Learning Objective

• Factors affecting dose selection.

The following are the factors that affect the selection of dose for a patient:

1. Age: In determining the dose of a drug, the age of the patient is of great importance, especially in the case of children and the elderly. The lower age group patients such as infants and children have striking physiological differences from adults. This is because the organs liver and kidney, which are responsible for biotransformation and excretion, are immature and still in the generative stage. The hepatic drug metabolizing system is inadequate in newborns—for example, chloramphenicol can produce gray baby syndrome. The blood–brain barrier is more permeable and drugs can attain a higher concentration in the central nervous system (CNS). Drug absorption may be altered in infants because of lower gastric acidity and slower intestinal transit. Growing children are more vulnerable to special adverse effects of drugs, for example, suppression of growth due to corticosteroids and discolouration of teeth due to accumulation of tetracycline.In the case of geriatrics (elderly patients), the liver and kidney functions progressively decline and the organs exhibit impaired ability to inactivate or excrete drugs. Due to lower renal and metabolic clearance, the elderly are more prone to develop cumulative toxicity while receiving prolonged medication. Absorption will be slow due to reduced blood flow and motility of intestines. The elderly are also likely to be on multiple drug therapy for hypertension, ischemic heart disease, diabetes, arthritis, and so on, which increases the chances of drug interactions.Therefore, the dose of drugs should be adjusted for pediatrics and geriatrics keeping in mind the physiology of the patients and the pharmacokinetic parameters of the drug.
2. Body weight: The recommended adult dose is based on the normal body weight of 70 kg but such a dose will be very less for a muscular person weighing about 100 kg and will be very high for a lean patient weighing about 40 kg. Child doses are usually calculated on the basis of body weight.
3. Sex/Gender: In general, women require lesser dose than men because of their smaller body size and also because they are more responsive and sensitive to certain drugs. Many drugs should be avoided or monitored carefully during menstruation, pregnancy, and lactation. The following precautions need to be taken while determining the dose for women:
   • Strong purgatives should be avoided during menstruation.
   • Drugs that induce contraction of uterus must be avoided during pregnancy (as it may lead to abortion or miscarriage).
   • During pregnancy, drugs such as barbiturates, narcotics, anesthetics, and alcohol, which readily cross the foetal circulation, should be avoided.
   • In lactating mothers, drugs such as tetracycline, antihistaminics, and morphine should be carefully prescribed.
   • A number of antihypertensives (such as clonidine, methyldopa, and β blockers) interfere with the sexual function in men but not in women.
   • Gynecomastia is a side effect of drugs such as ketoconazole, metoclopramide, and chlorpromazine that occurs only in men.
   • Androgens are unacceptable to women and estrogens to men.
4. Route of administration: The route of administration influences the efficacy of a drug in terms of drug response. Absorption of drugs is more rapid and complete by parenteral administration than by oral route. Drugs that are administered by parenteral route require lesser dose when compared to oral doses.A single drug may exhibit varied uses through different routes. For example, magnesium sulfate on oral administration results in purgative action, whereas it produces CNS depression and hypotension when given intravenously.
5. Time of administration: Drugs that are absorbed rapidly should be given on empty stomach, whereas drugs that are irritant to the gastrointestinal tract should be given after meals. For example, fatty meals enhance the absorption of griseofulvin, whereas food interferes with the absorption of ampicillin.
6. Presence of disease/Pathological conditions: It is not only drugs that modify disease processes, but the presence of diseases can also influence drug disposition and drug action. For example, gastrointestinal diseases can alter the absorption of orally administered drugs. Liver diseases can increase the bioavailability of the drugs that normally undergo high first pass metabolism. Kidney diseases can alter the clearance of drugs.
7. Environmental factors: Alcohol is better tolerated in a cold environment than in hot summer. The dose of sedative required to induce sleep during the day is more than that required in the night. Hypnotics taken at night and in quiet, familiar surroundings may work more easily.
8. Genetic makeup: Variations in response of different individuals to the same dose of a drug are sometimes due to differences in genetic makeup.
9. Rate of elimination: If age or disease impairs liver function, the breakdown of drugs may be delayed, whereas if the kidney activity is reduced, the excretion of drugs will be incomplete. Both the situations cause greater and prolonged activity of medicaments with a risk of toxic reactions.
10. Idiosyncrasy: This is a genetically determined abnormal reactivity to a chemical. This term is used to indicate exceptional and individual intolerance towards certain drugs. The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction. The following are some examples:
    • Quinine and quinidine causes cramps, diarrhea, and asthma in some patients.
    • The adverse effects of penicillin (seen in 0.1–1% of patients) include rashes, fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and pseudomembranous colitis (which is the cause of antibiotic-associated diarrhea (AAD) and is an infection of the colon).
    • Large doses of quinine cause tinnitus (ringing in the ears).
    • Barbiturates cause excitement and mental confusion in some individuals.
11. Tachyphylaxis: This is defined as the rapid development of tolerance on repeated doses of a drug in quick succession with a marked reduction in clinical response. (Tolerance refers to the requirement of a higher dose of a drug to produce a given response.) When certain drugs are administered repeatedly at very short intervals, the cell receptors get blocked by which the pharmacological response to that particular drug is decreased. Under such circumstances, even if the dose is increased, the necessary pharmacological response is not obtained. If the administration of the drug is stopped for a certain period of time and continued again, the response is observed. Examples of such drugs are ephedrine and nicotine.
12. Species and race: Differences in therapeutic efficacy to drugs are quite evident in different species or races.For example, in the case of human beings, blacks require higher concentrations of atropine and ephedrine to dilate their pupil, whereas Mongolians require lower concentrations for the same.
13. Synergism: When the action of one drug is promoted or enhanced by the other, the drugs are termed as synergistic in nature and the phenomenon as synergism. In a synergistic pair, both the drugs can show action in the same direction or one may be inactive but still enhance the action of the other when given together. The following are some examples of synergism:
    • Aspirin + paracetemol is used as an analgesic/antipyretic,
    • Amlodipine + atenolol is used as an antihypertensive.
    • Glibenclamide + metformin is used as a hypoglycemic.
14. Antagonism: Antagonism is a phenomenon in which one drug decreases or blocks the action of another. In an antagonistic pair, one drug is inactive as such but antagonizes the effect of the other. The following are some examples of antagonism:
    • Charcoal adsorbs alkaloids and can prevent their absorption—used in alkaloidal poisoning.
    • Potassium permanganate oxidizes alkaloids—used for gastric lavage in poisoning.
    • Tannins + alkaloids—insoluble alkaloidal tannate is formed.
    • Chelating agents (calcium disodium edetate) form complexes with toxic metals such as lead and arsenic.
15. Psychological factors: Patient’s beliefs, attitudes, and expectations remarkably affect the efficacy of the drug, especially in the case of centrally acting drugs. For example, a nervous and anxious patient needs more general anesthetic.