Pharmacokinetics | Transportation, Absorption, distribution, metabolism, excretion | imdip

Pharmacokinetics Detail Study :Transportation, Absorption, distribution, metabolism, excretion

Pharmacokinetics and pharmacodynamics are the basis of the pharmacology.

Pharmacokinetics = Pharmacon + kinetics.
Pharmacon means Drug and kinetics mean movement.

Pharmacokinetics meaning the movement of drug to the body.

Pharmacokinetics definition: 

Pharmacokinetic is the study to find out how the body act with the drug by understanding the movement of the drug from the administration(input) to the elimination(output) of the body.

Pharmacokinetics process:

In pharmacokinetics, involves the study of 

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

Before the absorption, we should know 

The process of transportation of the drug.

• Passive transport
• Active transport

Passive transport 

Passive diffusion: 

• Transportation of the drug from higher concentration to the lower concentration across the membrane.
• No carrier involves.
• No energy involves.
• Only the concentration gradient is the driving energy of the process of transportation.

Filtration:

• Transportation via the capillaries present between the cells.
• The transportation process is driven by the osmotic pressure and the hydrodynamic flows.

Carrier-Mediated transportation system:

Facilitated Diffusion:

• From high to low concentration.
• Solute transportation in the direction of the electrochemical gradient.
• No energy required.

Active transport

• From low to high concentration.
• Solute transportation against the electrochemical gradient.
• Energy required.
• Channel proteins are not needed in active transport but the carrier proteins are needed.

Two types of active transport systems are there according to the source of the driving force.

Primary active transport: 

• The required energy obtained directly from the hydrolysis of ATP (Adenosine triphosphate).
• Also known as uniport (one molecule, moves in one direction).

Secondary active transport:

• The required energy obtained not directly from ATP hydrolysis. It is obtained from the energy of ionic concentration differences between the two sides of a membrane.
• This is termed as antiport(two molecules, moves in opposite directions), symport(two molecules, moves in the same direction).

Pharmacokinetics Absorption:

After the administration, the drug is transported from the site of administration to the bloodstream.
The rate of absorption is very important.

But absorption is not needed if the route of administration is intravenous.

Factors affect on the absorption are...

The concentration of the drug solution: 

If the concentration of the drug solution is high then the rate of absorption is also high.

The surface area of the absorbent:

If the surface area is larger then the absorption is high. Route of administration:  This one is a factor because absorption varies according to the route of administration.

The effect of pH on drug absorption: 

The drugs with acidic nature are absorbed faster in acidic media. 
Example: Acidic drugs (like aspirin) absorbed better in the stomach(acidic media).

The drugs with basic nature are absorbed faster in basic or alkaline media.
Example: Basic drugs (like diazepam) absorbed better in the intestine(basic media).

Pharmacokinetics distribution:

After absorption, of the drug into the bloodstream. The next part is the distribution of the drug into the body. 

Basically, there are several proteins present in the blood. 
In the protein molecule, there are some receptors, that recept the drug and make drug-protein complex. Then move and distribute into the whole body.

There are several factors affect the distribution

• Lipid Solubility
• Protein Binding
• pKa of the drug
• The molecular weight of the drug etc.

Lipid solubility:

• Lipid soluble drugs are mainly non- ionized drugs. They can easily cross the membrane. So the distribution rate is high. 
• But water-soluble or ionized drugs cannot cross the cell membrane.

Protein binding:

• Plasma protein binding: Plasma proteins are those proteins, which are present in the blood plasma. Like: albumin etc. Plasma protein binding is the process of complex formation of drug and plasma proteins. After the drug-protein binding, the distribution occurs. 

•  Tissue protein binding: Tissue proteins are those proteins, which are present in various organs.Like: Actin

pKa of the drug:

The acid-base dissociation constant (pKa) of a drug is one physicochemical parameter that controls various characteristics. 

pKa is the factor that influences the solubility of the drug. And if the solubility of the drug is high then the distribution is also high.

The molecular weight of the drug:

• The drugs with low molecular weight can easily cross the cell membrane.
• The drugs with high molecular weight can't cross the capillary of the membrane.

Pharmacokinetics metabolism:

Metabolism is also known as biotransformation. Biotransformation means the chemical alteration of the drug into the body.

Inactivation of drug: 

Various drugs and their metabolites behave like less active or inactive.

Example: Ibuprofen.

Activation of drug:

There are lots of drugs that activate into the body but with the main drug, other metabolites are also activating and working. The effectiveness of the drug is the total amount of effectiveness of the main drug and its active metabolites.

Example: Codeine is the drug and the active metabolite is morphine

Activation of inactive drugs: 

Some drugs are entered into the body as an inactive drug. But after meeting with some active metabolites its converts as active drugs. These types of drugs are known as prodrugs. Some prodrugs are activated at the site of action.

Example: Levodopa is the prodrug and active form is dopamine.

Classification biotransformation reaction:

1. Phase -1 or Nonsynthetic or functionalization reaction.
2. Phase-2 or Synthetic or conjugation reaction.

Nonsynthetic or functionalization reaction:

In this one phase, the more functional groups are generated, that's why chemically more reactive.

The nonsynthetic reactions are oxidation, reduction hydrolysis, etc.

Synthetic or conjugation reaction:

Conjugation reaction needs high energy to perform.
Reactions are glucuronide conjugation, acetylation, methylation, sulfate conjugation, glycine conjugation, glutathione conjugation, ribonucleoside synthesis, etc. 

For the metabolism of drugs, such enzymes are needed. That's called Metabolic enzymes.

Classification of Metabolic enzymes:

• Microsomal Enzyme
• Nonmicrosomal Enzyme

Microsomal Enzyme:

This Types of enzymes are present in the smooth endoplasmic reticulum of the liver, kidney, lungs, etc.

It can catalyze oxidation, reduction hydrolysis, etc. reactions.

Example: Cytochrome P450, Glucouronyl transferase.

Nonmicrosomal Enzyme:

It presents in the mitochondria and cytoplasm of the hepatic cells, plasma, etc.

It can catalyze oxidation, reduction hydrolysis, etc. reactions without glucuronidation.

Example: Amidase, Esterase, etc.

Hofmann elimination:

Inactivation of the drug in the body due to spontaneous molecular rearrangement without the help of enzymes.

Ex: atracurium.

Inhibition of drug metabolism:

One drug can inhibit the metabolism of another drug. When both utilize the same enzyme or cofactors.

Example: Allopurinol is a drug, that inhibits the drug Diltiazem's metabolizing enzyme.

First pass metabolism:

First pass metabolism of a drug is the metabolism by which the amount of drug reduced before reaching the systemic circulation.

Pharmacokinetics excretion:

After metabolism of the drug. The next stage is excretion.

The drugs and its metabolites excreted through
Urine, Faeces, Saliva, Sweat, Milk, etc.

Renal excretion:

Renal excretion is the main way of excretion from the body. Most of the drugs are excreted through renal excretion.

Kinetics of elimination:

Kinetics of elimination of the drugs is one of the most important part of pharmacokinetics it contains several equations of kinetics. 

Prolongation of drugs: 

Prolongation of drugs means longtime action of a drug into the body. It has a lot of benefits.

• For some serious cases, drugs effect could be maintained overnight without disturbing patient.
• It can improve patients compliance.