bio transformation presentation
TRANSCRIPT
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Drug metabolism andDrug metabolism andexcretionexcretion
ARLENE M. DIAZ M.D, F.P.S.C.E.PARLENE M. DIAZ M.D, F.P.S.C.E.PPHARMACOLOGY DEPT.PHARMACOLOGY DEPT.
S.W.U- MHAMS.W.U- MHAM
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BiotransformationBiotransformationis a process wherein a drug undergoes ais a process wherein a drug undergoes achemical change due to its interaction with anchemical change due to its interaction with anendogenous enzyme system (due to a nonenzymaticendogenous enzyme system (due to a nonenzymaticreactions) resulting in an increase of polarity of thereactions) resulting in an increase of polarity of thedrug.drug.
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Why should a drug undergoesWhy should a drug undergoesBiotransformation?Biotransformation?
1. to convert a drug to a more excretable metabolite1. to convert a drug to a more excretable metabolite
3. to convert an active drug to an active
metabolite
5. to convert a drug into a more toxic
metabolite
2. to convert a pharmacologically activedrugto inactive metabolite
4. to convert an inactive drug to an activemetabolite
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Organs responsible for BiotransformationOrgans responsible for Biotransformation
A.A. Liver Major DMMSLiver Major DMMS
B. Kidney
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Organs responsible for BiotransformatioOrgans responsible for Biotransformatio
C. Lung
D. GIT
(intestines)
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Classification of the ChemicalClassification of the Chemicalreactions of enzymaticreactions of enzymatic
biotransformationbiotransformation
Phase I ReactionPhase I Reaction convert the parent drug to a convert the parent drug to amore polar drug metabolite by:more polar drug metabolite by:
Oxidation
Hydrolysis
Reduction
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Oxidation-is the addition of oxygen orthe removal of hyrogen from the original
compound
-Is carried out by a group ofmonooxygenases (oxidative enzymes foundin the hepatic endoplasmic reticulum). Thismonooxygeneses are usually a large family
of isozymes called cytochrome P450 whichactivates molecular oxygen using reducingequivalents such as Nicotinamide adeninedinucleotide phospate (NADPH).
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Oxidation
H2O
OxidizedDrug (ROH+)
Drug (RH)
Oxidized
Cytochrome P-450
O2
+
e-
Step 1
Step 3
FLA-PRO
FLA-PRO
NADP+
NADP
Drug-Fe3+
Drug-Fe2+
Step 2
drug Fe2+-O2
2H+
Reduced
Fe3
Step 4
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Reduction- the removal of oxygen orthe adding of hydrogen to the original
compound. Enzymes responsible, areusually located in the cell cytoplasm.
Redox Recycling is a kind of reduction
for Quinone containing drugs wherein this
quinone containing drug is reduced by a single
electron and is converted to an unstablesemiquinone which undergoes autooxidation
or molecular oxygen, forming free
radicals (superoxide which are toxic)
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Redoxrecycling:
O2
O2
O
O
O
O
NADPH
FLA-PRO
NADP+
superoxide
Molecularoxygen
1 2
Quinone
Semi-Quinone
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Phase I - Microsomal (enzymatic)
Drug Biotransformation Reaction
Aliphatic hydroxylation -Pentobarbital;
Phenylbutazone
N Hydroxylation 2 Acetylaminofluorene
Sulfoxidation -chlorpromazine
Epoxidation Benzo(a) pyrene; aflatoxin
O Dealkylation Codeine
Aromatic hydroxylation Phenytoin
N-DealkylationDiazepam,Prazepam, Methadone
Desulfuration Parathion
Dehalogenation Halothane
A. Oxidation Reaction
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B. Reduction Reactions
Nitro reduction Chloramphenicol
Clonazepam
Azo reduction Prontosil
Reductive dehalogenation
Carbon tetrachloride, DDT
Redox recycling Doxorubicin,
Mitomycin,Bleomycin
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C. Hydrolysis- the original compound is broken
into smaller parts. The enzyme resposible arelocated in the cytoplasm, the endoplasmic reticulumand circulating in the plasma
Amide - Procainamide,
Lidocaine, Indomethacin
Ester Hydrolysis - Acetycholine,Succinylcholine, Aspirin, Procaine
Peptide - Pro-insulin
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Phase II - Conjugation RXNS
RXN Type
a.Glucuronidation
b. Sulfation
c. Acetylation
d. Methylation
e. Glutathione
Enzyme
UDP-glucuronyl
transferases
Sulfotransferases
Acyl COA transferases
Mythyl transferases
GSH transferases
Example
Bilirubin, Diazepam
Chloramphenicol
Esterone, Andosterone
Acetaminophen
Isoniazide
Sulfonamide
Norepinephrine
Thiouracil
BromobenzeneEnthacrynic acid
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Induction of the Drug Metabolizing Microsomal System
How Does It Occur?
Induction of the Drug MetabolizingMicrosomal System
The inducer binds to the specific- receptor
molecule in the cytoplasm of the hepatocyteforming an inducer-receptor complex.
The receptor-inducer complex is the translocatedinto the nucleous and interact with DNA resultingto transcription of specific genes.
The MRNA transcribed from DNASubsequently translated leading to synthesisand incorporation of new cytochrome P450 intothe membrane of the endoplasmic reticulum.
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Significance of DMMS Induction
Inactivation or diminishing effect ofthe drug(development of tolerance)
There is an increase metabolismof other drugs takensimultaneously by the inducer.
There is an increase metabolism ofdrugs having the samebiotransformation pathway of the
inducer.
E l f D th t
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Example of Drugs thatEnhance drug Metabolism in
humansInducer Drug whose metabolism is
enhanced
Chlorcyclizine
Ethychlorvynol
Glutethimide
Griseofulvin
Steroid hormones
Warfarin
Antipyrine,glutethimide, warfarin
Warfarin
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Example of Drugs that Enhance drugMetabolism in humans
Phenobarbital
and otherbarbiturates
Barbiturates
ChloramphenicolChlorpromazine
Cortisol, coumarin
Anticoagulants,
Desmethylimipramine
Digitoxin,
Inducer Drug whose metabolism isenhanced
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Doxorubicin, estradiol
Phenylbutazone
Phenytoin
theophylline
Quinine
Testosterone
Example of Drugs that Enhancedrug Metabolism in humans
Inducer
phenobarbital
BARBITURATES
Drug whose metabolism isenhanced
E l f D th t
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cortisol, dexamethasone,digitoxin,
theophylline
Example of Drugs thatEnhance drug Metabolism in
humansDrug whose metabolism isenhanced
Inducer
Phenybutazone
Phenytoin
Rifampicin
Aminopyrine, cortisol, digitoxin
Coumarin, digitoxin, methadone,
glucocorticoids, metoprolol
Oral contraceptives, prednisone,
propranolol, Quinidine
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Drugs that inhibit metabolismof other drugs in human
Inhibitor Drugs whosemetabolism is inhibited
Allopurinol,
Chloramphanicol,Isoniazid
Antipyrine, dicumarol
probenecid, tolbutamide,
CimetidineChlordiazepoxide, diazepam,
warfarin
Dicumarol Phenytoin
Disulfiram Antipyrine, ethanol,
phenytoin warfarin
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Drugs that inhibit metabolism ofother drugs in human
Inhibitor Drugs whose metabolismis inhibited
Ketoconazole Cyclosporine,astemizole,terfenadinePhenylbutazone Phenytoin, tolbutamide
Erythromycin Amiodarone,digoxin,
antipsychotics,theophylline
Grapefruit juice terfenadine, calcium blockerETHANOL DIAZEPAM,
CHLORDIAZEPOXIDE
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Drugs ExertionDrugs
Distribution
Absorption
Metabolism
Biotransformation
Liver MainOrgan
Kidney
Lungs
GIT
Excretion
Kidney Main Organ
Minor Routes of Excretion
GIT Biliary/Fecal
Mamary Milk ExcretionLungs
Salivary - Saliva
Sweat Glands
Lacrimal - Tears
Hair/ Nails/ Skin
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3 Major Processes Involved in theRenal Handling of Drugs
1.Glomerular Filtration
3.Tubular Secretion
2.Tubular Reabsorption
of a drug at the glomerulus depends on themolecular size of the drugs
usually occurs in the proximal tabules andgenerally involves organic acids such as:
Penicillin, aspirin and diuretics
occurs in Proximal and Distal part of the
nephron
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Factors That Will Promote
Tubular Reabsorption
Ionization
Ph OfDrugs
Lipid Solubility
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Half Life (t1/2) is the time it takes forthe plasma cone or the amount of drugs in
the body to be reduced by 50%. Volume of distribution relates theamount of drugs in the body to theconcentration of drug in the blood or
plasma Clearance measure of the bodys
ability to eliminate a drug
Half Life of a drug is inversely relatedto its clearance and directly proportional
to its volume of distribution
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Clinical situations resulting in
increased drug half life
Diminished renal plasma flow, for ex: incardiogenic shock, heart failure or hemorrhage
With decrease excretion renal diseases
With addition of a second drug w/c displacesthe first drug from albumin, hence, increases
the volume of distribution of the drug
With decrease metabolism, for Ex. When another drug inhibits its
biotransformation
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Effect of urine Ph on renal clearance for
drugs that undergo tubular reabsorption
Cleared rapidly by makingurine more acidic
Amphetamine
Chloroquine
Levorphanol
Imipramine
Mecamylamine
Bases
Quinine
cleared rapidly bymaking urine alkaline
Acetazolamide
Nitrofurantoin
Phenobarbital
Probenecid
Salicylates
Acids
Sulfathiazole