Drugs and Drug Interactions

Drugs and drug interactions are central in health and treatment outcomes, even affecting patient safety. Knowledge of how different drugs interact with biological systems and interact with each other therefore becomes very important to appreciate the intricacies of the pharmacology discipline fully. Hence, drug-target interactions, especially mechanisms of action based on enzyme catalysis, become very important in determining the efficacy and safety of therapeutic regimens.

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This Story also Contains

1. Drug-Target Interactions
2. Type of Drug-Target Interaction
3. Antihistamines
4. Relevance and Application in Real Life
5. Some Solved Examples
6. Summary

Drug-Target Interactions

Drug-target interactions refer to specific modes of action of drugs with biological molecules, mainly enzymes, and receptors, in order to exhibit activities. One word: enzymes are proteins that catalyze biochemical reactions, so they are involved in drug metabolism. Being able to complex with an enzyme upon entering an organism, a drug can modify its activity. The result can be metabolic activation or inactivation of the drug or production of toxic metabolites. Other important classes of drugs targeting the active activity of enzymes include enzyme inhibitors. The inhibitors are further divided into two classes: competitive and non-competitive inhibitors. Competitive inhibitors bind to the active site of an enzyme, preventing substrates from binding to the active site of an enzyme. On the other hand, non-competitive inhibitors bind to another location on an enzyme, generally called an allosteric site, changing the form and role of that enzyme. Knowing how these interactions occur is important in being able to predict the efficacy and safety of drugs and in the development of new therapeutic agents.

Type of Drug-Target Interaction

It can be classified based on the mechanism and outcome of its interaction.

1. Enzyme inhibition:

When the drug reduces an enzyme's activity. Some antihistamines act this way, inhibiting certain enzymes that metabolize drugs, which increases their levels in the bloodstream, thereby increasing their response time in therapy but possibly resulting in toxicity when not monitored appropriately.

2. Enzyme Induction:

In contrast to inhibition, several drugs can induce the activity of enzymes involved in drug metabolism. In doing so, some drugs increase their own metabolism. This would decrease the drug's effect, which should therefore be compensated for by dosage adjustment. For example, the induction of cytochrome P450 enzymes by the antibiotic rifampin leads to interactions in the metabolism of a host of drugs.

3. Drug Absorption:

Antacids do this by altering the intragastric pH. This would have the following implications on the solubility of the co-administered drug and hence its absorption. For example, an antacid decreases the absorption of some antibiotics which could lead to suboptimal therapeutic responses.

Such interactions have to be understood so that health professionals may have appropriate and safe medication regimens for their patients.

Macromolecules of biological origin perform various functions in the body.

(1) Enzymes are proteins which perform the role of biological catalysts in the body
(2) Receptors are proteins that are crucial to the communication system in the body
(3) Carrier proteins carry polar molecules across the cell membrane.
(4) Nucleic acids have coded genetic information for the cell.
(5) Lipids and carbohydrates are structural parts of the cell membrane.

Catalytic Action of Enzymes

The first function of an enzyme is to hold the substrate for a chemical reaction. Active sites of enzymes hold the substrate molecule in a suitable position so that it can be attacked by the reagent effectively. Substrates bind to the active site of the enzyme through a variety of interactions such as ionic bonding, hydrogen bonding, van der Waals interaction or dipole-dipole interactions.

The second function of an enzyme is to provide functional groups that will attack the substrate and carry out the chemical reaction

Drug enzyme interaction:

Drugs inhibit any of the above-mentioned activities of enzymes. These can block the binding site of the enzyme and prevent the binding of substrate or can inhibit the catalytic activity of the enzyme. Such drugs are called enzyme inhibitors.

Drugs inhibit the attachment of substrate on the active site of enzymes in two different ways:

(1) Competitive inhibition

Competitive inhibitors compete with the natural substrates for their attachment to the active sites of enzymes

(2) Allosteric inhibition

Some drugs do not bind to the enzyme’s active site. These bind to a different site of the enzyme which is called allosteric site. This binding of inhibitor at the allosteric site changes the shape of the active site in such a way that the substrate cannot recognize it.

Antacids

Overproduction of acid in the stomach causes irritation and pain. In severe cases, ulcers are developed in the stomach. Until 1970, the only treatment for acidity was the administration of antacids, such as sodium hydrogen carbonate or a mixture of aluminum and magnesium hydroxide. However, excessive hydrogen carbonate can make the stomach alkaline and trigger the production of even more acid. Metal hydroxides are better alternatives because of are insoluble, these do not increase the pH above neutrality.

It is to be noted that these treatments control only symptoms and not the cause.

Antihistamines

A major breakthrough in the treatment of hyperacidity came through the discovery according to which a chemical, histamine, stimulates the secretion of pepsin and hydrochloric acid in the stomach.

Histamine has various functions. It is a potent vasodilator. It contracts the smooth muscles in the bronchi and gut and relaxes other muscles, such as those in the walls of fine blood vessels. Histamine is also responsible for the nasal congestion associated with the common cold and allergic response to pollen.

The structure of Histamine is given as

The drugs Cimetidine (Tegamet) and Ranitidine (Zantac) are used as anti-histamines. These prevent the interaction of Histamine with the receptors in the stomach wall.

Synthetic drugs, brompheniramine (Dimetapp) and terfenadine (Seldane), act as antihistamines. They interfere with the natural action of histamine by competing with histamine for binding sites of receptors where histamine exerts its effect.

Relevance and Application in Real Life

The relevance problem for drug-target interactions does not appear to be merely of theoretical origin; on the contrary, it carries very serious implications in the practical clinical and pharmacotherapy setting.

There are real-life cases in everyday practice when the clinical implications of drug interactions are very far-reaching. For example, if one is taking antihistamines due to allergies, drug interactions can probably be manifested by increasing the side effects, as in the case of antidepressants, or decreasing the efficiency of drugs through anticoagulants. This indeed suggests that good medication review and education are very important.

Also, antacids are widely used by patients with disorders in the gastrointestinal tract. Meanwhile, health professionals should keep in mind that such medications can impair the absorption of other medicines, including particular antifungals or cardiac drugs. Thus, the absorption of such a drug as ketoconazole may be sharply decreased in case of co-administration with antacids, thus exerting little or no action and, consequently, resulting in treatment failure.

Within the academic environment, in the case of students, it is impossible to do without knowledge about drug interaction in the process of training future medical professionals. Theoretical knowledge can be tried out in practice thanks to case studies and clinical simulations. Besides, research conducted within this field keeps the drug development process informed so that new medicines are developed having probable interactions in mind.

That makes pharmacology, medicine, and by extension of drug-target interactions the backbone of pharmacology and medicine. Such an explanation of how drugs interact with enzymes or any other compounds empowers the clinician to optimize treatment options for their patients in order to present them with optimal outcomes while minimizing side effects. Knowledge of these interactions is therefore of importance from clinical practice down to education. In fact, there is continuous research and training on this vital area of healthcare.

Some Solved Examples

Example 1

Question:
With respect to drug-enzyme interaction, identify the wrong statement.
1) Allosteric inhibitor competes with the enzyme's active site
2) Non-competitive inhibitor binds to the allosteric site
3) Competitive inhibitor binds to the enzyme's active site
4) Allosteric inhibitor changes the enzyme's active site

Solution:
The incorrect statement is:
1) Allosteric inhibitor competes with the enzyme's active site
This is incorrect because allosteric inhibitors bind to an allosteric site, not the active site. Therefore, the correct option is (1).

Example 2

Question:
The correct match between Item I and Item II is:

Item I
(A) Allosteric effect
(B) Competitive inhibitor
(C) Receptor
(D) Poison

Item II
(P) Molecule binding to the active site of an enzyme
(Q) Molecule crucial for communication in the body
(R) Molecule binding to a site other than the active site of an enzyme
(S) Molecule binding to the enzyme covalently

1) $(\mathrm{A}) \rightarrow(\mathrm{P}) ;(\mathrm{B}) \rightarrow(\mathrm{R}) ;(\mathrm{C}) \rightarrow(\mathrm{Q}) ;(\mathrm{D}) \rightarrow(\mathrm{S})$
2) $(\mathrm{A}) \rightarrow(\mathrm{R})$; (B) $\rightarrow$ (P); (C) $\rightarrow$ (S); (D) $\rightarrow$ (Q)
3) $(\mathrm{A}) \rightarrow(\mathrm{R})$; (B) $\rightarrow(\mathrm{P})$; (C) $\rightarrow(\mathrm{Q})$; (D) $\rightarrow$ (S)
4) $(\mathrm{A}) \rightarrow(\mathrm{P})$; (B) $\rightarrow$ (R); (C) $\rightarrow$ (S); (D) $\rightarrow$ (Q)

Solution:
The correct matching is:

$$
(\mathrm{A}) \rightarrow(\mathrm{R}) ;(\mathrm{B}) \rightarrow(\mathrm{P}) ;(\mathrm{C}) \rightarrow(\mathrm{Q}) ;(\mathrm{D}) \rightarrow(\mathrm{S})
$$

Therefore, option (3) is correct.

Example 3

Question:
The ability of a non-competitive inhibitor to bind to an active site in an allosterically controlled enzyme is ______ than the ability of a competitive inhibitor to bind to an active site in the same allosterically controlled enzyme.
1) Greater
2) Lesser
3) Approximately equal
4) Half

Solution:
The ability of a non-competitive inhibitor to bind to an active site in an allosterically controlled enzyme is lesser than the ability of a competitive inhibitor to bind to an active site in the same allosterically controlled enzyme. Hence, the answer is option (2).

Example 4

Question:
In the allosteric inhibition, the inhibitor
1) Competes for an allosteric site
2) Competes for an active site
3) Binds to the allosteric site without competing
4) Has no effect on inhibition

Solution:
In allosteric inhibition, the inhibitor binds to the allosteric site without competing for the active site. Hence, the answer is option (3).

Example 5

Question:
The effect of a reversible competitive inhibitor can be nullified by
1) Increasing the product concentration
2) Increasing the substrate concentration
3) Increasing the temperature
4) None of these

Solution:
The effect of a reversible competitive inhibitor can be nullified by increasing the substrate concentration. Hence, the answer is option (2).

Summary

The structure of drug-target interactions was discussed briefly and the module focused on catalysis by enzymes and how antacids and antihistamines work. Several concepts which are key to the way drugs interact, thus the inhibition or induction of enzymes, and the clinical implications of these have been covered in this module. Health professionals need to be well-informed about the nature of such interactions as they have a significant impact on both medication effectiveness and patient safety.