Pharmacokinetics defines what the body does to the drug. Pharmacokinetics is the study of a drug absorption, distribution, metabolism and elimination from the body. Pharmacodynamics describes what the drug does to the
body. These pharmacokinetic properties determine the onset, intensity, and the duration of drug action in body. First of all the drug absorption from the site of administration permits the entry of a drug to the plasma. Secondly drug then leave plasma and distribute to the interstitial and intracellular fluids. Third, the drug is metabolized by liver and other tissues. finally, drug and its metabolites are eliminated from the body in urine, bile and feces. Pharmacokinetics mean the drug and there movements in the body. In general terms, it can be explained as an effect of drug or chemical entity on body upon administration.
IUPAC pharamacokinetic definition:
“Its the process of the uptake of drugs by the body, the biotransformation they undergo, the distribution of the drugs and their metabolites in the tissues, and the elimination of the drugs and their metabolites from the body over a period “
ADME of pharmacokinetics :
If we look at the basics of pharmacokinetic study we get to know it is about four distinct features and actions that drug performs in the body upon ingestion which ultimately comprises of the effect produced by the moiety. This is also called as ADME Process.
These four features include:
- Absorption ( the rate and extent to which drug is absorbed by the body)
- Distribution(rate and extent to which drug is distributed in the bodily fluids and tissues from distinct absorption sites. This is expressed by volume of distribution(Vd)
- Metabolism (rate and extent to which drug undergo enzymatic action required to break down the drug into its active form or proceed to elimination)
- Elimination (it is another important key feature describing rate and extent to which drug is eliminated from the body after attaining peak plasma conc. And producing its desired action)
The fundamental characteristic of pharmacokinetic study is drug removal from the body. This can be calculated by “Analyzing relation between peak plasma levels of drug (Cs) with time factor”. Pharmacokinetics cannot be studied alone without a similar equal response that is produced by the body upon receiving the drug, called as PHARMACODYNAMICS.
It is another vast and major field studied to comprehend kinetic of drugs. It covers the components of therapeutic drug monitoring, the therapeutic index of drug and patient-related factors such as drug interactions, the adverse reaction produced by these moieties and medication errors.
Principals of Pharmacokinatics :
Pharmacokinetics is particularly based on mathematical calculations to determine the transit period it requires from absorption till elimination.
- Absorption rate constant
- The apparent volume of distribution
- Bioavailability of drug molecule
- The area under the curve
- Clearance of a drug and
- Elimination rate constant
These are few developed mathematical parameters to calculate drugs response and effect produced by it in the body.
Factors Affecting Pharmacokinetics :
If we need to understand the basics we must be aware of the fact that drug effect in the body cannot be directly measured for e.g. if we talk about Benzodiazepine it is a fat-soluble moiety and distribute more often in fat tissues. Thus making it difficult to determine its effects directly. The ideal method on which pharmacokinetics is based, hence, is to calculate concentration. of the drug at the site of action and then at regular intervals checking plasma concentration. to get to know the distribution and finally elimination from the body.
However, a number of factors can affect drug response in the body. There could be patient related matters such as renal failures, fatty liver, any sort of allergy to the drug component, enzyme alteration, genetic makeup and so on.
Other than patient-related factors many pharmaceutical aspects can even cause hindrance in calculating peak plasma concentration. Such as solubility of drug molecule at absorption site, the salt form of the drug, carrier involved in membrane diffusion etc. Altogether these and many other factors can contribute to the inappropriate determination of drug concentartion. in plasma. In such situation, pathophysiology is then considered an underlying issue needs to be resolved prior to apply kinetic parameters.
Overview of pharmacokinetics
Pharmacokinetics Absorption :
In this section we will discuss the root of drug administration, drug absorption, bioavailability, bioequalance and therapeutic equivalence
1) ROUTES OF DRUG ADMINISTRATION
The route of administration is determined by the properties of the drug for example water or lipid solubility, ionization or by the therapeutic objectives for example, the desirability of a rapid onset, the need for
long-term treatment, or restriction of delivery to a local site.
Major routes of drug administration are
- Parentral ( Intravenous IV, Intramuscular, Subcutaneous,
- Other ( inhalation, Intranasal, Intrathecal/Intraventricular, topical, transdermal, Rectal )
Most of the drugs are given through oral route from where the drug has to absorb from microvillus present in small intestine prior to distribution throughout the body. The rate at which drug is absorbed and the extent to which it absorbs plays a crucial role in suggesting peak plasma concentration. Drugs that are administered through parenteral route do not undergo absorption phase rather they are directly available in the bloodstream for further distribution.
2) Absorption of drugs
Absorption is the transfer of a drug from the site of administration to the bloodstream. Number of factors should be considered while studying absorption phase, such as drug coating, solubility, pH, lack of protein or mediator required for transportation, vulnerability to denature by enzymes in GI tract etc. in such cases less amount than desired would be available for distribution hence lesser would be the effect produced.
Mechanisms of absorption of drugs from the GI tract
- Passive diffusion
- Active transport
Hence absorption is directly linked to bioavailability of drug at a site of action. This ultimately is related to AUC(area under curve) ie. Active plasma drug concentration.
Factors influencing absorption
- Effect of pH on drug absorption
- Blood flow to the absorption site
- Total surface area available for absorption
- Contact time at the absorption surface
- Expression of P-glycoprotein
3) Bioavailability :
Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. Bioavailability is important factors for calculating drug dosages for nonintravenous routes of administration.
Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration.
Factors that influence bioavailability:
- First-pass hepatic metabolism
- Solubility of the drug
- Chemical instability
- Nature of the drug
4) Bioequivalence :
It can be described as when the two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations.
5) Therapeutic equivalence :
Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent i.e same in dose, same in route of administration and active ingredients
Pharmacokinetics of drug distribution:
Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and the tissues. following are factors that affect drug distribution.
- Blood flow: The rate of blood flow to the tissue capillaries varies widely. For example blood flow to the “vessel-rich organs such as brain, liver, and kidney is greater than that to the skeletal muscles.
- Capillary permeability: Capillary permeability is determined by capillary structure and by the chemical nature of the drug.
- Binding of drugs to plasma proteins and tissues
Volume of distribution Vd :
The apparent volume of distribution, Vd, is defined as the fluid volume which is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0).
V = Amount of drug in the body/C
Once drug moiety is available in the bloodstream it is then distributed in body tissues. Number of factors affect distribution rate such as circulation which tends to be higher in children than adults hence the rate of distributi
Drug distribution is widely monitored by volume of distribution. It refers to the extent to which drug is distributed in body’s compartments. The binding ability of a drug to tissues and proteins mainly albumin acts as a significant barrier to calculating Vd. Less Vd indicates the presence of a drug in blood mainly whereas higher Vd suggests drug distribution mainly in tissue.
Once drug effect is distributed it then undergo metabolism in the liver. Many drugs undergo first-pass metabolism where a significant amount of dose is inactivated by liver enzymes. This is kept in mind while the formulation of drugs. Fewer drugs are converted into their active form in the liver after which they produce their desired activity. Metabolism occurs in II phases.
Phase I reactions alter drug molecules either for phase II(conjugation and elimination) reactions or for direct elimination.
Phase I Metabolism:
Phase I reactions are that pharmacokinetics metabolism that convert lipophilic drugs into more polar
molecules. This occurs by introducing or unmasking a polar functional group, such as –OH or –NH2. Phase I reactions usually involve reduction, oxidation, or hydrolysis. Phase 1 depends upon following:
- Phase I Reaction utilizing 450 system
Phase II Metabolism :
This phase consists of conjugation reactions. If the metabolite from phase I metabolism is sufficiently polar, it can be
excreted by the kidneys. However, many phase I metabolites are still too lipophilic to be excreted.
Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being elimination through the kidney into the urine The rate of excretion depends upon the rate of distribution and metabolism as well as kidney functioning. Drug dosing interval is all based on elimination criteria of drug hence it is a vital phase while studying kinetic parameters.
Basic criteria behind pharmacokinetic are to determine clearance rate of the drug in the body. This functionally measures both distribution and elimination of drug moiety.
It refers to the actual removal of the drug from the body with time. By determining clearance we can calculate :
- Drug dose(therapeutic dose)
- The time interval between dosing
- And to some extent preferred route of administration can also be calculated with the help of drug clearance calculation.
Clearance(Cl)= volume of distribution(Vd) x elimination constant(K)
It is measured in terms of volume per unit time (ml/min).