PROF. Dr. ALSAYED ZAKI 1 Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA.
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Transcript of PROF. Dr. ALSAYED ZAKI 1 Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA.
PROF. Dr. ALSAYED PROF. Dr. ALSAYED ZAKIZAKI
1Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
It is the study of It is the study of substancessubstances
that that interactinteract with living systems with living systems
to to activate or activate or inhibitinhibit
normalnormal body processesbody processes..
2Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
It is the science of It is the science of substances (drugs)substances (drugs) used for: used for:
Treatment Treatment
oror
PreventionPrevention
oror
DiagnosticDiagnostic purposes. purposes.
3Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
ChemicalChemical name name
Generic nameGeneric name (official or non roprietary)
Trade nameTrade name (proprietary)
Acetyl salicylic acid
Aspirin Rivo
Drugs are identified by different names
4Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Most of drugs are restricted for sale by
prescription only.
Some drugs can be used by the public
without a prescription
(Over-The-Counter = OTC)
e.g:Nasal & oral decongestants
5Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
11--Animal sourcesAnimal sources::e.g. heparine.g. heparin..
22--Plant sourcesPlant sources
e.g. digoxine.g. digoxin..3-Microorganisms:
e.g. penicillin. 6Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
4-Synthetic drugs: e.g. sulphonamides.
5-Mineral sources : e.g. iodine
6-Biotechnology:
• Human insulin
• Tissue plasminogen activator (tPA)
7Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
What the drug does to body
Pharmacology
Pharmacokinetics Pharmacodynamics
What the body does to drug
8Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Absorption, Absorption,
Distribution, Distribution,
Metabolism (Biotransformation)Metabolism (Biotransformation)
ExcretionExcretion
It is a study of:
9Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Absorption into plasma
Sites of action
Receptors
Tissue storage
Plasma
Drug Metabolism )Liver, Lung, Blood,… etc Drug Excretion
)renal, Biliary, Exhalation,… etc
Drug administration(I.V., Oral, etc……)
Free drugDistribution to Tissues
Bound drug
10Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Extracellular
Bimolecular lipoid
(hydrophobic)
Membrane
water filled pores
carrier
DD
D
Intracellular
11Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
1) Passive 1) Passive transfer:transfer:
The passage of drugs across cell membranes occurs by any of the following processes:
2) Specialized 2) Specialized transporttransport: :
A.Simple diffusion
B. Filtration
a. Facilitated diffusion
b. Active transport
c. Pinocytosis
12Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
It is the most important.
A.Simple diffusion
Extracellular
lipidMembrane
D
Intracellular
aqueous
No energy
D
D
D
D
D
D
Not inhibited by metabolic inhibitors
Not saturable.
No carrier is required
Along concentration gradient
13Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
* Concentration gradient is maintained by removal
of the drug from other side of the membrane.
It depends on:A. Simple diffusion
1.concentration gradient
Extracellular
Membrane
D
Intracellular
D
D
D
D
D
D
D D
D D
14
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
lipid / water partition coefficient
2.Lipid solubility
lipid phase
water phaseD
D
D
D
DDD
D
DD
D
DIt is a Ratio of drug
Concentration in
A. Simple diffusion
It is measured by:
one immisciblelipid/water system
Concentration in
15Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
*Most of drugs are either
B
A- B+
A. Simple diffusion
3. Degree of ionization
A
non-ionized Lipid solubility
weak acids or weak bases
16
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
It is determined by:
• pKa of drug
• pH of environment
A. Simple diffusion
3. Degree of ionization
ionized
non-ionizedPKa =
(Dissociation constant)
17Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Clinical Significance of pKa:
Aspirin) weak acid, pKa3.5(
Acid mediumstomach
Amphetamine weak base (pKa9.8)
)Intestine(
A A-A A-
A
A
A
A
BB+B+ B+
BB
BB
Non-ionized
Non-ionized
Alkaline medium
18
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Acidification of urine• vitamin C • NH4Cl
weak basebase drugs
B+
B+
B+B+
B+
B+B+
Ionized
e.g. amphetamine
In AcidicAcidic medium
Excretion
Clinical Significance of pKa:
19Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Alkalinization of urine
weak AcidicAcidic drugs
Ionized
In AlkalineAlkaline medium
Excretion
e.g. aspirin
A-A-A-A-
A-A-A-
NaHCO3
Clinical Significance of pKa:
20Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
•concentration gradient
Extracellular
Membrane
D
Intracellular
D
D
D
D
D
D•degree of ionization
•Molecular size.
•Thickness of membrane Thickness of membrane
It depends on:
•lipid solubilityDD D
D
++
A.Simple diffusion
21Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
B. FiltrationD Extracellular
Membrane
Intracellular
Not affected by:Not affected by:
• Not saturable
• Lipid solubility
water filled pores
22Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
B. Filtration
limited by blood flowlimited by blood flow
capillaries
It depends on:
Hydrostatic pressureHydrostatic pressure Osmotic pressureOsmotic pressure
D
23Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Substances that are:Too large
Or Poorly lipid soluble
Carrier(Membrane transporters)
D+
D+
a. Facilitated diffusion:a. Facilitated diffusion:
= simple diffusion Require:
• Carrier
• Saturable
D+ D+ D+
24Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
D+
D+
b. Active transport:
Against concentration gradient
e.g. renal tubular secretion of organic acids
ATP
c.AMP
D+ D+ D+
Energy
25Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Influx of ions & essential nutrients
Efflux of toxins.
They have role in selective absorption & elimination
Located in gut, liver, kidney, placenta and CSF
Carrier(Membrane transporters)
They are proteins & control:
26Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Membrane carriers may be specialized for expelling foreign
molecules e.g.
D
P-glycoprotein transporters
D D D
D
D D
27Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
DD
where large molecules are engulfedengulfed inside cells,
e.g., absorption of B12 and intrinsic factor.
c. Pinocytosis:
Energy dependant
28Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
• Enteral
via gastrointestinal tract (GIT).– Oral – Sublingual– Rectal
• Parenteral administration = injections.
• Topical application
29Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
AdvantagesDisadvantagesEasyEasy
Self useSelf use
SafeSafe
ConvenientConvenient
cheapcheap
No need for No need for sterilizationsterilization
Slow effectSlow effect
No complete absorption No complete absorption (Low bioavailability).(Low bioavailability).
Destruction by GITDestruction by GIT
First pass effectFirst pass effect
GIT irritationGIT irritation
Food–Drug interactionsFood–Drug interactions
Drug-Drug interactionsDrug-Drug interactions
Not suitableNot suitable for vomiting, for vomiting, unconscious, emergency.unconscious, emergency.
30Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
First pass Metabolism
Metabolism of drug in the gut wall or portal circulation before reaching systemic circulation
• so the amount reaching system circulation is less than the amount absorbed
Where ? Liver Gut wall Gut Lumen
Result ?
Low bioavailability.
Short duration of action (t ½).31
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
First pass effect
32Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
Dosage forms
Capsules
Tablets
Syrup
Suspension
TabletsTabletsHard- gelatin Hard- gelatin capsulecapsule SpansuleSpansule
Soft- gelatin Soft- gelatin capsulecapsule
33
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
AdvantagesDisadvantages• Rapid effect (Emergency)Rapid effect (Emergency)• No first pass metabolism.No first pass metabolism.• High bioavailabilityHigh bioavailability• No GIT destructionNo GIT destruction• No food drug No food drug
interactioninteraction
Dosage form:Dosage form: friable tablet friable tablet
Not forNot for
irritant drugsirritant drugs
Frequent useFrequent use
34Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
AdvantagesDisadvantages Suitable forSuitable for–Vomiting & children. Vomiting & children. &unconsciousness&unconsciousness– Irritant & Bad taste drugs.Irritant & Bad taste drugs.– less first pass metabolism less first pass metabolism
(50%)(50%)
Dosage form:Dosage form:
suppository or enemasuppository or enema
Not forNot for – Irregular Irregular absorption & absorption & bioavailability.bioavailability.– Irritation of Irritation of rectal mucosa.rectal mucosa.
35Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
Intradermal (I.D.) (into skin)Subcutaneous (S.C.)
Intramuscular (I.M.)
Intravenous (I.V.) (into veins)
Intra-arterial (I.A.) (into arteries)
Intrathecal (I.T.) (cerebrospinal fluids )
Intraperitoneal (I.P.) (peritoneal cavity)
Intra - articular (Synovial fluids)
36Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
37Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
AdvantagesDisadvantages• high bioavailabilityhigh bioavailability• Rapid action Rapid action (emergency)(emergency)• No first pass metabolismNo first pass metabolism
Suitable forSuitable for–Vomiting &unconsciousnessVomiting &unconsciousness– Irritant & Bad taste drugs.Irritant & Bad taste drugs.– No gastric irritationNo gastric irritation– No food-drug interactionNo food-drug interaction
Dosage form:Dosage form:
Vial or ampouleVial or ampoule
– InfectionInfection– Sterilization.Sterilization.– PainPain– Needs skillNeeds skill– AnaphylaxisAnaphylaxis– Expensive.Expensive.
38Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Ampoule Vial
39Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Produce local effect to Skin (percutaneous) e.g. allergy testing,
topical local anesthesia Mucous membrane of respiratory tract
(Inhalation) e.g. asthma Eye drops e.g. conjunctivitis Ear drops e.g. otitis externa Intranasal, e.g. decongestant nasal spray
40Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
AdvantagesDisadvantages• Mucous membrane ofMucous membrane of
respiratory system respiratory system • Rapid absorption Rapid absorption
(large surface area)(large surface area)•Provide local actionProvide local action• Minor systemic effectMinor systemic effect• Low bioavailabilityLow bioavailability• Less side effects. Less side effects. • No first pass effect No first pass effect
Dosage form:Dosage form: aerosol, nebulizer aerosol, nebulizer
Only few Only few drugs can be drugs can be
usedused
41
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Nebulizer AtomizerNebulizer Atomizer
42Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
a medicated adhesive patch applied to skin
*Slow effect (prolonged drug action)
*produce systemic effect
e.g. the nicotine patches
43Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
It is the process of entry of drug
from site of administration into
systemic circulation.
44Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
A- Factors related A- Factors related to drugto drug
B- Factors related to the patient:
45Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
A- Factors related to drug
a) Physicochemical properties :
1-Degree of ionization:
2-Degree of solubility:
High lipid/water partition coefficient.
absorption
ionized absorbed
46Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
3-Chemical nature:
4-Valency:
so vitamin C increases absorption of iron.
b) Pharmaceutical form of drug:Absorption of:
Drug Factors
suspensions or tablets.
solutions
Ferrous salts ferric
Inorganic organic.
47Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
B- Factors related to the patient:
1-Route of administration:
alveolar mucosa
sublingual,
small intestinal
&rectal mucosa
Gastric mucosa
I.M. S.C.
48Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
2-Area and vascularity of absorbing surface:
absorption is directly proportional to both
Area &
Vascularity
49Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
4-Rate of general circulation:
•In shock,
peripheral circulation
•I.V. route is used.
3-State of absorbing surface:
Atrophic gastritis &
Mal-absorption syndrome
rate of absorption of drugs.
50Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
•Intrinsic factor of the stomach is essential for vitamin B12 absorption from lower ileum
•Adrenaline induces vasoconstriction so delay absorption of local anesthetics.
5-Specific factors and presence of other drugs:
51Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
* Factors related to the drug formulation:
Disintegration Rate of dissolution Excipients «additives» Molecular weight Lipid solubility Stability in gut contents Pka of the drug.
52Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
* Factors related to the patient:
1-State of absorbing surface, specific factors.
2-Surface area: Rate of absorption from intestine is greater than from stomach.
53Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
- Patient Factors:
Where absorption of weak acidic drugs starts in stomach
weak base drugs are absorbed from intestine.
Drugs which are:Destroyed by gastric juice
OrIrritant on stomach
Administered in enteric coated form e.g. sodium salicylate.
3-pH within the gut:
54Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Sustained release form
4-Rate of dissolution and gut motility:
Rate of dissolution
Absorption
Absorption of solid form of a drug is dependent on:
T1 T2 T3Prolong their duration.
- Patient Factors:
55Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Decreased gastric emptying
the rate of absorption of slowly dissoluted drug (digoxin)
that of rapidly dissoluted one (paracetamol).
- Patient Factors:
56Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
5-Presence of other substance within the lumen:
•Food, calcium and iron decrease tetracycline
absorption.
•Fatty meals can enhance griseofulvin absorption.
•Grapefruit juice increases oral bioavailability of some drugs
- Patient Factors:
57Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Portal v.
6-First pass effect (pre-systemic metabolism):
Benzyl penicillinBenzyl penicillin
digestive enzymesdigestive enzymes
mucosal enzymesmucosal enzymesTyramineTyramine
Systemic circulation
HME
Rectum
Buccal mucosa
pH
InsulinInsulin
58
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
To overcome hepatic first pass metabolism:
oral dose Use other routes
• IV lidocaine
• Sublingual nitroglycerin
Propranolol
59Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
and becomes available for biological effect
The percentage of drugthat reaches systemic circulation
unchanged
following administration by any route.
= 100% after IV administration.60Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
Oral bioavailability = Area under the curve (AUC) oral
Area under the curve (AUC) I.V.
pla
sm
a d
rug
co
nce
ntr
ati
on
Time
Oral dose
I.V. dose
x 100
61
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Oral bioavailability depends on:
Amount absorbed
Amount metabolized before reaching systemic circulation
(first pass metabolism).62Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
It is dependent on:
Lipid solubility
Ionization
Molecular size
Binding to plasma proteins
Rate of blood flow
Special barriers. 63
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
The body compartments
Extra-cellular
Cell membrane
Endothelium of capillary wall
Intracellular compartment
Interstitial compartment
Intravascular (Plasma) compartment
64Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Extra-cellular
Intracellular compartment
Interstitial compartment
Intravascular (Plasma) compartment
One compartment model (intravascular)
Dextran pp
1. High molecular weight2. highly bound to plasma proteins
65
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Extra-cellular
Intracellular compartment
Interstitial compartment
Two compartment model (extracellular distribution) and
+
Intravascular (Plasma) compartment
Mannitol .Quaternary ammonium
compounds66Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
Extra-cellular
Intracellular compartment
Interstitial compartment+
Intravascular (Plasma) compartment
Multicompartmental model (extracellular and intracellular distribution)
Phenytoin Alcohol 67Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
Selective distribution:
Iodide in thyroid gland
calcium in bones
Tetracycline in bone and teeth
68Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Selective distribution
Aminoglycosides as streptomycin in
Kidney Vestibular system
69Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Apparent volume of distribution (Vd):
it is a kinetic parameter of a drug that correlates dose with plasma level.
Vd = Amount of drug in body
Plasma concentration of drug
70Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Extra-cellular
Plasma compartment
Interstitial compartment
Intracellular compartment
4 L
10 L 12-14 L
Total Total body water
4242 LL
Vd= 3-4 L e.g. heparin
Vd= 12-14 L e.g. aspirin.
Vd= 42 LVd= 42 Le.g. phenytoin & e.g. phenytoin &
alcohol.alcohol.
71
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Vd of Digoxin= 500 L?
72Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Drugs with high Vd
(extensive tissue distribution).
Dialysis
73Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Estimation of the total amount of drug in body at any time.
Amount of drug =Vd x plasma concentration of drug at certain time.
74Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Loading dose = Vd x desired concentration.
Loading dose
?
75Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
pp
1-Free form: active,
diffusible, available for biotransformation &
excretion.
22--Bound formBound form inertinert , ,
non-diffusiblenon-diffusible , ,not available for metabolismnot available for metabolism
&&excretionexcretion . .
It acts as aIt acts as a reservoir reservoir for drug for drug . .76
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Significance of binding to plasma proteins:
e.g. diphenylhydantoin.pp
pp pp
pp
Hypoalbuminemia or lowered binding capacity of albumin
free fraction of some drugs
77Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Significance of binding to plasma proteins:
pp
Higher affinity for pp binding
sites
pp
free form78Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
pp
Highly bound drugHighly bound drug
pppp
Given I.V.,
Thiopentone is given at a relatively rapid rate.
Rapid injection
↑↑free form
79Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Astrocyte
Tight junction
Endothelial cells
Basement membrane
Passage of Drugs to CNS
Blood brain barrier
Lipid soluble non-ionized drugs
+
quaternary amines (ionized)
80Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Passage of Drugs to CNS
slightly
pass through the normal barrier,
But they penetrate
readily
in acute bacterial meningitis.
Penicillins
81
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
• Thalidomide ,
• Diphenylhydantoin ,
• Tetracyclines ,
• Corticosteroids ,
• Antithyroid drugs
•Aspirin .
Passage of Drugs to the Foetus
First trimester
82Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
so its duration depends on
redistribution rather than metabolism or excretion
Redistribution:
lipid soluble drug crossing BBB
thiopentone is initially accumulated in brain
due to high lipid solubility
blood flow
then redistributed to less perfused adipose tissue
83Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
84Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
lipid insoluble
Excreted unchanged
Ionized drugs
)water soluble(
85
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Alveoli
Volatile anesthetics
highly lipid soluble
Eliminated through
86Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Non ionized
Lipid soluble
Reabsorbed by renal tubules
Lipid insoluble)water soluble(
87Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Phases of biotransformationPhases of biotransformation : :
Phase I (Non synthetic) reactions Phase I (Non synthetic) reactions : :
• Oxidation
• Reduction
• Hydrolysis
88Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Phase I reactions Phase I reactions : :
Result in:
Drug inactivation
most of drugs
89Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Phase I reactions Phase I reactions : : Result in:
Inactive Active Cortisone Cortisol
90Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Phase I reactions Phase I reactions : : Result in:
Active Active
Phenacetin Paracetamol
91Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Phase I reactions Phase I reactions : : Result in:
Toxic metabolite
Methanol Formaldehyde
92Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
(Synthetic) reactions:
o Glucuronic acid
o Glutathione
o Sulphate
o Acetic acid
o Glycine
o Methyl group
Conjugation with:
Phase II
93Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Phase II (Synthetic) reactions:
usually
Inactivation with
few exceptions:
morphine-6- conjugate is active
Result ?
94Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Most of drugs pass through:
phase I phase II
95Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Acetylated Hydrolyzed
isonicotinic acid
phase I phase II
Isoniazid
96Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Sites of biotransformation
1- Microsomal Enzymes :
• Glucuronide conjugation.
• Oxidation by CYP450 enzymes
• Reduction.
• Hydrolysis
Affected By
Drugs & age
97Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
2- Non Microsomal :
Present in liver, kidney, plasma, skin and GIT…etc
• Conjugations
glucuronic acid.• Oxidation by soluble
enzymes in?
• Reduction.
• Hydrolysis.
activity is stable
throughout life.
98Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
• Microsomal enzymes
•Responsible for most of oxidative reactions
•Exist in multiple isoforms
•Substrate specificity
CYP1A2
theophyllinesmokingCYP1A2
CYP1A2
CYP450s
99Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Factors affecting drug metabolism
1-Drugs:
Induction: Enzymes
Degradation
Synthesis
Enzymes
100Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Enzyme inducers:
Examples: Phenobarbitone, phenytoin, carbamazepine,
Rifampicin, griseofulvin,
Testesterone, some glucocorticoids,
Tobacco smoking, ethyl alcohol (chronic).
101Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Importance of enzyme induction:
CYP1A2
theophyllinesmokingCYP1A2
CYP1A2
Decreases effect of other drug.
102Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Tolerance
Importance of enzyme induction:
CYP450
phenobarbitonephenobarbitoneCYP450
CYP450
Inducing its own metabolism
Pollutants
103Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Importance of enzyme induction:
phenobarbitone
Induces bilirubin conjugation
ttt Hyperbilirubinemia in newborn.
104Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Enzyme inhibition
(drugs that inhibit drug metabolism):
Faster than enzyme induction?
serious drug interactions.
105Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Enzyme inhibition Examples:
• Cimetidine
• Chloramphenicol, cotrimoxazole, ciprofloxacin, erythromycin, ketoconazole, isoniazid,
• Oestrogen, progesterone, sodium valproate,
• MAOIs, and grape fruit.
106Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
2-Genetics variation:
Genetically determined polymorphisms.
Fast SlowSlow prone toprone to
peripheral neuritisperipheral neuritis
prone to hepatic toxicity.
Acetylation rate of isoniazid :
107Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
3-Nutritional state•conjugating agents as:
• sulphate
sensitive to body nutrient level.
• glutathiaone
glycine.protein diet
108Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Dosage
D
E
E
D
DD
D
E
DD
D
D
D
DD
Saturation
Drug accumulation
Alternative Alternative pathwaypathway
DD
D
109
Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
5-Age:
Drug metabolism is reduced in
extremes of age.
110Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
Propranolol &
Lidocaine
Faster in men.
6 -Gender:
Diazepam Caffeine Paracetamol
Faster in women
Metabolism
111Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
7-Disease state:
Liver disease
drugs metabolism.112Prof.DR.AL SAYED ZAKI-BMC-
SAUDIA ARABIA
7-Disease state:
Heart failure
Hepatic flow
The effect of rapidly metabolized drugs
e.g. lidocaine
113Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
7-Disease state:
Kidney disease
The excretion of drugs
114Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
8-Circadian rhythm: In rats and mice, the rate of hepatic metabolism
of some drugs follows a diurnal rhythm. This may be true in humans as well.
9-Route of administration:1st pass effect occurs for drugs administered orally
Factors affecting drug metabolism
115Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
eliminated from the body
It is the process by which
a drug or metabolite is
116Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
o Passive glomerular filtration
o Active tubular secretion in proximal tubules
o Passive tubular reabsorption.
117Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Factors affecting renal excretion:
1-Glomerular filtration rate:
D
• Free • Water soluble • Low molecular weight
Filtered
118Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Acidification of urine• vitamin C • NH4Cl
weak basebase drugs
2-Change in urinary pH
B+
B+
B+B+
B+
B+B+
Ionized
e.g. amphetamine
In AcidicAcidic medium
Excretion
119Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Alkalinization of urine
weak AcidicAcidic drugs
2-Change in urinary pH
Ionized
In AlkalineAlkaline medium
Excretion
e.g. aspirin
A-A-A-A-
A-A-A-
NaHCO3
120Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
oIodides
oRifampicin
oSalicylates
Morphin
e
Tetracycline
Streptomycin
121Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
Portal v.
Bile
Ampicillin
Rifampicin
Biliary infection
Morphine
Enterohepatic circulation
122Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA
3-Sweat: e.g., rifampicin (red color), vitamin B1.
4-Lungs: e.g., gases and volatile anesthetics.
5-Milk: Morphine Amphetamine Chloramphenicol Oral anticoagulants
123Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA