basic concepts in pharmacology

1. Metabolism
Excretion
Prodrug
Therapeutic drug monitoring
Presented by
K.sreenivasulu Naidu 1st M.Pharm
Department of Pharmacology
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Presented to:
S.N. Manjula.
M Pharm, Ph.D. Professor & Head
Department of Pharmacology
JSS College of Pharmacy, Mysuru

2. Metabolism/Biotransformation:
 Chemical alteration of drug in the body is known as metabolism.
Drug metabolism involves :
Active Drug Active metaboliteEg:spironolactone to
canrenone.
Inactive Drug Active Form Eg: Levodopa to Dopamine.
Active Drug Inactive form or less active Eg:
Phenobarbitone to Hydroxy phenobarbitone.
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3. Where does Biotransformation occurs?
Main site: LIVER is the principal organ of drug metabolism.
Other sites: GI tract,kidney,Lungs,Blood,skin,Placenta.
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4. Pathways of drug metabolism:
Drug metabolic reactions are grouped in to two Phases:
1) PhaseⅠ or non-synthetic reactions.
2) Phase Ⅱ or Synthetic reactions.
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5. Metabolic reactions
PhaseⅠ
Both microsomal as well
as Non-microsomal.
Ex: Oxidation
Reduction
Hydrolysis
Cyclization
PhaseⅡ
Microsmal:Glucoronide
conjugation
Non-Microsomal:Glutathione
Glycine
Acetylation
Methylation
Sulfonation
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6. PhaseⅠ
 Oxidation: Microsomal oxidation involves the introduction of an
oxygen or the removal of a hydrogen atom or hydroxylation,
dealkylation or demethylation of drug molecule e.g. conversion of
salicylic acid into gentisic acid.
 Reduction: The reduction reaction will take place by the enzyme
reductase which catalyse the reduction of azo (-N=N-) and nitro (-
NO2) compounds e.g. prontosil converted to sulphonamide.
 Hydrolysis: Drug metabolism by hydrolysis is restricted to esters and
amines (by esterase’s and amidases) are found in plasma and other
tissues like liver. It means splitting of drug molecule after adding water
e.g. pethidine undergoes hydrolysis to form pethidinic acid. Other
drugs which undergo hydrolysis are atropine and acetylcholine.
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7. PhaseⅡ
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8. Metabolism of Phenytoin
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9. Drug metabolizing Enzymes:
They are broadly divided into two groups
Microsomal Enzymes Non-Microsomal enzymes
Location
Smooth endoplasmic reticulum of
cells,Liver,kidney,Lungs
Cytoplasm,Mitochondia,Plasma
Reactions
Most of the phaseⅠreactions and
Glucuronide conjugation
Oxidation,
reduction(few),Hydrolysis, All
conjugation except glucuronide
conjugation.
Examples
Cytochrome p450
enzymes,Glucoronyl Transferase
Oxidases, Dehydrogenases.
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10. Cytochrome P450 cycle in drug oxidations. RH, parent drug; ROH,
oxidized metabolite; e −, electron
The most important enzyme for Oxidation reaction is cytochrome p450.
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11. Cyp3A4 carryout biotransformation of largest number of drugs (50%).
CYP 3 A 4
Family Gene Gene number
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Approximately 11,500 subtypes identified in various species. But in
humans more than 50 isoforms are identified
Among these most important isoforms are:
CYP3A4,CYP1A2,CYP2D6,CYP2C9,CYP2C19.

12. Factors Effecting Metabolism
1. Age
2. Diet
3. Diseases
4. Genetic Factors
5. Simultaneous Administration of drugs
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13. 1)Age:
Neonates and elderly metabolize some drugs to a lesser extent than
adults. In these cases, it is due to diminished amount/activity of
Hepatic microsomal enzymes. Neonates conjugate chloramphenicol
slowly, hence develop toxicity(Grey Baby syndrome).increased
incidence of toxicity with propranolol and lignocaine in elderly is due
to decreased hepatic metabolism.
2)Diet:
Poor nutrition can decrease enzyme Function.
3)Diseases:
Chronic diseases of Liver may effect hepatic metabolism of some
drugs eg: increased duration of action of Diazepam, in patients with
Cirrhosis, due to its Impaired metabolism.
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14. 4)Genetic Factors:(Pharmacogenetics)These factors also influence
drug metabolism. The study of genetically determined variation in drug
response is called Pharmacogenetics.
Eg:
Slow and fast acetylators of isoniazid:
There is an incidence of peripheral neuritis with isoniazid in slow
acetylators. The fast acetylators require a large dose of the drug to
produce therapeutic effect.
Glucose-6-phosphate dehydrogenase(G6PD)deficiency and
hemolytic anemia:
G6PD activity is important to maintain the integrity of RBC”s.A
person with G6PD deficiency may develop haemolyis when exposed to
certain drugs like Sulphonamide,Primaquine,Dapsone.
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15. 5)Simultaneous Administration of drugs:
This can result in increase or decreased metabolism of drugs(Enzyme
induction or Enzyme inhibition).
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16. Enzyme Induction:
Repeated administration of certain drugs increases the synthesis of
microsomal enzymes. This is known as Enzyme induction. The drug
is referred to as an Enzyme Inducers.
Eg: Griseofulvin, Glucocorticoids, Phenytoin, Phenobarbitone,
Phenylbutazone, Rifampicin, Carbamazepine, Chloral hydrate,
Smoking.
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17. Clinical Importance of Enzyme induction:
 Enzyme induction may accelerate the metabolism of drugs, thus reducing the
duration and intensity of drug action leading to therapeutic failure. Eg:
rifampicin&oralcontraceptives. Rifampicin induces the drug metabolizing
enzyme of oral contraceptives, thus enhancing metabolism and lead to
contraceptive failure.
 Autoinduction may lead to development of drug tolerance Eg: Carbamazepine
enhances its own metabolism.
 Enzyme induction may lead to drug toxicity Eg: increased incidence of
hepatotoxicity with Paracetamol in alcoholics is due to overproduction of toxic
metabolite of paracetamol.
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18.  Prolonged Phenytoin therapy may produce Osteomalacia due to
enhanced metabolism of vitamin D3.
 Enzyme inducers can precipitate Porphyria due to overproduction of
porphobilinogen
 Enzyme induction can also be beneficial Eg: Phenobarbitone in
neonatal jaundice__phenobarbitone induces glucuronyl transferase
enzyme, hence bilirubin is conjugated and jaundice is resolved.
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19. Enzyme Inhibition:
Certain drugs inhibit the activity of drug metabolizing enzymes and
are known as enzyme inhibitors. Inhibition of metabolism of one drug
by another can occur when both are metabolized by same enzyme.
Enzyme inhibition is a rapid process as compared to enzyme induction.
Eg: cimetidine, cyclosporine, calcium channel blockers, ciprofloxacin,
clarithromycin, Diltiazem, Erythromycin, fluoxetine, fluvoxamine,
Grape fruit juice, HIV protease inhibitor, Itraconazole, Isoniazid,
Ketoconazole.
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20. Clinical importance of Enzyme
inhibition:
Enzyme inhibition can result in toxicity: increased incidence of
bleeding with warfarin due to concomitant administration of
Erythromycin or Chloramphenicol etc. These drugs inhibit drug
metabolizing enzyme of warfarin resulting in increased plasma
concentration of warfarin and enhanced anti-coagulant effect
(bleeding).
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21. Pro drug:
It is inactive form of drug which is converted to active form after
metabolism.
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22. Why to use pro-drugs?
Several pharmacokinetic reasons exist for developing prodrugs:
 To achieve more complete or predictable absorption of the drug.
 To reduce incomplete and variable systemic bioavailability by
preventing extensive presystemic metabolism.
 To improve access to the site of action, e.g. penetration of the blood-
brain barrier.
 To activate selectively a drug in the intended target tissue, thus
avoiding undesirable systemic effects.
 To optimize either the rate of onset or duration of action of a drug by
improving absorption, distribution or elimination characteristics.
 Improve patient acceptability (decrease pain on injection)
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23. Classification of Pro-drug:
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24. Carrier Linked prodrug:
Carrier linked prodrug has an inert carrier or transport which is coupled
covalently with active drug. They have ester or amide linkage. They
got bio transformed chemically or enzymatically and release the active
drug. The carrier-linked prodrugs should be non-toxic. They should
mask the unwanted side effects. They alter the physiochemical
properties of active drug.
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25. On the basis of carrier used, further it can be classified as follows:
a)pro-prodrug
It is a prodrug, where drug is derivatized in such a way that conversion
through enzymes is possible before it can break to release the active drug for
example Cefpodoxime proxetil.
b) Macromolecular prodrug
The carrier used here are large molecular weight compounds for example:
polysaccharides, cyclodextrins, polymers and proteins, e.g. Naproxen-2-
glyceride
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26. c)Site specific prodrug
Such prodrug is used for targeting the active drug at specific site, e.g.
sulfasalazine which consists of 5-aminosalicylic acid and
sulphapyridine. Both are pharmacologically active agents, linked by
azo linkage. The 5-aminosalicylic acid is released in the colon. The
advantage of this approach is it to release the drug in required
concentration at the active site)
d)Mutual prodrug
It consists of two pharmacologically active drugs joined with each
other. They are taken together with the aim to mask the side effects of
active drug and give the synergistic action. For example Estramustine
has a phosphorylated steroid (17- α- estradiol) coupled to Nor-mustard
which has carbamate linkage .
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27. Bio precursors: Here parent drug is obtained by redox transformation
through enzymes. Here prodrug result by chemical modification of
parent drug. The lipophilicity does not alter generally. For example
phenylbutazone which is a metabolic precursor prodrug of
oxyphenbutazone.
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28. APPLICATIONS OF PRODRUGS
Prodrugs are used to overcome pharmacokinetic and pharmaceutical
barriers to increase drug biological bioavailability. After overcoming
those barriers, the prodrug must be converted to the active form in the
targeted site of action. Pharmacokinetic applications:
1. Improvement of bioavailability by alteration of drug’s solubility.
2. Prodrugs for site selective drug delivery.
3. Prolongation of action.
4. Minimizing toxicity.
5. Protection from presystemic metabolism
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29. Excretion:
 Excretion of drugs means the transportation of unaltered or altered
form of drug out of the body. The major processes of excretion
include renal excretion, hepatobiliary excretion and pulmonary
excretion. The minor routes of excretion are saliva, sweat, tears,
breast milk, vaginal fluid, nails and hair.
 The rate of excretion influences the duration of action of drug. The
drug that is excreted slowly, the concentration of drug in the body is
maintained and the effects of the drug will continue for longer
period.
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30. Different routes of drug excretion
Renal excretion: A major part of excretion of chemicals is
metabolically unchanged or changed.
The excretion of drug by the kidney involves.
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
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31. Renal excretion of drugs. Filtration of small non–protein-bound drugs occurs through glomerular capillary pores.
Lipid-soluble and un-ionized drugs are passively reabsorbed throughout the nephron. Active secretion of organic
acids and bases occurs only in the proximal tubular segment.
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32. The function of glomerular filtration and active tubular secretion is to remove drug out
of the body, while tubular reabsorption tends to retain the drug.
Glomerular filtration: It is a process, which depends on the concentration of drug in
the plasma, molecular size, shape and charge of drug& glomerular filtration rate. Only
the drug which is not bound with the plasma proteins can pass through glomerulus. All
the drugs which have low molecular weight can pass through glomerulus e.g. digoxin,
ethambutol, etc. In congestive cardiac failure, the glomerular filtration rate is reduced
due to decrease in renal blood flow
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33.  Tubular reabsorption: The reabsorption of drug from the lumen of
the distal convoluted tubules into plasma occurs either by simple
diffusion or by active transport. When the urine is acidic, the degree
of ionization of basic drug increase and their reabsorption decreases.
Conversely, when the urine is more alkaline, the degree of ionization
of acidic drug increases and the reabsorption decreases
 Active tubular secretion: The cells of the proximal convoluted
tubule actively transport drugs from the plasma into the lumen of the
tubule e.g. acetazolamide, benzyl penicillin, dopamine, pethidine,
thiazides, histamine.
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34.  Hepatobiliary excretion: the conjugated drugs are excreted by hepatocytes
in the bile. Molecular weight more than 300 Daltons and polar drugs are
excreted in the bile. Excretion of drugs through bile provides a backup
pathway when renal function is impaired. After excretion of drug through
bile into intestine, certain amount of drug is reabsorbed into portal vein
leading to an enterohepatic cycling which can prolong the action of drug e.g.
chloramphenicol, oral oestrogen are secreted into bile and largely
reabsorbed and have long duration of action. Tetracyclines which are
excreted by biliary tract can be used for treatment of biliary tract infection.
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35.  Gastrointestinal excretion: When a drug is administered orally, a
part of the drug is not absorbed and excreted in the faeces. The
drugs which do not undergo enterohepatic cycle after excretion into
the bile are subsequently passed with stool e.g. aluminium
hydroxide changes the stool into white colour, ferrous sulphate
changes the stool into black and rifampicin into orange red.
 Pulmonary excretion: Drugs that are readily vaporized, such as
many inhalation anaesthetics and alcohols are excreted through
lungs. The rate of drug excretion through lung depends on the
volume of air exchange, depth of respiration, rate of pulmonary
blood flow and the drug concentration gradient
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36.  Sweat: A number of drugs are excreted into the sweat either by
simple diffusion or active secretion e.g. rifampicin, metalloids like
arsenic and other heavy metals.
 Mammary excretion: Many drugs mostly weak basic drugs are
accumulated into the milk. Therefore, lactating mothers should be
cautious about the intake of these drugs because they may enter into
baby through breast milk and produce harmful effects in the baby
e.g. ampicillin, aspirin, chlordiazepoxide, coffee, diazepam,
furosemide, morphine, streptomycin
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37. Clearance of drug:
It is the volume of plasma cleared of the drug by metabolism (hepatic)
and excretion (renal) and other organs. Total clearance will be
calculated by
Ct = Ch + Cr + C others
Ct = total clearance
Ch = hepatic clearance
Cr = Renal clearance
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38.  Order of kinetics: Drugs are used for the treatment of diseases but the modes of
administration of drugs are different. For example, atenolol is administered once
daily whereas paracetamol needs 3-4 times administration daily. Morphine is more
effective in intramuscular route, and insulin is in subcutaneous route. The mode of
administration is designed on the basis of absorption, distribution, metabolism and
excretion (ADME) of drugs. Drugs usually follow two processes for their
pharmacokinetic behaviour in the body. These are first order and zero order process.
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39.  First order: This is the most common process for many drugs. The
rate at which absorption, distribution, metabolism and excretion
occur are proportional to the concentration of drugs i.e. constant
fraction of this drug in the body disappears in each equal interval of
time.
 Zero order kinetic: It is independent of the amount of drug present
at the particular sites of drug absorption or elimination. Few drugs
follow this process e.g. ethanol, phenytoin, Tolbutamide,
Theophylline, Warfarin. Here constant amount of the drug is
eliminated in each equal interval of time. On repeated administration
of drug after certain stage it goes on accumulating in the body and
leads to toxic reactions.
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40. Therapeutic Drug Monitoring:
Monitoring drug therapy by measuring plasma concentration of a drug is known as
Therapeutic drug monitoring. (TDM)
Indications of TDM
1. Drugs with narrow therapeutic index, eg. Lithium, digoxin, Phenytoin,
aminoglycosides, etc
2. Drugs showing wide interindividual variations eg. Tricyclic Antidepressants.
3. For drugs whose toxicity is increased in the presence of renal failure eg.
Aminoglycosides.
4. In patients who do not respond to therapy without known reason
In drug poisoning, estimation of plasma concentration is done.
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41. TDM is not required in following conditions:
1)When clinical and biochemical parameters are available to asses
response:
• Blood pressure measurement for Anti-hypertensives.
• Blood sugar estimation for antidiabetic agents.
• Prothrombin time and international Normalized ratio (INR)for
anticoagulants
2)Drug producing tolerance Eg: Opioids
3)Drug whose effect persists longer than the drug itself Eg:
Omeprazole.
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42. Advances:
 The various drug metabolism enzymes identified in the nasal
mucosa are oxidative phaseⅠenzymes, conjugative
phaseⅡenzymes, proteolytic enzymes.
 The specific content of p-450 in nasal mucosa is relatively high
secondly to that of liver. The most striking feature is that the
catalytic activity of the p-450 enzymes in the nasal epithelium is
higher than in other tissue including liver.
 The phase 1 cytochrome p450have been studied extensively in for
their toxicological significance, since these enzymes metabolise
inhaled pollutants in to reactive metabolites which may induce nasal
tumours.
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43.  The delivery of peptides and proteins has been hindered by the
peptidase and protease activity in the nasal mucosa.
 Thus, in addition to permeation barriers there also enzymatic
barriers to nasal drug delivery. Which is created by metabolic
enzymes in nasal epithelium.
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44. Previous year Questions:
1) What is biotransformation? Explain phaseⅠand Phase Ⅱ
reactions?
2) What is excretion? Explain different routes of excretion?
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45. References:
 Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS.
 Modern pharmacology with clinical Applications by Charles Craig, Robert E.Stitzel.
 Basic & Clinical Pharmacology by Katz Ung.
 PRODRUGS: A REVIEW Article in World Journal of Pharmaceutical Research ·
January 2014.
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