Nephrotoxicity

Because just about every kind of molecular species except highly plasma-protein-bound molecules will be forced into the kidney tubules through the cells lining the tubules and then possibly reabsorbed further down the line, drugs and poisons can become concentrated in the cells of the tubules during their passage. Many of these materials can be extremely toxic to the functioning of the active transport systems, carrier proteins and metabolic proteins in those cells. The end result is destruction of the kidney or nephrotoxicity. One such example is the herbicide paraquat. In large doses it is acutely toxic to the lungs. But in sublethal concentrations it can reduce its own elimination because it destroys the kidney secretory system. If it is not excreted effectively it will remain in the blood and attack the lungs. Paraquat has been used to spray illegal marijuana fields both within and outside of the U.S.

paraquat paraquat

V. THE ACTIONS AND EFFECTS OF DRUGS AND POISONS

Up to this point we have been discussing pharmacokinetics, that is, the way in which the body acts upon a drug. It is now time to begin a consideration of pharmacodynamics or how a drug acts upon the body. It should always be kept in mind that drugs do not "cure" diseases or conditions. They alleviate symptoms until the body can recover by compensating for a deficiency or excess. Sometimes the body cannot recover and medication must be given for the course of a lifetime. Poisons cause temporary or permanent damage to the body which can result in partial incompacitation or fatality. When considering how drugs and poisons "do their thing" one must be careful to discriminate between the action of the material in question and its effect.

A. Terms

1. Drug Action - The action of a drug or poison refers to its biochemical mechanism. How does it interact on a molecular level? A drug may interferewith membrane permeability, for example. Or it may be an enzyme inhibitor, hormone analogue and competitor, or DNA intercalator. Let us consider some specific drug actions.

Penicillin is an antibiotic which destroys bacteria by covalently bonding a transpeptidase enzyme which closes up the cell wall during its biosynthesis. This is its biochemical mechanism of action. See Figure 15.

Simple Mechanism Action Aspirin

a penicillin stable enzyme-penicillin complex a penicillin stable enzyme-penicillin complex

Figure 15

The Action of Penicillins

Acetylsalicyclic acid, aspirin, inhibits the cyclooxygenase-catalyzed first step in the biosynthesis of prostaglandins, prostacyclins and thromboxanes. These latter substances are responsible for the inflammatory and pyretic effects of infection. It is believed that the chemical inhibition reaction involves the acetylation of the enzyme by the aspirin.

A mode of action need not involve enzyme inhibition. It could be a simple physical action. Cholestyramine resins are used to form nonpolar aggregates with lipophilic substances. With this action they constitute a good antidote for pesticide poisoning and can serve as a prophylactic in tying up dietary lipids in the s/^CH —CH2—CH—CH2s/\^

intestine so that they will not contribute to atherosclerosis. The pesticides are stored in fat tissue. As the molecules of pesticide are sequestered into the cholestyramine resin more molecules will move from the fat depots in order to reestablish disturbed equilibria in the blood and other body fluids. The resin itself is not absorbed by the intestine but is excreted in the feces.

ill cholestyramine (Questran®)

CH2N(CH3)3CL +

2. Drug Effects

The effects of a drug or poison refer to the observable biological responses such as bacteria dying when the host is treated with penicillin, fever and inflammation subsiding after aspirin therapy or the reversal of toxicity due to pesticide poisoning after a cholestyramine antidote is given. A primary effect is what is sought by the drug discoverer (or poisoner). Secondary effects are side effects, not usually desirable. Sometimes the side effects can be serendipitous such as those seen with sulfinpyrazone in the previous section on gout. Aspirin, used for its analgesic effect, lengthens the time it takes for blood to clot. General anesthetics can cause vomiting.

Sometimes secondary effects can be used therapeutically. Antihistamines, for example, have as their primary effect the alleviation of an immune response. Secondarily, they cause drowsiness and reduce nausea associated with motion. Over-the-counter sleep aides and antinausea preparations contain antihistamines such as dimenhydrinate (Dramamine®), meclizine (Antivert®) and doxylamine (Unisom®).

B. Sites of Action

The sites of action for drugs and poisons generally are either extracellular, on or within a membrane, or intracellular. Extracellular refers to the GI tract before absorption and the blood stream. Extracellular drug activity may be purely physical such as the cholestyramine sequestration of lipophilic materials mentioned above. The action of laxatives can also be physical. Laxatives loosen the stool by absorbing large quantities of intestinal water and stimulating peristaltic action. Cellothyl® and Colgel® contain methylcellulose a good water absorbant. Metamucil® is psyllium from the Plantago seed. When mixed with an equal volume of water it forms a mucillaginous mass. Caphulac® and Normase® contain lactulose which is poorly absorbed in the intestines and becomes extensively hydrated there.

Extracellular events may also be chemical in nature. Recall that antacids work by the reaction of bicarbonate with stomach acid. See the ASIDE on antacids, laxatives and antidiarrheals.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

Get My Free Ebook


Post a comment