A

D
M
E
 Aka. _______________________
 Major Organ: ________________
 What is Cytochrome P450? Most Common?
 What is First Pass Effect?
 Aka. Presystemic Metabolism
 Phase 1:  Phase 2:
 Functionalization Phase  Conjugation Phase
 Non-synthetic reaction  Synthetic Reaction
 Examples:  Examples:
 Oxidation  Glucuronidation
 Reduction  Acetylation
 Hydrolysis  Sulfate Conjugation
 Glycine Conjugation
 Glutathione Conjugation
 Methylation
 Glutamine Conjugation
Enzyme Induction Enzyme Inhibition
 Phenobarbital, Phenytoin  Grapefruit
 Chronic Alcoholism  Acute alcoholism
 Carbamazepine  Metronidazole
 Charcoal broiled foods  Erythromycin
 Cigarette smoke  Disulfiram
 St. John’s wort  Isoniazid
 Rifampicin  Cimetidine, Chloramphenicol
 Ketoconazole
 Valproic acid
Patient X. O. 50 y/o is taking Warfarin to prevent thrombosis.
The patient is also suffering from bacterial infections and is
prescribed to take Erythromycin. After 2 days the patient
experienced profuse bleeding.
What could have caused this incident?
Patient A. M. 23 y/o is suffering from tuberculosis and is
taking Isoniazid. To control his atrial fibrillation he was
prescribed to take Digoxin. After 3 days the patient was
observed to experience hypokalema.
What could have caused this incident?
A patient who is a lawyer loves San Miguel Beer. Everyday of
his life for 16 years he is having tons and barrels of San
Miguel Beer. He really loves the beer. He just can’t get
enough of it. Then suddenly he found out that he got
Parkinson’s Disease and was prescribed to take Dopamine.
If you are the doctor? Would you increase or decrease the
dose of dopamine?
 Major Organ: ________________
 ______________- Unit where excretion takes place
1. Glomerular Filtration
2. Tubular Secretion
3. Tubular Reabsorption
GLOMERULAR TUBULAR TUBULAR
FILTRATION SECRETION REABSORPTION
Rate order Zero Order First Order
Reaction Rate Independent Dependent
Equation C = -k0t + C0 ln C = -kt + ln C0
Half-life 0.5 C0/k0 0.693/k
Unit C/t 1/t
Tito Boy weighed exactly 10 g of a drug and dissolved it in 100 mL of
water. The solution was kept at room temperature and samples were
removed periodically and assayed for the drug. Tito Boy obtained the
following data:
Time (hr) Conc (mg/mL)
0 100
2 95 Compute for
4 90 rate constant
6 85
8 80
10 75
12 70
Tito Boy weighed exactly 10 g of a drug and dissolved it in 100 mL of
water. The solution was kept at room temperature and samples were
removed periodically and assayed for the drug. Tito Boy obtained the
following data:
Time (hr) Conc (mg/mL)
0 90.02
2 81.45 Compute for
4 73.70 rate constant
6 66.69
8 60.34
A solution of a drug was prepared at a concentration of 300 mg/mL.
After 30 days at 25C, the drug concentration in the solution was found
to be 75 mg/mL. Assuming first order kinetics, compute for the rate
constant.
Determine the half-life of an antihypertensive drug if it appears to be
eliminated from the body at a rate constant of 46% per hour. Assume
first order kinetics.
If a drug has an elimination rate constant (Ke) of 0.3 days-1, how much
time is required for elimination of 95% of the drug?
 EV

Cp
GRAPH
OPEN TWO-
COMPARTMENT MODEL?

Time
Formation of complex between a drug
and serum protein
A hypothetical volume of body fluid that
would be required to dissolve the total
amount of drug at the same
concentration as that found in the blood
 Vd = Dose/Cp

Volume (L)
Intracellular fluid 28
Extracellular fluid
• Interstitial fluid 10
• Plasma 4
TOTAL 42
 If 100 mg of drug was administered and resulted to
plasma concentration of 0.02 mg/mL, what is the
volume of distribution?
An initial higher dose of a drug that may
be given at the beginning of a course of
treatment to reach desired plasma
concentration
 Loading Dose (DL) = Vd X Cp
 If the target plasma concentration of a drug is 15
mg/L, what is the loading dose for a 60 kg patient if
the Vd of the drug is 0.5 L/KBW
 AREA UNDER THE CURVE (AUC)
 Trapezoidal Rule
Time (hr) Concentration
(mcg/mL)
0 0
4 2
8 6
24 0.1
Kel = 0.0138/hr
 Absolute bioavailability
 “True” fraction of administered dose that reaches the
systemic circulation
 Compares the amount of drug absorbed from an IV route
with any EV route
 Relative bioavailability
 The bioavailability of a certain drug product relative to an
second drug product that contains the same active moiety
Innovator vs. “me too”
EV route compared to another EV route
 ABSOLUTE BIOAVAILABILITY
AUCEV X DOSEIV
X 100%
AUCIV X DOSEEV
 RELATIVE BIOAVAILABILITY
AUCtest X DOSEstd
AUCstd X DOSEtest X 100%
Given the data below, compute for the absolute and relative
BA of the tablet:
AUC Dose (mg)
IV Bolus 17 50
Oral Tablet 120 500
Oral Solution 125 500
What is the creatinine clearance for a 68 y/o woman
weighing 160 lb and has a serum creatinine of 1.8
mg/dL?
Compute for the percentage of ionized species of a
weak acid drug with a pKa of 5 at a urine pH of 7?
Measure of drug elimination from the
body
Units: mL/min or L/hr
Volume of fluid cleared of drug from the body per
unit time
Formula:
ClT = ClR + ClH + Clothers
ClT = Vd x Kel
ClT = Dose/AUC
Determine the total body clearance for a drug in a 70-kg
male patient. The drug follows the kinetics of a one-
compartment model and has a 1st order elimination half-life
of 3 hours with an apparent volume of distribution of 100
mL/kg
Dose required to maintain steady state
concentration
 Maintenance Dose = CL x CpSSav

 CpSSav is the target average steady state drug

concentration
 What maintenance dose is required for drug A if;
 Target average SS concentration is 10 mg/L
 CL of drug A is 0.015 L/kg/hr
 Patient weighs 75 kg
What is the loading dose required for drug A if;
Target concentration is 10 mg/L
Vd is 0.75 L/kg
Patients weight is 75 kg
Most acidic:
a. Urine
b. Breast milk
c. Jejunum, ileum contents
d. Stomach contents
e. Vaginal secretions
Most drug permeation mechanism:
a. Passive diffusion
b. Active diffusion
Weak bases
a. Neutral molecules that dissociates into an anion and a
proton
b. Neutral molecule that dissociates to form cation upon
combining with a proton
c. Charged molecule that remains charged independent
upon pH
d. Neutral molecule that remains uncharged independent of
pH
e. None of the above
Lipid solubility of drugs
a. More of the weak acid drug will be in the lipid soluble
form at alkaline pH
b. More of the weak acid will be in the lipid soluble form at
acid pH
c. More of the weak base will be in the lipid soluble form at
alkaline pH
d. A & C
e. B & C
Driving force for passive flux of molecules down a
concentration gradient
a. Area/thickness
b. Difference in concentration
c. Permeability coefficient
d. Thickness
Which of the following statement is true?
a. Weak acids are usually excreted slower in alkaline urine
b. Weak bases are usually excreted faster in acidic urine
c. Both are True
d. Both are False
Drug-Receptor Interaction
Drug-Ligand
Receptor-Substrate
A macromolecular component of the organism that interacts
with the drug.
 CLARK ARIENS & STEPHENSON PATON
Occupancy Theory Modified Occupancy Rate Theory
Theory
Maximum response Occupancy + Intrinsic Response
when all drug occupied activity proportional to
total number of
encounters of the
drug with the
receptor per unit
time
1. Agonist
 Mimics effect of endogenous ligand
 AFFINITY (?) + INTRINSIC ACTIVITY (?)
2. Antagonist
 Does not mimic endogenous ligand
 Receptor antagonist
 Competitive
 Noncompetitive

 Physiologic antagonist
 Chemical antagonist
Bind to receptor but do not activate it
REVERSIBLE RECEPTOR ANTAGONIST

Extracellular Unbound Endogenous Activator (Agonist) of Receptor

Compartment

Cell Membrane
Inactive Cell Surface Receptor

Intracellular
Compartment
REVERSIBLE RECEPTOR ANTAGONIST

Extracellular Bound Endogenous Activator (Agonist) of Receptor

Compartment

Cell Membrane
Active Cell Surface Receptor

Intracellular
Compartment

Cellular Response
REVERSIBLE RECEPTOR ANTAGONIST
Displaced Endogenous Activator (Agonist) of Receptor

Extracellular
Compartment Bound Antagonist of Receptor (Drug)

Cell Membrane

Inactive Cell Surface Receptor Upon being Bound

Intracellular
Compartment
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Displaced Endogenous Activator (Agonist) of Receptor

Extracellular Bound Antagonist of Receptor

Compartment

Cell Membrane

Active Receptor Inactive Receptor

Intracellular
Compartment

Allosteric Inhibitor
Clinical Use:
Some important examples:

• Angiotensin Receptor Blockers (ARBs) for high blood pressure,

heart failure, chronic renal insufficiency
(losartan [Cozaar®]; valsartan [Diovan®])

• Beta-Adrenoceptor Blockers for angina, myocardial infarction,

heart failure, high blood pressure, performance anxiety
(propranolol [Inderal®]; atenolol [Tenormin®])
Clinical Use:
Some important examples:

• Mineralocorticoid Receptor Antagonists for edema due to

liver cirrhosis and for heart failure
(spironolactone [Aldactone®])

• Estrogen Receptor Antagonists for the prevention and

treatment of breast cancer (tamoxifen [Nolvadex®])
Produce effects opposite that of agonist by binding to a
different receptor
Does not use a receptor
Binds to and inactivates a drug
Drug showing both agonist and antagonist activities
Low Concentration – Agonist
High Concentration - Antagonist
Receptor have active and inactive forms
Shifts the equilibrium toward the inactive form reducing
INTRINSIC ACTIVITY
1. Transmembrane ion channels
2. G- protein linked receptors
3. Kinase linked receptors
4. Intracellular hormone receptors
5. Other mechanisms
 Cell membrane ion pumps
 Enzymes
 Classes of transmembrane ion channel
Two distinct properties of ion channels:
(1) ion selectivity - type of ions which can pass
(2) gating - conditions which influence opening and closing

voltage- ligand-gated stress-

gated activated
extracellular intracellular

+++ +++ out

--- --- in
closed

open

+ + out

- - in

 membrane potential molecule binds to channel mechanical

 Potency (P)
 Dose that produce 50% efficacy (E50)

 Efficacy (E)
 Maximum achievable response
 Ceiling effect

 Ceiling dose
 Minimum dose that produces efficacy

 Steep slope
 Small increase in dose produces a large change in response
 Median Effective dose (ED50)
 Dose producing beneficial effects in 50% of test population

 Median Toxic dose (TD50)

 Dose producing toxic effects in 50% of the test population

 Median Lethal Dose (LD50)

 Dose producing DEATH in 50% of test population
 SOME IMPORTANT TERMINOLOGIES

Measure of drug safety

Therapeutic index = Toxic Dose
Effective Dose
Definition: Therapeutic Index
a. ED50/LD50
b. Potency/selectivity
c. EC50/LD50
d. TD50/ED50
e. ED50