D.1.4 Discuss the terms therapeutic window, tolerance and side-effects.

The Therapeutic Window is the ratio of the lethal dosage of a drug over its effective dose.
The Lethal Dose (LD-50) is the amount of the medicine that will kill 50% of the participants in the trial (animal trial stage).
The Effective Dose (ED-50) is the amount of the medicine that caused a positive therapeutic effect to 50% of the participants in the trial.

They are typically depicted by means of graphing.

external image 28FF1.jpeg

Therefore, it is extremely important for doctors to be aware of therapeutic window when prescribing medicines, since a small difference in amount of prescription might result in fatal consequences, especially for those medicines that have small therapeutic window. The smaller the therapeutic window, the higher the risk of overdosing.

Drug tolerance occurs when a patient’s reaction to a drug decreases due to psychological or physiological factors, and thus more dosage of the drug is required in order to have the same effect as before the tolerance occurred. Depending on the drug, tolerance can develop over the course of several days or more gradually over a number of weeks.

The two major mechanisms for tolerance:

  • Dispositional tolerance occurs because of a decreased quantity of the substance reaching the site it affects.
  • Reduced responsiveness is the response to the substance is decreased by cellular mechanisms.

Tachyphylaxis is the medical term referring to the rapid development of drug tolerance.

Tolerance is often related to drugs that affect your body's brain and nervous system. It can have positive result such as a reduction in unpleasant side effects due to the medication. However, as your body becomes tolerant to the medication, becomes less effective as before. Due to this, the administration of the medicine gets more dangerous, because a higher dosage is required to achieve the desired effect for a patient with high tolerance, which brings the dosage closer towards LD-50 and greatly increases the risk of overdose.

Examples of medications which tolerance is developed for:
  • painkillers such as Oxycontin (oxycodone)
  • tranquilizers such as Valium (Diazepam)
  • over-the-counter sleep aids such as Benadryl (diphenhydramine)

A side-effect is a harmful or undesired effect resulting from a medication, drug or surgery. Side effects may vary for each individual depending on the person's disease state, age, weight, gender, ethnicity, general health and other variables. They may be the result of incorrect dosage or procedure of administration. Some side-effects tend to occur at the beginning of treatment, and either increase or decrease during the course of the intake of medication. Drugs such as morphine require dosages to be increased slowly, so that the patient develops tolerance to the side effects.
An adverse effect is NOT a side effect! Side effects are unwanted but natural and anticipated effects of a medication whereas adverse effects are rare and unforeseen effects upon the body. Adverse effects include allergic reactions to drugs, which cannot be anticipated by a medical professional and varies depending upon the person taking the drug.

Adverse Effects (AEs) include:
  • change in weight
  • loss of body function
  • severe weakness
  • irritation like ulcers in the throat from taking a tablet or oral medication Esophageal Reflux
    • This can cause nerve and muscle activity to slow down in the stomach. This slowing down causes the contents of the stomach to empty at a slower rate than normal.
    • irritation in the stomach lining - can create inflammation and this causes a weakening in the lining to resist against acids produced in the stomach. This is only caused by taking drugs that are non-steroidal anti-inflammatory. Some warning signs to an irritated stomach lining are: severe stomach cramps, pain or burning in the stomach or back, black, tarry or bloody stools, bloody vomit, severe heartburn or indigestion and diarrhea.

Serious Adverse Effects (SAEs) include:
  • death
  • permanent tissue damage; (brain, liver, kidneys, etc.)
  • birth defects
  • need for hospitalization