PCOL 350.6

1.  Study of the changes produced in living animals by chemical substances, especially the actions of drugs, used to treat disease.

2.  Branch of medicine that deals with the interaction of drugs with the systems and processes of living animals, in particular, the mechanisms of drug action as well as the therapeutic and other uses of the drug

Pharmakon, meaning magic charm for treating disease.  Over time, this Greek word has come to me a remedy or drug.

Any chemical agent that affects living processes.

1.  Chemical substance that affects the processes of the mind or body.

2.  Chemical compound used in diagnosis, treatment, or prevention of disease or other abnormal condition.

3.  Substance used recreationally for its effects on the CNS, such as a narcotic.

• 1.  Proprietary (brand) name (one or more)
• 2.  Nonproprietary (generic) name
• 3.  Pre-market manufacturer code
• 4.  Chemical name

Pharmacokinetics and pharmacodynamics.  PK is what the body does to the drug (involves ADME).  PD is what the drug does to the body (involves receptor binding, signal transduction, and biological effects).

1.  Adverse effect: due to interactions or some unknown mechanisms.

2.  Side effect: generally a secondary effect, which may be beneficial OR harmful.

3.  Iatrogenic effect: adverse effect or complication caused by a physician (resulting from medical treatment or device).

• 1.  Enteral--oral, sublingual, rectal.
• 2.  Parenteral (route other than the digestive tract)--IV, IM, SC, intra-arterial, intrathecal, intraperitoneal.

The passage of drug from the site of administration into the general circulation (except for drugs that are applied directly to the target tissue--skin patches, for ex.)

IV injection results in immediate and complete (100%) absorption.

• Better absorbed: non-ionized, small, lipid-soluble
• Poorly absorbed: ionized, large

1.  Penicillin G, insulin, and other peptides: destroyed by stomach acid or digestive enzymes.

2.  Tetracyclines: chelated to components of food to form insoluble complexes.

3.  Aminoglycoside antibiotics (streptomycin, gentamycin: so polar they won't cross cell membranes.

4.  Nitroglycerin, adrenaline, dopamine: undergo extensive metabolism.

The pKa of a drug is the pH at which half of the drug is ionized.

Acidic drug: protonated (uncharged) form is better absorbed.

Basic drug: unprotonated (uncharged) form is better absorbed.

At steady state, an acidic drug would accumulate on the more basic side of a membrane and a basic drug would accumulate on the more acidic side of a membrane.

A mother's blood plasma has a pH of 7.4.  In this environment, the non-ionized form of a basic drug is preferred over the ionized form.  The non-ionized form of a drug can easily pass across cell membranes.  A basic drug could pass into fetal plasma (pH 7.0-7.2) or the breast milk.  These environments are slightly more acidic than the mother's plasma.  In a more acidic environment the ionized basic drug accumulates because it can no longer cross the membrane freely.

We can use our knowledge of ion trapping to save someone who has been poisoned by acidification or alkinatization of the urine.  To increase excretion of acidic drugs (phenobarbital, salicylates), IV sodium bicarbonate is given.  To increase excretion of basic drugs (amphetamine) NH₃Cl or ascorbic acid may be given.

Some drugs are ineffective when given orally because of metabolizing enzymes in the intestinal wall and/or the liver.  First, much of a drug taken orally is metabolized in the intestinal wall, decreasing the amount that reaches the portal circulation.  Then, more of the drug is metabolized in the liver, leaving very little or no drug left to reach the general circulation.

Solutions: increase the dose, change ROA.

Foods such as cheese and wine containe the sympathomimetic amine tyramine, which is normally metavolized by MAO in the GI wall and liver.

However, if a patient is taking a MAO inhibitor, tyramine will be absorbed and will reach the circulation and nerve terminals wher it will release NE.  NE stimulates adrenergic receptors causing tachycardia and high blood pressure.

Parkinson's.  By inhibiting MAO, we can increase neurotransmitter levels endogenously.  Patients with Parkinson's have a dopamine deficiency, so MAO inhibitors are a viable solution.

The fraction of an orally given drug that reaches the circulation.  Fractional indicates that bioavailability values are a number between 0 and 1.

albumin, a₁-acid glycoprotein (a globulin)

Generally this results in no change in the overall effect of a drug or its adverse effects.  However, drugs with a very small volume of distrubtion are a special case (ex. Warfarin, which is 97% bound to albumin).

minimal; significant--and potentially dangerous.

The reversible movement of a drug between body compartments.

• 1.  ionization
• 2.  capillary permeability
• 3.  blood flow
• 4.  plasma protein binding

Liver and spleen.

Drugs will leave these capillaries regardless of whether they are poorly lipid soluble, charged, or polar.

tight junctions.

-specific carrier-mediated transport systems.

-only lipophilic drugs diffuse across brain capillaries (unless other drugs are actively transported across).

Because it cannot cross the blood-brain barrier (dopamine is metabolized by enzymes in the BBB).

Injury: BBB does not work properly in areas of infection or injury.

Tumors: develop new blood vessels/capillaries that have no tight junctions.  Substances like radioactive iodine-labeled albumin penetrate normal brain tissue slowly, but can enter tumor tissue and aid in diagnosis.