Home > Uncategorized > A Collection of All Pharmecutical Lectures

A Collection of All Pharmecutical Lectures

Lecture 1

Overview

Our pharmacology course began on the 25th of June.  I detailed the courses available in an earlier post.  It takes literally 1 minute to sign up:

http://wnthinktank.wordpress.com/2012/04/18/some-free-courseware/

They didn’t give an opening email.  I’m going to post the link to the first video of the first class.  It may not work for you if you are not logged in.  This costs 24 minutes but is free otherwise.  The video is a bit buggy.  This is the first lecture, not the introduction which I have skipped because its business as usual by now:

https://class.coursera.org/pharm101-2012-001/lecture/view?lecture_id=2

A quiz is due by July 2nd.  Quiz 1 is VERY brief, it is two questions long.  It is my personal goal to get 100% on everything and to crush all the Indians, Africans, and Chinese who are watching.  I don’t mind if a white man beats me.

Details

A drug is a chemical entity that affects living protoplasm.  Medicine is a chemical entity used to treat, cure, or prevent a disease.

CO Clinical Outcome

PD Pharmacodynamics and Drug Response

PK Pharmacokinetics

FA Molecular and Cellular Functional Assays

GN Genotype

Pre clinical testing of drugs takes 18 month: discovery, synthesis and purification, animal testing.  Then clinical R and D: phases 1 through 3.  Then NDA review, Then post marketing surveillance.

4 billion prescriptions in the US in 2011.

Pharmacodynamics describes a drug’s effect on the body – drug on the body.

Pharmacokinetics describes how the body acts on drugs  – body to the drug

PK: administration, absorption, distribution, metabolism,  excretion

PD: dose -response, receptor  activation

She then follows a drug as it is administered.  It enters general circulation where it begins to act and to break down.  It must reach the proper tissue to act.

Lecture 3

Overview

Our second lecture opened up on July 2nd.  There is a quiz that is only 3 questions long, but you get 3 attempts.  Try to get 100%.

This lecture is 31 minutes long and is on methods of drug administration.  It appears that this class will cost a half hour every week, which is very reasonable.

https://class.coursera.org/pharm101-2012-001/lecture/view?lecture_id=3

Details

Routes of Administration

Entral (Mouth)- Oral, rectal, sublingual

Parenteral – IV, IM, Sub Q

Other – Transdermal, Topical, Inhalation, Intranasal

Oral Administration

Advantages:

Easy to use, outpatient care, lower cost

Disadvantages:

Most complicated path, most variable response, effect of food in the stomach, effect of gastric pH, first pass effect, biotransformation in the liver/GI tract.

First Pass Effect

Oral administration into the GI tract.  This goes into the portal vein into the liver to the vena cava. There is much loss in this pathway.   Rectal administration goes right to the vena cava.

Dose is swallowed.  Some goes to feces.  Some is absorbed from the lumen of the GI tract into the GI endothelial cells.  Then into the portal vein.  Then into the liver, losing some as metabolism.  The rest into the vena cava to be circulated.

Rectal Administration

Advantages:

Relative ease of use, outpatient care, low cost, no pH, no food effect,

Disadvantages:

Complicated path, variable response, first pass effect, some of the administrated drug will be subject to biotransformation in the liber.

Most of the drug  goes through the submucosal membrane into the vena cava.  Some travels proximally where it goes through the usual route, experiencing the first pass effect.

Sublingual Administration

Advantages:

Ease of use, outpatient, rapid onset, bypass stomach and intestine, no first pass effect

Disadvantages:

Expensive, taste, limited availability, few formulations

This is like nitroglycerin used for angina.

Parenteral Administration – IV

Advantages: bypass stomach/intestine, no first pass, control of dosage, rapid onset

Disadvantages: invasive, pain, infection, expensive, unintentional overdosing, inpatient, supervised care

Intramuscular Administration

Advantages:

bypass first pass effect

For aqueous solution: fast onset,

For non-aqueous:

depot preparation, slow sustained response, used in neuroleptics/contraceptives

Disadvantages:

invasive, expensive, absorption, supervised.

Say we’d like a drug to last 9 months.  Use a non aqueous depot solution.  Quite painful.  Often at the buttocks, the site of delivery needs a good blood supply.

Subcutaneous Administration

Heprin is an example of this

The advantages and disadvantages are the same as above, the intramuscular case.

Transdermal Administration

This is applied to skin, wait for systematic absorption for effect.  It will bypass first pass effect, improve compliance, lipid solubility will determine absorption.  Examples include:

antihypertensive – clonidine

analgesic  – lidocain

antiemetic  – scopoloamine

smoking cessation/contraceptives/anti-anginal

Topical Drug Delivery

Apply directly to site of wanted action.  A dictim of dermatology is that if a condition is wet, dry it.  If overdry, wet it.

Intraoccular – artificial tears

Intrathecal/epidural – used in oncology drugs for cancer, spinal anesthesia

The natural progression is from topical to targeted drug delivery.  This would minimize side effects and toxicology.

Other Modes of Administration

Inhalation – Rapid delivery over large surface area.  Lung parenchyma is permeable to peptides.  There is lower metabolism in the lung tissue.  Molecular size can be a problem.  The bigger the molecule, the harder it is to transport.   Found in anesthetic gases, asthma drugs, insulin for diabetes, hugging, smoking pot/crack, nicotine

Intranasal – peptides, vasopressin, vaccines, inhaled insulin

The first pass effect refers to how the amount of a drug can be reduced by metabolism before it reaches the systemic circulation.

Intranasal goes through an intense sniff.  This leads to direct absorption across nasal passages.  The cribiform fascia at the top of the nose is thought to allow drugs to cross the brain-blood barrier.  This would allow a drug to enter the brain fluid circulation.

Contrast intranasal with inhalation.  There is a rapid inhalation of breath, providing access to trachia, bronchi and the lungs.

IV administration always allows for a rapid onset of action, IM administration is only rapid if the medication is an aqueous solution.  Non-aqueous medications administered IM allow for a slow and sustained response

Both sublingual and intravenous administration allow drugs to directly enter the systemic circulation while oral and rectal administration require a first pass through the liver.  Rectal administration only creates a partial first pass effect due to the dual blood supply of the rectum.

Review

PV = nRT

Work = Force x Distance

PE = U = mgh

KE = K = 0.5mv2

Momentum = mv

Lecture 3

Overview

The usual, mates.  This class costs 30 minutes plus a brief quiz per week.  The new lectures are released on mondays.  This week covers absorption.  Also, there is a quiz!  This quiz is 10 questions long and you get 3 attempts.  Please get 100%.  To assist you, I have left a guide at the end of this post.  Use it if necessary.

https://class.coursera.org/pharm101-2012-001/lecture/index

Details

We are still in pharmokinetics.  The transfer of a drug from the site of administration to systemic circulation.

For IV administration, absorption is complete: 100% of the drug reaches circulation and is bioavailable.

For all other routes of administration, absorption is variable and bioavailability is variable.

Most drugs are given by mouth.

Factors Affecting GI absorpiton

Blood Supply

Intestine >>> Stomach

Presence of fodd in the stomach

Food slows absorption.  WIth fozumax, food dramatically affects absorption.

Presense of other meds in stomach

Competition, one drug might bind another and prevent absorbtion.

Level of metabolism in the enterocyte

Disease states

Hypovolemic states reduce GI blood supply.  Prior GI surgeries reduce surface area for absorption.

Permeation principles

pH effects

Absorption and Permeation Principles – Fick’s Law

This is passive diffusion.  Molecules move from high to low concentration.  Pushes through a membrane.   Passes through the aqueous channel.

Aqueous Diffusion – Henerson Hasselhoff Principle

lipid diffusion

A molecule passing through the lipid bilayer.  The molecule is lipid soluble and the capacity to move across.

Special carrier mechanism

This is uniport/symport and so on.  From the lumen of the GI tract intot he portal circulation.

Endocytosis/exo

Endocytosis is taking into the cell.  Exocytos is pushing the drug out.

GI Absorption – Passive Diffusion

Concentration gradient across the cell membrane

Rate of flow increases linearly with concentration

High to low concentration, as per Fick’s Law.

Not Saturable

Water soluble drugs penetrat the cell membrane though aqueous channels.  Increases molecular size slows absorption.

Lipid soluble drugs pass through the membranes.  Size is no issue, but charge is.

GI Absorption – Lipid Diffusion

Many drugs are weak bases or acids.

Electrostatic charg of an ionized molecule attracts water and results ina relativley water soluble/lipid insolbule complex

Unchaged molecules are more easily absorbed.

For weak acids the HA can permeate the lipid membrane but A- cannot.

For weak bases, B can permeate but BH+ cannot.

The less charged, the more predictable

The ratio of charged to uncharged molecules can be calculated.

HKBA

pH = pK + log base/acid

This will tell you what proportion of the drug will be its unchaged state at any pH.  This will reveal drug absorption.  This determines where absorption occurs in the GIT.

Weak acids in the stomach, weak bases in the intestine.

This is important for patients on drugs that alter gastric pH like antacity, PPI (proton pump inhibitor) , H2 blockers.

pH Variation along the GIT

Stomach 1-3

Duodenum/Jejunum  5-7

Illeum  7-8

Specific carrier mechanisms are saturable.  Carrier mediated with specific protein carriers.  Energy dependent processes using ATP.  Can move drugs against a concentration gradient.  Rate of flow is a function of concentration until saturation.

For passive transport, rate of flux varies linearly with concentration.  For carrier mediated transport, it is assymotitic.

Bioavailability is the fraction of the adminstered drug reaching the systemic circulation in unchanged form.

Bioavailability = Oral dosage/Systemic circulation

You can also compare plasma level after oral admin verus plasma level after IV admin.

Bioavailabiltity = AUC oral/AUC injected x 100

Graph plasma concentration versus time.  AUC is the area under the curve.

Bioavailabiltiy is affected by anything affecting absorption – chemistry, carrier, solubility.  Does it experience the first pass effect?  A drug absorped into the portal circulation from GIT and brought to the liver.  If metabolized in the liver, the amount of unchanged drug that gets into systemic circulation decreases.

Route               Bioavailability       Characteristics

IV                                       100              most rapid

IM                                     87            large volume, painful

SubQ                           87             painful, smaller volumes than IM

Oral (PO)                 5-100               convenient, 1st pass

Rectal (PR)          30 – 100                less 1st pass

Inhalation       5 – 100                   rapid

Transdermal     90              slow, no 1st pass, prolonged

Bioavailability is not physiological effect.

Review

pH = – log [H+]

cation is positive, anion is negative

OIL RIG oxidation is loss, reduction is gain

Evolution: selection drift mutation migration inbreeding

Absorption: Weak acids in the stomach, weak bases in the intestine.

hydrogen helium

lithium beryllium boron carbon nitrogen oxygen fluorine neon

sodium magnesium aluminum silicon phosphorus sulfur chlorine argon

potassium calcium scandium vanadium titanium chrominm iron cobalt nickel copper zinc gallium germanium iodine krypton

Quiz Questions and Answers:

Question 1

A hospitalized patient with diarrheal disease is prescribed an antibiotic.  After administration, 60% of the administered dose is detected in the blood stream.  Which of the following statements cannot be true?
Your Answer   Score Explanation
The drug was administered intravenously Correct 1.00 Correct: For IV administration, absorption is always 100%.  100% of the administered drug always reaches the systemic circulation.
Total   1.00 / 1.00  

Question 2

50mg of a drug is administered orally.  Over time 40mg of the drug is delivered unchanged into the systemic circulation.  What is the bioavailability of the drug?
Your Answer   Score Explanation
80% Correct 1.00 Correct: Bioavailability = (AUC oral/AUC injected) x 100%
Total   1.00 / 1.00  

Question 3

Both Drug A and Drug B are administered orally and are identical except for where along the GI tract they are absorbed.  Drug A is absorbed in the stomach while Drug B is absorbed in the small intestine.  What effect will this have on their relative bioavailability?
Your Answer   Score Explanation
Drug B will have a greater bioavailability than Drug A Correct 1.00 Correct: The small intestine has a better blood supply than the stomach; therefore, more of Drug B can be absorbed.
Total   1.00 / 1.00  

Question 4

A patient is hospitalized following gastric bypass surgery.  Before surgery 50mg of Drug X was required to reach a particular blood concentration while 75mg was required to reach the same blood concentration of Drug X after surgery. Which of the following is a possible explanation for this phenomenon?
Your Answer   Score Explanation
All of the above Correct 1.00 Correct: Decreased surface area for absorption, decreased blood flow, and competing medications can all decrease absorption.
Total   1.00 / 1.00  

Question 5

Which properties (characteristics) of drugs are best suited for aqueous passive diffusion?
Your Answer   Score Explanation
Small, charged molecules Correct 1.00 Correct: Small, charged molecules are able to pass between cells via small water-filled pores.
Total   1.00 / 1.00  

Question 6

Which properties of drugs are best suited for lipid diffusion?
Your Answer   Score Explanation
All uncharged molecules Correct 1.00 Correct: Drugs must be uncharged to effectively diffuse across cell membranes; however, size is less important.
Total   1.00 / 1.00  

Question 7

Which mode(s) of enterocyte permeability enable(s) drug molecules to travel from an area of low drug concentration to high drug concentration?
Your Answer   Score Explanation
Active transport and endocytosis/exocytosis Correct 1.00 Correct: Both active transport and endocytosis/exocytosis utilize specific receptor binding and can, therefore, move drug molecules against their concentration gradients.
Total   1.00 / 1.00  

Question 8

Which of the following statements regarding enterocyte permeability is false?
Your Answer   Score Explanation
Exocytosis/endocytosis is only utilized for the transport of small molecules Correct 1.00 Correct: Endocytosis/exocytosis allows very large molecules and cellular debris to be transferred between the intracellular and extracellular environment.
Total   1.00 / 1.00  

Question 9

Drug A is a weak acid that is mostly in its cationic, uncharged state at a pH of 2. Where along the GI tract is it most likely to be absorbed via lipid diffusion?
Your Answer   Score Explanation
The stomach Correct 1.00 Correct: Weak acids are best absorbed in the stomach where the pH usually between 1-3.
Total   1.00 / 1.00  

Question 10

A patient taking Drug A (a weak acid) from the previous question is also taking omeprazole, a proton pump inhibitor, which decreases acid production by the gastric mucosa. What effect might this have on the absorption of Drug A?
Your Answer   Score Explanation
It will decrease absorption of Drug A Correct 1.00 Correct: A proton pump inhibitor will raise the pH in the stomach causing less of weak acid Drug A to be in its uncharged, absorbable state.
Total   1.00 / 1.00

Lecture 4

Overview

This week is a 25 minute lecture on drug distribution.  As usual, this class demands 30 minutes of time per week.  Several new classes will be starting up next week, and we hope to cover them as well.

There is of course a quiz, where you get 3 attempts at 5 questions.  If you are of unmixed white ancestry, you may look below and find some assistance.

https://class.coursera.org/pharm101-2012-001/lecture/index

Details

Drugs are distributed from their point of entry to the target tissue.

Distribution is the process by which a drug reversibly leaves the blood stream and enter the interstitum/tissues.  Once the drug enters the body, it goes to one of the three compartments or becomes sequestered to a particular tissue.  Drugs do not disseminate equally into all body compartment and they distribute in unique ways.

She goes through a few models:

1) The body as a reservoir of blood.  Here the drug level quickly peaks and holds a level of concentration.

2) The body as a cylinder of blood connected to the extravascular volume (EV).  Here the drug level peaks then falls to a steady state concentration.

Capillary permeability works differently in different tissues.  In the endothelial cells of the liver, large fenestrations allow drugs to exchange freely between blood and interstitum in the liver.  In the brain, at tight junctions, two adjoining cells merge so that the cells are physically joined and form a continuous wall that prevents many substances from entering the brain.  To enter the brain, you need a charged drug, lipid soluble drugs or carrier mediated transport.

There are several different “tanks” in the body.  There are 3 compartments:

Plasma 4L

Interstitial Fluid 10L

Extracellular Volume 14L  Plasma + IF

Intracellular Volume 28L

Total Body Water 42L Plasma + IF + ICF

Tissues: Bone, adipose tissue, pregnancy, fetus.

Determinants

1) Blood flow to a given site

2) Capillary permeability (BBB vs Liver)

3) Degree of hydrophobicity/lipophobicity

4) Binding to plasma proteins (BPP) which sequester drugs in a non-diffusible form in the plasma

Permeation Principles: Aqueous Diffusion/Lipid Diffusion/Special Carrier Mechanisms

Binding to Plasma Proteins – sequester drugs in a non-diffusible form in the plasma

The Role of Plasma Proteins in Distribution

Many drugs can bind to plasma proteins.  The drug is inactive when bound and binding is usually reversible.

Plasma proteins have varying binding capacity.  One/several drug molecules for each plasma protein.  Albumin binds weak acids and hydrophobic drugs.

There is competition for binding sites.  High affinity drugs will displace low affinity drugs.

The Clinical Importance of Plasma Protein Binding

If a drug is displaced from its binding sites:

Vd is small then the concentration in plasma will be high with increased toxicity risk.

Vd is large, then displaced drug can distribute into other compartments and the toxicity risk is lower.

Clinically drug displacement from PP is a common cause of drug-drug interaction.

Remember the play between PP binding and Vd

Vd = volume of distribution.  This is the hypothetical volume of fluid into which a drug is disseminated and prior to elimination.

Vd = Bioavailable Dose/Concentration in Plasma at T=0

Typically expressed as liters normalized for body weight (L/kg).

If drug distributed throughout the total body water the Vd would be 42L/70kg or 0.6L/kg.

What Does the Volume of Distribution Mean?

Vd gives one a sense of where a drug goes in the body.

A large Vd of >0.6 L/kg implies that the drug is distributed throughout the body.

A small Vd of <0.04 L/kg imples that the drug is contain within the plasma.  This type of information allows determination of the dose required to achieve a therapeutic effect.

Distribution – Tying it together

1) Plasma compartment only (4L)

Large molecular weight drug binds to plasma proteins.  Too big to pass into the interstitial fluid or bound to PP therefore not free to do so.

2) Extracellular Fluid (ECF) (14L) = plasma (4L) + IF (10L)

Low molecular weight hydrophillic.  Can move through endothelial slit juntions into IF.  These drugs distribute into a larger volume of plasma + IF

3) Total Body Weight

If the drug has low molecular weight and is lipophillic it can move through cell membranes and move through slit junctions.  These drugs therefore distribute into a volume of plasma and IF and intracellular volume.

4) Tissues

Drugs bound to receptors or to carrier mechanism.  Drugs sequestered in bone or fat tissue.

Physical Volumes of Some Body Compartment In Which Drugs May Be Distributed

Compartment              Volume        Examples

Total Body Water          0.6 L/kg     Small water soluble, ethanol

Extracellular Water       0.2 L/kg      Larger water-soluble molecules, gentamicin

Blood                                   0.08 L          Strongly plasma protein bound molecules and very large molecules, heparin

Plasma                          0.04 L               Same as above

Fat                                  0.2 – 0.35 L/kg     Highly lipid soluble molecules, DDT

Bone                              0.07 L/kg             Certain ions, lead/fluorine

Quiz Help

Question 4 is very hard!  You must forget all about Drug Y and only consider Drug X.  Recall from above: “Vd is small then the concentration in plasma will be high with increased toxicity risk. ”

The other questions are fairly straightforward.

Feedback —  Quiz 4.1

You achieved a score of 5.00 out of 5.00

Question 1

Which of the following statements pertaining to the functionally distinct compartments of body water is true?
Your Answer   Score Explanation
Extracellular fluid is composed of both interstitial fluid and plasma Correct 1.00 “Correct: Total body water includes intracellular and extracellular fluid.  Extracellular fluid can be further subdivided into interstitial fluid and plasma.”
Total   1.00 / 1.00  

Question 2

Drug B is able to distribute into both the interstitial fluid and plasma.  For a 70kg male, what is the approximate volume of distribution of Drug B?
Your Answer   Score Explanation
0.20 L/kg Correct 1.00 “Correct: Vd is typically reported as L/kg.  The approximate volume of extracellular fluid is 14L so 14L/70kg = an approximate Vd of 0.20 L/kg.”
Total   1.00 / 1.00  

Question 3

Drug C is able gain entry to the cerebral circulation (to enter the brain).  Which of the following statements is true?
Your Answer   Score Explanation
Drug C is likely lipophilic Correct 1.00 “Correct: The blood brain barrier prevents many substances from reaching the brain.  To enter, drugs must be lipophilic or have transporters to provide active transport.”
Total   1.00 / 1.00  

Question 4

Drug X binds to albumin with low affinity.  A patient taking Drug X has a second drug, Drug Y, added to his regimen.  Drug Y has a high affinity for albumin.  Which of the following statements is true?
Your Answer   Score Explanation
The patient will have an increased risk of toxicity of Drug X if the volume of distribution for Drug X is small Correct 1.00 “Correct: Drug X will be displaced because Drug Y has a higher affinity for albumin.  If the Vd of Drug X is small, it has a higher likelihood of causing toxicity than if its Vd was large.”
Total   1.00 / 1.00  

Question 5

Drug Z is a large molecule, is positively charged, and has a high affinity for albumin.  In which body compartment is Drug Z most likely found?
Your Answer   Score Explanation
Plasma Correct 1.00 “Correct: Large, plasma protein-bound molecules usually remain sequestered in the plasma.”
Total   1.00 / 1.00
Review
Tissues: epithelial, connective, muscular, nervous
Bone: FLIR  flat irregular regular long
Brain: frontal, temporal, parietal, occipital

Lecture 5

Overview

Please read this disclosure before starting.  Whew!  Long lecture this week at 54 minutes.  This lecture is heavily front loaded, meaning most of the new stuff is in the beginning.  All lectures are front loaded but today it is especially true.  Pay alot of attention for the first 30 minutes.

https://class.coursera.org/pharm101-2012-001/lecture/index

Details

Model of Drug Disposition

Oral Dose to Drug to Free Drug.  Either Adipose tissue storage, receptor binding, lung, kidney, liver, or plasma protein bound drug.  Things end with expired volatile metabolites, stool or the urine.

The point is, drugs move around in the body.

Metabolism/Biotransformation

Mostly happens in the liver.  Done to inactivate the drug, by converting it into a more excretable form.  Most drugs need biotransformation to be excreted.  Some drugs are administered as inactive compounds called prodrugs requiring biotransformation to become active.  Some drugs are metabolized to active drugs while others are excreted unchanged.

The more polar, the more easily the drug can be excreted by the kidney.  Prilosec is a prodrug being converted into its active form.

Locations of Major Enzymes

Extrahepatic Microsomal Enzymes (oxidation, conjugation) – brain, lungs, skin, urethra, small intestine

Hepatic Microsomal Enzymes (oxidation, conjugation) – liver

Hepatic Non-Microsomal Enzymes (acetylation, sulfation, GSH, alcohol dehydrogenase, hydrolysis, ox/re) – Liver/stomach

Drug Metabolism: General Concepts

Can happen in 2 ways:

Phase 1 Metabolism occurs by oxidation involving the cytochrome P450 system (CYP). This turns the drug into a more excretable form.

Phase 2 Metabolism involves couples an endogenous substrate to a drug or its Phase 1 metabolite.  This involves conjugation or adding stuff to the drug.  Examples:

Acetyl group via acetylation,

Blucuronyl group via Glucuronidation

Methyl group via methylation

Sulfa group via sulphation

Addition of gluthione

Drug in.  Then either accumulation, phase 1/2 metabolism, or excretion.

Phase 1 Metabolism by Oxidation

The CYP system is composed of many families of heme containing isozymes are located in most cells but especially in the liver and intestine.

CO binds to the reduced heme of the isozyme and absorbs at 450 nm.

CYP is a major catalyst of drug and endogenous compound oxidations.

NADPH + H+ + O2 + Drug = NADP + H2O + Oxidized drug

The oxidized drug is more polar, more soluble in water and you’ll piss it out.

Cytochromes P 45o (CYP) Nomenclature

CYP2D6

2 = family number (>40% homology sequence)

D = sub family letter (55% homology sequence)

6 = addition number for individual isozymes, each has overlapping specificity

CYP Families

There are 12.  Most drug metabolizers are CYP 1,2,3 families.  CYP3A4 metabolizes many drugs.  CYP3A4 in the GIT cause poor oral bioavailability of drugs that substrate this enzyme.  Differences in CYP activity between people account for drug metabolism differences.

Often we don’t know the metabolic pathways of drugs we prescribe.

CYP3A4

Acticity increased/induced by: Rifampin, St Johns Wort.  This will increase the metabolism of drugs that depend on CYP 3A4 which leads to them having decreased efficacy.

Activity decreased by grapefruit juice.  Decreases the metabolism of drugs that depend upon CYP 3A4 leading to prolonged effect and toxicity.

Treatment with St John’s Wort is associated with a drop in cyclosporine (immunodepressent) values below the therapeutic range and acute transplant rejection.  A dance with Mephisto.

St John’s Wort increases Indinavir metabolism with a lower peak.  The AUC or Area Under Curve is halved by St John’s Wort.  This may increase an HIV patients CD4 count.

Grapefruit juice affects Felodipine levels by increase the peak and slowing the metabolism rate.

In inhibition of CYP 3A4 occurs locally in the GIT, not in the liver.

How does interference impact bioavailability?

A drug with high BA.  Oral.  10% removed by GIT.  10% by the liver.  100 mg – 10 – 9 = 81 mg or 81% bioavailability.

A drug with low BA.  Given with grape fruit juice.  10% from liver.  100 mg – 10 = 90 mg or 90% bioavailability, an 11% increase.

A drug with low BA due to hepatic metabolism.  Lose 20% from faeces.  Lose 25% from GIT.  Lose 75% from liver.  100 – 20 – 20 – 45 = 15%.

Above with grape fruit juice.  100 -20 – 0 – 75 = 20%, an increase of 33%.

A drug with low BA due to intestinal metabolism.  100 – 20 – 60 – 15 = 15%

Above with GFJ 100 – 20 -0-20 = 60%, an increase of 300%.

This occurs in statins used for cholesterol management.  They rely on CYP 3A4.  If you drink GFJ, you increase bioavailability and toxicity, leading to myopathy.

Polymorphisms in CYPs are responsible for major differences in drug metabolism: CYP 2D6 used in oncology, antipsychotics, beta blockers, analgesics.  The number of functional CYP 2D6 affects the metabolism of drugs.

Oh yes.  Race matters!

Frequency of CYP 2D6 Polymorphisms

Poor Metabolizers

Caucasians 8%

Afro Americans 6%

Gene Duplication

Saudi Arabia, Ethiopia, Spain, Zimbabwe, Germany, China

Consequences of Altered Drug Metabolism

Toxicity or Death.  Increased metabolism can lead to loss of efficacy.  Drug interactions can result in inhibition or induction.

Quiz Review

The quiz today is 5 questions.  Please get 100% and beat all the vibrants.

Question 1

Which of the following is an outcome of biotransformation?
Your Answer   Score Explanation
d. All of the above Correct 1.00 “Correct: All of the above answers are potential outcomes of biotransformation.”
Total   1.00 / 1.00  

Question 2

2. Which of the following is an example of phase I metabolism?
Your Answer   Score Explanation
A drug is oxidized Correct 1.00 “Correct: Phase I metabolism consists of oxidation carried out by the Cytochrome P-450 system.  All other answers are examples of phase II metabolism.”
Total   1.00 / 1.00  

Question 3

You are prescribing colchicine, metabolized by CYP3A4, to a patient also known to be taking St. John’s Wort for the treatment of depression. What will be a possible outcome if the patient is taking standard doses of both colchicine and St John’s Wort?
Your Answer   Score Explanation
The plasma concentration of colchicine may not reach a sufficient level to have the desired therapeutic effect Correct 1.00 “Correct: St. John’s Wort is a CYP3A4 inducer; therefore, greater enzyme activity may lead to a more rapid degradation of colchicine and blood levels may not reach the desired concentration.”
Total   1.00 / 1.00  

Question 4

You are treating a 56-year-old man who has heart disease and a high cholesterol level with atorvastatin, a statin drug. Atorvastatin is metabolized by CYP 3A4.  The patient tells you that he takes the drug at night as prescribed and that he uses grapefruit juice to swallow his pills. What may be a possible outcome if the patient is prescribed a standard dose of atorvastatin?
Your Answer   Score Explanation
d. The plasma drug concentration will be higher than expected because of decreased biotransformation in the GI tract. Correct 1.00  
Total   1.00 / 1.00  

Question 5

Following a root canal, an Ethiopian man is prescribed codeine for pain.  He returns to your office shortly after being discharged complaining that the medication is not controlling his pain.  Given your scientific knowledge, what is a possible explanation for this phenomenon?
Your Answer   Score Explanation
The man has a duplication of the gene encoding the CYP2D6 enzyme Correct 1.00 “Correct: While this patient could be addicted to pain killers, it is important to recognize that certain ethnic groups including Ethiopians have high frequencies of CYP gene polymorphisms which may effect how they metabolize certain drugs.  In this case, a duplication of CYP2D6 gene would increase his rate of codeine metabolism and decrease its efficacy.”
Total   1.00 / 1.00

Lecture 6

Overview

Arrrrr!  Pirate shirt today.  The usual – a 55 minute lecture on the dose response relationship.

The quiz is up now.  It was not up Monday.  It is only 4 questions and relatively easy.  You may find a hint or two below.  This quiz is due in two week on Monday, August 27th.

https://class.coursera.org/pharm101-2012-001/lecture/index

Details

Dose response consists of efficacy and toxicity

Dose response curves clarify the proper dose of a drug that produces the therapeutic effect while limiting sides.  To analyze the relationship, use math.

Drug + Receptor =(k1/k2) Drug Receptor Complex =(k3) Effect

Kd = equilibrium dissociation constant = amount of drug producing half the maximum binding.  Gives a sense of the receptor’s affinity

Kd = K2/K1

K3 = intrinsic activity of the drug bound receptor

K3 = 1 is an agonist, K3=0 is an antagonist, 0<k3

Potency is the concentration of the drug required to achieve a certain effect.

EC50 = drug producing half of the max effect

EC50 = Kd unless there are spare receptors

Efficacy is the magnitude of the drug’s action at the limit of its concentration, Emax.

Picture a graph, drug effect versus drug concentration.  At drug effect  = 50, concentration is EC50 or Kd.  There is a Emax which is the maximum drug concentration.

The greatest amount of change is seen in the first half.  Convert to log dose to % response.  Threshold dose is when you begin to see a response. Ceiling dose is the maximum response or E max.

Potency is distance on the horizontal, efficacy on the vertical axis.

Types of Dose Response CUrves

Graded

increasing dose, increasing response

Oxycodone, alcohol, common assessment for safety and efficacy.

Quantal

All or non dose response

% of dead rats given a dose of phenobarbital, effectiveness of an oral contraceptive.  Common assessment for safety.

Binding site and activity site – a drug agonist needs to bind both.

Oxycodone is an opiate receptor agonist. k3 = 1.  Agonist come on, and go off.  Dynamic relationship.

Drug antagonists bind to binding site but block the activity site.

Drug partial agonist binds the binding site but only a bit of the activity site.

Opiates depress respiration

She keeps using the term “health care providers.”  This must be a buzzword or something.

Antagonists will compete with agonists.  You can also give a partial agonist to try to module effects.

Burphenphine is a opiate receptor.  K3 = 0.7.

Review of Antagonism Types

CCNP

Competitive

…involves receptors, completely reversible with enough agonist.

Chemical

…more than one drug at a time.  One drug binds another or blocks its absorption.  Divalent or trivalent cations with tetracycline.

Noncompetitivie

…involves receptors and agonists that bind so tightly that there is no reverse reaction.

Physiologic

…when one drug does the opposite of another and works at a different receptor.

Therapeutic Index

TI = LD50/ED50

Quiz

Feedback —  Quiz 8.1

You have submitted this quiz on Tue 14 Aug 2012  8:45:56 AM PDT. You achieved a score of 4.00 out of 4.00.

Question 1

The concentration of drug required to achieve a certain effect is the:
Your Answer   Score Explanation
Potency Correct 1.00  
Total   1.00 / 1.00  

Question 2

The magnitude of a drug’s action at the limit of its concentration (Emax) is its:
Your Answer   Score Explanation
Efficacy Correct 1.00  
Total   1.00 / 1.00  

Question 3

The EC50 of Drug A is 50mg and the EC50 of Drug B is 75mg. Which drug is more potent?
Your Answer   Score Explanation
Drug A Correct 1.00  
Total   1.00 / 1.00  

Question 4

Which of the following is an example of a Quantal dose response curve?
Your Answer   Score Explanation
Effectiveness of an oral contraceptive agent Correct 1.00  
Total   1.00 / 1.00

Lecture 7

Overview

Ah, yet another new shirt!  Why on Earth does she want us to look down her shirt?  Today is a 46 minute lecture on drug action.  Once again, this lecture is front loaded, heavy in the beginning and lighter in the end.  It will be much easier to read these notes and listen that to just listen.

***Warning!  Your quiz this week is 9 questions due by August 20th.  Help is below.  For some reason, as of right now, the scoresheet is not recording the points.  Wait for other students to whine to the teacher, who will correct the error. Then take the quiz and get 100%.  A day or two wait should do it. ***

https://class.coursera.org/pharm101-2012-001/lecture/view?lecture_id=9

Details

Pharmacokinetics describes what happens to a drug when given to a patient; what the body does to the drug.

Pharmacodynamics describes the body’s response to a given drug; what the drug does to the body.

…this covers the drug concentration at a site of action to pharmacologic effect to clinical response then toxicity or effectiveness.

Pharmacokinetics           Pharmacodynamics

Administration                   Receptor Activation

Absorption                          Dose Response

Distribution                       Efficacy

Metabolism                          Toxicity

Excretion

Pharmacodynamic Principles

Drug + Receptor/Effector = DR complex = Effect

D+R = DR = Effector Molecule = Effect

D+R = DR = Activation of coupling molecule effector molecule = effect

Inhibition of Metabolism of an endogenous activator = increased activator action on effector muscle = increased effort

Type of Drug Receptor Interactions

A receptor is a protein that binds to a signal molecule and generates its own signal.

Receptors exist in the inactive (Ri) form and the activated (Ra) form.  Some remain in Ra even with no agonist binding, called constitutive activity.  AKA, a receptor is active with no agonist.

An agonist is a molecule that binds to a receptor and activates it.  If a drug saturates a receptor pool, binds to the Ra form and stabilizes it so that most stays in Ra, it is a full agonist.

It’s like dominos.  One hits another and a chain of reactions exist.

If a drug binds to Ra and stabilizes it so it stays Ra, the drug is a partial agonist.  It has low intrinsic activity.

If a drug has higher affinity for Ri and causes many receptors to stay in Ri, then the constitutive activity of the receptor is lost.  This is an inverse agonist.

Antagonists prevent activation of receptors by an agonist.

Drug – Receptor -Effect

Things that change or modulate this are agonists, competitive inhibitors, allosteric activators, and allosteric inhibitor.

Allosteric activators increase affinity for agonists, allosteric inhibitors decrease affinity for agonists.  We can use allosteric activtors to decrease toxicity and to increase efficacy.

General Concepts

Cells contain large arrays of receptors for hormones, neurotransmitter or sensory inputs.  Receptors are activated by an array of endogenous compounds.  More than a thousand different receptors have been IDed.  Most drugs operate through receptors.  Receptors mediate the actions of both agonists and antagonists.

Receptors determine dose response relationship as well as selectivity and mechanism.

Most receptors are proteins.  The best understood receptors are regulatory proteins.  Other receptors include enzymes, transport proteins and structural proteins.

Signaling Mechanisms

Agonist = Proxmial Intracellular Effect = Conduit

Types of Agonists: horomones, NT, sensotry stimuli, autocrine, paracrine, drugs

***The 5 Transmembrane Signaling Mechanisms***

Intracellular, Cytoplasm, Tyrosine, Ion, G Protein

ICTIG

1) Lipid soluble signal crosses PM and acts on intracellular receptor – steroids alter protein synthesis.  Takes 30 minutes to several hours.  Can last several days because of slow enzyme/protein turnover.

2) Signal binds on EC domain of receptor, activating enzyme of the cytoplasmic domain – cytokine receptors have EC and IC domains, forming dimers.  After activation, new mobile protein tyrosine kinase molecules (JAK) activate.  STAT dimers travel to the nucleus, regulating transcription.  GH, erythropoeitin, interferon

3) Signal binds to the EC domain, activating a tyrosine kinase.  Signal is a hormone or growth factor.  From monomer to dimer.  Insulin, cancer chemo.

4) Signal binds/regulates ion channel.  Ligand and voltage gated ion channels.  Open transmembrane aqueous ion channel and allow ion passage into cytoplasm.  Serotonin, AC, glutamate.

5) Signal binds cell surface receptor linked to effector enzyme by G protein.

Quiz

Feedback —  Quiz 7.1

You have submitted this quiz on Mon  6 Aug 2012 10:46:56 AM PDT. You achieved a score of 0.00 out of 9.00.

Question 1

Which of the following is an example of pharmacodynamics?
Your Answer   Score Explanation
Drug Efficacy Correct 1.00  
Total   1.00 / 1.00  

Question 2

A receptor that stays in the active confirmation (Ra) even in the absence of agonist binding is called:
Your Answer   Score Explanation
Constitutively active Correct 1.00  
Total   1.00 / 1.00  

Question 3

A molecule that has a higher affinity for the inactive confirmation of the Receptor (Ri) and stabilizes the Ri-D form is called a(n):
Your Answer   Score Explanation
Inverse agonist Correct 1.00  
Total   1.00 / 1.00  

Question 4

An allosteric inhibitor…
Your Answer   Score Explanation
Binds to a unique binding site on the receptor and decreases the response to agonist binding Correct 1.00  
Total   1.00 / 1.00  

Question 5

Which of the following statements is NOT true?
Your Answer   Score Explanation
Most receptors are made of a combination of carbohydrates and lipids Correct 1.00  
Total   1.00 / 1.00  

Question 6

Receptors determine the…
Your Answer   Score Explanation
All of the above Correct 1.00  
Total   1.00 / 1.00  

Question 7

Which of the following are examples of Second Messengers:
Your Answer   Score Explanation
d. Both A and C Correct 1.00  
Total   1.00 / 1.00  

Question 8

Which of the following is the mechanism of action of a steroid hormone?
Your Answer   Score Explanation
It crosses the plasma membrane and acts on an intracellular receptor, which ultimately alters the synthesis of a protein Correct 1.00  
Total   1.00 / 1.00  

Question 9

Which of the following transmembrane signaling mechanisms work by dimerization?
Your Answer   Score Explanation
Tyrosine Kinase receptors Correct 1.00  
Total   1.00 /

Lecture 8

Overview

Short lecture this week at 38 minutes.  She’s still wearing the pirate shirt, but the hair has changed.

I have heard that coursera intends to keep the courseware free but to charge for the certifications.  There are 8 questions in the quiz.  As usual, there is assistance below.  Please get 100%.

https://class.coursera.org/pharm101-2012-001/lecture/index

Details

Development of a New Drug

Drug Discovery, Pre Clinical, Clinical

Pre Clinical Testing, clinical R and D, NDA Review, Post Marketing Surveillance

Drug Discovery

Predictable.  Takes 1-5 years.  Highly regimented, planned, regulated, costly and time consuming.  Often done in academia.

Broad Search and Screen Clinical Serendipity – minoxidil/rogaine Design Based upon Structure of Natural Substance Molecular Knowledge of Receptor or Enzyme Endogenous Proteins Me-Too Approach

Approaches to Drug Discovery

Rational ID of Target

Screen assays for drug action

Proof of principle in model systems

Selection of lead compound

Selection for clinical development

Pre Clinical

Organ system specificity Safety Metabolism and PK in Animals Develop, purify and stabilize drug

Purpose of Pre Clinical Drug Development

1) Determine the safety margin between efficacious dose and toxic dose

MTD max tolerated dose

MED min effective dose

LD lethal dose

2) Define safe starting dose in man

1/10th to 1/100th of the animal no effect dose

3) Characterize the toxicity

ID organ systems at risk

Determine mechanisms

4) Evaluate PK Profile

AADME – administration, elimination…

Bioavailability

Gender differences, racial differences, disease states, drug interactions

6 Types of Animal Studies

Acute single dose toxicity

Sub acute toxicity

Chronic toxicity

Teratogenicity

Carcinogenicity

Mutagenicity

Acute Toxicity

Find:

No effect dose, MTD, LD

Using the intended route for administration

IV to find bioavailability from oral routes

2 species, 2 routes – rat and rabbit

Sub Acute Toxicity

2 species, one non-rodent, from 2 weeks to months

3 dose levels studies:

safe dose several multiples of projected human starting dose

dose causing minimal toxicity that is reversible

dose causing frank toxicity

Risk assessment and therapeutic index

Duration of treatment matches clinical use

clinical chemistry, hematology, histopathology,

Cohorts of Animals:

plasma, urine levels.  PK following single and repeated administration

Chronic Toxicity

Long term administration is intended.  Greater than 6 months.  2 species, one non-rodent, rabbit.  Same outcomes as sub acute.  Doesn’t have to be done by the time you start studying man.

PK profile, route of metabolism, AUC with activity, age, impaired renal function, gender, race, drug interaction

Others

24 month duration in animal equivalent to a lifetime

2 species, rabbit and rat

Mating behavior, parturition, progeny, birth defects, postnatal development

gross and histopathologic pathology

is the drug intended for long term use?

genetic stability and mutation in cells/bacteria

Limitations

Time consuming/expensive

Large numbers of animals

Ethical concerns

Extrapolation to toxicity and efficacy may not apply to man

Rare adverse effects may not show in animals

Quiz

Feedback —  Quiz 9.1

You have submitted this quiz on Mon 20 Aug 2012 10:41:00 AM PDT. You achieved a score of 8.00 out of 8.00.

Question 1

Approximately how long does drug development take?
Your Answer   Score Explanation
1 year Correct 1.00  
Total   1.00 / 1.00  

Question 2

Animal Testing is part of which stage in Drug Development:
Your Answer   Score Explanation
Pre-Clinical Testing Correct 1.00  
Total   1.00 / 1.00  

Question 3

True or False: Drug development ends when the drug is approved by the regulatory authority.
Your Answer   Score Explanation
False Correct 1.00  
Total   1.00 / 1.00  

Question 4

Which of the following is/are true regarding pre-clinical animal safety studies:
Your Answer   Score Explanation
e. B and C Correct 1.00  
Total   1.00 / 1.00  

Question 5

Which of the following is NOT a component of Sub acute toxicity testing?
Your Answer   Score Explanation
Determining the No Effect Dose, the Maximum Tolerated Dose, and the Lethal Dose Correct 1.00  
Total   1.00 / 1.00  

Question 6

Which of the following is NOT considered to be one of the goals of Pre-clinical drug development?
Your Answer   Score Explanation
To test off-label uses of the drug Correct 1.00  
Total   1.00 / 1.00  

Question 7

True or False: Chronic Toxicity animal studies must be completed before the drug can be studied in humans.
Your Answer   Score Explanation
False Correct 1.00  
Total   1.00 / 1.00  

Question 8

True or False: Animal studies usually bring to light all of the possible adverse effects of the drug being tested.
Your Answer   Score Explanation
False Correct 1.00  
Total   1.00 / 1.00

Lecture 1.1

Overview

Sea shells today!  I’m going to break up the last lecture into two parts; I will post part two notes tomorrow.  This first part comes from a 32 minute lecture.

https://class.coursera.org/pharm101-2012-001/lecture/view?lecture_id=13

There is one quiz due, 4 questions.  The usual – help is below.  It appears they changed an answer last week after I took the quiz at 100%, costing me one point.  I’m very sorry if you got the question wrong because of me.

Details

Drug development is a nightmare!  There is tremendous regulation.  It’s a miracle anything get done…

Drug development requires extensive planning, is heavily regulated, and is costly/time consuming.

Investigational New Drug = IND

Regulatory approval is needed before giving a new drug to a human for the first time or if there is a plan to study an already approved drug for a new purpose.

Layers of Oversight

A very complex process.  FDA, NIH, IRB, CRO, sponsor, investigator, research team are involved.

Phases of Clinical Drug Development

1 Safety and Tolerability

2 Dose Finding and Safety

3 Therapeutic Ratio and Safety

Submit NDA to FDA for approval

4 Post Marketing Surveillance

Factors to Consider

Background, hypothesis, endpoint, efficacy, safety, study population, controls, randomization, blinding conditions, statistical analysis, quality, data management, oversight

Primary Hypothesis

Phase 1 = xxx can be safely administered to man

Phase 2 = xxx dose dependently inhibits.

Phase 3 = As compared to yyy, xxx decreases mortality.

Hypothesis

Also IDs the response variable.  Lists secondary hypothesis and variable.  Continues to list safety and adverse effect profile throughout all phases.  Phase 2 and 3 start to see subgroups hypothesis.

Primary Endpoint

Phase 1

determine safety, PK, MTD (maximum tolerated dose)

Phase 2

determine the effect of multiple dosing regimines, MED (minimum effective dose)

Phase 3

determine the mortality rate in treated versus untreated patients

Assessments/Dependent Variables

Phase 1

safety parameters/PK (ADME)

Phase 2

safety, PD, surrogate markers

Phase 3

clinical endpoints, surrogate markers

Study Population/Eligibility Criteria

Phase 1

Age 18-40

Males and females with no childbearing potential

Healthy (n=10s), 10-20 studies

Pure population

No meds

Treatment of single doses, short multiple doses

Phase 2

Age 18-70

Males and females with no childbearing potential

Low risk population with n = 100 patients

Some essential concomitant meds

Short term multiple doses

Phase 3

Target population of 1000 patients

Risk level of disease

long term

Quiz

*** Important!  I got the last one wrong.  Something is screwy with that question.***

Feedback —  Quiz 10.1

You have submitted this quiz on Mon 27 Aug 2012  7:14:05 PM PDT. You achieved a score of 3.00 out of 4.00.

Question 1

After which phase of clinical drug development is a New Drug Application submitted to regulatory authorities for approval?
Your Answer   Score Explanation
Phase III Correct 1.00  
Total   1.00 / 1.00  

Question 2

Safety is a goal in which of the following phases of Drug Development:
Your Answer   Score Explanation
All of the above Correct 1.00  
Total   1.00 / 1.00  

Question 3

Which phase of clinical drug development is typically completed in a healthy population?
Your Answer   Score Explanation
Phase I Correct 1.00  
Total   1.00 / 1.00  

Question 4

In which of the following situations would the Data Safety Monitoring Board consider early termination of a clinical drug trial?
Your Answer   Score Explanation
If a serious adverse event occurred Incorrect 0.00  
Total    
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