Factors influencing dosedependent adverse drug reactions Medical Assignment Help


The active agent represents only a small proportion of the total weight of a tablet or capsule .. Similarly, drugs for injection require solubilization or suspension in a fluid vehicle of varying complexity. Other constituents of dosage forms, called excipients, are not necessarily inert, and may play an important part in facilitating or hindering  the absorption of a drug. The proportion of an administered drug dose that reaches its site of action in the systemic circulation is known as its bioavaiIability. If the drug is given intravenously its bioavailability is 100%. The dose-dependent adverse effects of many drugs are related to higher blood levels than those necessary for  their therapeutic action. A formulation that results in such high blood levels may, therefore, produce unacceptable effects. In the case of a poorly soluble drug, its physical form may be important in determining its dissolution rate and, therefore, its rate of absorption. For example, when the particle size of digoxin was reduced by a manufacturer, many patients experienced digitalis toxicity because the rate and extent of absorption was increased. Similarly, the influence of a change of the excipient on a drug’s bioavailability was seen in Australia when a manufacturer of phenytoin capsules changed  from using the relatively water-insoluble calcium sulphate to the much more soluble lactose. This led to an increase in the bioavailability of phenytoin, which was even more marked because of the ‘saturation kinetics’ that phenytoin exhibits.
Modification of the physical form of a drug, and changes in other constituents, permits the development of ‘controlled release’ formulations. These produce sustained levels within the therapeutic range and prevent early peak blood levels that enter the toxic range. This effect is particularly useful in drugs with a short half-life.

Relationships between blood drug concentration

Relationships between blood drug concentration

Route of administration

Parenteral administration of a drug may produce higher peak levels than are produced by oral administration, and may therefore produce more marked concentrationrelated adverse effects. For example, the intravenous administration of many drugs, particularly as bolus injections, may cause unwanted cardiac or central nervous effects. Intrathecal penicillin can produce encephalopathy and convulsions due to the toxic effects of high concentrations on the central nervous system; this route is nowadays seldom used.
Adverse reactions may occur owing to accidents during administration; for example, arterial rather than venous injectio  of thiopentone results in vascular spasm, arterial thrombosis and gangrene.


Some drugs given in the first 3 months of pregnancy may cause congenital abnormalities and are said to be teratogenic. The best known example of a teratogenic drug is thalidomide, which resulted in bizarre and therefore easily recognizable abnormalities such as absent or grossly abnormal limbs (amelia, phocomelia). Stilboestrol administration during pregnancy produced adenosis and adenocarcinoma of the vagina in the female offspring when they reached their late teens or early twenties. This was recognized because of the normally relatively low incidence of this carcinoma in this age group. Low-grade teratogens that cause only minor deformities infrequently are likely to be unrecognized or demonstrated only with difficulty. Other drugs that are known or suspected to be teratogenic are given.
Drugs given after the period of organogenesis may affect the growth or function of normally formed fetal tissues or organs. The more important of these drugs.


Some drugs produce specific adverse effects at the extremes of life.

Agents known or suspected to be teratogenic in humans.

Agents known or suspected to be teratogenic in humans.

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