Pharmacokinetics

DEFINITION

Pharmacokinetics is the branch of pharmacology that Is concerned with what the body does to the drug, it refers to the movement of drug into the body & the activities or the reaction that takes place through the administration of the drug.

COMPONENTS OF PHARMACOKINETICS

• LIBERATION
• ABSORPTION
• DISTRIBUTOPN
• METABOLISM
• INTERACTION
• EXCRETION

LIBERATION

It is the first step in the process by which the medication, when administered inside the body liberates its active Ingredient into the body i.e. the pharmaceutical drug or substance is released or separated from its formulation that it was mixed with while manufacturing.

STEPS IN LIBERATION

• Disintegration:
  • When a drug is taken orally will pass through the oesophagus and into the stomach.
  • Disintegration is a physical process that occurs when a dosage form (e.g. tablet or gelatine capsule) breaks up into smaller particles.
• Disaggregation:
  • For immediate release of the drug products in vivo the breaking up (disaggregation) process of the dosage form of drug in to smaller parts usually starts in the stomach where it is completed depending upon the formulation, duration and volume of gastric fluid
• Dissolution:
  • The stomach has an aqueous environment, & it is the first place where the pill can dissolve. The rate of dissolution is a key element in controlling the duration of a drug's effect.
  • For this reason, different forms of the same medication can have the same active ingredients but different dissolution rates. If a drug is administered in a form that is not rapidly dissolved, the drug will be absorbed more gradually over time and its action will have a longer duration.

ABSORPTION

It Refers to the processes whereby the drug reaches the bloodstream (systemic circulation). Drugs that are administered by the intravenous route, or agents that are designed to have a direct local effect, other drugs must first be absorbed into the circulation before they can be distributed to the site of action.

MECHANISM OF ABSORPTION

• Passive Diffusion:
  • Drugs diffuse across a cell membrane from a region of high concentration (eg, gastrointestinal fluids) to one of low concentration (eg, blood).
  • The un-ionized form is usually lipid soluble (lipophilic) and diffuses readily across cell membranes such as fat soluble vitamins A, D, E, K.
• Active Transport:
  • Active transport requires energy to facilitate the transport of drug molecules against a concentration gradient, which usually occurs at specific sites in the small intestine.
  • The majority of drugs that are absorbed via active transport have a similar structure with endogenous substances such as ions, vitamins, sugars and amino acids.
• Filtration:
  • Filtration involves the aqueous channels or pores through which hydrophilic drugs can enter the blood stream. Filtration occurs in the jejunum and proximal tubules of kidneys. It is absent in the stomach and the lining of the urinary bladder.
  • Certain drugs are filtered through pores in the cell membrane (especially for small water soluble molecules such as glucose, ions such as sodium, magnesium etc.)
• Facilitated Diffusion:
  • Facilitated transport involves the drug moving down the concentration gradient by the help of transport proteins. This type of transport is also specific and saturable.
  • In facilitated transport is that lipid insoluble drugs become lipid soluble by combining with the carrier. E.g. iron binds with apoferritin and certain catecholamines enter the nerve cells by this process.

METABOLISM

• Drug metabolism is the chemical alteration of a drug by the body.
• Most drugs must pass through the liver, which is the primary site for drug metabolism. Once in the liver, enzymes convert pro-drugs to active metabolites or convert active drugs to inactive forms.
• The liver's primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes.

PHASES OF DRUG METABOLISM

• Non synthetic Phase/ Phase-I Reactions:
  • Phase I reactions are non-synthetic & involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis).
• Synthetic/ Phase-II Reactions:
  • Phase II or synthetic reactions involve conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine).
  • Metabolites formed in synthetic reactions are more polar and thus more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in non-synthetic reactions.

PHASE-I REACTIONS OF DRUG METABOLISM

• Oxidation:
  • Oxidation reactions involves in the addition of oxygen and/or the removal of hydrogen.
  • An example of an oxidation reaction is the hydroxylation of amphetamine to 4-hydroxyamphetamine and norephedrine.
  • The enzymes of oxidation include mixed-function oxidases, monoxygenases, and cytochrome P450 enzymes.
• Reduction:
  • Reduction reactions involves the addition of hydrogen and/or the removal of oxygen.
  • An example of a reduction reaction is the inactivation of warfarin by the transformation of a ketone group to a hydroxyl group (hydrogenation).
  • Enzymes involved in reduction reactions are called reductases.
• Hydrolysis:
  • Hydrolysis is a a reaction with water, a bond in the compound is broken, resulting in two compounds. At the same time the water molecule splits in two, with a hydrogen transferring to one of the compounds and a hydroxide to the other compound.
  • The conversion of cocaine to benzoylecognine and ecognine methyl ester are examples of hydrolysis reactions.
  • The enzymes of hydrolysis reactions include esterases, peptidases, and amidases.

PHASE-II REACTION OF DRUG METABOLISM

• Conjugation :
  • Conjugation reactions usually involve metabolite activation by a high–energy intermediate, in which an activated conjugating agent combines with substrate to yield the conjugated product, and  in which the substrate is activated and then combined with an amino acid to yield a conjugated product.
  • The most important conjugation reactions, are glucuronide conjugation, sulfo-conjugation, acetylation, amino acid conjugation, glutathione conjugation and methylation.

DRUG DISTRIBUTION

• Drug distribution refers to the movement of a drug to and from the blood and various tissues of the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in the tissues & organs of the body.
• Water-soluble vitamins and minerals will rapidly distribute to the extracellular fluid and be taken up by cells.  Like, Absorption Lipid-soluble vitamins will follow passive diffusion, most drugs follow passive diffusion along a concentration gradient.
• Diffusion is reversible i.e. when tissue levels of the drug exceed those in Extra-cellular Fluid (ECF) and circulation, then the drug will passively diffuse back to the bloodstream.

DRUG DISTRIBUTION DEPENDS ON THE FOLLOWING

• Volume of Distribution:
  • The volume of distribution is the volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma.
  • For example, if 1000 mg of a drug is given and the subsequent plasma concentration is 10 mg/L, that 1000 mg seems to be distributed in 100 L (dose/volume = concentration; 1000 mg/x L = 10 mg/L; therefore, x= 1000 mg/10 mg/L = 100 L).
• Binding:
  • The extent of drug distribution into tissues depends on the degree of plasma protein and tissue binding. In the bloodstream, drugs are transported partly in solution as free (unbound) drug and partly reversibly bound to blood components (eg, plasma proteins, blood cells).
  • Acidic drugs are usually bound more extensively to albumin; basic drugs are usually bound to alpha-1 acid glycoprotein, lipoproteins, or both.
• Blood Brain Barrier (BBB)
  • Drugs reach the central nervous system (CNS) via brain capillaries and cerebrospinal fluid (CSF). Although the brain receives about one sixth of cardiac output, drug penetration is restricted because of the brain’s permeability characteristics. Although some lipid-soluble drugs (eg, thiopental) enter the brain readily, polar compounds do not. The reason is the blood-brain barrier, which consists of the endothelium of brain capillaries and the astrocytic sheath.
  • The endothelial cells of brain capillaries, which appear to be more tightly joined to one another than those of most capillaries, slow the diffusion of water-soluble drugs.
  • With aging, the blood-brain barrier may become less effective, allowing increased passage of compounds into the brain

DRUG INTERACTION

•  Drug interactions involve combinations of a medication with other substances that alter the medication’s effect on the body.
• Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations.

Types of Drug Interactions

• Drug-drug Interactions:
  • A drug-drug reaction is when there’s an interaction between two or more drugs.
  • Eg. Interaction between warfarin (Coumadin), an anticoagulant and fluconazole, an antifungal medication. Taking these two drugs together can lead to a potentially dangerous increase in bleeding.
• Drug-Food Interactions:
  • This happens when food or beverage intake alters a drug’s effect.
  • Eg. When Statins (Lipolytic Agents) when administered with Grape Juice can cause Liver or Kidney Failure & Rhabdomyolysis (Skeletal Muscle Breakdown).
• Drug-Alcohol Interactions:
  • Many medications can cause serious side effects when taken with alcohol.
  • Over the counter drugs with alcohol can cause tiredness and delayed reactions. Cough syrup when taken with Alcohol can lead to Drowsiness.
• Drug-Disease Interactions: 
  • Certain drug alters or worsens a disease. Condition, Also some medical conditions can increase the risk of side effects from specific drugs.
  • E.g. some decongestants administered for colds can increase blood pressure. And Metformin worsens the Kidney Disease.

EXCRETION

• Drug excretion is the removal of drugs from the body, either as a metabolite or unchanged drug.
• There are many different routes of excretion, including urine, bile, sweat, saliva, tears, breast milk, and stool.
• The most important excretory organs are the kidney and liver.

IMPORTANT EXCRETORY ORGANS

• Renal Excretion:
  • The kidneys are responsible for the majority of excretion of water-soluble substances.
  • polar compounds, such as most drug metabolites, are not reabsorbed and are excreted from the body in the urine.
  • Smaller molecules are usually excreted in the kidneys
• Hepatic Excretion:
  • The biliary system can also excrete drugs that are not reabsorbed from the gastrointestinal tract.
  • Some drugs and metabolites can be excreted in the bile because they cross the biliary epithelium via active secretory transport. When the concentration of the drug in the body is high, the secretory transport carriers can become saturated and the drug is excreted.
  • Drugs that are excreted through bile are large, with a molecular weight <300 g/mol, and usually have polar and lipophilic groups.
• Pulmonary Excretion:
  • The lung is the major organ of excretion for gaseous and volatile substances.
  • The quantitative pulmonary excretion of ethanol can be identified using a breathalyzer test.
  • Most of the gaseous anesthetics are extensively eliminated in expired air.
• Salivary Excretion
  • The drug will usually be swallowed and reabsorbed, by a process called 'salivary recycling'.
  • Drug excretion into saliva appears to be dependent on pH partition and protein binding, Hence the dose of the drug can be adjusted by determining the salivary drug concentration.
  • The drug concentrations in saliva might be a good indication of plasma drug concentration
  • Salivary excretion of  certain drugs can result in localized side-effects
• Excretion Through Skin & Sweat glands:
  • Non-Ionized, Lipid soluble drugs are excreted through the epithelial cells via sweat glands depending on the pH partition
  • Passive excretion of the drug through the skin can cause localized hypersensitivity reactions
• Glandular excretion (via breast milk):
  • Drugs can be excreted through breast milk, so it is important to avoid such drugs to Nursing mothers as they can feed their babies.
  • Lipid soluble drugs are excreted through mammary glands via passive diffusion
  • Highly plasma bound drug like Diazepam is less secreted in milk.
  • Drugs are excreted by binding with the proteins in the breast milk.