The series of chemical alterations of a drug that occurs within the body is called biotransformation or metabolism of drug. This is how the activity of drug is terminated or altered. Some drugs are filtered through the kidney and do not need biotransformation while the majority requires metabolism before they loose their function and elimination from the body.
The lipophilic characteristic of drugs that promote their passage through biological membranes and subsequent access to their site of action hinder their elimination from the body. Therefore these lipophilic drug are converted into hydrophilic metabolites for the termination of their biological activity and elimination of their metabolites from the body.
SITES
Major site of biotransformation is liver, while other organs involved are kidneys, gastrointestinal tract, skin and lung. Phase I reaction occurs mainly in smooth endoplasmic reticulum and phase II in cytosol.
ENZYMES
The metabolic conversion of drugs requires certain enzymes. The important enzyme system is cytochrome P-450 system that includes:
• Cytochrome P-450 enzyme
• NADPH-cytochrome P-450 reductase
P-450 is a family of enzymes that occur in most cells, but that are particularly abundant in the liver.
Enzyme induction
Many drugs area able to induce elevated levels of cytochrome P-450, resulting in an increased rate of metabolism of the inducing drug, as well as other drugs, therefore reducing action and duration of the drugs.
Enzyme inhibition
Many drugs inhibit the P-450 system and may potentate the action of other drugs that are metabolized by this system.
PHASES OF BIOTRANSFORMATION
There are two phase of biotransformation, majority or drugs undergo first phase I and then phase II, but some drugs pass through phase II and then phase I. Some drugs
directly undergo through phase II without prior phase I metabolism.
1. Phase I reaction
2. Phase II reaction
PHASE I REACTION
The phase I reaction may result in:
1. Phase I reaction generally result in loss of pharmacological activity of a drug, although it can increase pharmacological activity such as prodrugs that are pharmacologically inactive become active after metabolism.
2. Conversion of the drug to a toxic compound.
Reaction included in type I reaction are:
Oxidative reaction ( cytochrome P-450 ) dependent)
• Deamination
• Desulfuration
• S-Oxydation
• N-Oxydation
• O-Dealkkylation
• N-Dealkylation
• Aliphatic hydroxylation
• Aromatic hydroxylation
Oxidative reaction ( cytochrome P-450 independent )
• Dehydogenation
Reduction reaction
• Azo reduction
• Nitro reduction
• Carbonyl reduction Hydrolysis
PHASE II REACTION
Phase II reaction involve “conjugation” of the parent compound with certain; radical or amino acids. If the metabolite phase I metabolism is sufficient polar, it can excreted by the kidneys. However many metabolites are too lipophilic to be excreted and they must undergo conjugation reaction with an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid or an amino acid resulting in polar, usually more water soluble compounds that are most often therapeutically inactive. Conjugation with glucuronic acid is the most common reaction.
Phase II reactions results in inactivation of the parent drug but not always.
• Chloramphenicol conjugates with glucuronic acid
• Phenol conjugates with sulfate
• Salicylates conjugate with glycine.
Note: The microsomal exzymes produced by the hepatic smooth endoplasmic reticulum, catalyze glucuronide conjugation and mowtof the oxidation of drug. While he readution and non- microsomal Enzymes. These enzymes are also present in kidney and GIT.
Phase II reaction are:
• Glucuronidation
• Acetylation
• Glutathione conjugation
• Sulfate conjugation
• Methylation
• Water conjugation
FACTORS AFFECTING BIOTRANSFORMATION
Different people have different in drug distribution metabolism and elimination due to the following factors:
Individual differences
Different people have different level of metabolism.
Genetic factors
Genetic factors influence enzyme levels resulting in difference drug metabolism.
Diet and environmental factors
Certain vegetable ad fruits induce or inhibition enzymes affecting the drug metabolism Cigarette smokers metabolize some drugs are rapidly than non-smokers do.
Age & Sex
Drugs have more effect and more toxicity in very young and old patients due to decreased drug metabolism. In newborn the enzymes in the liver are not developed. If drug like chloramphenicol is given to the newborn, it proves toxic as glucuronide is not fully developed. Males have more rapid drug metabolism than females.
Drug-Drug interaction
Some drugs induce and some inhibit enzymes those results in decreased or increased metabolism of the same or other drugs. Phenobarbitone induces enzymes and increases the metabolism of several drugs.
Interaction between drugs and endogenous compounds
Various drugs require conjugation with endogenous substrates such as glutathione, glucuronic acid, and sulfate for their inactivation. Different drug may compete for the same endogenous substrates, and the faster-reacting drug may effectively deplete endogenous substrates levels and impair the metabolism of slow -reacting drug.
Disease affecting drug metabolism
Acute or chronic disease that affect liver architecture or function markedly affect hepatic metabolism of some drugs.
Pharmacokinetic factors
As long as drug is bounds to plasma protein, it will not be metabolized .
Drugs which are localized in tissue are protected from metabolism e.g. Chloroquine in liver.
DRUG ELIMINATION
Drugs in the free form and in the form of their degradation products are eliminated though on or more of the following channel of excretion.
1. RENAL EXCRETION:
In renal excretion three processes are evolved:
• Filtration: Rate of filtration is determined by degree of drug bound to plasma Protein.
Only free fraction for the dug in filtrated.
• Active tubular secretion and reabsorption: Many drugs are actively secreted by the tubules e.g. penicillin and uric acid. There is competition between different drugs e.g. probenecid competes with penicillin for excretion and stops excretion of penicillin, thus increasing its duration of action.
• Passive diffusion: It depends upon whether it is ionized or unionized. Drugs which are unionized are reabsorbed.
2. LUNGS:
The lungs excrete gaseous and volatile general anesthetics as well as gaseous drug
product such as CO 2
3. ALIMENTARY SYTEM
Thiocynate and iodides are excreted though saliva while morphine is excreted in bile.
CLEARANCE OF DRUG
Rate of elimination of drug by all route normalized to the concentration of drug in some biological fluid is called drug clearance. Major organs that clear the drug are kidney and liver Initially the clearance of each organ is calculated, then they are added target total body clearance.
The clearance of most drugs is of two types:
First order kinetics:
If a constant fraction of drug is eliminated per unit time it is called first order kinetics e.g. 5% or 10%/min.
Zero-order Kinetics:
If a constant amount of drug is eliminated per unit time it is called first order kinetics 5mg of 10mg/min.
Importance
Assuming complete bioavailability, the steady state will be achieved when the rate of drug elimination equal the rate of drug administration. Thus if the desired steady-state concentration of drug in plasma or blood is known, the rate of clearance of drug by the patient will decade the rate at which the drug should be administered.
FIRST PASS EFFECT:
The enzymes systems concerned in the metabolism of many drugs are located in liver. A drug
that is absorbed from the stomach and intestine must fist pass through the liver before it reaches the systemic circulation. If the metabolic system of the liver is over active for this drug, the drug will be metabolized before reaching the circulation e.g. nitroglycerine. To avoid this , such drugs are given sublingually.
ENTEROHEPATIC CIRCULATION:
Drugs and their metabolites that are secreted into bile are carried by the bile duct and the
common duct to the duodenum. Some drug may then be absorbed from the lumen of the intestine and appear again unchanged in the blood. This recycling of drug is termed enterohepatic circulation.
HALF-LIFE
The time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50% is called half-life of a drug.
Half-life provides a good indication of the time required to reach steady state after a dosage
regimen is initiated, the time of a drug to be removed from the body, and means to estimate the appropriate dosing interval.
0.693
Half-life =
x volume of distributi on Clearance of drug
FACTORS AFFECTING HALF-LIFE
• As the clearance decreases due to some disease process the half-life increases, as in renal failure.
.If the volume of distribution is increased, half-life is increase e.g. half-life of diazepam increases in old age due to increased volume of distribution.
• Change in the protein binding may result in change in the volume of distribution and
drug clearance in the leads to change in the half-life. Increased plasma binding increases half-life.
STEADY STATE
A steady state concentration of drug occurs when the rate of drug elimination is equal to the rate of drug administration. Steady state plasma concentration is directly proportional to rate of infusion and inversely proportional to the total body clearance of the drug.
DOSAGE OF DRUGS
The minimum quality of the drug needed to produce measurable biological response is called dose of a drug. A rational dosage regimen is based on the assumption that there is a target concentration that will produce desired therapeutic effect.
Dose usually has range i.e minimum and maximum limits. Dose is not always fixed amount and it can be change according to the severity of the disease.
THERAPEUTIC DOSE OR EFFECTIVE DOSE (ED50)
The average dose required to produce therapeutic effect in 50% of the population treated is called therapeutic for effective dose.
MAXIMAL TOLERATED DOSE
The largest dose of a drug that can be taken safely is called maximal tolerated dose.
INITIAL DOSE
The dose used at the start of treatment is called initial dose.
MAINTENANCE DOSE
The dose required to maintain the therapeutic effects (steady state of target level) attained by the initial dose is called maintenance dose.
LOADING DOSE
The loading dose is one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly. A loading dose may be desirable if the time required to attain steady state by the admonition of drug at a constant rate (four elimination half-lives) is long relative to the demand of the condition. It is unnecessary for drugs having short half-life. In loading dose the amount of the drug should be increased not the of administration.
Loading dose = Vd × TC
Vd = volume of distribution TC = target concentration
INEFFECTIVE DOSE
The dose below the effective dose is called ineffective dose.
TOXIC DOSE
The dose above the effective dose produces undesirable effects and is called toxic dose.
LETHAL DOSE (LD50)
The dose which produces death in 50% of population treated is called lethal dose.
THERAPEUTIC INDEX
The relationship between the dose of the drug required to produce desired and undesired effects is termed as therapeutic index or margin of safely.
Therapeutic index =LD50/ED50
Higher the therapeutic index, safer will be the drug
FACTORS MODIFYING THE DOSAGE OF DRUGS
Age, weight, and body surface area:
• Children require smaller doses of drug than adult
• Greater the body weight, the bigger the dose required.
• Greater the body surface area, larger the dose required. Sex:
• Females usually require smaller dose than males
Routes of Administration
• Intravenous dose is less then oral dose
• Subcutaneous and intramuscular dose are also smaller the oral dose but larger than intravenous dose.
Time of Administration
• Absorption of drugs occurs more rapidly in an empty stomach than after meals. However,
it is better to take irritant drugs after meals.
Diseased condition
Drug metabolized in liver are not destroyed during liver disease. Drugs excreted by kidney are not excreted in renal disease; therefore the dose should be reduced.
Drugs Interactions:
When two or more drugs are combined together one of the following four phenomena may be observed:
• Summation:
The resultant action is the algebraic sum of the individual actions of the two drugs
combined. In such cases only one half of the normal dose of each drug is required to produce the desired effects.
• Synergism:
When combined the net effect is greater than the sum of their individual effect e.g. ethyl alcohol and barbiturates.
• Potentiation:
When one drug has no apparent action by itself on one system but increase the effect of another drug is termed potentiation e.g. barbiturates potentiate the analgesic action on their own.
• Antagonism:
This occurs when drugs with opposing actions are administered simultaneously. It may be of several types:
Physiological
Histamine + Adrenaline
Chemical
Protamine + Heparin
Pharmacological: Competitive:
Acetylcholine + Atropine
Non-competitive: AcetylcholineSuxamethonium.
Placebo Effect:
This is the influence of the emotional state of the patient on response to drugs. Placebos are inert dosage forms usually tablets or capsules containing sucrose or lactose. They have no pharmacological effect but produce improvement due to psychological effects.
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