Different types of doses

Effective dose

It is the amount of drug which will produce a specific intensity of effect i.e.; either
to treat the disease or prevent the disease successfully.

Median effective dose (ED50)

It is the amount of a drug that produces the desired therapeutic effect in 50% of experimental animals.
OR
1. It is the dose of a drug required to produce a specific intensity of effect in 50% of individuals.
2. It is the measure of the effectiveness of a drug.

Lethal dose

It is the amount of a drug that will kill a certain percentage of experimental animals to whom the drug is administered.

Fatal dos

When a lethal dose reaches 100% or LD100 is known as a fatal dose.

The median lethal dose (LD50)

It is the amount of a drug that is fatal to 50% of the experimental
animals
1. [i.e.; which kills 50% of the experimental animals]
2. It is the measure of acute toxicity of drugs.

Initial loading dose

In some conditions, certain drugs are given in large doses, in the beginning, to obtain an effective blood level rapidly, this is known as the initial loading dose.

Maintenance dose

After achieving the desired blood level by initial loading dose, a smaller quantity of drug is then required to maintain the blood level, this is known as a maintenance dose.

Loading Dose

Dose = Cp(Target) x Vd

Maintenance Dose

= CL x CpSSav
1. CpSSav is the target average steady-state drug concentration
2. The units of CL are in L/hr or L/hr/kg
3. Maintenance dose will be in mg/hr so a total daily dose will need to multiply by 24.

Different types of doses in renal and hepatic disease

Adjustment of Dosage in Renal Impairment:

1. Inpatient with renal failure, the half-life of the drug is increased and its clearance drastically decreases if it is predominantly eliminated by way of excretion.
2. Hence, dosage adjustment should take into account the renal function of the patient and the fraction of unchanged drug excreted in the urine.
3. There are two additional methods for dose adjustment in renal insufficiency if the Vd change is assumed to be negligible.

General Approach:

• No change in the desired or target plasma concentration.
• Diminished renal clearance but unchanged non-renal clearance.
• Unaltered drug-protein binding & volume of distribution in the renally impaired patient.
• Unchanged drug absorption from the GIT.

Three Major Approaches are:

• Dose adjustment based on Total body clearance.
• Dose adjustment based on Elimination rate constant or half-life.
• Dose adjustment in renal failure.

Dose adjustment based on Total body clearance:

The average drug conc. at steady-state CSS,av is a function of maintenance dose X0, the fraction
of dose absorbed F, the dosing interval & זclearance Cl T of the drug.
Css,av = Fxo / ClT ז

Dose adjustment based on Elimination rate constant or Half-life:

The average drug conc. at steady-state CSS,av is a function of maintenance dose X0 , the fraction
of dose absorbed F, the dosing interval & ז volume of distribution vd & t1/2 of the drug.
CSS, av =1.44 FXo t ½ Vd ז
1. Diseases are the major source of variation in drug response.
2. Both pharmacokinetic and Pharmacodynamic of many drugs are altered by a disease other than the one which is being treated.

Disease state:

• Renal dysfunction – It greatly impairs the elimination of drugs, especially those primarily excreted by the kidney. Causes of renal failure are hypertension, diabetes mellitus.
• Uremia is characterized by impaired glomerular filtration and accumulation of fluid and protein metabolism. In both cases, the half-life of the drug is increased as a consequence drug accumulation and toxicity increases.
• Adjustment of Dosage in Hepatic Impairment:
• The influence of Hepatic disorder on drug bioavailability & disposition is unpredictable because of the multiple effects that the liver produces.
• The altered response to drugs in liver disease could be due to decreased metabolizing capacity of the hepatocytes, impaired biliary elimination, due to biliary obstruction.
• Impaired Hepatic blood flow leading to an increase in bioavailability caused by a reduction in first-pass metabolism (e.g Bioavailabilities of Morphine and Labetalol have been reported to double in patients with Cirrhosis)
• Decreased protein binding and increased toxicity of drugs are highly bound to plasma protein (e.g. Phenytoin, Warfarin) due to impaired albumin production and the altered volume of distribution of drugs due to increased extracellular fluid (e.g. Rifampicin accumulates in obstruction jaundice).
• Edema in liver disease may be increased by drugs that cause fluid retention (e.g.Acetylsalicylic acid, Ibuprofen, Prednisolone, Dexamethasone).
• Generally, drug doses should be reduced in patients with hepatic dysfunction since clearance is reduced & bioavailability is increased in such a situation.
• Renal function determination:
• Glomerular filtration rate can be determined by following two methods :
• Insulin clearance
• Creatinine clearance