Pharmacology BEQ

Introduction to Pharmacology
Biopharmaceutics/
Pharmacokinetics
Bart David A. Quibod, RPh, CPS
From the greek pharmakon The study of the rational use of drugs in
management of diseases?
(drug) + logos (study)
A. Pharmacotherapeutics
Study of drugs B. Pharmacodynamics
Study of doses? C. Pharmacokinetics
D. Clinical Pharmacy
E. Pharmacology

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General Concepts REMEMBER BY 💖

DRUG DOSE LIBERATION BIOPHARMACEUTICS
ADMINISTRATION
ABSORPTION
DISINTEGRATION
PHARMACEUTICAL of DRUG DISTRIBUTION PHARMACOKINETICS
PHARMACOKINETICS ABSORPTION/DISTRIBUTION/ METABOLISM
METABOLISM/EXCRETION
EXCRETION
DRUG/RECEPTOR
PHARMACODYNAMICS INTERACTION RESPONSE PHARMACODYNAMICS

PHARMACOTHERAPEUTICS
DRUG EFFECT or TOXICITY TOXICOLOGY
RESPONSE
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4 5 6

Biopharmaceutics
Study of pharmacotechnical
factors in drug products (DDS
BIOPHARMACEUTICS 👊😱) that can affect CELL MEMBRANE
pharmacokinetics of drugs
Only biopharmaceutics process?
Liberation

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Nature of Cell Membrane Nature of Cell Membrane
Lipid Bilayer/ Unit Membrane Parts of Lipid Bilayer:
Theory Hydrophilic Head - Facing Protein
Proposed by Davson & Danielli layers
2 Layers of phospholipid bet. 2 Hydrophobic Tail - Aligned in the
surface layers of proteins interior

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10 11 12

Theories on Cell
Structure
Fluid Mosaic Model
Proposed by Singer & Nicolson
Globular proteins embedded in a
dynamic fluid, lipid bilayer matrix
“Protein iceberg in an oily sea”

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13 14 15

Theories on Cell
The Cell Membrane
Structure
Modified Fluid Mosaic Model Semi-permeable membrane
Proteins are embedded but used as Selective Barrier
receptors & for transport
Drugs can transport via several
mechanisms

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16 17 18
 TRANSPORT BASIC REQUIREMENT
Mechanism of drug movement across For a drug to undergo transport -
the cell membrane
drug must be in aqueous solution
Passive Diffusion
TRANSPORT SYSTEMS Carrier-Mediated EXCEPT if transport is by PINOCYTOSIS
Active transport Requirement: Micelle Form
Facilitated Diffusion
Micelle-forming agents: Bile acids/salt
Convective transport
Ion-Pair Transport Deoxycholic & Chenodeoxycholic acid
Pinocytosis e.g. Griseofulvin, Emulsion (oil globules
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stabilised by surfactants)
21

19 20 21

1. Passive Diffusion Governing Principle Fick’s Law of Diffusion

Dominant transport mechanism but Drug must be small and lipid-soluble
the SLOWEST
transport across the lipid bilayer
NOT energy requiring
Downhill Transport / Movement
Movement along ALONG a conc. gradient
HIGH solute to LOW solute
concentration
Driving force: Concentration Gradient
Difference between concentration,
the greater the transport
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FICK’S LAW
dQ = D●A●K●(CGI - CP)
dT h
Where
dQ/dT: rate of diffusion
D: diffusion coefficient
A: surface area
K: partition coefficient
h: thickness of membrane
CGI: concentration in GI
CP: concentration in24 plasma

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Factors affecting Passive

Permeability barrier Permeability barrier
Diffusion
(1) Particle Size (2) Lipophilicity of drug
FACTORS RELATIONSHIP
• Lipophilicity: Diffusion
SA: Passive transport • Smaller Particle Size, in Coefficient
SURFACE AREA
(Lungs > Small Intestine > Stomach) diffusion coefficient (smaller
particle size will occupy SA)
• 2 Determinants:
CONCENTRATION Concentration Gradient:
GRADIENT rate of transport 1. Degree of Dissociation or
THICKNESS OF • Application (Micronization) - e.g. Ionization
MEMBRANE
Thickness: ➡rate of transport 2. Lipid-Water Partition Coefficient
Rifampicin (2-10) microns
DIFFUSION Constant: Related to
COEFFICIENT permeability barrier
25 26 27

25 26 27
 Degree of Dissociation
Rule of Thumb
Drugs should exist as Non-Ionized
in order to pass the lipid bilayer
Key Principle: Non-ionized is the
lipophilic form
Degree of Dissociation Degree of Dissociation
Rule of Thumb Weak acid in solution:
Most Drugs: Weak acids & bases HA ⟺ H+ + A-
➜ in solutions both exist as Non-Ionized (Ka) Ionized Form
ionized + non-ionized forms Ka = dissociation rate constant of a
weak acid
Ka = [H+][A-] ⟺ Ionized
[HA] ⟺ Non-Ionized

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28 29 30

Degree of Dissociation Degree of Dissociation Degree of Dissociation

For a weak acid: Effect of pH of environment on weak
DRUGS Ka pKa Ratio
Higher proportion of: acids in solution
Ionized ➜ Hydrophilic form A 1 x 10-3 3 1/1,000 Weak acids exist more in a non-
Non-Ionized ➜ Lipophilic form
ionised form in a more acidic
High Ka (ABSORBED!) B 1x 10-4 4 1/10,000
environment
1 x 10-2 = 1/100
Low Ka C 1x 10-5 5 1/100,000 More non-ionised form = more
1 x 10-3 = 1/1000 lipophilic = more absorbed!
D 1x 10-6 6 1/1,000,000
pKa = - log(Ka)
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31 32 33

Conclusions for a Weak Conclusions for a weak

Degree of Dissociation
Acid Base
Favorable conditions for passive Weak base in solution: For Weak Bases:
transport of weak acids: BH+ ⟺ H+ + B Higher Ka,
Ionized Form (Ka) Non-Ionized Lower pKa,
(1) Lower Ka or Higher pKa Ka = (weak base) More Basic pH (pH > pKa)
(2) A more acidic environment ( pH) would favor the non-ionised form
(3) A pH that is lower than pKa of a Ka = [H+][B] ⟺ Non-Ionized (Lipophilic) hence Absorption
weak acid (pH < pKa) [BH+] ⟺ Ionized

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34 35 36
 Partition Coefficient Partition Coefficient Partition Coefficient
2. Partition Coefficient Experiment: Octanol - Water System Compute for Kpartition:
ratio of solubility of a drug in oil
Drug = 900mg V =50mL
to its solubility in H2O (Lipid-H2O Kpartition = CLipids = 900mg/50mL
partition coefficient) OCTANOL CWater 100mg/100mL
Drug = 100mg V =100mL
Kpartition = Lipid Solubility = CLipids WATER Kpartition = 18
Water Solubility CWater Interpretation: Drug is 18 x more soluble in
lipid than water.
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37 38 39

2. Carrier-mediated 2. Carrier-mediated
Partition Coefficient
Transport Transport
Which will undergo the fastest rate Carrier = Transporters - Active Transport
of transport? Cell membrane proteins with 1. Energy-Requiring
DRUG K specific binding sites & can 2. Movement: AGAINST concentration
A 100 undergo conformational change to gradient (UPHILL movement)
B 10 allow movement of molecules Low solute conc. ➜ High solute conc.
C 1 across the membrane 3. FASTEST transport system
D 0.1

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40 41 42

2. Carrier-mediated 2. Carrier-mediated 2. Carrier-mediated

Transport
Facilitated Diffusion
1. Non-energy Requiring
2. Movement: ALONG a concentration
gradient (DOWNHILL movement)
High solute conc. ➜ Low solute conc.
3. vs Passive Diffusion: Only difference
is that this has carriers
Transport Transport
3 Processes: A. Selectivity or specificity
Recognise/allow transport of certain
A. Specificity or Selectivity
molecules and not others
B. Subject to competition / inhibition / Amino acid transporter (e.g. Phe, F)
antagonism L-DOPA ➜ Dopamine (does not
C. Saturability cross BBB)
A/E: “Wearing-off ” phenomenon

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43 44 45
 2. Carrier-mediated 2. Carrier-mediated 2. Carrier-mediated
Transport Transport Transport
B. Subject to competition / inhibition / B. Subject to competition / inhibition / B. Subject to competition / inhibition /
antagonism antagonism antagonism
e.g. administration of L-DOPA before a L-DOPA Dopamine Isoniazid & Vitamin B6
meal (breakfast) DOPA Decarboxylase Peripheral Neuropathy - corrected by B6
Rationale: Amino acids from meals can They utilize same transporter in intestines
(×) Carbidopa
interfere in absorption & distribution Hence they will compete for same
L-DOPA 3-Methyldopamine
by competing w/ Levodopa in amino carrier
Catechol-O-MethylTransferase
acid transporters timing/ dosing regimen
3-Methyldopa ➜ can cross BBB & compete
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w/ L-DOPA 47 48

46 47 48

2. Carrier-mediated 2. Carrier-mediated 2. Carrier-mediated

Transport Transport Transport
B. Subject to competition / inhibition / C. Subject to Saturability C. Subject to saturability
antagonism Basis: Limited # of carriers Michaelis-Menten Kinetics
Digoxin & Quinidine aka: Rate of Transport = dQ = Vmax [S]
Carrier for tubular secretion Saturable Kinetics dT [S] + Km
- - - predispose to digitalis toxicity; Capacity-Limited Kinetics Where
Thus, NEVER given at the same time Non- Linear Kinetics Vmax = maximum rate of transport
to the same patient Michaelis - Menten Kinetics [S] = Concentration of drug
Km = Michaelis-Menten Constant
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49 50 51

2. Carrier-mediated
RATE KINETICS
Transport
C. Subject to saturability Zero- Order Kinetics
First-Order Kinetics Rate of reaction is INDEPENDENT
Low Dose (unsaturated) of the concentration of the drug
when concentration of substrate [S] :
RATE KINETICS remaining
Rate of Transport Remember by 💖
Zero-Order Kinetics C t = - k 0t + C 0
High Dose (saturated)
when concentration of substrate [S] :
Rate of transport
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is CONSTANT 54

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 TRY THIS OUT! 👊 RATE KINETICS
1. A suspension (125 mg/mL) decays by First- Order Kinetics
zero order kinetics with a reaction Rate of reaction is DEPENDENT of
rate constant of 0.5 mg/mL/hr. What the concentration of the drug
is the concentration of drug remaining
remaining after 3 days? Remember by 💖💖💖
Ct = C0e × (-kt)
log Ct = (-kt)/ 2.303 + log C0
ln Ct = -kt
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TRY THIS OUT! 👊
2. An ophthalmic solution of a
mydriatic drug at 5 mg/mL exhibits
1st order degradation with a K =
0.0005/day. How much will remain
after 120 days
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55 56 57

RATE KINETICS TRY THIS OUT! 👊 TRY THIS OUT! 👊

Half-life 3. A pharmacist dissolved 10g of a drug Time (hr) Concentration (mg/mL)
Time it takes for the drug in 100 mL of water. The solution was
concentration to decrease by 50% kept at a room temperature and 0 100
samples were removed periodically 2 95
Remember by 💖💖💖
and assayed for the drug. Based on 4 90
Zero Order
the following data obtained by the 6 85
T1/2 = (0.5)C0 / k0 8 80
First Order pharmacist, compute for the rate
constant 10 75
T1/2 = 0.693/k 12 70
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58 59 60

TRY THIS OUT! 👊 TRY THIS OUT! 👊

Solution
Check the trend or graph = zero order 4. A solution of a drug was prepared at
a concentration of 300mg/mL. After
(C - C0)/-t = -k0t/-t 30 days at 25C, the drug
k0 = (C - C0)/-t concentration in the solution was
Use any value as long as 75mg/mL. Assuming first order
corresponding kinetic, compute for the rate
constant
(70mg/mL-100mg/mL)/(-12 hrs)
k = 2.5mg/mL/hr
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61 62 63
 TRY THIS OUT! 👊 TRY THIS OUT! 👊 TRY THIS OUT! 👊
Solution
C0 = 300 mg/mL 5. Determine the half-life of an 6. If the half-life for the degradation of
T = 30 days antihypertensive drug if it appears a drug is 12 hours, compute for the
to be eliminated from the body at a 1st order rate constant
C = 75 mg/mL
rate constant 46% per hour. Assume
k = X; (1st order) 1st order kinetics.

(ln 75mg/mL) - (ln 300mg/mL)/(-30

days)
k = 0.0462/day
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64 65 66

TRY THIS OUT! 👊 SHABU PA MORE! 👊 3. Convective Transport

7. The Half-life of a given drug is 6 Movement through water-filled pores = channels
hours. How much remains in the Pore size/diameter: 7 - 10 Angstrom
body after one day? Allows transport of molecules / ions w/
MW < 150 - 400

Charge of pore lining

Allows movement of ions w/ charge
opposite of pore lining

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3. Convective Transport 5. Vesicular Transport PINOCYTOSIS

Movement through water-filled pores = channels
“Movement by solvent drag”
ions move along the same direction w/ H2O
Movement ALONG an
ELECTROCHEMICAL gradient
takes into consideration the Net Charge &
Concentration difference
General term. Envagenation of a cell
membrane (vesicle)
2 Types based on direction:
Endocytosis - “Enter” (absorption)
Pinocytosis - liquid (cell drinking)
Phagocytosis - solid (cell eating)
Features
Vesicle-mediated transport
Requirement
energy requiring process
Micelle form of drug
Transport mechanism for large lipids
e.g. Vitamin A, D, E, K; Griseofulvin

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Exocytosis - Exit (release/secrete)
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 Griseofulvin
PINOCYTOSIS
Drug of Choice for ___(BEQ)___ infection?
Micelle - Formation
1. Given with fatty Meals
2. Fats ➜ induces gall bladder
contraction LIBERATION
3. Contraction ➜ Release of Bile (Bile
acids + Bile salts = Surfactants!)
4. Surfactants will be available for
forming micelles w/ Griseofulvin
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Factors Affecting Factors Affecting

LIBERATION
Liberation Liberation
Definition: Release of drug from the drug
product (or dosage form/drug delivery Pharmacotechnical Factors Pharmacotechnical
system) Factors (e.g. Tablet
Factors that are inherent in the
dosage form)
drug product
Objective: Drug in aqueous sol’n (1o Tablet Hardness
requirement) As a consequence of formulation
& quality that is built into the Disintegration
Exceptions (w/out liberation): product Dissolution (Most
Per Orem solution, Parenteral Important factor!)
solution, Syrups, elixirs etc.
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II. Routes of Drug

DISSOLUTION Liberation
Principle: Noyes-Whitney Equation Administration
Rate of Dissolution: A highly modifiable process Parenteral Intraarticular
dQ = D x A x (Cs - Cb) Easily changed Intravenous Intradermal /
dt h Modified release drug products (PO) Intraarterial Intracutaneous
Where: 1. Delayed-Release (Enteric-coated) Intracardiac Intrathecal
D = Dissolution rate constant Intraspinal
A = Surface Area of particles 2. Extended-Release: Intramuscular
h = Thickness of stagnant layers (area where a. Sustained-Release Subcutaneous Epidural
there is highest conc. of dissolved drug)
Cb = Concentration of bulk region/layer b. Prolonged-Release
(area surrounding drug)
Cs = Concentration of stagnant layer
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 II. Routes of Drug II. Routes of Drug
Administration Administration
Enteral Respiratory Skin Miscellaneous
Buccal Intranasal Transdermal Ophthalmic
Sublingual Inhalational /Percutaneous Otic
Topical
PHARMACOKINETICS
Peroral/oral Urethral
Rectal Vaginal

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PHARMACOKINETICS PHARMACOKINETICS PHARMACODYNAMICS

Dynamics mean power
Kinesis means motion Study of the kinetics of drug ADME
or change in rate
Biochemical &
Elimination = Metabolism + physiological effects
Fate of drugs in the of drugs
body (ADME) Excretion
Mechanism of Action
What the Disposition = Distribution +
body(“Katawan”) does Elimination What the Drug does to
to the drug the body
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85 86 87

PHARMACOKINETICS ABSORPTION
Study of the Transport
Physiologic definition:
different Liberation (Biopharm)
Rate and Extent of DISAPPEARANCE
processes a
of the drug from the site of
drug undergoes Absorption ABSORPTION administration
as it reaches & Distribution
exits the
biological site Pharmacokinetic definition:
Metabolism
Rate and Extent of drug entry into the
Excretion
SYSTEMIC CIRCULATION
ELIMINATION
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 BEQ Factors affecting absorption
FACTORS RELATIONSHIP
Which organ has the greatest surface
Dose Size Dose = Rate & Extent of
area available for absorption?
FACTORS AFFECTING A. Intestines
Administered Absorption
SA = Rate & Extent of
ABSORPTION B. Stomach
Surface Area Absorption
(Lungs > Small Intestine > Stomach)
C. Lungs pH of the Weak Acid: Favorable pH ➜ acidic
absorbing env’t Weak Base: Favorable pH ➜ basic
D. Skin Degree of Blood Perfusion/Supply = Rate &
perfusion of Extent of Absorption
absorbing env’t *Application: Use of vasoconstrictor
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BEQ Factors affecting absorption Factors affecting absorption

This drug may be added to local For P.O. drugs For P.O. drugs
anaesthetic solutions on order to A. Gastric Emptying Time (GET) B. Gastric Emptying or Gastric
prolong its action? GET: Time it takes for stomach to Emptying Rate is ∝ 1/GET
A. Epinephrine completely empty its contents (N= “Kitchen Sink Effect” - Massive
2-3 hours) muscle contraction
B. Atropine sulfate
GET = ➡ Rate of absorption Basis: Stomach is a poor absorbing
C. Sodium carboxymethylcellulose
➡GET = Rate of absorption environment. Why?
D. Norepinephrine (RATE NOT EXTENT)
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94 95 96

Factors affecting absorption Factors affecting GET Factors affecting GET

Factors that GET (Delay in Factors that ➡ GET (increase
Why stomach is a poor absorbing env’t? Absorption) Absorption)
1. Small surface area High amount of food Cold drinks & Hot food at > 600C
2. Less blood perfusion High protein/fatty meals (extremes of food temp ➡GET)
3. Lined by a very thick mucus Gastric ulcers Spicy food
(exceptions: Aspirin & Ethanol) Gastrectomy
Stress, Heavy exercise
Lying on the left side Mild exercise
Anti motility drugs: Opioids & Anti- Diabetes Mellitus - incretins
97
cholinergics (also TCA)
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97 98 99
 Factors affecting GET Factors affecting GET Factors affecting GET
Factors that ➡ GET (increase rate of Drugs w/ increased absorption with Drugs w/ increased absorption with
Absorption) food: food:
Lying on the right side G- Griseofulvin
Pro-motility drugs: Cholinomimetics, A- Acarbose
Anti-dopaminergic drugs e.g. M- Metoprolol
Metoclopramide (Plasil), I- Itraconazole
Domperidone
T- Theophylline

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100 101 102

Factors affecting GET Factors affecting GET

Drugs w/ decreased absorption with food: Drugs w/ decreased absorption with food:
Q Quinolones
A Alendronate
C Captopril
Measures of Absorption-
P Penicillin related Parameters
I Isoniazid
P Penicillamine
E Ethacrynic acid
T Tetracycline
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Parameter Measured Parameter Measured Parameter Measured

Bioavailability or BA (F)
Measure of the rate & extent of
drug entry in to the systemic
circulation
106
Bioavailability or BA (F)
Methods in determining BA:
1. Cumulative urinary excretion
data
2. Drug plasma concentration vs
time data (Most common)
Subjects: Most healthy volunteers
(minimum of 6)
107
Bioavailability or BA (F)
2 Types of BA study:
1. Absolute BA (Fabs) - the
measure of the TRUE rate &
extent
2. Relative BA (Frel)
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 2 Types of BA 2 Types of BA TRY THIS OUT! 👊
Absolute BA (Fabs) Relative BA (Frel) 8. Compute for Relative BA & Absolute
BA
Fabs = BA of a drug in a non - IV drug product Frel = BA of a drug in a non - IV drug product DRUG
DOSE (mg) AUC (µg-hr/mL)
PRODUCT
BA of same drug in same dose given IV BA of same drug in same dose of a non-
Ora Tablet
Fabs = AUCEV x DOSEIV IV innovator drug product
(Generic) 200 89.5
AUCIV x DOSEEV Frel = AUCTEST x DOSESTD Oral Tablet
(Innovator) 200 86.1
AUCSTD x DOSETEST
Reference: Innovator drug product IV Bolus
Reference: IV Form (BA = ?)
Injection 50 37.8
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109 110 111

3 Most Important BA 3 Most Important BA 3 Most Important BA

Parameters Parameters T
Parameters
CMAX CMAX MAX

Definition: Highest drug plasma Time to reach CMAX

TMAX
concentration achieved Measure rate only
Area Under the Curve (AUC)
Problem: most variable parameter
Most Reliable & Important
( Intra-/Inter-individual AUC
variability) The most important BA parameter
Order or priority: AUC > TMAX >
CMAX Measure of extent only

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112 113 114

In between MTC & MEC = Therapeutic

range
Area Under the Curve
Therapeutic Index = TD50 / ED50 Measure of the amount of the drug
TD50 = dose cause 50% in population in the body
Intensity toxicity Reflects the total amount of active
Duration
ED50 = dose cause 50% in population drug
effect Measures the extent of drug
Pdyn ➜ Quantal Dose-Response Curve bioavailability
Onset Steady state plasma concentration Computed using trapezoidal rule
Intensity, Duration, Onset of action ➜
Modified release
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115 116 117

 Area Under the Curve TRY THIS OUT! 👊 Solution
Trapezoidal Rule 9. One compartment extravascular (Kel Trapezoidal Rule
= 0.2402/hr) Compute for AUC0➜∞ AUC0➜t = [(C1 + C2)(t2 - t1)]
AUC0➜t = [(C1 + C2)(t2 - t1)] +….+
Data # Time (hr) Plasma conc. (ng/mL) 2
2 1 0 0
AUC0➜0.25 = [(0 + 19)(0.25 - 0)]
AUCt➜∞ = Clast / kel 2 0.25 19
3 0.5 96.1 2
4 1 130
5
= 2.38 ng-hr/mL
AUC0➜∞ = AUC0➜t + AUCt➜∞ 2 163
6 3 165 AUC0.25➜0.5 = [(19 + 96.1)(0.5 - 0.25)]
7 4 145 2
8 6 95
9 8 56.5 = 14.39 ng-hr/mL
118 10 12 119 22.3 120

118 119 120

Solution Answer
AUC0.5➜1 = 56.53 ng-hr/mL
TRY THIS OUT! 👊
10. Given the data below, compute for the AUC0➜∞ AUC0➜t = 99.87 mcg-hr/mL
AUC1➜2 = 146.5 ng-hr/mL using the trapezoidal rule (Kel = 0.0138/hr)
AUC2➜3 = 164 ng-hr/mL AUCt➜∞ = 7.25 mcg-hr/mL
Time (hr) Concentration (mcg/mL)
AUC3➜4 = 155 ng-hr/mL 0 0 AUC0➜∞ = 107.12 mcg-hr/mL
AUC4➜6 = 240 ng-hr/mL 1 3.13
2 4.93
AUC6➜8 = 151.5 ng-hr/mL 5 6.28
AUC8➜12 = 157.6 ng-hr/mL 7 5.81
10 4.66
AUC0➜12 (sum of all = 1087.9 ng-hr/mL) 18 2.19
AUCt➜∞ = 22.3/0.2402 = 92.84 ng-hr/mL 24 1.2
32 0.54
AUC0➜∞ = 1087.9 + 92.84 = 1180.74
121 48 122 0.1 123

121 122 123

Answer
TRY THIS OUT! 👊
11. Given the data below, compute for the AUC0➜∞ using the
AUC0➜t = 95.37
trapezoidal rule 2 compartment model (Kel = 0.0325/hr)
Time (hr) Concentration (mcg/mL)
AUCt➜∞ = 16
0 0 AUC0➜∞ = 111.37
1 3.13
2 4.93
5 6.28
7 5.81
10 4.66
18 2.19
24 1.2
32 0.54
48 124 0.1 125 126

124 125 126

 Bioequivalent Drug
Bioequivalence
Products is established when two drug products
Are pharmaceutical equivalents that have similar bioavailability (no
have similar bioavailability when statistical difference ANOVA and paired
T test)
given in the same molar dose and
studied under similar experimental Approaches
conditions 1. In vivo pharmacokinetic studies
involving blood or urine
2. In vivo pharmacodynamic studies
3. Comparative clinical trials
4. Comparative in vitro tests
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127 128 129

Bioequivalence Example Drugs BEQ

Important regulatory requirement
Marketing tool
measure of similarity in the
bioavailability of a generic drug
product to the bioavailability of the
reference / innovator drug product
Rifampicin compared to Rifadin
caps (innovator drug) What is the adverse effect for
Rifampicin?
Gliclazide compared to Diamicron A. Red-Orange urine
MR
B. Red-Green color blindness
C. Optic Neuritis
D. Peripheral neuropathy
E. Hepatotoxicity

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130 131 132

BEQ Bioequivalence Bioequivalence

Analysis based on AUC ratio, CMAX, Similarity is establish if each of the
What is the adverse effect for
Ethambutol?
TMAX ratio ratios fall within 0.8-1.25 *80-125%
AUC ratio = AUC generic at 90% confidence interval
A. Red-Orange urine
AUC reference
B. Red-Green color blindness
CMAX ratio = CMAX generic Should PERFECTLY FALL WITHIN
C. Optic Neuritis THE RANGE
CMAX reference
D. Peripheral neuropathy
TMAX ratio = TMAX generic
E. Hepatotoxicity
TMAX reference
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133 134 135


Bioequivalence
Generic drug A BioE study as follows:
AUC ratio = 78 -120%
CMAX ratio = 81-126%
TMAX ratio = 80-120%
Biopharmaceutics
Classification System
BCS
A scientific framework for
classifying drugs based on their
aqueous solubility and intestinal
permeability
Biopharmaceutics
Classification System
Class 1 - No problems in
terms of absorption;
usual problems arise
from excipients e.g.
Amlodipine

80-125%
Class II - e.g. Clopidogrel
Conclusion: Generic A is not BioE w/
Class IV - Challenging
test drug (Never Round Off the value)
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136 137 138

BCS BCS In vitro equivalence testing

BCS class I = exempted BE Dissolution testing that includes
HIGH LOW comparison of the dissolution profiles
Permeability Permeability
BCS class IV = required
of a generic & a comparator product
BCS II & III = waivable
in three media pH: 1.2, 4.5 and 6.8
HIGH
CLASS I CLASS III
Solubility Biowaivers - Similar factor (F2)
F2 = 50 - log {[1 + (1/n)E(RT-Tt)2]0.5 x
LOW Oral solution = no BE
CLASS II CLASS IV 100}
Solubility
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139 140 141

Generic Substitution
Process of dispensing a different
brand or unbranded drug product in
place of the prescribed drug
Important Terms product

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142 143 144

Pharmaceutic Alternatives BEQ BEQ
Drug products that contain the
What is the DOC for Cholera? What is the DOC for Pseudomembranous
same therapeutic moiety but as colitis?
different sals, esters or complexes A. Azithromycin
A. Azithromycin
e.g. Tetracycline phosphate or B. Penicillin G
Tetracycline HCl equivalent to 250 B. Penicillin G
C. Ciprofloxacin C. Ciprofloxacin
mg tetracycline base
D. Doxycycline D. Doxycycline
E. Vancomycin E. Vancomycin

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145 146 147

Pharmaceutic Alternatives Pharmaceutic Equivalents Pharmaceutic Substitution

Different dosage forms and
strengths within a product line by a
SINGLE MANUFACTURER
e.g. an extended-release dosage
form and a standard immediate-
release dosage form of same active
ingredient
148
Drug product with same Process of dispensing a
Active pharmaceutic ingredient pharmaceutic alternative for
Dosage form prescribed drug product
Dosage strength Example
ampicillin suspension in place of
Mode of Administration
ampicillin capsules
Standard of Quality
Tetracycline HCl in place of
tetracycline phosphate
149 150

148 149 150

Therapeutic Alternatives BEQ BEQ

Drug products containing different
the NSAID of Choice for patients with the Brand name Arcoxia is?
active ingredients that are indicated chronic renal failure?
for the same therapeutic or clinical A. Rofecoxib
objectives A. Aspirin
B. Celecoxib
e.g. Ibuprofen instead of aspirin B. Ketorolac
C. Meloxicam
C. Parecoxib
D. Ibuprofen D. Etoricoxib
E. Mefenamic Acid E. Valdecoxib

151 152 153

151 152 153

 BEQ BEQ Therapeutic Equivalence
Regulatory parameter
Rofexcoxib, aka Vioxx by Merck was The publication that identifies drug products
withdrawn in the market due to? approved on the basis of safety and Measure of interchangeability of a
A. Neurotoxicity
effectiveness by the FDA is commonly known as: generic product with the reference
A. Green Book drug product
B. Cardiotoxicity B. Blue Book US FDA Publication: “Orange Book”
C. Nephrotoxicity C. Orange Book
Handbook of drug products with
D. Hepatotoxicity D. Black Book
therapeutic equivalence
E. Pulmonary fibrosis E. Red Book
evaluations
154 155 156

154 155 156

Therapeutic Equivalent Therapeutic Substitution

Are drug products that can be used
interchangeability in clinical practices
Requirements (US FDA):
Pharmaceutic equivalents
(alternatives - WHO)
Approved as safe and effective
Adequately labeled
Manufactured in compliance to
cGMP regulations
Bioequivalent 157
Process of dispensing a therapeutic
alternative in place of the
prescribed drug product
DISTRIBUTION
e.g. Ampicillin for amoxicillin
158

157 158 159

Distribution
Process of drug movement from
systemic circuit to different body
compartments / parts
Drug reaches the site if action
'Carrier' of drug to different
compartments from the blood
160
Distribution
Volume of blood pumped
out by heart in 1 min.
= 2.2-3.5 L/min/m2 BSA
Expression of rate - how fast
blood is moving
CHF - ____?____ cardiac
output state
Delay in drug distribution in
reaching a therapeutic
concentration of drug
161

160 161 162

 Factors affecting
Distribution Distribution
Distribution
Fraction of CO that is delivered to Implication Rate of Distribution
specific tissues or organs Treatment in these areas, it will Membrane permeability
e.g. Liver (25% CO), Kidneys (25% CO), take some time to reach tissue Capillary wall structure
___?___ (100% CO) Drug’s pKa and blood pH
concentration
Areas with poor regional blood flow Blood Perfusion
(NOT > 1% CO) Extent of Distribution
e.g. Bones, Adipose tissues Osteomyelitis (Bone infection)
> 6 weeks treatment regimen [IV] Lipid solubility
Highest perfusion rates:
Pneumonia (Lung infection) pH-pKa
Brain, Kidney Liver and Heart
Plasma-protein binding
7 - 14 days [Oral]
Tissue localization
163 164 165

163 164 165

Factors affecting Factors affecting

Distribution
Distribution Distribution
●Rate of Distribution ●Extent of Distribution 2 Important distribution parameters:
●Membrane permeability ●Lipid solubility
Volume of Distribution
●Lipophilic drugs accumulate in adipose tissue
●Recall: capillaries are lined with Protein Binding
●Polar drugs (e.g. aminoglycosides) do not
endothelial cells that overlap & junction distribute well into fat tissues & BBB
between cells are discontinuous ●pH-pKa
●Ionized drugs have difficulty crossing
●Thus, capillary cells are quite permeable membranes
●Lipid-soluble drugs pass easily ●Tissue Localization
●Low MW drugs pass via passive ●Binding to tissue proteins or nucleic acids or
diffusion dissolution in the lipid material
166 167 168

166 167 168

Protein Binding Protein Binding Protein Binding

Storage or Reservoir
Weak forces (Van der Waals & Ionic Bonds)
Only the free drug is available for receptor
interaction
PROTEIN Reversible (Except N-mustards) Free / Unbound Drug - Pharmacologically
Active Form
PROTEIN
Delays urinary excretion Bound Drugs - Pharmacologically Inactive
Form
The protein-bound drug:
Subject to drug displacement reactions
• large molecule whose distribution is restricted Increases elimination half-life
• Only the free drug can readily cross the cell Warfarin + Phenylbutazone ➜ Haemorrhage
membrane and exert a pharmacological effect Tolbutamide + Sulfonamides ➜ HYPOglycemia
169 170 171

169 170 171

Factors affecting Distribution
●Plasma protein binding
●Bound drugs do not cross membranes
●Depends on other protein-bound drugs
– compete with same binding site,
freeing the drug with less affinity
●Malnutrition = !albumin = " free drug
172
172
Protein Binding Equilibria
Fraction Unbound (𝛂)
(𝛂) = Free Drug concentration
Total Drug concentration
Clinical Importance:
To interpret measured drug concentration
𝛂 ≤ 0.1 (≤10% free) significant protein binding
changes; adjust normal therapeutic range
𝛂 > 0.5 - Clinically significant
175
175
BEQ
What is the hypothetical volume/apparent
volume of body fluid that is necessary to
dissolve a given dose or amount of drug to a
concentration equal to that achieved in plasma?
A. Regional blood flow
B. Plasma volume
C. Volume of distribution
D. Volume of absorption
178
178
Factors affecting Distribution PROTEIN BINDING
●Blood Proteins
●Albumin - Dominant, structure non- DRUGS BINDING SITES
selective, preferentially binds weak acids
Bilirubin, Bile Acids, Fatty acids,
Vitamin C, Salicylates,
●Alpha-1-acid Glycoprotein - Structure non- Sulfonamides, Barbiturates, Albumins
selective preferentially bind weak Base Phenylbutazone, Penicillins,
Tetracycline, Probenecid
Adenosine, Quinacrine, Quinine, Globulins, Alpha1,
●Globulin - Selective for hormones Streptomycin, Chloramphenicol, Alpha2, Beta1,
Digitoxin, Ouabain, Coumarin Beta2, Gamma
173 174
173 174
TRY THIS OUT! 👊 TRY THIS OUT! 👊
1. The 𝛂 of the drug is 0.90, equating to 3. What is the Cp free for a ureic
0.55 ng/mL. What is the Cp total of patient with a reported phenytoin
the drug? conc. of 4 mcg/mL & an 𝛂 = 0.25?
Fraction unbound (𝛂) = Free Drug Conc.
Total Drug Conc. Fraction unbound (𝛂) = Free Drug Conc.
2. If fat at equilibrium, two thirds of Total Drug Conc.
the amount of drug substance in the
blood is bound to protein, what is 𝛂?
176 177
176 177
______BEQ______ Volume of distribution (Vd)
●hypothetical or apparent volume of body ●Conc = mass ----- V = m/C
fluid that is necessary to dissolve a drug vol
to a conc. equal to that of plasma conc.
Vd = D Vd= A
Co Cp
●Not a real blood volume (computed only)
●D = dose size administered
●Co = extrapolated drug plasma conc at t=0
●A = amt of drug in the body
● Cp = conc of drug in plasma at a given time
179 180
179 180
Important applications of
Answer TRY THIS OUT! 👊
Vd
1. Estimating Loading Dose (DL) Given: 1. Compute the VD of a drug that has a
VD = D / C0 plasma concentration of 10 mg/L
At what DL should a drug be given if the DL / Ctarget when the DL is 700 mg
Vd is 5 L/kg BW and desired drug DL = VD x Ctarget Answer:
plasma concentration is 5 mg/L. Patient DL = [(5 L/kg) x 60 kg)] x 5 mg/L VD = D / Co
weighs 60 kg. DL = = 1500 mg VD = 700 mg / 10mg/L
VD =70 L

181 182 183

181 182 183

TRY THIS OUT! 👊 Volume of Distribution Distribution of Body Fluids

2. A patient received an IV dose of 10 Important applications of Vd:
mg of a drug. A blood sample was Compartment % Body Weight 70 kg
Predict the likely extent of drug
drawn and it contained 40 mcg/ distribution a. Intracellular 40% 28 L
100mL. Calculate the Vd for the drug 60% (Total
(where is the drug located) - Body Fluid)
3. A Vd of 32.5 L after a 0.025g dose of compare Vd w/ the body fluid b. Extracellular 20% 14 L
the drug was administered. What is volumes Interstitial 15% 10 - 11 L
the resulting plasma concentration 20%
in mg/mL? Intravascular 5% 3-4L

184 185 186

184 185 186

Relevance of Volume of
BEQ Extent of Distribution
Distribution
Given the VD of the ff drugs: Drug A – 1L, Drug B – 29L,
Large Vd
Drugs Vd Assume: 70 kg individual
drug C – 3L, Drug D – 12L. Which can be removed by widely distributed - extent approx.
hemodialysis? A 40 L TBF
Total / Intracellular Body Fluid
A. Drug A B 5,000 L TBF Large Vd e.g. Chloroquine, Atropine, B-
B. Drug B C 30 L INTRACELLULAR blockers, weak bases (in general)
C. Drug C D 10 L INTERSTITIAL Low/Small Vd
D. Drug D E 2L INTRAVASCULAR Small Vd Extracellular or within intravascular
E. All of these F 5L INTRAVASCULAR e.g. Warfarin, Midazolam, weak acids
(in general)
187 188 189

187 188 189

 Pharmacokinetic Model
Recognises that drugs are in a
dynamic state within the body
COMPARTMENT Based on hypothesis and simplifying
assumptions that describe biological
MODELS systems in mathematical terms in
order to predict drug action
Compartment Model
Compartment
A hypothetical volume that contains a
certain drug concentration
Space or region on the body where you
can locate the drug (in reality multi-
million compartment per cell)

191 192

190 191 192

Compartment Model Compartment Model

One compartment
Central compartment ➜ the compartment Body is a single compartment where a
with the blood stream certain volume remains constant
Instantaneous distribution - peripheral
Peripheral compartment ➜ all others… distribution is negligible METABOLISM
Two - compartment
Open Compartment (what comes in comes (1) Central Compartment ➜
out) - input/output (2) Peripheral Compartment
Transport ➜ reversible process
Elimination ➜ Irreversible process
193 194

193 194 195

Metabolism Exemption to Metabolism Exemption to Metabolism

aka Biotransformation 1. Prodrugs 2. Active drug w/ active metabolites
Formerly: Detoxification An inactive parent drug that has to be Diazepam (active) ➜ N-
Major Organ: Liver metabolised to the active form desmethyldiazepam (Nordiazepam) ➜
Objective: Convert drugs into forms which are: e.g. Enalapril ➜ Enalaprilat active
Less active or inactive Responsible for the antihypertensive ➜ Oxazepam (active)
Less toxic or non-toxic effect ➜ Glucuronide (inactive)
Polar or water-soluble (to be easily excreted) Clopidogrel, Allopurinol Peripherally prolongs half-life of drug

196 197 198

196 197 198

Exemption to Metabolism
3. Nontoxic drug metabolised to a toxic drug
Acetaminophen (non-toxic) ➜
Enzyme: CYP1A2
➜ N-AcetylParabenzoQuinone Imine
(NAPQI) ➜ Hepatotoxic
Conjugation with GSH ➜ Mercapturic
acid form (inactive/nontoxic)
Examples of Prodrugs
__________________➜ Chloramphenicol
Levodopa ➜ _____________
___________ ➜ Monoacetylmorphine ➜
Morphine
Prednisone ➜ _____________
___________ ➜ Morphine
Enalapril ➜ ______________
____________➜ Salicylic acid (Anti-RA)
Examples of Prodrugs
Chloramphenicol palmitate ➜
Chloramphenicol
Levodopa ➜ Dopamine
Heroin ➜ Monoacetylmorphine ➜ Morphine
Prednisone ➜ Prednisolone
Codeine ➜ Morphine
Enalapril ➜ Enalaprilat
ASA ➜ Salicylic acid (Anti-RA)

199 200 201

199 200 201

Important Metabolising First-Pass Effect /

Organs
Liver - most important
GIT (Stomach, intestines)
Blood (plasma: portal, systemic)
Kidneys
Imipenem (dihydropeptidase enzyme in
kidney)
Cilastatin (Dihydropeptidase inhibitor)
Lungs, Placenta, Aqueous humor of eyes
202
Liver
Hepatic microsomal enzyme system
e.g. Cytochrome P450 superfamily
has several isoenzymes
CYP1A2, CYP2A6, CYP2C9,
CYP2D6, CYP2E1, CYP3A4
203
Metabolism
aka: Pre-Systemic Metabolism
phenomenon where drugs are
metabolised initially following
absorption but before reaching the
systemic circulation
Significance - FPE can dec. oral BA of a
drug
204

202 203 204

Phase I Metabolism Phase I Metabolism

aka Functionalization phase
PHASES OF DRUG Non-synthetic reactions (addition or
METABOLISM unmasking of a functional group)
Oxidation - ______________➜ Most
Dominant reaction
Reduction - reductase
e.g. Chloral hydrate ➜
______BEQ______ (CNS Depressant)
Hydrolysis - Hydrolases

206 207

205 206 207

 Phase I Metabolism PROTEIN BINDING Phase I Metabolism
CYP FAMILIES SUBSTRATES
Oxidative reactions: CYP1A2 Acetaminophen, Theophylline, Caffeine Reduction reactions:
1. CYP - mediated 1. Nitro reduction ➜
CYP2C19 Propranolol, PPI, Clopidogrel
e.g. CYP-450 mixed oxidase system Chloramphenicol
aka? CYP2C9 Phenytoin, Sulfonylureas, S-Warfarin 2. Carbonyl reduction - Naloxone
2. CYP - Independent Codeine, Dextromethorphan, Most (DOC for Opioid toxicity);
Monoamine oxidases (MAO), CYP2D6 antidepressant & anti-psychotics, Methadone
Debrisoquin (Most studied enzymes)
Alcohol & Aldehyde Dehydrogenase, 3. Azo Dye Reduction - Prontosil
Macrolide, Amiodarone, CCB, Azole
Flavin Mono-oxygenase CYP3A4 Anti-fungals, Proteases inhibitor,
208 209
Antihistamine 210

208 209 210

Phase I Metabolism Phase II Metabolism Phase II Metabolism

aka Conjugation reactions / Glucuronidation
Hydrolysis reactions: Synthetic phase or reactions Acetylation
Esters
Glutathione conjugation
Amides
Glycine & Glutamate conjugation
B-lactams Involves addition of a POLAR Sulfation
conjugate Methylation
Water conjugation

211 212 213

211 212 213

Glucuronidation Phase II Metabolism Phase II Metabolism

Major/Dominant conjugation reaction
among adults
Enzyme involved: Glucuronosyl Acyl-
Transferase (poorly expressed in < 28 days)
Endogenous substrate: UDP-Glucuronic Acid
a. ____BEQ_____ - DOC for typhoid fever
b. ____________
c. Morphine
Convulsant metabolite: ______BEQ______
Analgesic metabolite: ______BEQ______
214
Acetylation Glutathione conjugation
Enzyme: NAT / N-acetyltransferase Scavenger for ____________ ➜
Drugs: electrophilic in nature
S Detoxification of ROS
H Anti-oxidant for NAPQI toxicity:
____________ ➜ Replenishes
I
P glutathione in the body
Toxic APAP dose: ______ / day
215 216

214 215 216

 BEQ Phase II Metabolism BEQ
Glycine conjugation
The only true mucolytic: An example of Glycine Conjugation
A. Ambroxol Most common endogenous amine pathway:
B. Bromhexine
for conjugation with organic acids
Reduced in infants and the elderly A. Benzoic Acid to hippuric acid
C. carbocisteine
Glutamine conjugation B. Antabuse to dithiocarbamic acid
D. N-Acetylcysteine C. Phenol to Phenol sulfate
Enzymes localised in liver &
kidneys D. Noradrenaline to epinephrine

217 218 219

217 218 219

Phase II Metabolism Phase II Metabolism Phase II Metabolism

Glycine / Glutamine conjugation Sulfate conjugation Methylation
Amino acid conjugation Sulfate pool ➜ limited, easily Minor pathway
____________ Moieties depleted Enzyme: Methyltransferases
Dominant phase II in newborn
e.g. Benzoic acid + Glycine ➜ e.g. COMT - Catecholamines
(easily saturated)
______BEQ_______ Endogenous substrate: SAM
Enzyme involved: _____________
e.g. Salicylic acid + Glycine ➜ example:
_________________ Paracetamol/Acetaminophen
Phenol
220 221 222

220 221 222

QUIZ QUIZ QUIZ

Hydralazine Salicylic Acid Hydralazine = Acetylation Salicylic Acid = Glycine/Glutamate
NAPQI Chloramphenicol NAPQI = Glutathione conjugation conjugation
Paracetamol = Sulfation & Glucuronidaton, Chloramphenicol = Glucuronidation,
Paracetamol Sulfonamides Oxidation, Glutathione conjugation Reduction
Chloral Hydrate Morphine Chloral Hydrate = Reduction Sulfonamides = Acetylation
Benzoic Acid Lidocaine Benzoic Acid = Glycine/Glutamate
Morphine = Glucuronidation
Isoniazid Ceftriaxone conjugation
Isoniazid = Acetylation Lidocaine = Hydrolysis
Procainamide Levarterenol Procainamide = Acetylation Ceftriaxone = Hydrolysis
Pen G Pen G = Hydrolysis Levarterenol = Methylation, Oxidation
223 224 225

223 224 225

 BEQ
If Drug A induces metabolism of drug B:
ENZYME INDUCERS/ A. Increase in Drug A plasma levels
INHIBITORS B. Decrease in Drug B plasma levels
C. Increase in Drug B plasma levels
D. Decrease in Drug A plasma levels
Enzyme Induction
Stimulate activity or production of
hepatic enzymes
Results to FASTER metabolism
Effects depends on the substrate
Enzyme Inducers:
Enzyme activity: Drug
metabolism: ➡Drug effect

227 228

226 227 228

Enzyme Induction Enzyme Inducers Enzyme Inducers

If substrate is a Prodrug
in amount of active metabolite
risk of toxicity
e.g. Codeine ➜ morphine
Enhanced analgesic effect
Risk: Respiratory Depression
Opioid Poisoning Triad?
229
G Griseofulvin
O Omeprazole
P Phenobarbital, Phenytoin
R Rifampicin
C Carbamazepine, Chronic
S Alcoholism,
Smoking, St John’s Wort (Hypericin)
230 231

229 230 231

BEQ Enzyme Inhibition Enzyme Induction

M
Decrease activity or production of E
If Drug A inhibits metabolism of drug B: hepatic metabolising enzymes D
A. Increase in Drug A plasma levels Results to SLOWER metabolism V
effect or possible toxicity I
B. Decrease in Drug B plasma levels Effect depends on substrate C
C. Increase in Drug B plasma levels Enzyme Inhibitors: K
➡Enzyme activity: ➡Drug G
D. Decrease in Drug A plasma levels metabolism: Drug effect A
232 233
S 234

232 233 234

 Enzyme Inhibitors Alcoholism
Metronidazole, Macrolides
Erythromycin Verbose
Disulfiram, Diazepam Jokose
Valproic acid, Vancomycin Bellicose GENETIC
Isoniazid, Itraconazole, Indinavir Morose
Cimetidine, Chloramphenicol, Repose
POLYMORPHISM
Clarithromycin, Clotrimazole
Ketoconazole (Miconazole, Fluconazole)
Comatose
Grapefruit Juice (Bergamotin) Rigormatose
Acute Alcoholism
Saquinavir (Ritonavir)
235 236

235 236 237

3 Groups based on quantity of

Genetic Polymorphism enzymes produced or expressed NAT2 Polymorphism
Variability in the expression or EM = Extensive metabolizers N-AcetylTransferase 2 enzyme
production of enzymes based in Produce normal or adequate Catalyses acetylation
genetic characteristics of amount of enzymes) - Median group “SHIP” or “HIPS”
individuals UM = Ultra metabolisers Sulfonamide
Produce excessive amounts of
Hydralazine
enzyme
PM = Poor metabolisers
Isoniazid
Produce inadequate amount of Procainamide
enzyme A/E: SLE-like
238 239 240

238 239 240

NAT2 Polymorphism Excretion

EM - rapid acetylators (“EAST”) Final loss of drug from the body
Egyptians General Requirement: Water-
Asians soluble
eSkimos EXCRETION Polar
PM - slow acetylators (>50% of Small MW (< 400-600)
caucasians & African-American)
Western races
Consequences: Poorly metabolize
“SHIP” (TOXICITY!)
241 243

241 242 243

 Excretion Renal Excretion Renal Processes
Renal Major organ: Kidney Glomerular
Biliary Nephron - actual unit where Filtration
Lungs - for volatile lipophilic elimination takes place Tubular
substance Secretion
Skin & Sweat Glands Requirement: Tubular
Mammary Glands Polar Reabsorption
GIT Small MW (< 400-600)

244 245 246

244 245 246

Glomerular Filtration Glomerular Filtration

Estimation of the GFR
Rate (GFR) Rate (GFR)
Occurs in Bowman’s capsule If GFR goes down (poor kidney Creatinine clearance (CrCl)
(Glomerulus) function) Most common method
Filtration of low MW molecules Filtration goes down
Measured using a drug/substance Impaired filtration leads to drug Modified renal diet method (MDR)
that is solely eliminated thru retention (TOXICITY!) PC programs, plot in values
filtration
Inulin
Creatinine
247 248 249

247 248 249

Creatinine Clearance Sample Problem Estimation of the GFR

Based on a 24 - hr urine collection
CrCl (mL/min)
= [UCR] x [mL of urine (24hrs)]
[PCR] x 1440 mins
UCR = Urine creatinine conc.
PCR = plasma creatinine conc.
250
Urine creatinine conc = 24 mg/dL Cockcroft and Gault Equation
Plasma creatinine conc = 1.2 mg/dL CrCl (male) mL/min
Volume of urine in 24 hrs = 2880mL = [(140 - age in yr) (BW in kg)]
CrCl (mL/min) = [72 x PCR in mg/dL]
CrCl (female) = CrCl (male) x 0.85
= [UCR] x [mL of urine (24hrs)]
= [(140 - age) x BW(kg) x Constant]
[PCR] x 1440 mins
[PCR in mmol/L]
CrCl (mL/min) = ? *where constant is 1.23 (men) & 1.04
(women)
251 252

250 251 252

Estimation of the GFR
Jellife Equation
GFR for male:
= [98 - 0.8 x (age - 20) x BSA]
[1.73 x Serum Creatinine]
GFR for female:
GFR (females) = GFR (males) x 0.9
where,
BSA = Body Surface Area
253
Renal Impairment TRY THIS OUT! 👊
What is the creatinine clearance for a
Normal: >85 mL/min 68 year old female wishing 160lb and
Mild Impairment: 60-85 mL/min having a serum creatinine of 1.8 mg/
Moderate Impairment: 30-59 mL/min dL?
Severe Impairment: <30 mL/min CrCl (female) =
= [(140 - age in yr) (BW in kg)] x 0.85
[72 x PCR in mg/dL]
254 255

253 254 255

Application Tubular Secretion Tubular Reabsorption

Dose adjustment of renaly excreted Occurs in the proximal convoluted Occurs in the distal convoluted
drugs among pxt w/ renal tubule tubule
insufficiency Molecules surrounding capillaries
are transported into the tubules Filtered molecules can be
Normal: 80-120 (100) mL/min Subject to inhibition: transported back into the blood
Dose adjusted B-lactams + Probenecid
= (CrCl Px) x Regular Dose Digoxin + Quinidine The ionised form of the drug is
(CrCl normal) excreted
256 257 258

256 257 258

Tubular Reabsorption
depends or influenced by
_____ of the urine
_____ of the drug
Principle: _______________Equation
Urinary alkaliser: ?
Urinary acidifier: ?
Biliary excretion
Renal Excretion
● Requirement
“Ion Trapping”
Weak Acids + Basic Urine ➜ Ionised
● Polar
Weak Base + Acidic Urine ➜ Ionised
● MW > 400-600 (bigger than renal)
e.g. Amphetamine (Weak Base)
Reabsorbed if urine pH is
alkaline
DOC for Amphetamine toxicity?

259 260

259 260 261

Biliary excretion
● if a drug is excreted through the bile, there is a
possibility of drug reabsorption
● (biliary recycling / enterohepatic recirculation)
● >> bile is excreted in duodenum so drug can still be
reabsorbed in duodenum, jejunum and ileum
● Prolong the duration of the drug
Mammary Excretion Drug Excretion Into Sweat
● Many drugs pass into breast milk and may ● Passive diffusion of the non-ionized
attain a higher concentration in milk than in moiety
plasma ●Non-ionized cmpnds: alcohol,
● Nursing mothers should avoid taking drugs antipyrine, urea
● Antithyroid, lithium, chloramphenicol, ● Weak acids: sulfonamides, salicylic acid
anticancer drugs # DO NOT NURSE
● Weak bases: thiamine
● Extremely narrow therapeutic index
gentamicin, kanamycin# TAKE SPECIAL ● Metals: I, Br, Hg, Pb
CARE

262 263 264

Drug Excretion Into Expired Air Genital Excretion

● Less soluble anesthetics
● Prostate secretions DRUG CLEARANCE
● Soluble gases
● Other volatile compounds: alcohol,
● Seminal fluid : anticancer drugs #
ethereal oils Malformations
● Vaginal discharge (particularly during
birth delivery)

265 266 267

Drug Clearance Drug Clearance Total Body Clearance

● Pharmacokinetic term describing drug elimination ● Volume of plasma eliminated of drug per unit time ● Sum of individual clearances by various organs ~
from the body without identifying the mechanism of liver + kidney
the process ClT = elimination rate plasma
concentration ● CLt = CLh + CLr
● Drug clearance
● The fixed volume of fluid (containing the drug) where CLh = hepatic clearance
ClT =kVD
cleared of drug per unit time CLr = renal clearance
OR
● Units
● Volume/time
CLt = CLh + CLr + CLothers

268 269 270

Calculation of Clearance Calculation of Clearance
Drug Clearance
CL = D where D = dose b. CL = Vdk where k = elimination rate constant ● Used to determine the MAINTENANCE dose rate
Vd = apparent volume of distn required to achieve a target steady state plasma
AUC AUC = area under the curve calc by TRAPEZOIDAL
concentration
RULE Since k = 0.693/t1/2

CL = 0.693Vd OR t1/2 = 0.693Vd

CL = mg/conc x time or mL/min
t1/2 CLh + CLr
CL = FD where F = fraction of the dose of PO drugs
AUC

271 272 273

Drug Clearance Computations Solution

● Steady state
rate of drug administered = rate of drug eliminated
~ plasma drug conc is constant
SS: Kel = maintenance dose rate (DR)
DR = clearance x steady state drug conc Css
For intermittent doses:
DM = dosing rate x dosing interval
● A target plasma theophylline concentration of Ro = Cl x Css
10 mg/L is desired to relieve acute bronchial = 2.8L/hr x 10 mg/L
asthma in a patient. If the patient is a = 28 mg/hr
nonsmoker & otherwise normal except for the
asthma, mean clearance is 2.8L/hr. The drug Maintenance dose = Ro x dosing interval
is to be given as an IV infusion; dosing
= 28 mg/hr x 12 hrs = 336 mg
interval is 12 hrs. Determine the rate of
infusion (or dose rate) and maintenance dose.

274 275 276

Computations Solution Computation

● What is the Cl of a drug that is infused at a rate of 4mg/min Ro = Cl x Css

and produces a Cpss of 6mg/L in the plasma? Cl = Ro / Css
= (4mg/min ) / (6mg/L) Calculate the Ro for aminophylline which would
Ro = Cl x Css
= 0.67 L/min produce the target level of 15mg/mL if the
estimated drug clearance is 2.8L/hr.

Ro = Cl x Css

277 278 279

 Solution

Ro = Cl x Css THANK YOU & GOD BLESS

= 2.8L/hr x 15 mg/mL x1,000ml/1L ☺😊😀😬😁😃😉🙂😇🤗
= 37, 500 mg/hr

280 281