than the other routes listed.
Pharmacokinetics: Absorption

Parenteral Route
 Intravenous*
 Intramuscular
 Subcutaneous
 Intradermal
 Intrathecal
 Intraarticular
*Fastest delivery into the blood circulation
Pharmacokinetics: Absorption

Topical Route
 Skin (including transdermal patches)
 Eyes
 Ears
 Nose
 Lungs (inhalation)
 Vagina
Pharmacokinetics: Distribution

The transport of a drug in the body by the bloodstream to its site of action.
 Protein-binding
 Water soluble vs. fat soluble
 Blood-brain barrier
 Areas of rapid distribution: heart, liver,
kidneys, brain
 Areas of slow distribution: muscle, skin, fat
Pharmacokinetics: Metabolism
(also known as Biotransformation)

The biologic transformation of a drug into

an inactive metabolite, a more soluble compound, or a more potent metabolite.
 Liver (main organ)
 Kidneys
 Lungs
 Plasma
 Intestinal mucosa
Pharmacokinetics: Metabolism

Factors that decrease metabolism:

 Cardiovascular dysfunction
 Renal insufficiency
 Starvation
 Obstructive jaundice
 Slow acetylator
 Erythromycin or ketoconazole drug therapy
Pharmacokinetics: Metabolism

Factors that increase metabolism:

 Fast acetylator
 Barbiturates
 Rifampin therapy
Pharmacokinetics: Metabolism

Delayed drug metabolism results in:

 Accumulation of drugs
 Prolonged action of the effects of the drugs

Stimulating drug metabolism causes:

 Diminished pharmacologic effects
Pharmacokinetics: Excretion

The elimination of drugs from the body

 Kidneys (main organ)
 Liver
 Bowel
 Biliary excretion
 Enterohepatic circulation
Instructors may wish to use
EIC Image #5:

Renal Drug Excretion

Pharmacokinetics

Half-Life
 The time it takes for one half of the original amount
of a drug in the body to be removed.
 A measure of the rate at which drugs are removed from the body.
 Routes of Administration
 Oral
 Given by mouth and swallowed
 Advantage
 Easiest and safest method
 Most economical method

 Disadvantage
 Slow method of absorption
 Possibility of being destroyed by gastric juices
Routes of Administration

 Sublingual
 Placed under the tongue – dissolves in saliva
 Advantage
 More rapid absorption rate than oral
 Higher concentration of medication reaches bloodstream

 Disadvantage
 Not convenient route of administration for bad-tasting medications or irritating medications
 Routes of Administration
 Buccal
 Placed in mouth next to cheek (tablet form)
 Advantage
 More rapid absorption rate than oral
 Higher concentration of medication reaches bloodstream

 Disadvantage
 Possibility of swallowing the pill
 Routes of Administration
 Inhalation
 Medication is sprayed or inhaled into nose, throat, and lungs
 Advantage
 Good absorption due to large surface contact area
 Provides rapid treatment

 Disadvantage
 Sometimes difficult to regulate dose
 Not suitable method for medications that irritate mucous membrane lining
 Routes of Administration
 Rectal
 Medication inserted into rectum and is slowly absorbed into mucous membrane lining of
rectum (suppository)
 Advantage
 One method of choice when patient is nauseated or cannot take medications orally

 Disadvantage
 Absorption is slow and irregular
 Routes of Administration
 Vaginal
 Medication is inserted into the vagina in the form of a suppository, cream, foam, or tablet
 Advantage
 Easiest method for treating the specific area

 Disadvantage
 Medications sometimes stain underwear
 No other disadvantages
 Routes of Administration
 Topical
 Medication is applied directly to the skin or mucous membrane for a local effect to area
 Advantage
 Easy method, convenient

 Disadvantage
 Slow absorption through skin
Routes of Administration
 Transdermal
 Method of applying a pre-measured amount of medicine to unbroken skin through an
adhesive-backed disk
 Advantage
 Good method for administering medications slowly into bloodstream over a period of time

 Disadvantage
 Units can be dangerous if they come in contact with skin of children or pets
 Routes of Administration
 Parenteral
 Administered by injecting medication into body using a needle and syringe
 Must be in liquid form
 Administered by one of following methods
 Intradermal
 Intramuscular
 Intravenous
 Subcutaneous
Routes of Administration
 Intradermal
 Small amount of medication is injected just beneath epidermis
 Used for allergy testing, tuberculin skin testing, and some vaccinations
 Needle Angle: 10 to 15-degree
 Routes of Administration
 Intramuscular
 Medication is injected directly into muscle
 Used for administering antibiotics, medications that might be irritating to layers of the
skin, and medications that require dosages larger than amount allowed for subcutaneous
injections
 Needle Angle: 90-degree
Routes of Administration
 Intravenous
 Medication is injected directly into the vein, entering the bloodstream immediately
 Used when medication is needed quickly
 Used for infusing medication over a period of time, by adding the medication to a bag of
intravenous fluids
 Needle Angle: 25-degree
 Routes of Administration
 Subcutaneous
 Medication is injected into subcutaneous layer, or fatty tissue of skin
 Used for administering insulin, hormones, and local anesthetics
 Needle Angle: 45-degree
Parenteral
Routes of Administration
 Section 1

Drug Transport

Ch. 2
Absorption
drug transport
distribution
excretion through membranes

metabolism biotransformation
 一、 Drug transport across membranes

Cell membrane
1) GI epithelial cells
2) vascular endothelium
3) blood brain barrier (BBB)
4) subcellular membranes
 Transfer of drugs across Membranes
Extracellular
Carrier-mediated
Simple diffusion transport
Filtration
(Aqueous diffusion) (Lipid diffusion) 1. Active transport
2. Facilitated diffusion

Intracellular
 1 ． Simple diffusion
 Diffusion through lipid bi-layer
 Passive process, concentration gradient
dependent, requires no energy
 Molecules move from area of high
to low concentration
 Rate of diffusion is proportional to:
1. lipid solubility, the greater the lipid solubility
the faster the rate of diffusion
2. pKa of molecules
3. Concentration difference between both sides
Acidic drug: HA  H+ + A (ionized)
Basic drug: BH+  H+ + B (unionized)
Ion trapping
 Cell membranes are less permeable to
ionized compounds

H+ H+
A- B BH+
HA

HA A- B BH+

H+ H+
 Ionization depends on pH and pKa

[ H+ ] [ A ]
Acidic Ka =
[HA]
drug ：
[ A ]
pKa = pH - log
[HA]

[ A ]
10 pH-pKa =
[HA]
Basic drug ：pKa-pH
 Example
Cromolyn Sodium ( 色甘酸钠 ) pKa=2, Acidic

Stomach ： Plasma ：
pH=4 pH=7
Total HAH+ + A A + H+HA Total
101 1 102 105 1 100001

[ A ] [ A ]
10pH-pKa = 10pH-pKa =
[HA] [HA]
= 104-2 = 107-2
= 102 = 105
 2. Filtration

 Small molecules diffusion

through aqueous channels

 Water solubility
 Small molecular
─ Diameter of aqueous channels in
Capillary wall: 4-8Å （ =1010m )
─ Only for water, urea filtration

─ >100 not permeable

 Intracellular cleft: big hole
Intracellular cleft: 40Å,
all solute in blood are
permeable except
protein

Intracellular
cleft
 3. Carrier-mediated transport
1. Requiring carrier
2. Structure specific
3. Saturable (functional protein
molecules are limited)
4. Competitive inhibition

Active transport
 Against concentration gradient

 Requires coupling of energy (hydrolysis of ATP)

Facilitated diffusion
 Along concentration gradient

 Requires no energy