Pharmacokinetics is an essential aspect of pharmacology that deals with the study of the movement of drugs within the body. It encompasses drug absorption, distribution, metabolism, and elimination from the body. Understanding pharmacokinetics is critical for medical professionals, including those taking the NEET PG exam.
Given the importance of pharmacokinetics in drug therapy, let’s learn more about this topic for NEET PG exam preparation. Read on.
Pharmacokinetics studies the four different phases through which the drug goes through after it enters our body. This is called the ADME study. The four parameters that comes under ADME study are as follows:
A basic drug cannot cross an acidic medium and an acidic drug cannot cross a basic medium. Because, they can become water-soluble in opposite mediums and can get ionized. Acidic drugs like aspirin can easily cross the stomach. Whereas, basic drugs like morphine get absorbed from the intestines as the medium is alkaline.
Practically almost every drug, whether they are acidic or basic, gets absorbed from the intestine. The reason being, the intestines have large surface area and hence, the drug stays in the intestine for a longer period of time. Diseases that affect the intestine which decreases the transit time such as diarrhea, reduces drug absorption as the drugs stay for a shorter period of time in the intestine.
BIOAVAILABILITY OF A DRUG
Once a drug is administered into the patient orally, it will initially reach the liver through the portal circulation and a part of the drug remains non-absorbed. A part of the drug that has been absorbed by the liver gets metabolized in the liver. The non-metabolized part reaches the systemic circulation from the liver.
The percentage of non-metabolized drug that reaches the systemic circulation is known as the bioavailability of the drug. Bioavailability depends upon two factors. One being, the percentage of drug that has been absorbed (the more the absorption, the more the bioavailability). The second factor that affects bioavailability is the percentage of drug that has been metabolized in the liver. This is known as first pass metabolism or FPM (the more the FPM, the less the bioavailability).
PLASMA CONCENTRATION-TIME GRAPH OF BIOAVAILABILITY (PC-T GRAPH)
Plasma concentration is marked on the Y-axis and time on the X- axis. The PC-T curve reflects the amount of drug that has reached systemic circulation in a given time.
C Max represents the highest concentration of a drug that has reached systemic circulation. It is the maximum plasma concentration that can be obtained with that particular dose. Tmax is the point corresponding to Cmax (in the Y-axis) in the X-axis. It is the time in which we can obtain the maximum plasma concentration of a drug. Therefore, Tmax represents the rate of drug absorption. If Tmax is lower, the drug is absorbed quickly and visa-versa.
AREA UNDER THE CURVE (AUC): The total area that comes under the PC-T curve is known as AUC. It reflects the extent of drug absorption.
Suppose the area under the PC-T curve for drug A is 100. When drug A is mixed with drug B, the area becomes 150.This indicates that drug B has increased the availability of drug A in the blood.
This is made possible by inhibiting the first pass metabolism of drug A.
The distribution or disbursement of an unmetabolized part of the drug as it passes through the blood is known as distribution of drugs. It is measured by using a parameter called volume of distribution called Vd. Vd = amount of drug injected/ plasma concentration obtained. Higher the Vd, the more is its concentration in the tissues. Hence, less amount of drug will be present in the plasma.
Volume of distribution depends upon the following factors:
Lipid solubility (LS): The more the lipid solubility of the drug, the more easily it can cross the membrane. Hence, the easier it can get distributed.
Plasma protein binding (PPB): If a drug is bound to proteins in the plasma, it cannot cross the membranes as proteins themselves are unable to do the same. Hence, the drug gets retained in the plasma, which ultimately decreases the volume of distribution (Vd). Hence, PPB and Vd are inversely proportional.
Barriers: Vd depends upon barriers. If a drug has a higher ability to cross barriers, the more is its ability for distribution.
CLINICAL IMPORTANCE OF VOLUME OF DISTRIBUTION
Vd helps us to measure loading dose (LD).
It is the initial dose given to achieve a particular plasma concentration.
LD = Vd × Target plasma concentration.
The dose given to maintain the loading dose is known as the maintenance dose (MD).
MD = Clearance × target plasma concentration.
Acidic drugs usually bind to albumin protein.
Basic drugs usually bind to alpha acid glycoprotein.
The purpose of biotransformation is to convert the non-metabolized drug into water-soluble form so that it can be easily excreted from the body. There are two phases of drug metabolism which are phase 1 and phase 2.
PHASE 1 OF DRUG METABOLISM: The drug gets inactive in this phase of drug metabolism. The following catabolic reactions/non-synthetic reactions occurs in this phase:
PHASE 2 OF DRUG METABOLISM: Conjugation reactions/synthetic reactions take place in this phase of drug metabolism. Drug can combine with substances like:
The most common Phase 1 reaction is oxidation and the most common phase 2 reaction is glucuronide conjugation. The purpose of phase 1 is to make the drug sticky so that it can get attached to the conjugation group/functional group. Purpose of phase 2 is to make the drug water soluble.
Both the phases are catalyzed by enzymes. There are 2 kinds of enzymes:
These are the enzymes which are present in the endoplasmic reticulum. They can be induced or inhibited.
Cytochrome P450/CYP is one of the most important microsomal enzymes.
CYP3A4: Some of the important drugs metabolized by an isoform of CYP called CYP3A4 are: (code to remember is CT SCAN)
C - Cyclosporin
T - Tacrolimus (these are immune-suppressant drugs)
S - Statins (most of the statins are metabolized by CAP3A4)
CAT- Cisapride, Astemizole and Terfenadine. (These drugs may lead to a QT prolongation called Torsades-de-Pointes)
A - Amiodarone
N - Navir (Navirs are protease inhibitors of HIV)
CYP2D6: Some of the common drugs metabolized by CYP2D6 are
Antidepressants (most depressants like TCA, SSRI, SNRI etc. are metabolized by CYP2D6).
Most of the commonly prescribed anti-arrhythmic drugs are metabolized by CYP2D6.
Warfarin, which is an anticoagulant, is metabolized by CYP2C9.
CYP2C19: Drugs metabolized by CYP2C19 are
Clopidogrel (this is a pro-drug. It becomes inactive with the help of CYP2C19. Hence, when enzyme inhibitors like omeprazole are administered, clopidogrel becomes ineffective.)
NON-MICROSOMAL ENZYMES: They cannot be induced or inhibited. Hence their level remains constant. An enzyme inducer increases the metabolism of a drug. Hence the drug becomes inactive very quickly. An enzyme inhibitor stops the metabolism process and thereby increases the drug concentration which will lead to toxicity.
IMPORTANT ENZYME INDUCERS: (code to remember is “GPRS Cell Phone”)
G - Griseofulvin
P - Phenytoin
R - Rifampicin
S - Smoking
Cell - Carbamazepine (CBZ)
Phone - Phenobarbitone
IMPORTANT ENZYME INHIBITORS: (code to remember is “ vit K cannot cause enzyme inhibition)
Vit - Valproate
K - Ketoconazole
Can - Cimetidine
Cause - Ciprofloxacin
Enzyme - Erythromycin
Inhibition - Isoniazid (INH)
Important information Erythromycin like drugs inhibits the metabolism of drugs like cisapride, astemizole and terfenadine. This will lead to their toxicity
Due to certain genetic conditions, an individual may have less amount of CYP2C19. In such people, clopidogrel is not effective.
Most of the drugs are excreted by the kidney.
Some drugs like Lithium can be excreted through saliva and sweat.
The three stages of excretion are
Drugs are filtered across the glomerulus.
Both lipid-soluble and water-soluble drugs can be filtered by glomerulus. Hence, there is no barrier to glomerular filtration. Because, there are pores present in the glomerulus.
If a drug has more plasma protein binding (PPB), it cannot be filtered by the glomerulus.
Most of the drug is reabsorbed after filtration.
Only lipid-soluble drugs can be reabsorbed as the tubular membrane is devoid of pores.
Drugs can be made water-soluble inside the tubules. The property can be used in drugpoisoning, for example aspirin poisoning.
In aspirin poisoning, we make the medium basic (as aspirin is acidic in nature). Hence it becomes water-soluble. As a result of this, aspirin cannot be reabsorbed.
In case of acidic drug poisoning like aspirin poisoning, we give sodium bicarbonate to make the urine alkaline, so that the drug is excreted.
In case of basicdrugpoisoning, ammoniumchloride is administered which makes the urine acidic. Thereby, the drug becomes water-soluble and gets excreted.
Some drugs are excreted through the tubules.
The secretion process is saturable. Hence, only one drug can be secreted at a time.
Penicillin is very quickly secreted. But when penicillin is given along with probenecid, (probenecid is secreted by the same pump but it has more affinity) penicillin cannot be secreted. As a result of which, they remain in the blood itself. Hence, the plasma concentration of penicillin increases, which makes them long acting.
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