A PRIMER OF DRUG ACTION

1
PHARMACOLOGY 1391

• Studies the effects of drugs and how they exert
  their effects.
• acetylsalicylic acid (ASA)
• reduce inflammation,
• pain and fever
• inhibit the action of cyclooxygenase
• Fluoxetine
• SSRI
• Selective serotonin re-uptake inhibitors

.
2
PHARMACOLOGY 25 2 1391

Pharmacodynamics (PD) What the drug does to the
body Pharmacokinetics (PK) What the body does
to the drug
3
Pharmacodynamics (PD)
Lock and Key phenomenon for the drug and its
receptor site
4
Pharmacokinetics1391

• F. Keyhanfar Ph.D, D.I.C.

5
INSECTICIDES
HERBICIDES
COSMETICS
POISON
Living Tissue
DRUG
Effect
FOOD ADDITIVES
MEDICINE
AIR POLLUTANTS
6
SYSTEMIC CIRCULATION
BLOOD
SITE OF ACTION
DRUG
EFFECTS
7
The drug must be capable of reaching the site
of action
must remain at the site of action long enough
BLOOD
DRUG
SITE OF ACTION
EFFECTS
Drug must have necessary properties to be
transported From its site of administration
To its site of action
The drug must achieve these criteria without
inducing unacceptable toxicity in the patient
SYSTEMIC CIRCULATION
8
How the drug comes and goes.
9
Who took the largest dose of Tylenol?
65 kg 75 kg
10 kg 2.5 kg 300 mg
600 mg 100 mg 50 mg
10
Calculating Dose
50 mg ? 2.5 lb 20 mg/kg
300 mg ? 62.5 kg 4.8 mg/kg
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Typical dose-response curve
100
response
50
Log scale dose (mg/kg)
0
10
100
1000
12
Response changes with concentrationThe intensity
of response is related to concentration of the
drug at the site of action
Maximal response
Linear response
(20-80)
No response
Receptor
Drug Molecule
(semi-log)
13
Dose-Response Curve for Alcohol
Death
Labored breathing
Unconscious
Deep sleep
Response
Sleep
Giddy
No effect
No effect
Dose
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Dose-Response Curve for Vitamin D
Toxic
Healthy
Response
Unhealthy
Dose
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Dose - Response

• Effective dose
• ED50 - the dose producing the desired
  (therapeutic) effect in 50 of the test animals
• Toxic dose
• TD50 - the dose toxic to the specified organ
  in 50 of the test animals administered by the
  stated route
• Lethal dose
• LD50 - the dose lethal to 50 of test animals
  when administered by stated route

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Therapeutic Index

• Therapeutic index toxic dose/effective dose
• This is a measure of a drugs safety
• A large number a wide margin of safety
• A small number a small margin of safety

Must be gt1 for drug to be usable
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WarfarinA Small Therapeutic Index
100
Desired Therapeutic Effect
Unwanted Adverse Effect
Percent of Patients
50
0
0
Log Drug Concentration
Digitalis has a TI of 2
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Penicillin TI gt100A Large Therapeutic Index
100
Desired Therapeutic Effect
Unwanted Adverse Effect
Percent of Patients
50
0
0
Log Drug Concentration
19

PARAMETERS
LD50 - ED50 TD50 LD50 TD50

H
A
ED50
ED50
Margin of safety (TI)

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Therapeutic ratio index

• Remifentanyl 330001
• THC 10001
• Diazepam 1001
• Morphine 701
• Cocaine 151
• C2H5OH 101
• Digoxin 21

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NSAID (IBUPROFEN) Wide TINormal dose 400-3200
mg/day (THEOPHYLLINE) BLOOD CONC 10-20
µg/mlbelow this conc (not much effect )above
20 µg/ml (serious toxicities)
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General Concepts
Pharmaceutical
Pharmacokinetics
Pharmacodynamics
Pharmacotherapeutics
23
Processes involved in drug transport
24
Standard Dose

• Healthy volunteers
• Patients with average ability to
• ADME

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Routes of Drug Delivery
Parenteral (IV)
Inhaled
Oral
Transdermal
Parenteral (SC, IM)
Topical
"How does the medicine know where to go".
Rectal
26

• Pharmaco dynamics
• study the mechanisms by which drugs work
• also study endogenous agents
• Receptors spare R
• Affinity, Efficacy, Potency
• EC50, Emax, Kd, Bmax, ED50, TI
• Agonist, antagonist .

27
Fluoxetine and tramadol both increase
availability of serotonin leading to the
possibility of serotonin overload This
happens without a change in the concentration of
either drug.
Fluoxetine inhibits the metabolism of
amitriptyline and increases the plasma
concentration of amitriptytline.
PK
PD
Dose
28
Pharmacodynamics (PD) What the drug does to the
body Pharmacokinetics (PK) What the body does
to the drug
PK along with PD tells the clinician how
much how often how long to dose.
The drug will appear at the target organ
How rapidly? In what concentration? For how long?
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DRUG THERAPY

• Goal
• To Rapidly Deliver and Maintain therapeutic (non
  toxic) levels of drugs in the target tissues.

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7 Rights of Safe Medication Administration

• Right Drug
• Right Dose
• Right Time
• Right Route
• Right Patient
• Right Reason
• Right Documentation

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Drug Body

• Molecular size
• Lipid solubility
• Ionization

• Absorption
• Distribution
• Elimination

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WHAT IS DRUG ABSORPTION?
Unless injected directly into the blood
stream, drugs must be absorbed.
The movement of drug molecules across
biological barriers (mostly layers of cells) from
the site of administration to the blood stream.
Site of Administration
DRUG
Vascular System
BIOLOGICAL BARRIER
33
Membranes and Absorption
Lipid Bilayer
Small, uncharged
H2O, urea, CO2, O2, N2
Swoosh!
Large, uncharged
Glucose Sucrose
DENIED!
Small charged ions
H, Na, K, Ca2, Cl-, HCO3-
DENIED!
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Many drugs are weak organic acids or bases (weak
elctrolytes)

• Weak acids aspirin in intestines are mostly
  ionized
• (intestinal pH ranges from 6.6 to 7.5)
• Weak bases atropine in stomach are mostly
  ionized
• (stomach pH ranges from 1 to 2)

Weak acids Weak bases DISSOCOATE R-COOH
R-COO- H R-NH2 H R- NH3 Degree of
Ionization depends on
pH of Medium
pKa of the molecule What
is pKa?
36
IONIZATION decreases membrane permeability
Ionized forms of compounds have low lipid
solubilityWhy?

• non-ionized forms of drugs are more soluble in
  lipids and absorbed better
• than water-soluble, ionized forms of drugs

Acidic drugs are ionized in basic
environment Basic drugs are ionized in acidic
environment
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Henderson Hasselbach
pKa pH at which 50 of a substance
Is ionized

• pH pKa Log ----------------

A-
HA
pKa Dissciation constant
38
Henderson-Hasselbach equation
pKa pH at which 50 of a substance is ionized
A-
pH pKa log
WEAK acid
HA
B
pH pKa log
WEAK base
BH
39
Henderson Hasselbach
I

• ----------------

pH - pKa

10
U
WEAK ACID
Benzoic Acid
40
Henderson Hasselbach
I

• ----------------

pKa - pH

10
U
WEAK BASE
Aniline
41
Henderson Hasselbach

Morphine pKa 8

Stomach pH 2 Plasma pH 7.4
Where Why ?
42
Henderson Hasselbach

Lidocaine pKa 7.9

pH 6.4 pH 7.4 normal
???????????????
43
Moral of the story...

• Acidic drugs are best absorbed from acidic
  environments

Basic drugs are best absorbed from basic
environments
44
So...
To ? absorption of an acidic drug acidify the
environment
To ? absorption of an acidic drug alkalanize the
environment...
45
Concen in blood may not be indentical to conc at
the site of action
46
Pharmacokinetic Parameters----------------------
------
Clearance Volume of distribution Half
life Bioavailability
47
CONCEPT OF DRUG CLEARANCE (CL)
Quantifies ELIMINATION
DRUG
Think of drug clearance as removal of drug from
body by bodys garbage disposal systems!
48
DRUG CLEARANCE
Example
Rate of Drug Elimination (Excretion rate) 10
mg/hr
DP (Concentration) 4 mg/L
10 mg/hr
CL
2.5 L/hr
4 mg/L
Is the volume of body fluid cleared of drug per
time unit (L/h, mL/min)
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Clearance (CL)

• Blood, Plasma, Serum
• Which Particular fluid assay ?
• ----------------------------------------

Serum Clearance (CL) of 200 ml/minIn one
minute all of the drug could have been eliminated
from 200 ml of serum
50
Total Body Clearance (CL)

• -------------------------------------
• CL (CLliver CLg.i. tract CLkidney CLlung
  ...)

• Dose / Area under the curve (AUC)
• e.g. mg / (mg.h /L) L/h

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Clearance

• Clearance also plays a role in determining the
  steady-state concentration of a drug or toxicant
• Csteady-state Rate of administration/ CL

52
Cl is a major determinant of DP at STEADY
STATE (DPSS)
INPUT
STEADY STATE LEVEL
(Kidney Liver)
OUTPUT
53
Drug Distribution

• At any given time, only a very small portion of
  the total amount of a drug that is in the body is
  actually in contact with its receptors. Most of
  the administered drug is found in areas of the
  body that are remote from the drugs site of
  action.

54
Drug Distribution

• Wide distribution often accounts for many of the
  side effects of a drug

• It takes time for a drug to distribute in the
  body
• Drug distribution is affected by elimination

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THE BODY AS COMPARTMENTS----------------------
----

• 1. Highly Vascular
• PLASMA, RED CELLS
• LUNGS
• LIVER, BRAIN SPLEEN

56
THE BODY AS COMPARTMENTS----------------------
----

• 2. Low Vascular
• FAT DEPOSITS

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rapid I.V. bolus injection
Drugs Circulate through the bloodstream to the
rest of the body where they cause an effect, be
ignored, be absorbed or be biotransformed
Distribution depends on the drug itself and on
blood volume of the person (6-8 quarts in an
adult, 3-4 in child)
58
So What?

• It takes time for a drug to distribute in the
  body
• Drug distribution is affected by elimination

1.5
Drug is not eliminated
Serum Concentration
1.0
Elimination Phase
0.5
Distribution Phase
Drug is eliminated
0
Time
0
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rapid I.V. bolus injection
Often a one compartment model is not sufficient
to represent the pharmacokinetics of a drug. A
two compartment model often has wider
application. Here we consider the body is a
central compartment with rapid mixing and a
peripheral compartment with slower distribution.
The central compartment is uniformly mixed very
shortly after drug administration, whereas it
takes some time for the peripheral compartment to
reach a pseudo equilibrium.
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WHY BE CONCERNED ABOUT WHERE DRUGS GO?
Where drugs go determines Where Drugs Act

• Ciprofloxacin Cipro penetrates the prostate
  gland and
• therefore is effective in bacterial prostatitis,
  whereas
• most antibiotics do not enter the prostate and
• are therefore ineffective in prostatitis.

• Fexofenadine Allegra is largely excluded from
  the brain
• and therefore is a nonsedating antihistamine,
  whereas
• most antihistamines freely enter the brain and
• cause marked drowsiness.

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WHY BE CONCERNED ABOUT WHERE DRUGS GO?
Where drugs go influences How Long Drugs Last
In the Body

• Raloxifene Evista) (for treatment of
  osteoporosis in
• postmenopausal women) is transported by the liver
  into the
• intestines where it is reabsorbed (enterohepatic
  recirculation).
• This greatly increases the time raloxifene lasts
  in the body.

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• Drugs may be deposited in fatty tissue which may
  become a resevior
• low blood flow cannot absorb or release quickly
• bone teeth may accumulate drugs which bind to
  calcium, tetracycline

63
Pharmacokinetic Parameters----------------------
------
Clearance Volume of distribution Half
life Bioavailability
64
Volume of Distribution (Vd)

• The apparent volume of distribution
• A theoretical volume only
• NO PHYSICAL BASE
• NO PHYSIOLOGICAL BASE

Volume in which drug appears to distribute Vd not
physical volume. Vd is proportionality
constant Vd Dose(known)/Cp(known)
65
Volume of Distribution (Vd)

• Vd D / C
• Quantifies Distribution
• - Drug Concentration (C) mg/L
• Amount of drug in the body (D) mg

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VOLUME OF DISTRIBUTION OF DRUGS DETERMINANTS OF
VD
Plasma Protein Binding
A
??VD

??CP
??CP
67
VOLUME OF DISTRIBUTION OF DRUGS DETERMINANTS OF
VD
Distribution into Fat
?? Cp
A
?? VD

?? CP
68
Volume of Distribution

• An abstract concept
• Gives information on HOW the drug is distributed
  in the body
• Used to calculate a loading dose

69
Binding of some BDZs

• Flurazepam 10
• Alprazolam 70
• Lorazepam 90
• Diazepam 99
• No generalization for a pharmacological or
  chemical class

70
Pharmacokinetic Parameters----------------------
------
Clearance Volume of distribution Half
life Bioavailability
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Half Life
72
Half - Life (t1/2)
0.693 . Vd

• t1/2 ----------------

CL
Both Vd and CL may change independently. Therefore
t1/2 is not an exact index of drug elimination.
t1/2 Diazepam increases with age Its Clearance
does not Secondary pharmacokinetic parameter
and depends on CL Vd
73
Half - Life (t1/2)
0.693 . Vd

• t1/2 ----------------

CL
Is the time it takes for the concentration to
fall to half of its previous value Secondary
pharmacokinetic parameter and depends on CL Vd
74
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
Amount
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Significance

• Say a patient is taking a drug and has a toxic
  blood level of 16mg/L
• Say
• The blood level you want is 2mg/L
• Drug half life is 8 hours

How long will it take for the blood level to fall
back to the level you want?
76
Significance
Half life time taken for blood level to reduce
by 50 Therefore 16mg to 8mg 8 hours 8mg to
4 mg 8 hours 4mg to 2mg 8 hours Total 24
hours
77
Time Course of drug action

• Distribution Half Life
• time for drug to reach 50 of its peak
  concentration
• Elimination Half Life
• time for drug concentration to fall 50
• Steady State Concentration
• the level of drug achieved in blood with
  repeated, regular-interval dosing

78
Time to Steady State

• Time to steady state depends on half life

Tss 4 x t½
Steady-state occurs after a drug has been given
for approximately 4-5 elimination half-lives.
Half life DOES NOT depend on Dose Dosage
Interval
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Pharmacokinetic Parameters----------------------
------
Clearance Volume of distribution Half
life Bioavailability
80
Bioavailability
Destroyed in gut
Not absorbed
Destroyed by gut wall
Destroyed by liver
to systemic circulation
Dose
81
(AUC)o (AUC)iv
Bioavailability

i.v. route
oral route
Plasma concentration
Time (hours)
82
Bioavailability

• 100 mg Oral , 70 mg absorbed unchanged
• Bioavailability 70
• Iv admin 1 Oral admin lt 1
• lidocaine bioavailability 35 due to
• destruction in gastric acid and liver metabolism
• Blood from the gastrointestinal tract passes
  through the liver before entering any other
  organs.
• First Pass Effect

83

• The phenomenon of
• first pass effect
• or
• first pass metabolism
• and its clinical relevance
• so the amount reaching system circulation is less
  than the amount absorbed
• Some drugs are ineffective when given orally
  examples
• nitroglycerine, nor-adrenaline, insulin

84

• First pass effect

• A good way to tell if a drug has significant
  first pass effect is to compare oral with IV
  doses.
• If the oral dose is large, compared to the IV
  dose, it probably has extensive 1st pass effect

85

• 50 YEARS OLD MAN
• JUST RECEIVED HEART TRANSPLANT
• DISCHARGED HOME
• ORAL CYCLOSPORINE IS GIVEN
• ALSO DILTIAZEM?
• MAN DOES NOT HAVE HYPERTENSION.

86
Oral Cyclosporine ia an immunosuppressant drug
used to prevent transplant rejection. Low
bioavailability .So what ?
87
Drug Concentrations in the Plasma
50 40 30 20 10
But whats missing here that is needed for this
info to be of any use?
Drug Concentration in Plasma (Cp) mcg/mL
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time since administration of drug (hours)
88
Drug Concentrations in the Plasma
50 40 30 20 10
Drug Concentration in Plasma (Cp) mcg/mL
Subtherapeutic Concentrations
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time since administration of drug (hours)
89
BUCKET with a HOLE
Water level DRUG
Elimination
90
Example Oral Dose

• A single oral dose will give you a single peak
  plasma concentration
• The drug concentration then continuously declines
• Repeated doses result in oscillations in plasma
  concentration

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CONCEPT OF DRUG CLEARANCE INTRODUCTION TO Cl
Toxic Threshold
DPSS
(Therapeutic Window)
Therapeutic Threshold
DP (mg/L)
Multiple Doses
Single Dose
Time (hrs)
DPSS DP at steady state
93
???? ??? ???? 24 ????
???? ?? ???
2
SS
???? ?? ???
1
SS
6
4
94
toxic
plasma conc
effective
Time
95
toxic
plasma conc
Loading Dose Vd x plasma conc
effective
Cumulation and use of loading doses
Time
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Multiple dosing

• In a medical/dental context some drugs are given
  as single doses but this is unusual.
• Most are given as a course of therapy, one or
  more doses per day for several days or weeks

98
Multiple dosing

• On multiple dosing plasma concentration will rise
  and fall with each dose and body load will
  increase until
• Rate in Rate out
• administration elimination
• i.e. steady state is reached.

99
At Steady State

• Rate in Rate out
• F x Dose / Dosing Interval SSC x CL
• Dosage Plasma level
• F fraction of dose administered

Cpss Dose Rate/ CL 2 x Cpss 2 x Dose Rate/ CL
100
Target plasma concen for drug A 8 mg/L to
relieve symptoms

• Non smoker and normal 70 kg
• Cl 1.8 L/h
• Iv
• INFUSION RATE ?????
• --- keep the plasma level
• --- use oral drug A every 8 h extended release
  formulation
• --- f 0.95 oral maintenance dose
• A day ?????

101
Patient 1

• CL 40 ML/MIN
• VD 80L
• WHAT LOADING DOSE ? IV
• SSC 10MG/L

102

Patient 2

• ANTOBIOTIC
• CL 160 ML/MIN
• VD 80L
• WHAT MAINTENANCE DOSE IV
• EVERY 8H
• SSC 8 MG/L

103
DRUG METABOLISM

• F. Keyhanfar Ph.D, D.I.C.

(were still talking about Pharmacokinetics)
104
Chemicals to which we are exposed can be
classified as endogenous or environmental

• endogenous- chemicals of which our bodies are
  composed
• a. carbohydrates d. water
• b. proteins e. salts c. lipids
• 2. environmental
• a. air c. food
• b. water d. therapeutic drugs
• Plus chemicals to which we are exposed in
• a. home d. laboratory
• b. school e. pharmacy
• c. workplace f. drug manufacturing facility
• g. etc.
• As a group these are termed xenobiotic
  chemicals

105
Living with xenobiotic chemicals
Throughout biological history species have
developed and, over time, have become extinct.
When Darwin used the term survival of the
fittest, one test of fitness was the ability
to either make effective use of chemicals in the
environment, and protect oneself against the
adverse effects of chemicals in the environment.
ADME
106
Living with xenobiotic chemicals
Physiological disposition was a major tool in
either hastening the disappearance of a species,
or insuring that it lasted for a long period of
time.
ADME
107
Humans (and all other biological species) have
been exposed to xenobiotics in their environment
for as long as we have been on earth. However,
because they are not endogenous chemicals
biological systems have had to learn to handle
them. Metabolism results in changes in the
structure of the chemical. Since the same rules
apply to all chemicals the result may be a
metabolite of the chemical which has Similar
biological activity, is useful to the body, or is
more toxic. If metabolism results in a more
biologically active chemical, i.e., either a
better drug or a more toxic compound, is call
metabolic activation.
108
Biotransformation
Relatively harmless
Potentially toxic xenobiotic
Metabolic activation
Detoxification
Inactive metabolite
Reactive intermediate
109
METABOLISM (BIOTRANSFORMATION)-------------------
-----------------

• Acetaminophen, NSAIDs inhibit cyclo-oxygenase
• Amitriptylline Cimetidine
• Phenytoin
• Diazepam -
• Dopa Carbidopa
• Succinycholine
• Isoniazid

110
METABOLISM (BIOTRANSFORMATION)-------------------
-----------------

• Benzene
• Ethylene Glycol
• Malathion
• Phenelzine
• Histamine
• Thyroid Hormones

111
Terminology

• Metabolism (Gk metabole change)
• Metabolite metabolism produce metabolite
• Xenobiotics xeno (Gk foreign) biotics
• Inhibition (Latin inhibitus, ) to prohibit from
  doing something
• Induction (Latin inducere) to induce to call
  forth or bring about by influence or stimulation
• Cytochrome P450s (CYPs)

112
Rate limiting/ Affected by genetic and
environmental factors
Active/Inactive/Toxic/ Mutagenic/Carcinogen

• Phase I
  Phase II
• DRUG METABOLITE
  CONJUGATE
• Expose or introduce a
  Conjugate the functional
• functional group that
  groups exposed or introduced
• can be conjugated by
  during Phase I biotransformation
• Phase II enzymes
• Small ? in water solubility
  Large ? in water solubility
• Termination of Pharmacological activity or
  introduce toxicity
• The rate and extent to which a drug is
  metabolized determines the dose of the drug and
  the duration of the effect of the drug

O
H
O
G
l
u
c
u
r
o
n
i
d
e
113
Two-phase biotransformation

• Phase I (functionalization) reactions
• Oxidation, Reduction, and hydrolytic reactions
  (makes the drug more polar, but not necessarily
  inactive)
• Phase II (conjugation) reactions
• Conjugation to polar groups glucuronidation,
  sulfation, acetylation (most of these result in
  drug inactivation)

• Ultimate effect is to facilitate elimination

114
Phase I Reactions
OXIDATION REDUCTION HYDROLYSIS

• Phase I (functionalization) reactions
• Oxidation, Reduction, and hydrolytic
• (makes the drug more polar, but not
  necessarily inactive)
• introduction of functional group
• hydrophilicity increases slightly

115
Converting lipophilic to water soluble compounds
Lipophilic (non-polar)
Xenobiotic
Phase I - Activation
Reactive intermediate
Phase II - Conjugation
Conjugate
Water soluble (polar)
Excretion
116
Phase I Metabolism
Polar groups are exposed on or introduced to a
molecule

R

R
OH

R

R
COOH
R

R
SH



R

R
NH
2
117
Cytochromes P-450 (CYP) Flavin Monooxygenase
(FMO) Monoamine Oxidase (MAO) Aldehyde
dehydrogenase Alchohol dehydrogenase Various
amidases/esterases

• Phase I Reactions
• Oxidation
• Reduction
• Hydrolytic cleavage
• Alkylation (Methylation)
• Dealkylation
• Ring cyclization
• N-carboxylation
• Dimerization
• Transamidation
• Isomerization
• Decarboxylation

118
Drug Metabolism - Phase II

• Conjugation reactions
• Glucuronidation by UDP-Glucuronosyltransferase
• (on -OH, -COOH, -NH2, -SH groups)
• Sulfation by Sulfotransferase
• (on -NH2, -SO2NH2, -OH groups)
• Acetylation by acetyltransferase
• (on -NH2, -SO2NH2, -OH groups)
• Amino acid conjugation
• (on -COOH groups)
• Glutathione conjugation by Glutathione-S-transfera
  se
• (to epoxides or organic halides)
• Fatty acid conjugation
• (on -OH groups)
• Condensation reactions

119
METABOLISM (BIOTRANSFORMATION)-------------------
-----------------

• The processes by which foreign molecules
  (Xenobiotics) are chemically altered by a living
  organism.

120
METABOLISM (BIOTRANSFORMATION)

• The body recognizes these molecules and, if it is
  unable to eliminate them unchanged, is able to
  increase their water solubility by a variety of
  enzymic reactions

121
Result------------

• Water soluble metabolites
• Increased Excertion
• Reduced Biological Half-life
• Minimum Toxicity

122
Can metabolism decrease water solubility and
reduce excretion ?

• YES
• Acetylation decreases the solubility
• Of sulphonamides in urine
• Crystallization in the kidney tubules
• Necrosis of the tissue

123
An Example of Drug Metabolism
Non specific Hydrolytic enzyme
124
Complex Metabolism
125
t½ 20-80 hr
t½ 20 hr
t½ 30-100 hr
126
Metabolism
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes (oxidation,
conjugation)
Hepatic non-microsomal enzymes (acetylation,
sulfation,GSH, alcohol/aldehyde
dehydrogenase, hydrolysis, ox/red)
127
Sites of biotransformation

• where ever appropriate enzymes occur plasma,
  kidney, lung, gut wall and
• LIVER
• the liver is ideally placed to intercept natural
  ingested toxins (bypassed by injections etc) and
  has a major role in biotransformation

Skin Blood Brain
128
The liver
Hepatocytes
smooth endoplasmic reticulum
bile
portal venous blood
microsomes
contain cytochrome P450 dependent mixed function
oxidases
systemic arterial blood
venous blood
129
The CYP-450 reaction cycle
A
G
(B)
C
F
E
D
130
What is the Metabolic Significance of
the Cytochrome P450 System

• v Two Important Points to Remember
• Each isozyme can metabolize MANY different drugs,
  and many drugs can be metabolized by more than
  one isozyme
• Since very few compounds are conjugated directly,
  PHASE I metabolism is a very important line of
  defense

131
Important CYP Isoforms (12 )

• CYP3A4 3A5 3A7
• CYP2D6
• CYP1A1 1A2
• CYP2A6
• CYP2B6
• CYP2C8 2C9 2C19
• CYP2E1

132
Important CYP Isoforms (12 )

• CYP3A4 VERAPAMIL (CA CHANNEL BLOCER)
• CYP2D6 VERAPAMIL
• CYP1A1 1A2
• CYP2A6
• CYP2B6
• CYP2C8 2C9 VERAPAMIL
• CYP2C19
• CYP2E1

133
Important CYP Isoforms

• CYP3A4
• Midazolam, triazolam, cyclosporine,
  erythromycin, Ca channel blockers
• THE MOST PREDOMINANT IN HUMAN
• AMOUNT IN THE LIVER VARIETY OF
  DRUG BEING SUBSTRATES
• 50 of all CYP-mediated drug oxidations
• also involved in the greatest number of
  drug-drug interactions.
• active site is large , accept substrates up
  to M.wt 1200
• drugs bind in different regions of the
  enzyme active sites

134
CYP3A4

• Two drugs are metabolized by this enzyme.
• Will coadministration result in a
• drugdrug interation ?
• drugs bind in different regions of the enzyme
  active sites
• Two drugs can occupy the active site
  simultaneously both being available for
  metabolism by the enzyme.
• absent interations

135
CYP3A5

• Amino acid sequence is similar to that of CYP3A4,
  
• It is not present in all individuals.
• Patients expressing both CYP3A4 3A5
• Shows increased metabolism of
• CYP3A substrate

136
CYP3A7

• Expressed only in the fetus
• Disappears following birth and replaced by
  CYP3A4 3A5
• Different enzyme expression patterns and thus
  different drug metabolism capabilities throughout
  the various stages of life.

137
CYP2D6

• Tricyclic antidepressants, codeine,
  dextromethorphan, antipsychotics
• antiarrhythmics etc
• Its relative abundance in the liver is low.
• Exhibit genetic polymorphism

138

• 40 YEARS OLD WOMAN
• REMOVAL OF WISDOM TEETH BY SURGERY
• ACETAMINOPHEN 300 MG
• CODEINE 30 MG
• AFTER TWO DAYS PAIN IS STILL THERE.
• --------------------------------------------------
  --------------------------------
• CODEINE (weak analgesic)
• Metabolized to MORPHINE (ACTIVE METABOLITE) by
  CYP450 2D6
• LADY MAY BE DEFICIENT IN CYP2D6

139
Metabolism

• Amitriptylline is metabolized by CYP1A2
• Cimetidine inhibits CYP1A2
• Coadministration results in elevated
  Amitriptylline levels

140

• 50 YEARS OLD MAN
• JUST RECEIVED HEART TRANSPLANT
• DISCHARGED HOME
• ORAL CYCLOSPORINE IS GIVEN
• ALSO DILTIAZEM?
• MAN DOES NOT HAVE HYPERTENSION.

141
Oral Cyclosporine ia an immunosuppressant drug
used to prevent transplant rejection. Low
bioavailability .So what ?
142
Cimetidine, Ritonavir, amiodarone, diltiazem,
ketoconazole

• Inhibit CYP3A4
• Cimetidine, Fluoxetine, amiodarone
• Inhibit CYP2D6
• Cimetidine, Ketoconazole, Omeprazole
• Inhibit CYP2C19

143
CYP4503A4 is the enzyme responsible for the
presystemic metabolism of cyclosporineORAL
CYCLOSPORINE has low bioavailability.Diltiazem
will inhibit CYP4503A4 in the gut and increases
its bioavailability. ----------------------------
------------------Cyclo is not
cheap.Hypertension is the adverse effect of
cyclo

• 50 YEARS OLD MAN , JUST RECEIVED HEART TRANSPLANT
• DISCHARGED HOME
• ORAL CYCLOSPORINE IS GIVEN
• ALSO DILTIAZEM?
• MAN DOES NOT HAVE HYPERTENSION.

144
Barbiturates, Carbamazepine, Phenytoin,
pioglitazone, glucocorticoids,

• Induce CYP3A4
• Enhancing the rate of its synthesis
• Reducing its rate of degradation
• Phenobarbital, dexamethasone
• Induce CYP2A6 2B6 2C9
• Smoking (benzoapyrene) , Omeprazole
• Induce CYP1A1 1A2

145
Nomenclature of cytochrome P450 enzymes
57 functional genes and 58 pseudo genes code
active CYP in humans CYP1, 2, 3 families are
involved in the biotransformation of xenobiotics
and chemicals CYP4, 11, 17, 19, 21 are involved
in the biotransformation of endogenous molecules
146
Humans have 18 families of cytochrome P450 genes
and 43 subfamilies

• CYP1 drug metabolism (3 subfamilies, 3 genes, 1
  pseudogene)
• CYP2 drug and steroid metabolism (13 subfamilies,
  16 genes, 16 pseudogenes)
• CYP3 drug metabolism (1 subfamily, 4 genes, 2
  pseudogenes)
• CYP4 arachidonic acid or fatty acid metabolism (5
  subfamilies, 11 genes, 10 pseudogenes)
• CYP5 Thromboxane A2 synthase (1 subfamily, 1
  gene)
• CYP7A bile acid biosynthesis 7-alpha hydroxylase
  of steroid nucleus (1 subfamily member)
• CYP7B brain specific form of 7-alpha hydroxylase
  (1 subfamily member)
• CYP8A prostacyclin synthase (1 subfamily member)
• CYP8B bile acid biosynthesis (1 subfamily member)
• CYP11 steroid biosynthesis (2 subfamilies, 3
  genes)
• CYP17 steroid biosynthesis (1 subfamily, 1 gene)
  17-alpha hydroxylase
• CYP19 steroid biosynthesis (1 subfamily, 1 gene)
  aromatase forms estrogen
• CYP20 Unknown function (1 subfamily, 1 gene)
• CYP21 steroid biosynthesis (1 subfamily, 1 gene,
  1 pseudogene)
• CYP24 vitamin D degradation (1 subfamily, 1 gene)
• CYP26A retinoic acid hydroxylase important in
  development (1 subfamily member)
• CYP26B probable retinoic acid hydroxylase (1
  subfamily member)
• CYP26C probabvle retinoic acid hydroxylase (1
  subfamily member)

147
Metabolic Overloading

• Chemical being metabolised by an alternate
  pathway, not necessarily comparable
• to metabolic stress in human
• exposure situations
• The chemical may be unmetabolised
• and accumulate
• or stored in the body or be
• excreted unchanged.

148
Phase II Metabolism (conjugation)
GlutathioneGlucuronidationSulfationGlycine
Acetylation Methylation Coenzymes needed
various

149
Paracetamol Overdose

• Most common drug taken in overdose
• Few symptoms or early signs
• As little as 12g can be fatal
• Hepatic and renal toxin
• Centrolobular necrosis
• More toxic if liver enzymes induced or reduced
  ability to conjugate toxin

150
Acetaminophen and p-Aminophenols
Acetanilide, 1886 (accidental discovery
of antipyretic activity high toxicity)
Phenacetin or acetophenetidin, 1887
(nephrotoxic, methemoglobinemia)
75-80
70-90
Recognized as active metabolite of acetanilide
and phenacetin in 1948 (Brodie Axelrod)
popular in US since 1955
Acetaminophen, 1893
151
Acetominophen Metabolism
60
35
CYP2E1 CYP1A2 CYP3A4
induced by ethanol, isoniazid
Protein adducts, Oxidative stress Toxicity
NAPQI N-acetyl-p-benzoquinone imine
152
Paracetamol Metabolism
153
Management

• General measures
• lt8 hours
• Take level after four hours
• Start N-aceylcysteine
• Patients are usually declared fit for discharge
  from medical care on completion of its
  administration.
• Patients should be advised to return to hospital
  if vomiting or abdominal pain develop or recur

154
N-acetylcysteine

• Supplies glutathione
• Dosage for NAC infusion - ADULT
• (1) 150mg/kg IV infusion in 200ml 5 dextrose
  over 15 minutes, then
• (2) 50mg/kg IV infusion in 500ml 5 dextrose over
  4 hours, then
• (3) 100mg/kg IV infusion in 1000ml 5 dextrose
  over 16 hours
• Side-effects
• Flushing, hypotension, wheezing, anaphylactoid
  reaction
• Alternative is methionine PO (lt12 hours)

155
Acetaminophen Toxicity

• Acetaminophen overdose results in more calls to
  poison control centers in the United States than
  overdose with any other pharmacologic substance.
• The American Liver Foundation reports that 35 of
  cases of severe liver failure are caused by
  acetaminophen poisoning which may require organ
  transplantation.
• N-acetyl cysteine is an effective antidote,
  especially if administered within 10 h of
  ingestion NEJM 3191557-1562, 1988
• Addition of N-acetyl cysteine to acetaminophen
  tablets proposed to prevent liver toxicity.
  British Medical Journal, Vol. 323, Sept. 15,
  2001

156
Metabolism
What factors can affect
metabolism of a drug
157
Factors affecting drug metabolism
Main site of drug metabolism LIVER

• Drug metabolism can be affected by
• First pass effect
• Hepatic blood flow
• Liver disease
• Drugs which alter liver enzymes

158
Factors affecting drug metabolism

• Genetic factors
• e.g acetylation status
• Other drugs
• hepatic enzyme inducers
• hepatic enzyme inhibitors
• Age
• Impaired hepatic enzyme activity
• Elderly
• Children lt 6 months (especially premature babies)

159
Factors affecting biotransformation

• age (reduced in aged patients children)
• sex (women slower ethanol metabilizers)
• species (phenylbutazone 3h rabbit, 6h horse, 8h
  monkey, 18h mouse, 36h man) biotransformation
  route can change
• clinical or physiological condition
• other drug administration (induction (not CYP2D6
  ) or inhibition)
• food (charcoal grill CYP1A)(grapefruit juice
  --CYP3A)
• first-pass (pre-systemic) metabolism

160
Factors Influencing Activity and Level of CYP
Enzymes
Red indicates enzymes important in drug metabolism
161
(No Transcript)
162
Enantiomer

• Drug Shape
• Lock and Key phenomenon for the drug and its
  receptor site
• More than half of all useful drugs are chiral
  molecules and exist as enantiomeric pairs
• Ex Carvedilol has a single chiral center and
  two enantiomers
• S(-) isomer potent Beta receptor blocker
• R() isomer 100-fold weaker at Beta receptor
• One drug enantiomer is often more susceptible
  than the other to drug-metabolizing enzymes
• One enantiomer could have a longer or shorter
  duration of action than the other

163
Racemic mixtures

• Drug Shape
• As of now, most clinical studies of drugs have
  only tested racemic mixtures (two enantiomer
  pairs)
• 55 of drugs are only available as racemic
  mixtures where a patient is receiving 50
  inactive or actively toxic drug

164
Pharmacogenetics

• For pharmacokinetics, change may occur in
• drug transporters
• drug metabolizing enzymes
• more active enzymes
• Inactive enzymes
• semi-active enzymes

165
Succinylcholine

• Used during anesthesia to induce muscle paralysis
• Paralysis usually lasts minutes, but in some
  individuals, it may last up to one hour
• Due to altered kinetics of pseudocholinesterase

166
Isoniazid

• Used in the treatment of tuberculosis
• Observed variation in the amount of unchanged
  isoniazid in the urine
• Differences were due to an individuals ability to
  convert isoniazid to acetylisoniazid.
• Caused by mutations in the N-acetyltransferase-2
  enzyme (NAT2) on chromosome 8
• Some individuals develop isoniazid toxicity
  manifested as peripheral neuropathy