Posology – Definition, Factors Influencing Dose with Examples

Age (Factor 1 in Posology):

• Age is considered one of the significant factors determining a drug’s dose. It is because the pharmacokinetics of many drugs change with age. For your information, the term pharmacokinetics means what the body does to the drug, which is absorption, bioavailability, distribution, metabolism, and excretion.
• Newborn infants(pediatric) are abnormally sensitive to certain drugs because of the immature state of their hepatic and renal function by which drugs are inactivated and eliminated from the body. 
• Failure to detoxify and eliminate drugs results in their accumulation in the tissues to a toxic level. 
• Whereas elderly patients show a decline in hepatic and renal functions that may slow drug clearance and increase the possibility of drug accumulation in the body leading to drug toxicity. 
• Elderly people are also more sensitive to some drug effects, e.g., hypnotics which may produce confusion. 
• Elderly individuals may also respond abnormally to the usual amount of a drug because of changes in drug-receptor sensitivity or because of age-related alterations in target tissues and organs.

Here are a few interesting examples that show the effects of drug dosage with age:

• In newborn

• • Chloramphenicol causes grey baby syndrome because of inefficient metabolism resulting in drug accumulation. 
  • Absorption of Amoxycillin is higher because of less gastric acidity.

• In Children (Paediatrics)

• • They need a lesser dose than the usual adult dose because of their pharmacokinetic profile (metabolism & excretion).
  • Children can tolerate relatively more significant amounts of belladonna, digitalis, and ethanol, whereas elderly patients are more sensitive to hypnotics and tranquilizers, which may produce confusion states in them. 
  • Children’s blood-brain barrier (BBB) is not well developed, so they are more sensitive to CNS stimulants.

• In Old aged People (Geriatrics age >60 years)

• • They need lesser doses because of their pharmacokinetic profile. 
  • More sensitive to diazepam and morphine

Various rules of dosage in which the paediatric dose was a fraction of the adult dose

Sex (Factor 2 in Posology):

• Women don’t always respond to the pharmacological action of a drug in the same manner as men. 
• Women are more susceptible to the effects of certain drugs than men. Special care should be taken when drugs are administered during menstruation, pregnancy &lactation. 
• Strong purgatives like Aloes should be avoided during menstruation.
• Pregnant women and nursing mothers should use medications only with the advice and guidance of their physicians. Examples of drugs that are transported from the maternal to the fetal circulation, e.g., alcohol, anesthetic gases, barbiturates, narcotic drugs, anticoagulants, etc
• Similarly, the drugs which may stimulate the uterine smooth muscles, e.g., drastic purgative, antimalarial drugs, and ergot alkaloids, are contraindicated during pregnancy.
• Since the drug detoxification and excretion mechanisms present in the fetus are underdeveloped, concentrations of drugs may reach a higher level in the fetus than in the maternal circulation.
• The transfer of drugs from the mother to the nursing infant through the mother’s milk may occur with various drugs, with the drug effects manifesting in the infant. During lactation, morphine and tetracycline are avoided because they are excreted through milk and effects babies.

Body Weight (Factor 3 in Posology):

• The average dose is mentioned either in terms of mg/kg body wt or as a total single dose for an adult weighing between 50-100 kg.
• The ratio between the amount of drug administered and the size of the body influences the drug concentration at the site of action. Therefore, drug dosage may require adjustment from the usual adult dose for malnourished patients, children, or obese patients and should be calculated only according to the body weight.
• The determination of drug dosage for children based on body weight is more dependable than that based on age.

Clark’s Rule: 

Dose for child = Adult dose x Weight (in Ib) / 150 (average weight of adult in Ib)

Route of Administration (Factor 4 in Posology):

• Route of administration affects the therapeutic efficacy of a drug. The route of administration generally controls the effectiveness of drug formulation.
• Drugs administered intravenously enter the bloodstream directly; thus, the whole amount of the drug is in the blood.
• In contrast to the IV drug formulations, drugs administered orally are rarely fully absorbed due to the various physical, chemical, and biological barriers to their absorption, including interactions with gastric and intestinal contents.
• Therefore, a lesser IV injectable dose of a drug is required than the oral dose to achieve the same blood levels. The onset of action is quick in IV formulations, and there may be higher chances of drug toxicity in the IV route

Time of Administration (Factor 5 in Posology):

The time at which a drug is administered sometimes influences dosage. This is especially true for medications taken through the oral route, which relates to meals.

• Absorption proceeds more rapidly if the stomach and upper portions of the intestinal tract are free of food. An amount of a drug that is effective when taken before a meal may be ineffective if administered during or after eating.
• Drugs that cause gastric irritation are better tolerated by the patient if food is present in the stomach to dilute the drug’s concentration. 
• For example, medication with iron, arsenic & cod-liver oil should be given after meals as they irritate the gastric lining & antacid drugs should be taken before meals.

Environmental Factors (Factor 6 in Posology):

• Daylight acts as a stimulant, enhancing the effect of stimulating drugs and diminishing the effect of hypnotics. 
• Darkness acts as a sedative, so hypnotics are more effective at night. 
• Stimulant types of drugs are taken in the daytime, and sedative types of drugs are taken at night. So, the dose of a sedative required during day time will be much higher than at night. The amount of barbiturate required to produce sleep during the daytime is much higher than the dose required to produce sleep at night.
• Alcohol is better tolerated in winter than in summer.

Psychological State (Factor 7 in Posology):

• The psychological state of mind can affect the response of a drug, e.g., a nervous and anxious patient requires more general anesthetics.
• Disorders like angina pectoris and bronchial asthma are known to be cured using placebos which produce a therapeutic benefit to the patients. Placebo is an inert dosage form without the active drug and resembles the actual medicine in physical properties and ingredients. Placebos are more often used in clinical trials of drugs.
• Women are more emotional than men and, therefore, might require fewer doses of certain drugs to get the desired effect.

Pathological States (Factor 8 in Posology):

Several diseases may directly affect the therapeutic activity of drugs when taken. The effects of certain drugs may be modified by the patient’s pathological condition and must be considered in determining the dose.

• Achlorhydria is a condition of reduced gastric secretions, especially hydrochloric acid. This gastrointestinal disease might directly affect the decrease in the absorption of acetylsalicylic acid (Aspirin)
• Metabolism of drugs like morphine, pentobarbitone, etc., is noted to be decreased with diseases like liver cirrhosis. 
• Patients with increased body temperature (like fever) can tolerate high doses of antipyretics than a normal individual.
• Patients with diseases or disorders affecting kidney filtration and elimination efficiency might have issues with excreting drugs like streptomycin, which mainly gets excreted through the kidneys.
• In certain kidney diseases, the excretion of drugs like aminoglycosides, digoxin, and phenobarbitone is reduced. Therefore, fewer doses of these drugs are administered.

Warning, precautions, or contraindications are used in the drug labeling to alert the physician to certain restrictions in using a particular drug.

• Precautions are used to advise the prescriber of some possible problems attendant with the use of the drug. It is less restrictive than a warning. Ex: The use of tetracycline antibiotics may result in the overgrowth of fungi. In such a case, the physician may prescribe an alternate drug.
• A warning is used when the potential for patient harm is greater than in instances where the precaution is used. Ex: If tetracycline is used in the presence of renal impairment, it may lead to drug accumulation and possible liver toxicity. So, lower than usual doses are indicated. If therapy is prolonged, blood serum levels of the drug should be taken, and the patient monitored at regular intervals to ensure the maintenance of the drug’s non-toxic levels.
• Contraindication term is used to indicate an absolute prohibition of drug use in the presence of certain stated conditions. It is the most restrictive of the warnings that limit drug use.

Accumulation (Factor 9 in Posology):

• When a drug’s absorption rate is greater than its rate of elimination, then any drug would accumulate in the body. 
• Drugs that have a lower rate of elimination are the ones that often accumulate and cause toxicity. Example: prolonged uses of chloroquine cause retinal damage. Other examples are digitalis, emetine, and heavy metals.  
• Usually, such drugs are not recommended for repeated administration for a prolonged time.

Drug-drug interactions (Factor 10 in Posology):

• When two drugs are simultaneously administered to the body, they might produce an increased or decreased effect. The concurrent administration of another drug may modify the effects of a drug.
• These drug-drug interactions are due to chemical or physical interaction between drugs or alteration of the drug’s absorption, distribution, metabolism, or excretion patterns.
• The effects of drug-drug interactions may produce either a beneficial or detrimental effect on the body.
• An additive effectis produced when the total pharmacological action of two or more drugs administered together is equivalent to the sum of their pharmacological action.
• A synergistic effectis produced when two or more drugs are used in combination to either increase the pharmacological action of a drug or decrease the elimination rate of a drug.
• Synergism is very useful when desired therapeutic result needed is difficult to achieve with a single drug.
• A decrease in the elimination rate of drugs helps prolong the drug’s action in the body. A combination of procaine and adrenaline produces an example of such an effect to increase the duration of action of procaine.
• An antagonistic effectis produced when two or more drugs are used on the same physiological system either to decrease the pharmacological action of a drug or to increase the rate of elimination of a drug.
• The use of antagonistic responses to drugs is valuable in the treatment of acid poisoning. For example, the alkaline effect of milk of magnesia neutralizes the effect of acid poisoning

There are three types of antagonistic effects namely:

• Competitive/reversible antagonism: It is a phenomenon where competitive antagonists compete with agonists for a common binding site on a receptor. For example, atropine, a competitive antagonist, competes with acetylcholine for binding sites on muscarinic receptors to prevent conditions like cardiac dysrhythmia, heat block, etc.
• Non-competitive/irreversible antagonism: If an antagonist binds to the receptor and precludes agonist activation of that receptor by its occupancy, then no amount of agonist present in the receptor compartment can overcome this antagonism is termed non-competitive. This can occur either by binding to the same binding domain of the agonist or another (allosteric) domain. 

For example, Phenoxybenzamine and adrenaline at α-receptor. Phenoxybenzamine is a medication used to manage and treat paroxysmal hypertension and sweating resulting from pheochromocytoma. It is in the nonselective, irreversible antagonist of the alpha-adrenergic receptors class of drugs.

• Physiological antagonism: This phenomenon describes the behavior of a substance that produces effects counteracting those of another substance (a result similar to that produced by an antagonist blocking the action of an agonist at the same receptor) using a mechanism that does not involve binding to the same receptor. In simple terms, it is the binding of agonist and antagonist at two different receptors, but their action is opposite. For Examples: Adrenaline (bronchodilatation) and histamine (bronchoconstriction).

Few practical examples of drug effects:

Idiosyncrasy (Factor 11 in Posology):

Also called an allergy, idiosyncrasy is an extraordinary drug response in selective individuals, which differs from its characteristic pharmacological action. Examples include:

• • • Aspirin causes asthma or gastric hemorrhage.
    • Penicillin and sulphonamide cause irritating rashes on the skin or severe toxic effects.

Tolerance (Factor 12 in Posology):

• A condition occurs when the body gets used to a medicine so that either more or different medicine is needed. In simple terms, it is a person’s diminished response to a drug.
• Continuous usage of a substance would enhance the inability to endure the influence of a drug substance. People with drug tolerance require higher doses of the same drug to produce the desired pharmacological effect. For example, Frequent smokers have a tolerance towards nicotine, and the same drug, when administered intravenously, might have diminished or no effect when normal doses administered intravenously. 
• Normal sensitivity to a drug may be regained by suspending the drug administration for some time. The development of tolerance can be minimized by initiating therapy with the lowest effective dose and avoiding prolonged administration

Here are a few types of tolerances for your information:

• Natural Tolerance: Very few races are inherently less sensitive and tolerant toward normal doses of drugs. For example, rabbits and the black race (Africans) are more tolerant of atropine.
• Acquired tolerance: We have discussed this above. Repeated drug use in an individual for a long time requires a larger dose to produce the same effect obtained with a normal dose previously.
• Cross toleranceis the development of tolerance to pharmacologically related drugs, e.g., alcoholics are relatively more tolerant to sedative drugs.

Tachyphylaxis (Factor 13 in Posology):

• Tachy means fast, and phylaxis means protection. It is a rapid development of tolerance. When drug doses are repeated in quick succession, a reduction in response is called tachyphylaxis. This is usually seen in ephedrine and nicotine.
• When certain drugs are administered repeatedly at short intervals, the cell receptors get blocked up, and pharmacological response to that particular drug decreases. This decreased response cannot be reversed by increasing the dose.
• For example, when given in repeated doses at short intervals in the treatment of bronchial asthma, ephedrine may produce very less response due to tachyphylaxis. – Similarly, drugs like amphetamine, cocaine, and nitrates behave similarly

Metabolic Disturbances (Factor 14 in Posology):

• Changes in water-electrolyte balance and acid-base balance, body temperature, and other physiological factors may modify the effects of drugs. Salicylates reduce the body temperature only if an individual has a rise in body temperature. They have no antipyretic action.
• Iron absorption from the gastrointestinal tract is maximum if the individual has an iron deficiency anemia.

Genetic Diseases (Factor 15 in Posology):

• Few people having genetic defects are prone to being devoid of some vital enzymes. In such cases, a few drugs are contraindicated.
• Example: Patients lacking Glucose-6-phosphate dehydrogenase enzyme should not be given Primaquin (an antimalarial drug) because it will cause hemolysis.

Drug dependence or Addiction (Factor 16 in Posology):

• Drug dependence is a chronic, progressive disease characterized by significant impairment directly associated with persistent and excessive psychoactive substance use.
• In simple terms, it means that you might need more and more of the same drug to give you the same feeling as the smaller amount you used when you first started taking that drug. Some drugs that cause dependence include nicotine, morphine, heroin (also known as diamorphine), cocaine, amphetamine, and alcohol.

There are two types of drug dependence:

• Physical dependence: A condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms.
• Psychological dependence: It is a dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia). Here patients show signs of a high rate of drug use, craving for the drug & tendency to relapse after stopping use.