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Summary of Pharmacology So Far

I thought it might be good for us to review what we’ve done so far.  I’ve collected all of the lectures up to now into one post, so it’s right up at the top.  Nothing new, just the old material refreshed and reheated.

Lecture 1

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 2

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.

Lecture 3

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 absorption

Blood Supply

Intestine >>> Stomach

Presence of food in the stomach

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

Precense of other meds in stomach

Competition, one drug might bind another and prevent absorption.

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 – Henderson 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 penetrate 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 charge of an ionized molecule attracts water and results in a relatively water soluble/lipid insoluble complex

uncharged 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 unchanged 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 absorbed 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.

Lecture 4

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 implies 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 junctions 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

Lecture 5

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.

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