BDS 2nd Year DM Notes

Lesson 4: Drug metabolism & Drug
elimination
Subject code: BDSMED106
1
©M. S. Ramaiah University of Applied Sciences
Intended Learning Outcomes of General & Dental
Pharmacology and Therapeutics
1. Describe pharmacokinetics, pharmacodynamics, indications, contraindications,
adverse drug reactions and interactions of drugs used in general and dental
practice
2. Choose appropriate drugs for specific disease conditions and special situations
with emphasis on efficacy & safety
3. Prepare and dispense commonly used medicinal preparations in dental and
medical practice
4. Prescribe appropriate drugs in common dental and medical conditions based on
sound clinical rationale
5. Critically analyze fixed dose combinations of marketed drugs, identify adverse
drug reactions and interactions of commonly used drugs in dental practice.
6. Collate, analyze and organize information related to recent advances in dental
pharmacology and therapeutics
2
Specific learning objectives
At the end of the class, student will be able to

1. Define biotransformation & first pass metabolism
2. Enumerate different Phases & biochemical reactions of
biotransformation with examples
3. Define enzyme induction & inhibition with examples & clinical
importance
4. Enumerate different routes of drug excretion with examples
5. Define clearance, plasma half life & different types of kinetics
of drug elimination, loading dose, maintenance dose
3
References
• Tripati KD. (2011), Essentials of pharmacology for

dentistry. 2ndEdition, Jaypee Brothers.
• Sharma HL, Sharma KK and Gupta DK.(2014),
Dental pharmacology. 2ndEdition, Paras
publications.
• Padmaja U. (2013), Textbook of Pharmacology for
dental & allied health sciences. 3rdEdition, Jaypee
Brothers.
4
Drug Biotransformation
• Enzyme catalyzed biochemical transformation of

drug within the living organism
• Most of the pharmacologically active organic

molecules - lipophilic
• Lipophilic xenobiotics - polar and more readily

excretable products
5
Sites of biotransformation
 Liver, kidney, intestine,

adrenal cortex, lungs,
placenta & skin
 Sub cellular level –
• Endoplasmic Reticulum
• Mitochondria
• Cytosol
• Lysosomes
• Nuclear envelope
6
Consequences
• Active drug – Inactive metabolite

Phenobarbitone - Hydroxyphenobarbitone
• Inactive prodrug – Active metabolite

Levodopa - Dopamine
Talampicillin - Ampicillin
• Active drug- Active metabolite

Codeine - Morphine
Diazepam - Oxazepam
Amitryptiline - Nortryptiline
7
First–pass metabolism
• The drug metabolism occurring before the drug

enters the systemic circulation
• Net result- reduced bioavailability
• Liver - Propranolol, isosorbide dinitrate, morphine,
imipramine
• Intestinal mucosa - levodopa, progesterone
• Lungs - Nicotine, isoprenaline
8
Phases of Drug Metabolism
9
Drug metabolizing enzymes
1. Microsomal enzymes: 2. Non-microsomal

• Located on the smooth - • Cytoplasm, mitochondria of
surfaced ER of liver, hepatic cells & plasma
intestinal mucosa, lungs & • Monoamine oxidase,
kidney esterases, amidases,
conjugases
• Cytochrome P450,
• Catalyze most of the phase
Glucuronyl transferase
II & few phase I reactions
• Mainly concerned with • Non-inducible
phase I reactions
• Inducible
10
Phase I reactions - Oxidation
11
 Reduction : Addition of H+ ions or Oxygen removal.
Eg : chloramphenicol, clonazepam, warfarin
 Hydrolysis: Cleavage of drug molecule by taking
up a molecule of water. Eg : Esters - Procaine,
succinylcholine, Amides - Procainamide, lidocaine
 Cyclization :Formation of ring structure from a
straight chain compound. Eg: Proguanil
 Decyclazation : Opening up of the ring structure of
cyclic drug molecule. Eg : Barbiturates , phenytoin
12
Phase II reactions
13
Enzyme induction
• Several drugs on repeated administration –

stimulates or induce growth of smooth ER- enhanced
microsomal enzyme activity
• Occurs gradually (1-2 weeks), Reversible
• Decrease in the pharmacologic action of the inducer
and also of co-administered drugs
• In the case of drugs metabolically transformed to
reactive metabolites -mediated toxicity
14
15
Enzyme inhibition
One drug may inhibit the metabolism of other:

• Increase in circulating levels of co-administerd drug
• Prolangation & potentiation of pharmacological

effects
• Rapid process but reversible
16
Enzyme inhibition
17
Drug Excretion
• Excretion is the passage out of systemically

absorbed drug
18
Renal excretion
• Most important channel of

excretion for majority of
drugs
• Excretes all water soluble

substances
• Renal excretion =
(Glomerular filtration +
Tubular secretion) –
Tubular reabsorption
19
Glomerular filtration Tubular reabsorption
• Glomerular capillaries- larger • Depends – Lipid solubility,
pores ionization of drug at urinary pH
• Non protein bound drug
present in the glomerulus is • 99% glomerular filtrate is
filtered reabsorbed
• Depends - Protein binding,

renal blood flow • Lipid soluble drugs-
reabsorbed in the tubules
• Normal GFR- 120 ml/min
• Non-lipid soluble & highly
• Declines progressively after ionized- not reabsorbed
the age of 50 years (aminoglycosides)
20
Effect of changes in urinary pH on
reabsorption
• Weak bases ionize more and are less reabsorbed in
acidic urine.
• Weak acids ionize more and are less reabsorbed in

alkaline urine
• Clinical significance: Utilized for facilitating

elimination of the drug in poisoning, i.e. urine is
alkalinized in barbiturate & salicylate poisoning
21
Tubular secretion
• Active transfer of organic • Transport processes are bi-

acids & bases by 2 directional
transporters OAT & OCT-
PCT • Exogenous substances-
secretion predominates
• Efflux transporters P-gp &
MRP2 are located in the • Endogenous substrates -
luminal membrane of PCT predominantly reabsorbed
cells
(Uric acid)
22
Clinical significance
• Drugs utilizing the same active transport compete

with each other:
• Probenecid is an organic acid which has high affinity

for the tubular OATP. It blocks the active transport of
both penicillin & uric acid
• Net excretion of the penicillin is decreased that of

the uric acid is increased
23
Faeces
• Most of the drug present in faeces - derived from bile
• Liver actively transports into bile- organic acids,

organic bases, lipophilic drugs & steroids
• MW > 300 - preferentially eliminated in the bile
• Erythromycin, ampicillin, rifampin, tetracycline, oral

contraceptives
24
• Exhaled air: (Lungs)
Gases & volatile liquids (general anaesthetics, alcohol)
• Saliva & sweat: (Minor) - Lithium, pot. Iodide, rifampin, heavy

metals
• Milk: Important for the suckling infant

Drugs enter breast milk - passive diffusion & lipid soluble & less
protein bound drugs cross better
25
Kinetics of Elimination
• Drug elimination is the sum total of metabolic

inactivation and excretion
26
 Importance of kinetics of elimination:
• To devise rational dosage regimens and to modify
them according to individual needs
 Three fundamental pharmacokinetic parameters:

• Bioavailability (F)
• Volume of distribution (V)
• Clearance (CL)
27
Clearance (Cl)
• It is the theoretical volume

of plasma from which the
drug is completely removed
in unit time
• CL= Rate of elimination

Plasma concentration
28
First order kinetics Zero order kinetics
• Majority of drugs - • Few drugs- eliminating process

elimination process are not are saturable
saturable
• Rate of elimination remains
• Rate of elimination α constant irrespective of drug
Plasma drug concentration concentration (CL ↓
(CL remains constant) with ↑ in drug concentration)
• A constant fraction of the • A constant amount of the drug

drug present in the body is is eliminated in unit time
eliminated in unit time
• Ethyl alcohol
29
Michaelis- Menten kinetics
• Kinetics changes from first order to zero order at higher

doses
• Enzymes responsible for metabolism /elimination

become saturated
• Plasma concentration ↑ disproportionately with increase

in dose
• Phenytoin, tolbutamide, theophylline, warfarin
30
Plasma half life (t1/2)
• The time taken for its plasma concentration to be

reduced to half of its original value
31
Steady state plasma concentration
• On repeated drug
administration -
accumulates in the body
until elimination balances
input and a Steady state
plasma concentration
(Cpss) is attained
32
Loading dose Maintenance dose
• Single or few quickly • Dose to be repeated at
repeated doses given in specified intervals after
the beginning to attain the attainment of target
target concentration Cpss so as to maintain
rapidly the same by balancing
elimination
33
Summary
• Define biotransformation & first pass metabolism

• Enumerate different Phases & biochemical reactions
of biotransformation with examples
• Define enzyme induction & inhibition with examples
& clinical importance
• Enumerate different routes of drug excretion with
examples
• Define clearance, plasma half life & different types of
kinetics of drug elimination, loading dose,
maintenance dose
34

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Lesson 4: Drug metabolism & Drug

At the end of the class, student will be able to

• Tripati KD. (2011), Essentials of pharmacology for

• Enzyme catalyzed biochemical transformation of

• Most of the pharmacologically active organic

• Lipophilic xenobiotics - polar and more readily

 Liver, kidney, intestine,

• Active drug – Inactive metabolite

• Inactive prodrug – Active metabolite

• Active drug- Active metabolite

• The drug metabolism occurring before the drug

1. Microsomal enzymes: 2. Non-microsomal

• Several drugs on repeated administration –

One drug may inhibit the metabolism of other:

• Prolangation & potentiation of pharmacological

• Rapid process but reversible

• Excretion is the passage out of systemically

• Most important channel of

• Excretes all water soluble

• Depends - Protein binding,

• Weak acids ionize more and are less reabsorbed in

• Clinical significance: Utilized for facilitating

• Active transfer of organic • Transport processes are bi-

• Drugs utilizing the same active transport compete

• Probenecid is an organic acid which has high affinity

• Net excretion of the penicillin is decreased that of

• Most of the drug present in faeces - derived from bile

• Liver actively transports into bile- organic acids,

• MW > 300 - preferentially eliminated in the bile

• Erythromycin, ampicillin, rifampin, tetracycline, oral

• Saliva & sweat: (Minor) - Lithium, pot. Iodide, rifampin, heavy

• Milk: Important for the suckling infant

• Drug elimination is the sum total of metabolic

 Three fundamental pharmacokinetic parameters:

• It is the theoretical volume

• CL= Rate of elimination

• Majority of drugs - • Few drugs- eliminating process

• A constant fraction of the • A constant amount of the drug

• Kinetics changes from first order to zero order at higher

• Enzymes responsible for metabolism /elimination

• Plasma concentration ↑ disproportionately with increase

• Phenytoin, tolbutamide, theophylline, warfarin

• The time taken for its plasma concentration to be

• Define biotransformation & first pass metabolism

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