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Unformatted text preview: TA: Amir Motamedi
Email: [email protected] TA: Amir Motamedi
Email: [email protected] Slide 2|1:
Pharmacogenetics examines the effects of genetic factors to variations in the drug
I. Asian flush:
•Happens due to accumulation of acetaldehyde (toxic).
•Normally: Alcohol ----(Alcohol Dehydrogenase)---> Aldehyde --(Aldehyde Dehydrogenase) ---> carboxylic acid
•Three mutations can happen for enzymes involved in alcohol metabolism:
1. Alcohol Dehydrogenase mutation --> becomes Less active --> slow
conversion of EtOH to acetaldehyde --> accumulation of EtOH You fell drunk but not sick.
2. Alcohol Dehydrogenase mutation --> becomes more active --> rapid
conversion of EtOH to acetaldehyde --> accumulation of
3. Acetalaldehyde Dehydrogenase mutation – becomes less active-->
slow conversion of acetaldehyde to acetic acid --> accumulation of
acetaldehyde directly and accumulation of EtOH indirectly You
feel drunk and sick
II. Codeine resistance:
Not from lecture
•Codeine is weak pain killer.
•Morphine is strong pain killer.
•Normally: Codeine (precursor drug) ----( gets metabolized by P450 enzyme)
•Mutation can cause some people to have less active form of P450 enzyme -->
Less metabolism of codeine to morphine --> Codeine remains unchanged. TA: Amir Motamedi
Email: [email protected] Slide 3|1:
•Drugs are divided into three major groups.
Refer to the drug or procedure aimed to prevent disease.
Ex: vaccines and vitamins and supplements.
Refer to the drug or procedure aimed to relieve symptoms.
The vast majority of the drugs in the market belong to this group.
Ex: Drug that reduce high blood pressure. The drug relieve the
symptoms for a while but the symptoms comes back and more drug is
needed to be used.
Refer to a drug or procedure aimed to cure disease.
Ex: antibiotics, cancer drugs.
After the drug is used, the disease is cured and does not come back.
Relatively small number of drugs in the market belong to this group. Some drugs can be categorized in two different category.
Ex: Antihypertensive medication are both :
1. Prophylactic (prevent heart disease such as heart failure and stroke),
2. Palliative (reducing high blood pressure which is by itself a disease
that has been caused due to a number of factors). TA: Amir Motamedi
Email: [email protected] Slide 3|1:
Effective dose (ED50):
Effective dose is the concentration of drug at which 50% of the patients show a
Ex: ED50 is the dose by which 50% of the patients show drop in blood pressure.
This is not the dose by which blood pressure (effect) drop by 50%.
LD50 is the dose of drug by which 50% of the patient die.
Efficacy is the inherent capability of a drug to produce desirable effect.
Ex: different drugs have the same efficacy as long as they have the same effect (the
extent of the effect (relative effectiveness) is not presented by efficacy).
Codeine and morphine have same efficacy as pain killer.
Compare the relative effectiveness of drugs to produce desirable effects
Both Aspirin and Ibuprophine have the same efficacy as anti-inflammatory drugs
but we need more aspirin than Ibuprophine to reach the same desirable effect.
(Ibuprophine have higher potency).
Sample Question: compare efficacy and potency? Same efficacy, and lower potency for B TA: Amir Motamedi
Email: [email protected] Slide 5&6&7|1:
Also known as digitalis.
Used to treat heart failure (cardiac insufficiency).
Narrow therapeutic index.
Using a chemical which produced same symptoms as the dieses at high dose, can
cure the disease at low dose.
The remedy is extract from plants, animal and mineral.
The higher the dilution the more powerful the drug.
Isolation, purification and chemical characterization of the active compound:
1. Allowed administration of a controlled dose
2. Allowed administration of the active component of herbal mixtures to be given
Some extract have more than one active compound which dependant on their
nature can have good or toxic effect. EX: Castor bean contains castor oil ( has
therapeutic effect as laxative) and ricin (has toxic effect).
3. Allowed definition of mechanism of action, leading to synthesis of improved
Greater selectivity, Greater potency, Altered duration of action
Ex: morphine is used as a pain killer and an anti-diarrhea agent and cough
suppressant. Chemical modification of basic morphine structure allows to
separate these three function. Slide 8&9&10|1: TA: Amir Motamedi
Email: [email protected] Aspirin:
Salicin (active ingredient) --> salicylic acid (tough on stomach) --> acetyl
salicylic acid (A.K.A. Aspirin)
1. Sulfonamide : Sulfanilamide
2. Arsenic compounds : Arsephenamine= Salvarsan
New drug Discovery:
1. Analogues to existing drugs
2. Finding new application for existing drugs:
3. Drug screening:
4. Rational drug design
2. Thiazide diuretics
3. Sulfonylurea hypoglycemics
1. Anti- aggregatory --> Cardioprotective
2. Pain killer
3. Anti-inflammatory Slide 19&21&22|1: TA: Amir Motamedi
Email: [email protected] Testing for toxicities including:
Birth defect or malformation
Only related to the fetus
Cancer, and altering genetic information
3. Reproductive toxicity
Related to the reproductive system of parents. All medicines must have evidence of efficacy, except for:
1. Dietary supplements
2. Pure soap
Example of dietary supplements: Leptoprin contains,
synthetic adrenaline, band from dietary supplements,
increase metabolism (thus good for weight loss), however heart
rate and blood pressure goes up.
Diuretic, just temporary weight lost
Source of iodine --> increase production of thyroid hormone
--> increase basal metabolism.
However, this excess iodine which does not change the
Might potentially have weight loss effect Slide 24+sommary of few slides|1:
Establishing safety and efficacy: TA: Amir Motamedi
Email: [email protected] •Preclinical study is done in either cell line
or animal model. It is not performed in
human. The purpose is to establish a
pharmacological profile. (pharmacokinetics + toxicity)
•Phase 1 is performed in healthy human
with the intention of study (pharmacokinetics + toxicity)
Pharmacokinetics of drugs:
Disposition, metabolism, elimination of
Thus, helps to figure out dose and route
of administration of drug.
Both phase 2 and 3 are performed in
patients (human) with the intention of
Phase 3 focuses on placebo effect, and side
Type A: Predictable
Type B: Unpredictable
Phase 4: Post marketing Surveillance
Ongoing monitoring of drug safety
under actual conditions of use in large
numbers of patients. (Pharmacovigilance) Slide 24+sommary of few slides|1 : TA: Amir Motamedi
Email: [email protected] Sample Question: Which phases of the licensing process are aimed to establish the
efficacy of a new drug candidate in humans:
1. Preclinical studies
2. Phase I
Answer is C and D
3. Phase II
4. Phase III
5. Post-marketing surveillance
Sample Question: To which category do beta-1 receptor blockers as antihypertensive
Answer is A and C
4. None of the above
What was the goal of the Orphan Drug Act of 1983?
Answer: To promote the development of drugs that affect less than 200,000 people
in the US TA: Amir Motamedi
Email: [email protected] End Of Lecture 1 TA: Amir Motamedi
Email: [email protected] Slide 1-7|2: TA: Amir Motamedi
Email: [email protected] Oral Drug Administration:
1) Pills 2)Tablets 3)Sublingual Tablet 4)Coated Tablets (CT)
6) Matrix Tablets(MT)
Function of Coat:
1) Facilitate swallowing
2) Cover bad taste
3)Protect active ingredient (Main Function)
Orally administered drugs should pass the highly acidic
environment of stomach. Some active ingredient are
denatured in acidic environment, thus they need to be
Function of Matrix Tablets:
Extended or targeted (intestinal) release
Usually: (This is not a rule)
•The coating around entire
drug alters the location of
release of drug.
•The coating around the
particles (pellets) alters the
rate of release. Slide 8|2: Topical (Percutaneous) drugs: TA: Amir Motamedi
Email: [email protected] •Remember: Skin is composed of many layers of lipid bilayer (lipophilic
environment). Thus strongly passes lipophilic substances.
•Remember: Movement of molecules from one environment to another is a
1. Membrane permeability: In this case, skin is mostly permeable to
Lipophilic (hydrophobic) molecules.
Thus Lipophilic molecule gets absorbed readily.
Hydrophilic molecule are not absorbed readily.
2. Driving force: In this case, depends of the solubility of molecule in each
•The inside environment is always constant.
•We can only change outside environment to alter absorption.
Lipophilic molecule is more soluble in Lipophilic environment --> tend
to stay outside.
Lipophilic molecule is less soluble in hydrophilic environment --> does
not tend to stay outside. Slide 10-13|2: Topical (Percutaneous) Drug Administration:
1. Ointment and Lipophilic Cream
3. Lotion and Hydrophilic Cream
5. Transdermal Drug Delivery Systems =“Patches”
6. Eye Drops
7. Sterile; Isotonic; pH-neutral
8. Nose Drops/Nasal Sprays
9. Viscous Solutions
10. Pulmonary Formulations
•Liner - Protects the patch during storage. The
liner is removed prior to use.
•Drug - Drug solution in direct contact with
•Adhesive - Serves to adhere the components of
the patch together along with adhering the patch
to the skin
•Membrane - Controls the release of the drug
from the reservoir and multi-layer patches
•Backing - Protects the patch from the outer
environment TA: Amir Motamedi
Email: [email protected] TA: Amir Motamedi
Email: [email protected] Slide 14&15|2:
Parenteral Drug Administration:
Sterile: no live pathogen
Pyrogen free: no live or dead bacteria in the drug.
2. Single and Multi-dose Vials
3. Cartridge ampules
– 100% “Absorption”
– Drug enters general circulation without hepatic passage -->
No first-pass hepatic elimination
– Better bioavailability of hydrophilic drugs
•Intravenous (i.v.): Fastest (infusions; cardio-vascular drugs)
•Intramuscular (i.m.): Medium (anti-inflammatory; antibiotics)
•Subcutaneous (s.c.): Slowest (vaccines; insulin; depot contraceptives)
Note : all of the above result in 100% absorption, but the rate of
absorption of each on is different.
Sample Question: Which pharmacokinetic process is known as “First Pass Elimination”?
Answer: Drugs taken up in the intestine first reach the liver via the hepatic vein, and are therefore
subject to hepatic metabolism prior to entering the general circulation. Sample Question: What is bioavailability? Answer: Bioavailability is a measure of how much of an administered drug is absorbed into the
bloodstream, actually reaching the intended site of action in the body. (defined as percentage of the
drug that is detected in the systemic circulation after administration) Question: What is the route of insulin administration and why? Answer: Subcutaneous. This is because we want to have insulin released in the blood stream at
constant rate over a long period of time so it would keep the blood sugar at constant level. Slide 16&17&18|2: TA: Amir Motamedi
Email: [email protected] Overview of Pharmacokinetics:
•Route of administration:
Oral, Topical (including rectal and vaginal), Pulmonal (inhalation) , Parenteral (i.v., i.m., s.c., i.t.)
•Absorption and distribution:
No matter what the route of administration is, the absorbed drug ends up in the plasma (blood
Absorption and distribution requires passage through two barriers:
1. Epithelium: external absorption barrier in contact with outside environment.
Tightly connected to each other by Zonulae occludens (tight junction).
2. Endothelium: Internal blood tissue barrier. These are cells that line interior wall of
blood vessel. Drug can pass this barrier mostly in capillary bed.
Different permeability at different tissue, which provide the tissue with different
level of protection:
Following are very important
Cardiac muscle: high endo- and transcytotic activity
Endocrine glands, gut: Fenestrations with diaphragms. (passage of small molecules)
Liver: Large fenestration without diaphragms -> drugs exchange freely.
Why Large fenestration? Liver is main detoxifying organ in body which
requires toxic material to enter it for detoxification.
Disadvantage: liver is the least protected organ.
CNS, Placenta: Transcellular diffusion of drug of specific physicochemistry. Endothelia lack pores and little trans- cytotic activity
Advantage: Most protected organ
Disadvantage: Not all drugs targeted for the brain can pass the bloodbrain barrier. Slide 16&17&18|2: Overview of Pharmacokinetics (Cont.): TA: Amir Motamedi
Email: [email protected] •Metabolism:
Metabolism is a process through which drugs gets converted into a form so they can be
eliminated from body. (If the elimination is through urine, metabolism coverts drug into
Liver is principal site of drug metabolism.
Not all drugs need to get metabolized, meaning that some drugs can be eliminated from body in
there original form.
-Usually these drugs are expelled through milk, sweat glands, and expired air.
EX: lipophilic sex steroid through sweat gland and inhalation anesthetics diffuse out
of blood stream into air in lungs and gets expelled from body.
Note: Metabolites are the product of metabolism of the drug. (drug is no longer in original form).
Most prominent route of elimination:
(Kidney -->Urine) < (Gut --> Faeces) << (Breast& sweat glands -->Milk & sweat) ~ (Lungs
--> Expired air) TA: Amir Motamedi
Email: [email protected] Slide 16|2:
•Pathway of oral Administration of drug, also known as First Pass Effect: Intestinal metabolism absorption of drug through guts (Intestine) --> hepatic
portal system (blood stream which goes to liver) --> liver (site of drugs
metabolism) --> Three things might happen:
1. Drug cannot get metabolized (neither in liver nor in any other part of
body) and the original form of drug cannot be eliminated from body
(lipophilic drug, more on this later) --> drug keep circulating in the blood
stream and cannot be eliminated.
2. Metabolized drug or drug in original form gets released into blood stream
--> kidney --> Urine.
(default pathway of all orally absorbed drugs).
3. Entrohepatic circulation: Some of the Metabolites or drug in original
form gets incorporated into the bile (bile is made in the liver) --> bile is
released in the intestine by liver --> bile containing drug gets reabsorbed
in the intestine --> hepatic portal system... Question: Which route(s) of drug administration
lacks "First Pass Elimination"?
Answer: Any route in which abortion through
gut is not part of the pathway. Ex:
Percutaneous (including rectal and vaginal),
Parenteral (I.V., I.M., S.C.), Pulmonal
(inhalation). TA: Amir Motamedi
Email: [email protected] Slide 19|2:
Movement of drug through membrane:
1. Passive diffusion:
•Remember: Movement of molecules from one environment to another is a function of:
1. Membrane permeability: In this case, membrane is permeable to Lipophilic
(hydrophobic) molecules which means drugs in uncharged (unionized) form.
Majority of Drugs are weak acids and bases.
Blood has a slightly basic pH, and Urine has a slightly acidic pH.
Weak acids are uncharged in acidic (Low) pH --> membrane permeability.
They become charged (ionized) in basic (high) pH --> no permeability.
Weak bases are uncharged in basic pH --> membrane permeability.
They become charged in acidic pH --> no membrane permeability.
2. Driving force: In this case, depends of the concentration of molecule in each side of
The higher the difference between concentration molecule on each side of
membrane, the higher driving force towards the side with lower concentration
•Remember: The ionized and non-ionized form of one drug are not considered as the
same molecule. Once drug is ionized, the concentration of drug (non-ionized form) is
actually reduced. Case study: A drug that is weak base travels in blood in non-ionized form
and reaches kidney. Drug is:
1. High in concentration in blood & low in concentration in urine Driving force towards urine is high.
2. Non-ionized has lipid solubility (membrane permeability)
Due to 1 and 2 drug crosses the membrane into the urine (one might
think that steady state will reach after a while by increasing the
concentration of drug in the urine), however acidic environment of urine
ionizes the drug into a different molecule (ionized form of drug) the
concentration of drug on urine side still stay low driving force stays
high. Additionally, ionized drug on the urine side does not have
membrane permeability to cross over into the blood gets expelled Slide 19|2: TA: Amir Motamedi
Email: [email protected] Movement of drug through membrane (Cont):
Effect of broccoli on drug elimination:
•This is an example of Drug food interaction (more on this later):
•Broccoli increase pH of urine to alkaline (basic pH, 7-8).
•Case study: A weak basic drug reaches kidney and passes the membrane into urine
which now has a high pH. Thus, drug does not get ionized concentration of drug on
the urine side will increase (also the membrane is permeable to non-ionized form of drug
on the urine side) driving force keeps decreasing as the concentration of drug on urine
side increase Concentration of drug on urine side become equivalent to concentration
drug on blood side driving force =0 steady state reaches drug does not get
excreted into the urine (or excretion is very slow) drug elimination occurs very slowly half life of drug increase (more on half life later).
•Diet that is more on plant side than grain side cause urine to be more basic.
•Diet that is more on protein causes more acidification of urine.
•Metabolic syndrome can also change pH of urine.
3. Active transport: Drug uses transport mechanism that are in the body to transport some
molecule that are required by body.
Receptor mediated Endocytosis: drug binds a cell surface receptor and the complex of
drug and receptor gets internalized to form endosomal vesicle.
This mechanism is used to transport toxic molecule into the cell. It is used for cancer
therapy in the way that if there is a unique cell surface receptor on the surface of a
cancer cell, you make an antibody for the receptor and complex the antibody with a
toxic molecule. Thus antibody binds the receptor, and the complex gets internalized the toxic conjugated with the antibody will kill the cancer cell. TA: Amir Motamedi
Email: [email protected] Slide 21&23|2:
•Bioavailability is a measure of how much of an administered drug is absorbed into the
bloodstream, actually reaching the intended site of action in the body (functionally
available) = the AUC of the (orally) administered drug divided by the AUC of the
intravenously administered drug.
During administration, drug is being absorbed and eliminated at the same time.
Once administration is complete, the curve reaches its peak and starts dropping. At
this point drug is only being eliminated from body.
•Volume of distribution:
•Is not a real volume. It is a theoretical volume.
•Drugs have different affinity for proteins in the blood. Once drug binds the
plasma protein, it is no longer available to perform its activity.
•What we measure and mean by drug concentration of plasma is the concentration
of free drug in the plasma.
•Formula: Vd = Amount of drug administered [mg]/ plasma concentration of drug [mg/ml] •Example:
•A 70Kg patient has approximately 2.8L plasma volume available for drug.
If this person take 100mg of a drug:
If all drug stay in the plasma: plasma Concentration of drug is
Thus volume of distribution= 100mg / (100mg/2.8L) = 2.8L = 2.8L
If 90% of drug gets bound to plasma protein--> only 10% of drug in
plasma: Plasma concentration drug is 0.1(100mg)/2.8L
Thus volume of distribution = 100mg/ (0.1(100mg)/2.8L) = 28L
This is the same as saying we have 100mg of drug in 28L Remember: amount of binding of drug molecules to plasma protein alters half
life of drug. TA: Amir Motamedi
Email: [email protected] Slide 24& 25|2:
• Rate of elimination:
•Both filtration (kidney) and metabolism (liver) follow first-order kinetics meaning
that rate of elimination depends in plasma concentration of drug.
•There are only three drugs that have zero-order elimination (independent of
concentration drug in the plasma). •Clearance is the volume of plasma cleared of all drug per unit of time.
•Drug has a plasma concentration. The rate at which this concentration of drug is being
eliminated from body is considered as clearance. Slide 26&27|2: TA: Amir Motamedi
Email: [email protected] •Half life is the time required for the concentration of a drug to fall by 50%
•Only drug that follow first order kinetics have constant half life. •Remember: In order to calculate these values, we experimentally
measure Vd and half life.
•Steady state concentration is the plasma concentration of drug at which
amount of drug administered per time unit equals the amount eliminated per
•Remember: the way you administer the drug does not change the steady
•Remember: you cannot calculate Css at any time. You have to wait until
you reach steady state, then you measure infusion rate and clearance, and
then you calculate Css. TA: Amir Motamedi
Email: [email protected] Slide 28|2:
•In order for the drug to have an effect in the body, it need to reach a specific plasma
concentration. Loading dose is used to reach this specific concentration. •Once we reach desired drug concentration in the plasma, we need to maintain this
concentration to maintain the effect. Thus we use maintenance dose. •Possible effects of drug protein binding:
1. Drug with high protein binding stays in body for longer period of time --> longer half life.
2. Effects of drug-drug interaction:
•Drug A and B both bind to a protein. We first administer drug A which first bind two
this specific protein. Then we administer drug B, which wants to binds to protein, but it
cannot since the site of binding is occupied by drug A. Thus one or both of the following
Drug B reaches toxic concentration in plasma
II. Drug B is eliminated faster than expected because of having higher
concentration than what it is suppose to have.
3. Liver is site of albumin (plasma protein) synthesis. People with liver damage (or
malnutrition) have less production of albumin --> less binding of drug to albumin -->
higher concentration drug --> same effect that mentioned for drug B. Slide 33|2: TA: Amir Motamedi
Email: [email protected]
•Effective dose is the
concentration of drug at which
50% of the patients show a
•LD50 is the dose of drug by
which 50% of the patient die. End Of Lecture 2 ...
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This note was uploaded on 04/13/2010 for the course BIMM bimm 118 taught by Professor David during the Winter '09 term at UCSD.
- Winter '09