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..


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.


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


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


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


Absorption, Absorption,

Distribution, Distribution,

Metabolism (Biotransformation)Metabolism (Biotransformation)

ExcretionExcretion

It is a study of:


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


Extracellular

Bimolecular lipoid

(hydrophobic)

Membrane

water filled pores

carrier

DD

D

Intracellular


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


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


* 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


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


It is determined by:

• pKa of drug

• pH of environment

A. Simple diffusion

3. Degree of ionization

ionized

non-ionizedPKa =

(Dissociation constant)


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


Acidification of urine• vitamin C • NH4Cl

weak basebase drugs

B+

B+

B+B+

B+

B+B+

Ionized

e.g. amphetamine

In AcidicAcidic medium

Excretion



Alkalinization of urine

weak AcidicAcidic drugs

Ionized

In AlkalineAlkaline medium

Excretion

e.g. aspirin

A-A-A-A-

A-A-A-

NaHCO3



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


B. FiltrationD Extracellular

Membrane

Intracellular

Not affected by:Not affected by:

• Not saturable

• Lipid solubility

water filled pores


SAUDIA ARABIA

B. Filtration

limited by blood flowlimited by blood flow

capillaries

It depends on:

Hydrostatic pressureHydrostatic pressure Osmotic pressureOsmotic pressure

D


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+


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


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:


Membrane carriers may be specialized for expelling foreign

molecules e.g.

D

P-glycoprotein transporters

D D D

D

D D


DD

where large molecules are engulfedengulfed inside cells,

e.g., absorption of B12 and intrinsic factor.

c. Pinocytosis:

Energy dependant


SAUDIA ARABIA

• Enteral

via gastrointestinal tract (GIT).– Oral – Sublingual– Rectal

• Parenteral administration = injections.

• Topical application


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.


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


First pass effect


SAUDIA ARABIA

Dosage forms

Capsules

Tablets

Syrup

Suspension

TabletsTabletsHard- gelatin Hard- gelatin capsulecapsule SpansuleSpansule

Soft- gelatin Soft- gelatin capsulecapsule

33


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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


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.


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)



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.


Ampoule Vial


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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


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


Nebulizer AtomizerNebulizer Atomizer


SAUDIA ARABIA

a medicated adhesive patch applied to skin

*Slow effect (prolonged drug action)

*produce systemic effect

e.g. the nicotine patches


It is the process of entry of drug

from site of administration into

systemic circulation.


A- Factors related A- Factors related to drugto drug

B- Factors related to the patient:


A- Factors related to drug

a) Physicochemical properties :

1-Degree of ionization:

2-Degree of solubility:

High lipid/water partition coefficient.

absorption

ionized absorbed


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.


B- Factors related to the patient:

1-Route of administration:

alveolar mucosa

sublingual,

small intestinal

&rectal mucosa

Gastric mucosa

I.M. S.C.


2-Area and vascularity of absorbing surface:

absorption is directly proportional to both

Area &

Vascularity


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.


•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:


* Factors related to the drug formulation:

Disintegration Rate of dissolution Excipients «additives» Molecular weight Lipid solubility Stability in gut contents Pka of the drug.


* 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.


- 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:


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:


Decreased gastric emptying

the rate of absorption of slowly dissoluted drug (digoxin)

that of rapidly dissoluted one (paracetamol).

- Patient Factors:


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:


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


To overcome hepatic first pass metabolism:

oral dose Use other routes

• IV lidocaine

• Sublingual nitroglycerin

Propranolol


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


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


The body compartments

Extra-cellular

Cell membrane

Endothelium of capillary wall

Intracellular compartment

Interstitial compartment

Intravascular (Plasma) compartment


Extra-cellular




One compartment model (intravascular)

Dextran pp

1. High molecular weight2. highly bound to plasma proteins

65


Extra-cellular



Two compartment model (extracellular distribution) and

+


Mannitol .Quaternary ammonium

compounds66Prof.DR.AL SAYED ZAKI-BMC-

SAUDIA ARABIA

Extra-cellular


Interstitial 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


Selective distribution

Aminoglycosides as streptomycin in

Kidney Vestibular system


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


Extra-cellular

Plasma 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


Vd of Digoxin= 500 L?


Drugs with high Vd

(extensive tissue distribution).

Dialysis


Estimation of the total amount of drug in body at any time.

Amount of drug =Vd x plasma concentration of drug at certain time.


Loading dose = Vd x desired concentration.

Loading dose

?


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


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


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


Astrocyte

Tight junction

Endothelial cells

Basement membrane

Passage of Drugs to CNS

Blood brain barrier

Lipid soluble non-ionized drugs

+

quaternary amines (ionized)


Passage of Drugs to CNS

slightly

pass through the normal barrier,

But they penetrate

readily

in acute bacterial meningitis.

Penicillins

81


• Thalidomide ,

• Diphenylhydantoin ,

• Tetracyclines ,

• Corticosteroids ,

• Antithyroid drugs

•Aspirin .

Passage of Drugs to the Foetus

First trimester


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



lipid insoluble

Excreted unchanged

Ionized drugs

)water soluble(

85


Alveoli

Volatile anesthetics

highly lipid soluble

Eliminated through


Non ionized

Lipid soluble

Reabsorbed by renal tubules

Lipid insoluble)water soluble(


Phases of biotransformationPhases of biotransformation : :

Phase I (Non synthetic) reactions Phase I (Non synthetic) reactions : :

• Oxidation

• Reduction

• Hydrolysis


Phase I reactions Phase I reactions : :

Result in:

Drug inactivation

most of drugs


Phase I reactions Phase I reactions : : Result in:

Inactive Active Cortisone Cortisol



Active Active

Phenacetin Paracetamol



Toxic metabolite

Methanol Formaldehyde


(Synthetic) reactions:

o Glucuronic acid

o Glutathione

o Sulphate

o Acetic acid

o Glycine

o Methyl group

Conjugation with:

Phase II


Phase II (Synthetic) reactions:

usually

Inactivation with

few exceptions:

morphine-6- conjugate is active

Result ?


Most of drugs pass through:

phase I phase II


Acetylated Hydrolyzed

isonicotinic acid

phase I phase II

Isoniazid


Sites of biotransformation

1- Microsomal Enzymes :

• Glucuronide conjugation.

• Oxidation by CYP450 enzymes

• Reduction.

• Hydrolysis

Affected By

Drugs & age


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.


• Microsomal enzymes

•Responsible for most of oxidative reactions

•Exist in multiple isoforms

•Substrate specificity

CYP1A2

theophyllinesmokingCYP1A2

CYP1A2

CYP450s


Factors affecting drug metabolism

1-Drugs:

Induction: Enzymes

Degradation

Synthesis

Enzymes


Enzyme inducers:

Examples: Phenobarbitone, phenytoin, carbamazepine,

Rifampicin, griseofulvin,

Testesterone, some glucocorticoids,

Tobacco smoking, ethyl alcohol (chronic).


Importance of enzyme induction:

CYP1A2

theophyllinesmokingCYP1A2

CYP1A2

Decreases effect of other drug.


Tolerance


CYP450

phenobarbitonephenobarbitoneCYP450

CYP450

Inducing its own metabolism

Pollutants



phenobarbitone

Induces bilirubin conjugation

ttt Hyperbilirubinemia in newborn.


Enzyme inhibition

(drugs that inhibit drug metabolism):

Faster than enzyme induction?

serious drug interactions.


Enzyme inhibition Examples:

• Cimetidine

• Chloramphenicol, cotrimoxazole, ciprofloxacin, erythromycin, ketoconazole, isoniazid,

• Oestrogen, progesterone, sodium valproate,

• MAOIs, and grape fruit.


2-Genetics variation:

Genetically determined polymorphisms.

Fast SlowSlow prone toprone to

peripheral neuritisperipheral neuritis

prone to hepatic toxicity.

Acetylation rate of isoniazid :


3-Nutritional state•conjugating agents as:

• sulphate

sensitive to body nutrient level.

• glutathiaone

glycine.protein diet


Dosage

D

E

E

D

DD

D

E

DD

D

D

D

DD

Saturation

Drug accumulation

Alternative Alternative pathwaypathway

DD

D

109


5-Age:

Drug metabolism is reduced in

extremes of age.


SAUDIA ARABIA

Propranolol &

Lidocaine

Faster in men.

6 -Gender:

Diazepam Caffeine Paracetamol

Faster in women

Metabolism


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


7-Disease state:

Kidney disease

The excretion of drugs


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


eliminated from the body

It is the process by which

a drug or metabolite is


o Passive glomerular filtration

o Active tubular secretion in proximal tubules

o Passive tubular reabsorption.


Factors affecting renal excretion:

1-Glomerular filtration rate:

D

• Free • Water soluble • Low molecular weight

Filtered


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


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


oIodides

oRifampicin

oSalicylates

Morphin

e

Tetracycline

Streptomycin


Portal v.

Bile

Ampicillin

Rifampicin

Biliary infection

Morphine

Enterohepatic circulation


3-Sweat: e.g., rifampicin (red color), vitamin B1.

4-Lungs: e.g., gases and volatile anesthetics.

5-Milk: Morphine Amphetamine Chloramphenicol Oral anticoagulants


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PROF. Dr. ALSAYED ZAKI 1 Prof.DR.AL SAYED ZAKI-BMC-SAUDIA ARABIA.

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