Ch.

6 Pharmacology

Altered Renal Excretion

Drugs can alter all three phases of renal excretion

- filtration
-reabsorption
-active secretion

One drug can alter the renal excretion of another. Glomerular filtration can be
decreased by drugs that reduce cardiac output, which in turn decreases renal blood
flow, and therefore decreases drug filtration at the glomerulus, decreasing the rate
of drug excretion.

By altering urinary pH, one drug can alter the ionization of another and thereby
increase or decrease the extent to which that drug undergoes passive tubular
reabsorption.

Competition between two drugs for active tubular secretion can decrease the renal
excretion of both agents.

Interactions involving P-Glycoprotein

PGP is a transmembrane protein that transports a wide variety of drugs out of cells,
including cells of the intestinal epithelium, BBB, liver, & kidneys. PGP is subject to
induction and inhibition by drugs, and can have the following impact on other drugs:

– Reduced absorption – by increasing drug export from cells of intestinal

epithelium into intestinal lumen
– Reduced fetal drug exposure – increasing drug export from placental cells to
maternal blood
– Reduced brain drug exposure – increasing drug export from cells of brain
capillaries into the blood
– Increased drug elimination – increasing drug export from liver into the bile
and from renal tubular cells into urine

** drugs that inhibit PGP will have the opposite effect

Pharmacodynamic interactions
May be potentiative or inhibitory

Occur in 2 types:

1) interactions in which the interacting drug act at same site

- almost always inhibitory. (inhibition occurs when an antagonist drug blocks
access of an agonist drug to its receptor.) some reduce therapeutic effects and
others reduce toxic effects.
2) interactions in which the interacting drugs act at separate sites.
- if both drugs influence the same physiologic process, then one drug can
alter responses produced by the other. May be potentiative or inhibitory

Combined toxicity
As a rule, drugs w/ overlapping toxicity are not used together. (unless it is inevitable
– as in tuberculosis w/ isoniazid and rifampin.)

Clinical significances of Drug-drug interactions

Interactions are especially important for drugs that have a low therapeutic index,
since a shift in increased or decreased drug levels can be detrimental.

Minimizing adverse drug-drug interactions

Best plan is to minimize the # of drugs a patient receives and to take a thorough
drug history. Be aware of the possibility of un reported illicit drugs or OTC’s.
- adjust the dosage if an inducer is added
- monitor for early signs of toxicity
- be vigilant when pt is taking drugs w/ low therapeutic index

Drug Food interactions

Impact on food on drug absorption

Decreased absorption
Food frequently DECREASES the rate of drug absorption, delaying the onset of
effects. Reducing the extent of absorption reduces the intensity of peak responses.

– Ca++ containing foods and tetracycline antibiotics: tetracyclines bind w/ ca+

+ to form an insoluble and nonabsorbable complex. There for absorption is
reduced and antibacterial effects may be lost.
– High fiber foods – can reduce absorption of some drugs (digoxin – cardiac
disorders) causes therapeutic failure

Increased Absorption
Food increases the extent of absorption. When this occurs, peak effects are
heightened. A high calorie meal more than doubles the absorption of saquinavir
(HIV drug). W/o food, absorption may be insufficient for antiviral activity.

GRAPEFRUIT – impact on drug metabolism

Grapefruit can inhibit the metabolism of certain drugs, raising their blood levels. It
does so by inhibiting metabolism, specifically CYP3A4, and isozyme of cytochrome
P450 found in liver and intestinal wall. Causes peak effect to intensify. Does not
affect drug metabolism after they are absorbed.

The more grapefruit juice a pt drinks, the more inhibition. Can vary from pt to pt.
Impact of food on drug toxicity
sometimes increases toxicity. If MAO inhibitor is combined w/ foods rich in tyramine
(aged cheese, yeast, chianti) BP can rise to life threatening level, so Pts must be
given list of foods to avoid.

– Theophilline (asthma med) plus caffeine – excessive CNS stim

– K+ sparing diuretics (eg. Spironalactone) plus salt substitutes, result in
dangerously high K+ levels.
– Aluminum containing antacids (Maalox) plus citrus beverages, result in
excessive absorption of aluminum

Impact of food on drug action

Most drug food interactions concern drug absorption, or drug metabolism, food may
also have a direct impact on drug action (as in food rich in Vit K (broccoli, cabbage)
reduce effects of warfarin since warfarin acts by inhibiting vitamin K dependent
clotting factors.

Timing of drug admin w/ respect to meals

Admin of drugs at the appropriate time w/ respet to meals is an important facet of

drug therapy. Some drugs can be significantly decreased by food, and opposite is
also true. So follow medication orders.

Drug herb interactions

Herbal supplements create potential for frequent and significant interactions w/

conventional drugs. Reliable interaction info is lacking.