Pharmacokinetics and Pharmacodynamics

Introduction

Pharmacokinetics is the study of the behavior of the body towards the drug and Pharmacodynamics is the study of the behavior of drugs towards the body.

Pharmacokinetics is the study of absorption, distribution, metabolism, and excretion of the drug. When a drug is administered to the body through a dosage form, it is ready to release and is absorbed in the tissues and extravascular tissues.

After that drug is distributed and eliminated from the body which varies for patients. Pharmacokinetic consists of the study of the behavior of the body towards drugs from absorption till elimination from the body.

Pharmacodynamics is the study of the therapeutic effect of the drug, its mechanism of action and the relationship between the drug concentration and its effects. It also deals with the toxic effects of the drug.

Four principles of Pharmacokinetics

 Four basic principles of pharmacokinetics are

  1. Absorption
  2. Distribution
  3. Metabolism
  4. Excretion

Absorption

After administration, the therapeutic agent is absorbed in the site of absorption. According to pharmacokinetics drug absorption depends on the physicochemical properties of the drug and its dosage form.

Factors affecting drug absorption are solubility, permeability, stability, and ionization of the drug. Drugs have been classified depending on their solubility and permeability. It is called BCS (bioavailability classification system).

BCS 1: high solubility and high permeability

BCS 2: low solubility and high permeability

BCS 3: high solubility and low permeability

BCS 4: low solubility and low permeability

Class 1 drugs are easy to be absorbed and class 4 drugs are very difficult to be absorbed.

Lipinski’s Rule of 5: Christopher A Lipinski was the scientist who talked about Rule of 5 in 1997. According to him, a drug must follow the rule for the therapeutic effect and bioavailability. Lipinski’s Rule of 5 is as follows

  1. The drug has a molecular weight less than 500g
  2. Log p has a value of less than 5
  3. Hydrogen bond donor of the drug is less than 5
  4. Hydrogen bond acceptor of the drug is less than 5

This rule helps for the selection of new chemical formulas for study as a drug.

Distribution

After absorption, we study about distribution of a drug in pharmacokinetics. The drug is distributed to the body by the circulatory system. Blood carried the drug to the target site i.e receptors or other tissues. The distribution also depends upon the physicochemical properties of the drug and its affinity to bind any barrier.

The permeability of the drug very much depends upon the blood-brain barrier, blood taste barrier or blood placenta barrier. And the permeability affects the distribution of the drug. Moreover, distribution also depends upon the protein binding nature of the drug. Unbinding drugs are distributed easily. Drug distribution is calculated via the volume of distribution

The volume of distribution, Vd in the pharmacokinetic model is used to estimate the extent of the volume of drug distribution in the body. The hydrophilic medicines such as gentamicin, tolbutamide, and lithium have a low volume of distribution Vd and high plasma concentration. While an increase in Vd will result in high plasma concentration for lipophilic medicines such as diazepam and propranolol causing an increase in plasma half-life.

Half-life

half-life (t1/2) refers to the time taken for half the initial dose of medicine administered to be eliminated from the body. For example, the half-life of ciprofloxacin is 6 hours. Half of the dose is eliminated from the body in urine, 50-70% of it is unmetabolized and 10% is metabolized when excreted from the body.

Metabolism: it is the term used for the chemical reaction taking place in the body to covert the chemical compounds in different other chemical forms. It is the combination of catabolism (the breakdown of compounds) and anabolism (synthesis of new compounds). Drugs undergo metabolism at different sites i.e liver or kidney and convert into metabolites. Metabolites may be more or less (prodrug) active than parent medicine. The liver is the major source of enzymes (P450 enzymes). The Pharmacokinetic of the drugs is affected by metabolism.

Drug metabolism consists of three phases. Phase 1 ( CYP 450 enzymes), Phase 2 ( Conjugation), Phase 3 ( excretion).

The Toxicity of drugs and drug interactions depend upon metabolism.

Metabolism of Itopride Hydrochloride: Itopride HCl undergoes extensive hepatic metabolism. It converts into three metabolites. Itopride HCl is metabolized by a flavin-dependent mono-oxygenase (FMO3). The abundance and efficiency of FMO isozymes can be subject to genetic polymorphism, which can lead to a rare autosomal recessive condition known as trimethylaminuria (fish odor syndrome). The half-life of itopride HCl is six hours.

Excretion:

The drug is excreted from the body through various routes; such as kidney or bile, sweat, tears, breast milk. The drug is excreted from the body in its active chemical state or in the form of metabolites. The polarized form of drug or hydrophilic drug is easily eliminated through urine. The lipophilic drug is needed hepatic pathway to be converted into metabolites to easily excrete in urine. The drugs which pass through the liver for the first-pass effect are entered in bile and use the pathway of the small intestine to excrete.

Bioavailability is the rate and extent to which drug in the form of the active moiety is absorbed from a drug product and becomes available at the site of action. Pharmacokinetics deals with the bioavailability of the drugs so that it should give therapeutic effects. For the development of new dosage forms, the researchers study all pharmacokinetic parameters of the drug for its maximum availability.

Pharmacodynamics:

Pharmacodynamics is the study of biochemical and physiological effects of drugs on the body; mechanism of drug action and relationship between drug concentration and effect.

For example, the pharmacodynamics of ciprofloxacin is; it inhibits DNA gyrase to prevent DNA replication. E.coli is sensitive to ciprofloxacin. Ciprofloxacin inhibits its DNA replication leading to inhibit its infection.

Therapeutic effects are achieved at the minimum effective dose of the drug. At this dose, the drug shows its mechanism of action at the target site and we achieve the therapeutic effect.

Toxicity effects are achieved when the drug crosses the maximum therapeutic concentration and it leads to adverse effects or damage to the body. Pharmacodynamics is also the study of the therapeutic and the toxic effects of the drug.  

For example, digoxin is a drug used to treat heart failure or Atrial fibrillation. The therapeutic serum concentration of digoxin should be 0.8-2.0 ng/mL. It has a narrow therapeutic index. As the concentration of digoxin exceeds to toxic level it causes adverse effects like nausea, hyperkalemia, dysrhythmias, and malaise.

Pharmacodynamic interactions: Pharmacodynamic interactions means the interaction of two drugs. The action of one drug is changed in the presence of another. There are four main groups of pharmacodynamic interactions.

 The variability of such interactions may be further complicated owing to significant genetic differences between individuals.

The first main group of pharmacodynamic interactions is of synergistic interactions. The action of a drug is enhanced by another, such as the analgesic action of one NSAID agent being enhanced when a second NSAID agent is given concurrently.

The second group of interactions is antagonistic when the main action of an index drug is opposed or minimized by another, such as between cholinergic antagonists (atropine) and cholinergic agonists (acetylcholine).

The third group of pharmacodynamic interactions is interactions secondary to changes in drug transport mechanisms, such as occur at adrenergic nerve terminals when the actions of adrenergic neuron-blocking drugs such as guanethidine may be blocked by phenothiazine-type drugs or other indirectly acting sympathomimetic amines and tricyclic antidepressants (thereby negating their antihypertensive actions).

 The final group of pharmacodynamic interactions is interactions due to disturbances in fluid and electrolyte balance. Significant interactions with antihypertensive agents involve the thiazide diuretics and lithium. Thiazide diuretics block the secretion and excretion of lithium into the renal tubules, leading to increased lithium concentrations and subsequent toxicity.

The pharmacodynamics of a drug is affected by some physiologic changes. These changes are

  1. A disorder or disease
  2. Aging process
  3. Other drugs

Disorders that affect pharmacodynamic responses include genetic mutations, thyrotoxicosis, malnutrition, myasthenia gravis, Parkinson’s disease, and some forms of insulin-resistant diabetes mellitus. These disorders can change receptor binding, alter the level of binding proteins, or decrease receptor sensitivity.

Aging tends to affect pharmacodynamic responses through alterations in receptor binding or in post-receptor response sensitivity (see table Effect of Aging on Drug Response).

Pharmacodynamic drug-drug interactions result in a change in effects as discussed above.

Difference between Pharmacokinetics and Pharmacodynamics

The role of pharmacokinetics to derived dosing regimens to achieve therapeutic drug concentrations for optimal safety and efficacy. While pharmacodynamics refers to the relationship between drug concentration at the site of action (receptor) and the observed pharmacologic response.

New Drug development

is very much dependent on the pharmacokinetics and pharmacodynamics of the drug. The experimental aspects of pharmacokinetics and pharmacodynamics involve the development of biologic sampling techniques, analytical methods for the measurement of drugs and metabolites, and procedures that facilitate data collection and manipulation. The application of statistics is an integral part to study new drug development.