Revise pharmacokinetics in a Q&A format, with helpful tables, lists, and tags for SAQ, LAQ, and Viva questions.
What do you mean by pharmacokinetics?
Pharmacokinetics:(Kinetic means movement) (drug movement in the body) Drug moves inside the body, undergoes absorption, distribution, biotransformation, and excretion. So Pharmacokinetics is the study of absorption, distribution, biotransformation, excretion of a drug. Includes half life, duration of action, onset of action, bioavailability.
What do you mean by pharmacodynamics?
Pharmacodynamics: (Dynamic means one who brings about change, one who makes effect) So Pharmacodynamics is the study of effects of drug on the body. It includes pharmacological actions/effects of a drug, its mechanism of action, interactions with receptors, adverse effects.
What is first pass metabolism/Pre-systemic metabolism? Give examples and mention its implications.
First pass metabolism/Pre-systemic metabolism: is the metabolism or degradation of a drug that takes place even before it reaches the systemic circulation.
(Pre=before, systemic=before reaching systemic circulation)
It is also called first pass metabolism, which means the metabolism of a drug which happens when it reaches a particular organ for the first time before reaching systemic circulation. Thus when a drug reaches the liver via portal circulation for the first time, the breakdown taking place may be called first pass hepatic metabolism.
In fact, breakdown of a drug may start by saliva, as early as when a tablet is in the oral cavity itself. There onwards, at various places the pre-systemic or first pass metabolism may take place. Example: the destruction by salivary enzymes or gastric hydrochloric acid in stomach or by the enzymes in the intestinal wall or the liver (where the drug reaches first through the portal vein).
– The first pass metabolism or pre-systemic metabolism is highest when the drug is given by oral route of administration and is lowest by intravenous route of administration.
– This is one of the reasons for lowest bioavailability by oral route and highest bioavailability by intravenous route.
If the presystemic metabolism of a particular drug is so high that leads to low oral bioavailability, then such drugs may be needed in higher doses to produce a given effect.
Examples of drugs with high first pass metabolism: Propranolol, Verapamil, Nitroglycerin, Pethidine, Morphine.
On the other hand, If the presystemic metabolism is too high so that the oral bioavailability is almost negligible, then such drugs may not be given at all by oral route.
Examples (Never used by oral route): Isoprenaline, Lidocaine, Hydrocortisone, Testosterone
Define “Bioavailability”. Mention the various factors affecting absorption / bioavailability.
Bioavailability is the actual amount of drug that is available to the patient at the site of action.
It is the fraction of the total dose available for action.
It may be expressed as –
Bioavailability (F) = Amount absorbed / Amount administered
For example, if amount given is 100 and the amount absorbed is 50, then-
Bioavailability = 50/100 = ½ = 0.5 or 50 percent
Bioavailability of 1 means 100 percent.
Bioavailability is highest (100%) by intravenous route, and is almost 100% by sublingual route (for certain drugs), and is lowest by oral route of administration. This is because the first pass metabolism is highest by the oral route.
Factors affecting absorption/bioavailability
A. Drug related factors
- Physical properties of the drug
-Physical state: Solid or Liquid: Liquids are better absorbed than solids.
-Water solubility: Optimum water solubility is essential for the substance to get dissolved.
-Lipid solubility: Lipid soluble drugs are able to cross the mucous membranes better, because most of the human cell walls are abundant in lipids
- Nature of dosage form
-Particle size: Smaller the particle size, better is the absorption
-Disintegration time: Time required for the tablet to get broken down. More the disintegration time, slower will be the absorption.
-Dissolution time: Time required for a substance to get dissolved. More the dissolution time, slower will be the absorption.
- Route of administration
Intravenous and sublingual routes have highest bioavailability followed by the intramuscular and subcutaneous routes. Oral route is supposed to have the lowest bioavailability.
B. Patient related factors (Physiological/Pathological factors)
- pH of the medium: A drug shall get better absorbed through the medium with similar pH as the drug. Acidic drugs are better absorbed through stomach. Basic drugs are better absorbed through the intestines due to the alkaline pH in the intestines.
- Ionization: Ionization decreases the absorption of a drug. Less the drug is ionized, better is the absorption. Acidic drugs get less ionized at the acidic pH of the stomach and hence get better absorbed through stomach, while the alkaline drugs get less ionized at the alkaline pH of the intestines and hence alkaline drugs are better absorbed through intestines.
- GI transit time: is the time required for a drug to pass through the gastrointestinal tract. If the GI motility is increased due to any condition, then the drug will pass the GIT quickly and shall get less chance to get absorbed.
- Presence of food: In general, food decreases absorption of most of the substances. Especially food is known to decrease rifampicin absorption to a great extent, so rifampicin is always given early in the morning on empty stomach.
- Presence of other drugs: Some drugs may decrease or increase the absorption of some other drugs by various mechanisms. Examples: Tetracyclines chelate the positive ions and hence they decrease the absorption of calcium, magnesium, aluminium, iron, phosphorous.
- Surface area of absorption: More the surface area available, better is the absorption.
- Circulation/blood flow: More the blood flow, better is the absorption.
– By producing vasoconstriction with adrenaline, the blood flow to the area is reduced. So the systemic absorption of local anesthetics is reduced, thus leading to prolongation of their duration of action.
- Metabolism: More the first pass metabolism, less is the amount of drug absorbed.
- Genetic factors affecting absorption: Deficiency of intrinsic factor of Castle shall inhibit the oral absorption of vitamin B12. This condition is called pernicious anemia, and in this condition, vitamin B12 must be given by parenteral routes of administration.
- Presence of disease: Diseases of the gastrointestinal tract like celiac diseases, Crohn disease, hepatic diseases, cardiovascular diseases like heart failure as well as other diseases like diabetes mellitus may affect the absorption and bioavailability of various substances.
Define “Biotransformation” and enumerate its sites.
Mention various reactions in biotransformation with examples.
Biotransformation: Chemical modification or alternation of drugs with a purpose of finally making them easily excretable. To make excretable, substances will be converted from nonpolar to polar forms, more lipid soluble into less lipid soluble forms or nonionized into more ionized forms; so that the renal tubules cannot reabsorb the substances. Usually the process leads to detoxification of substances. [Occasionally, a toxic metabolite may be formed]
Thus, final purpose of biotransformation is to convert substances from:
Less excretable ➔ more excretable
Nonpolar ➔ polar
More lipid soluble ➔ less lipid soluble
Nonionized ➔ ionized
(Remember – Nonpolar,Lipid-soluble, Nonionized substances are absorbed or reabsorbed better. Polar, less lipid-soluble, more ionized forms are eliminated better.)
During biotransformation –
- An active drug may be inactivated… or
- An inactive drug (prodrug) may be activated ..or
- An active drug may get converted into active metabolite.
Sites for biotransformation: Liver, Kidneys, Intestines, Lungs, Plasma, and others
Reactions in biotransformation
Phase I (also called NONSYNTHETIC)
- Oxidation: Addition of oxygen (-vely charged radical) or removal of hydrogen (+vely charged radical)
Cytochrome P-450 dependent (Microsomal enzymes)
N-oxidation: Acetaminophen (paracetamol)
S-oxidation: Cimetidine, chlorpromazine
Hydroxylation: Phenobarbitone, phenytoin
N-dealkylation: Morphine, caffeine, theophylline
Cytochrome P-450 indepdendent (Non-Microsomal enzymes)
Dehydrogenation: (alcohol dehydrogenase – ethyl alcohol, methyl alcohol, aldehyde dehydrogenase- acetaldehyde),
Amine oxidation: (Monoamine oxidase – MAO) (epinephrine)
- Reduction: Addition of hydrogen (+vely charged radical) or removal of oxygen (-vely charged radical) (reverse of oxidation): chloramphenicol, warfarin, dantrolene, halothane, clonazepam,naloxone
- Hydrolysis: (Hydro / Lysis): Breaking down or cleavage with addition of water
Esters (succinylcholine, procaine, aspirin, clofibrate), Amides (procainamide, lidocaine, indomethacin), and peptides are hydrolyzed. The enzymes accordingly are called Esterases, Amidases or Peptidases. Example: Ester + water —(esterases)-➔ Acid + alcohol
- Cyclization: Formation of a cyclic/ring structure: proguanil
- Decyclization: Opening up of a ring structure: Phenobarbitone, phenytoin
Phase II (Synthetic): are usually conjugation type:
Usually covalent attachment of groups to form a conjugation product (Conjugation reactions)
- Glucuronide conjugation/Glucuronidation:
chloramphenicol, acetaminophen, morphine, diazepam, digoxin, digitoxin
Chloramphenicol: defective conjugation leads to accumulation and gray baby syndrome
INH, procainamide, hydralazine, dapsone, sulfonamides, clonazepam
Acetylator status of an individual may decide fast or slow acetylation of these drugs.(called genetic polymorphism). Slow acetylation may lead to excess effect or toxicity of such drugs – SLE-like symptoms with joint involvement seen with INH/procainamide/hydralazine.
- Methyl conjugation/methylation:
Epinephrine, norepinephrine, methyldopa, dopamine, histamine.
Catechol-O-methyl transferase (COMT) metabolizes epinephrine, norepinephrine
- Sulfate conjugation/sulfation: acetaminophen, methyldopa, estrone
- Glycine conjugation: salicylic acid, nicotinic acid, deoxycholic acid
- Glutathione conjugation: ethacrynic acid, reactive phase I-metabolite of acetaminophen
- Ribonucleotide/side synthesis: 6 mercaptopurine, 5-fluorouracil, cytarabine
A substance may undergo Phase I, then Phase II, and then get eliminated; or may skip Phase I and straightaway enter Phase II and get eliminated. A drug or its metabolites may move in these phases many times.
Enzymes taking part in biotransformation may be:
- Microsomal: Present on smooth Endoplasmic Reticulum (sER) of the microsomes
(These enzymes can be influenced by drugs)
Microsomal enzyme systems are Cytochrome P450 (CYP) dependent. Also called Mixed Function Oxidase systems.
Important subfamilies of enzymes are: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19…
- Nonmicrosomal: Present on mitochondria, cytoplasm, plasma
(These are less influenced by drugs)
Define “Prodrug” with examples and write advantages of prodrugs/write its implications.
Prodrug is an inactive form of a drug which stands in place of a drug
After entering the body, it gets converted into a pharmacologically active form.
Prodrugs may get activated intracellularly or extracellularly.
Uses /application of Prodrugs:
- To Improve drug delivery
- To Improve pharmacokinetics
- To Overcome toxicity
- To Provide targeted delivery to specific cells or tissues and overcome the lack of site specificity
- To Overcome chemical instability
Examples and implications/advantages of prodrugs:
Prodrug ➔ Active Drug
- Levodopa ➔ Dopamine
Dopamine is deficient in parkinsonism and is required for treatment; however, it cannot cross blood brain barrier. So its prodrug Levodopa, which can cross the blood brain barrier is administered. It enters the central nervous system, and then gets converted into dopamine. Thus, here the prodrug overcomes the barrier of entry.
- Fosphenytoin ➔ Phenytoin
Fosphenytoin is a prodrug of phenytoin preferred in acute convulsions, because phenytoin has erratic bioavailability, and fosphenytoin is a safer option.
- Valaciclovir ➔ Acyclovir
- Famciclovir ➔ Penciclovir
Acyclovir and Penciclovir have low aqueous solubility and low bioavailability, hence their ester prodrugs namely valaciclovir and famciclovir were developed, which produced better bioavailability.
- Dipivefrine ➔ Epinephrine
Dipivefrine, a prodrug of epinephrine used for glaucoma, has fewer ocular and systemic adverse effects as compared to epinephrine
- Bacampicillin ➔ Ampicillin
- Tamampicillin ➔ Ampicillin
Bacampicillin and talampicillin are esters of ampicillin with more complete absorption and better bioavailability as compared to ampicillin.
- Enalapril ➔ Enalaprilic acid (Enalaprilat)
- Proguanil ➔ Proguanil Triazine
- Mercaptopurine ➔ Methylmercaptopurine
- Loratadine ➔ Desloratadine
- Prednisone ➔ Prednisolone
Give examples of active drugs getting converted to active metabolites. What is its implication?
Some drugs are active and when they get metabolized in the body, they get converted into active metabolites, which have same action as the original drug. The active metabolite further continues the same action. The next active metabolite may further break down into another active metabolite, so on and so forth, to thus continue the action of the original drug for a longer duration.
Thus the reason behind the longer action of many drugs is – their property of getting converted into active metabolites.
Implication: A drug that gets converted into active metabolites has a longer duration of action.
|Active Drug ➔ Active Metabolite|
|1. Phenacetin ➔ Paracetamol |
2. Diazepam ➔ des-ethyl /desmethyldiazepam, oxazepam
3. Primidone ➔ Phenobarbitone
4. Amitriptyline ➔ Nortriptyline
5. Digitoxin ➔ Digoxin
6. Codeine ➔ Morphine
7. Morphine ➔ Morphine-6-glucuronide
8. Allopurinol ➔ Alloxanthine
Define “Pharmacogenetics”. Give examples of genetic factors modifying drug effect.
Pharmacogenetics is the study of genetic factors modifying drug effects. Genetic factors may alter the effect of the drug at a pharmacodynamic or pharmacokinetic level or both.
1. Atypical plasma pseudocholinesterase leading to succcinylcholine apnea. The enzyme butyrylcholinesterase is genetically atypical or ineffective in certain individuals, so it modifies the breakdown of succinylcholine (a skeletal muscle relaxant). This leads to slow breakdown of succinylcholine ➔ Neuromuscular paralysis and apnea. Since the enzyme responsible for succinylcholine breakdown is in fault, the treatment of this condition is going to be cholinesterase enzyme, which will be supplied through fresh blood transfusion. Hence treatment of succinylcholine apnea is fresh blood transfusion and artificial respiration.
2. N-Acetylation (slow acetylators) (AR): (INH, procainamide, hydralazine): This is called genetic polymorphism. Certain individuals have an autosomal recessive trait of slowly acetylating certain substances. The defect is in N-acetylation. In such individuals, certain drugs like INH, procainamide, hydralazine are metabolized slowly over a long period of time. This leads to their prolonged effects or toxic responses e.g. Lupus erythematosus like symptoms with joint swelling and joint pains. This is exhibited in about 5-% of white and African-Americans in US.
3. Hemolysis in G6PD deficiency: Primaquine, sulfa drugs
4. Malignant hyperthermia – halothane – abnormal Rynodine receptor
What is Hoffman Elimination? Write its implications.
Hoffman elimination means Spontaneous molecular rearrangement leading to breakdown and inactivation of certain drugs without any enzyme. The exact cause of the phenomenon is not known.
Examples: Atracurium, Cisatracurium
These drugs are skeletal muscle relaxants. Their property of getting inactivated by Hoffman elimination proves to be beneficial. Because in conditions in which hepatic enzymes may be deficient or where there may be renal insufficiency, other skeletal muscle relaxants would accumulate and produce toxicity.
Whereas Atracurium and cisatracurium do not need hepatic enzymes for their breakdown, so they can easily get metabolized and eliminated. Hence in conditions like hepatic or renal insufficiency, and in neonates and patients with old age, these drugs can be safely used.
What is “Therapeutic drug monitoring”? (TDM). Write its implications.
Therapeutic drug monitoring (TDM): is the measurement/estimation and monitoring of plasma levels of certain drugs in a given specialized situation.
TDM is important for:
Digoxin, lithium, tacrolimus, cyclosporine
When the drug has a narrow therapeutic margin, it is necessary to maintain the plasma concentration of a drug within the therapeutic range, so as to have the optimal effect of the drug without leading to severe drug toxicity. In such situations, it is of value to know the exact plasma concentration of a drug.
Also in the following situations, TDM is of importance.
1. Renal failure: Because increase in the plasma concentration of certain drugs may worsen the renal failure.
2. Poisoning: The plasma concentration of a drug may be of value when drug overdose has taken place, so as to monitor the response to treatment.
3. Failure of response: In certain situations, despite continued therapy there is lack of expected response, so it is worthwhile to check if the drug is achieving the expected plasma concentration.
4. To check the patient compliance: To confirm if the patient is taking the drug in a given dosage.
Write short note on: Methods of prolonging duration of action of a drug
Methods of prolonging duration of action of a drug:
By applying various principles of pharmacokinetics, it may be possible to use the drug in such a form in which it will have a longer duration of action. Some of the methods of prolonging duration of action of a drug are as follows:
1. To Prolong absorption of a drug
-Oral route: My making sustained release (SR) tablets, capsules, spansules
-Parenteral –with binding agent, insoluble form, oily solution, pellet /sialistic/biodegradable implants, injecting with vasoconstrictor (Local anesthetic injected with epinephrine), Transdermal therapeutic systems (patches of fentanyl, buprenorphine, diclofenac)
2. Preparing drug congeners with more plasma protein binding capacity so as to have a longer duration of action
3. Decreasing the rate of metabolism of a drug: eg. Cilastatin combined with imipenem – cilastatin inhibits renal dehydropeptidase and decreases the rate of breakdown of imipenem so that it is reabsorbed and acts for longer duration, ritonavir is combined with other anti-HIV drugs to inhibit their metabolism and to increase their duration of action
4. Decreasing elimination of a drug: Probenecid is combined with penicillins, because probenecid decreases the renal clearance of penicillins and increases their duration of action.
Define volume of distribution with examples. Mention the implications of high volume of distribution.
Volume of distribution is the amount of volume that a drug would require to get uniformly distributed throughout the body with the concentration same as in plasma.
It is the extent of drug getting distributed in the body relative to its amount in plasma.
It can be expressed as —
Volume of distribution (Vd) =
Total amount of drug in the body / Amount of drug in plasma
Example 1: Let us suppose for Drug A, amount of drug in plasma is 3 and in the extravascular compartment it is 27, then Vd will be –
Vd = total amount in body (3 + 27 =30) / amount in plasma (3)
= 30 / 3 = 10
Example 2: Suppose for Drug B, amount of drug in plasma is 27 and in the extravascular compartment it is 3, then Vd will be –
Vd = total amount in body (3 + 27 =30) / amount in plasma (27)
= 30 / 27 = 1.1
Volume of distribution of Drug A is 10 and of Drug B is 1.1.
This means Drug A has higher volume of distribution, means it gets distributed more in tissues as compared to the plasma.
High Vd or non-homogenous distribution: When the drug gets distributed more to the tissues, it is called High Vd or non-homogenous distribution.
E.g. Chloroquine, digoxin, warfarin
Implications of High Vd:
- Drugs with high Vd, get more deposited in the tissues.
- They are likely to have specific beneficial effects on the tissues where they get deposited.
- They are also likely to produce adverse effects specific to the tissue storage.
- It is difficult to remove such drugs out of the body in case of drug overdose.
If the drug has low volume of distribution (homogeneous distribution), means the drug remains more in the vascular compartment.
Volume of distribution determines the loading dose of a drug.
For practical calculation of Volume of distribution, apparent Vd is used.
Apparent Vd = Dose administered by IV route / Plasma concentration achieved
Enumerate the factors modifying drug distribution.
Factors modifying drug distribution
- Lipid solubility
- pH and Ionization
- Plasma protein binding
- Affinity of a drug for a particular tissue
- Regional blood flow
- Body fat (changes with age)
- Heart failure
- Liver cirrhosis
Mention Enzyme induction with examples and its implications.
Induction is a process of increase in the number of enzyme molecules.
Most of the drugs are metabolized in the body by the hepatic microsomal enzyme system (HMES) or also called the cytochrome P450 enzyme system (CYP 450 / CP 450), which contains various families responsible for specific reactions. These families include CYP3A4, CYP2D6, CYP 1A2, CYP2C9, CYP2C19 etc.
Some drugs given over a period of long time (at least weeks to months or more) have the property of inducing certain enzyme system/s. (This means there is increased number of enzyme molecules. Thus the drugs supposed to be metabolized by those particular enzymes will be metabolized quickly and their effect shall decrease). Drugs which induce the enzymes are called inducers.
INDUCERS – Examples
Barbiturates, Carbamazepine , Phenytoin (all three are antiepileptic drugs)
Ethanol (Ethyl alcohol)
Clinical implications of induction
1. Drug interactions leading to decreased effect.
Example: A 23-year-old woman on oral contraceptive pills is placed on a benzodiazepine medication for 3 months for complaint of disturbed sleep. Benzodiazepines are inducers of microsomal enzymes. So they may induce the enzymes responsible for breakdown of oral contraceptives. This will lead to more breakdown of contraceptives. Due to this there could be contraceptive failure, manifesting into pregnancy.
2. Self induction. Barbiturates or benzodiazepines can induce their own metabolism, and thus lead to decrease in their own effect when used over a long time, thus responsible for the phenomenon of their tolerance.
3. Barbiturates produce induction of enzymes responsible for porphyrin synthesis, thus precipitating a serious condition, called acute intermittent porphyria. (Hence this is a contraindication to the use of barbiturates)
4. In a condition called Kernicterus, wherein there is defective conjugation of bilirubin, Barbiturates can induce the glucuronide conjugation of bilirubin, and thus useful to treat this condition.
Mention“Enzyme inhibition” with examples and its implications.
Inhibition is a process of decrease in the number of enzyme molecules.
Drugs are metabolized hepatic microsomal enzyme system (HMES) or also called the cytochrome P450 enzyme system. This system has various families responsible for specific reactions. These include CYP3A4, CYP2D6, CYP 1A2, CYP2C9, CYP2C19 etc.
Some drugs have the property of inhibiting certain enzyme system/s. (This means there is decrease in the number of enzyme molecules. Thus the drugs supposed to be metabolized by those particular enzymes will be metabolized slowly and their effect shall increase or it may lead to toxicity of those drugs)
Inhibition (as compared to induction) is a fairly rapid process which may start even within hours or days
Ketoconazole, fluconazole (Azole antifungals)
Macrolides (erythromycin, clarithromycin)
Amiodarone, fluoroquinolones, Omeprazole, valproic acid
Implications of enzyme inhibition
- Decreased metabolism of other drugs
- Increased therapeutic effect of the drugs whose metabolism is inhibited
- Toxicity of the drug, whose metabolism is inhibited
- Drug interactions
The table below describes some effects of inhibition.
|Enzyme inhibitor||Decreases the breakdown and increases the levels of –||Effect|
|Erythromycin/clarithromycin||Warfarin (an oral anticoagulant)||Excess anticoagulation (Bleeding)|
|Fluoxetine||Terfenadine, astemizol, cisapride||Cardiac Arrythmia|
|Ritonavir||Other Anti-HIV drugs||Increased effect of anti-HIV drugs – (useful interaction)|
What is “Disulfiram-like effect?”(Antabuse-like effect). Give examples of drugs producing such effect and its clinical application
Disulfiram like effect is the effect or the action similar to a drug disulfiram.
Disulfiram (Antabuse) is an acetaldehyde dehydrogenase inhibitor used in the management of alcohol addiction.
Ethyl alcohol (by alcohol dehydrogenase) gets converted to acetaldehyde, and acetaldehyde (by acetaldehyde dehydrogenase) gets converted to acetic acid and water. Disulfiram inhibits the second step, leading to accumulation of acetaldehyde, and thus the patient gets severe symptoms (Facial flushing, Nausea, Vomiting, Headache, hypotension, hypoglycemia, dizziness, sweating, confusion, exhaustion, and sleep). [This is typically called as alcohol intolerance].
Due to this phenomenon, the patient gets discouraged from consuming alcohol. This is why this action of disulfiram is taken advantage of, and is used as “aversive therapy” in the treatment of alcohol addiction. (Aversion = dislike / disinclination) Aversion therapy or aversive therapy is a form of therapy in which an aversive stimulus (causing a strong feeling of dislike or disgust = the unpleasant symptoms produced by consumption of alcohol, in presence of disulfiram) is paired with an undesirable behaviour (urge for consuming alcohol) in order to reduce or eliminate that behavior.
Certain drugs capable of producing the same effect, when a patient consumes alcohol. Then this effect produced by those drugs is called “disulfiram or antabuse like effect”.
|Drugs having disulfiram or antabuse like effect|
|MetronidazoleCephalosporins, Trimethoprim, Sulfa drugs, Cotrimoxazole, Fluoroquinolones Macrolids (Erythromycin)ChlorpropamideH2 blockers (Cimetidine)|
Hence when the patient shall take any of the above drugs and consume alcohol, it will lead to a severe reaction of alcohol intolerance.
Hence whenever a patient is prescribed any of the above drugs, the patient should be warned not to consume alcohol. Or else, the physician needs to think of alternative drugs in such situations.
Disulfiram-like effect or antabuse like effect is an example of inhibition of metabolism.
Define “toxic metabolism” with an example.
Usually when the drugs are used in normal doses, they get broken down into harmless metabolites and get excreted. However, some drugs when used in larger doses, may exhaust the usual metabolic pathways, and may get converted into reactive toxic metabolites harmful to the body. This phenomenon is called “toxic metabolism”.
Example: Acetaminophen (Paracetamol) when used in normal doses gets converted into a harmless glucuronide and sulfate metabolite. However, when it is used in larger doses, especially in children, the normal metabolic pathways get exhausted, and the drug leads to formation of a REACTIVE TOXIC METABOLITE, called N-acetyl-p-benzoquinone imine. (NABQI). This is called toxic metabolism. The metabolite damages the essential hepatic cell proteins leading to cell death. It may further lead to renal damage.
The treatment of acute paracetamol poisoning is done with N-acetyl cysteine, which helps by breaking down the toxic metabolite by donating sulfhydryl group.
Define “cumulation” with examples.
Cumulation is the process of deposition of a drug in particular tissues. Drugs that have high or non-homogenous distribution have high affinity for certain tissues and a tendency to get deposited into those tissues. Such drugs may produce beneficial effects on those tissues. So also, there is a risk of toxicity to these tissues due to drug cumulation. Increased frequency of administration, administration in higher dosages, and prolonged administration shall obviously increase the susceptibility for adverse effects of such drugs.
1. Tetracyclines – Teeth, Bones
2. Chloroquine – Retina, liver
3. Streptomycin – Vestibular apparatus
4. Emetine, digoxin – Heart
5. Iodine, Amiodarone – Thyroid, lungs, skin, liver
6. Dapsone, Clofazimine – Skin, RES
What is Plasma protein binding of drugs? Give examples. Write 2 implications of plasma protein binding.
Plasma protein binding of drugs: Various drugs after being absorbed into the blood, may get bound to the plasma proteins. The bound form of the drug is inactive and the free form in the plasma is active, and there is a constant turnover between these two forms. When the concentration of the free form decreases, again some more drug is released from the protein-bound form, thus “high plasma protein binding” drugs have a long duration of action.
In general, acidic drugs have higher affinity for albumin, and alkaline drugs have higher affinity for alpha1 acid glycoprotein.
Plasma protein binding drugs: Examples:
|Acidic drugs (albumin)||Basic drugs (alpha 1 acid glycoprotein)|
|NSAIDs, Sulfa drugs. Tolbutamide, WarfarinBarbiturates, valproate, phenytoin, Benzodiazepines,Penicillins, steroids, fibrates||Beta blockersVerapamil, quinidine, disopyramide, Lidocaine, bupivacaine, imipramine, Methadone, prazosin|
1. Drug interactions due to plasma protein binding and displacement: Suppose the two drugs A and B have affinity for same plasma protein binding sites, and if the affinity of A is higher than that of B, then A can displace B from the protein binding sites, and the free concentration of B in plasma will become more, thus leading to excess action or toxicity of drug B.
Thus, simultaneous administration of two such drugs may produce a drug interaction. Example: NSAIDs may displace oral antidiabetic ( like Tolbutamide) and manifest as hypoglycemia.
Phenytoin may displace Warfarin (anticoagulant), and manifest as bleeding.
2. When there is hypoalbuminemia, because albumin available for binding is less, the free concentration of certain drugs may increase and may lead to unexpected adverse effects. E.g. Phenytoin, digitoxin
Define biological half life and write its significance
Biological half life or biological half time (t ½ ) is time required for original concentration of drug to become its 50 percent. = Time required for the original concentration of the drug to fall to its half.
Half life is independent of the dose.
Shorter the half time, more frequent is the need for dosing.
Longer the half time, less frequent dosing may be needed
The term half life may be applied to concentration of the drug in plasma or a tissue fluid or any particular tissue and then would be described as plasma half life or tissue half life.
Half time may be governed by various factors.
1. Hepatic diseases may increase t1/2.
2. High Plasma protein binding will lead to longer half time.
3. Drugs getting converted into active metabolites have a longer half time.
4. Tissue distribution of a drug
5. Renal diseases shall affect the elimination of the drug and prolong half time.
The term half time can also be applied to the process. So the half time of a process is the time required for any process to get 50% percent completed or time required for any process to come to its half way. Eg. Elimination half-time, Absorption half-time
Half time depends on the volume of distribution as well as clearance, and the interdependent formula is –
t ½ = (0.693) x (Vd) / CL ,
where, Vd = volume of distribution, and CL= clearance
At the end of one half time, 50% of the drug is supposed to get excreted, so by the following calculation, almost 93.75% of the drug gets excreted within 4 half times (near-complete elimination).
|1 t ½||50||50||50|
|2 t ½||25||50 + 25 = 75||25|
|3 t ½||12.5||75 + 12.5 = 87.5||12.5|
|4 t ½||6.25||87.5 + 6.25 = 93.75||6.25|
Therefore, we want to achieve a constant plasma concentration of a drug, then the next dose of the drug must be repeated at least before the 4 half times are over.
Define First order kinetics. Write its implications.
First order kinetics means the rate of elimination of a drug is proportional to the concentration of the drug.
It means a fixed proportion / fraction / percentage of the drug gets excreted.
This is the usual method of elimination for most of the drugs when the drugs are used in usual therapeutic doses.
Because the elimination is proportional, it creates a straight line. So this is called “Linear kinetics”.
Naturally the effects of such drugs following first order kinetics are predictable, and the doses of drugs can be increased or decreased safely. It means the plasma concentration of the drug rises or falls proportionally with the dose.
Define Zero order kinetics. Write its implications.
Zero order kinetics is defined as the method of elimination of a drug in which the fixed quantity or amount of the original drug gets excreted irrespective of its concentration. Therefore this is called “non-linear kinetics”.
Because the excretory mechanisms are saturated, even if larger doses are given, the body fails to excrete more amounts. Therefore it is also called “saturation kinetics”.
Therefore small increases in the doses can lead to unpredictably excess effects and toxicity.
Some drugs follow zero-order kinetics and many drugs at higher concentration start following zero order kinetics, because it is not possible for the body to handle the extra amount of drug.
First order kinetics: Examples:
Alcohol, phenytoin, tolbutamide, warfarin, theophylline, and salicylates at higher doses)
Implications of first order kinetics:
1. Small increases in dose may produce unpredictably high concentration.
2. It can lead to severe adverse effects.
3. Such drugs have less therapeutic margin/safety.
4. Doses for such drugs should not be suddenly changed.
Mention the various methods of transport of a drug across cell membranes.
Methods of drug transport across a membrane
- Passive diffusiona
- Aqueous diffusion (along the concentration gradient) (Follows Fick’s law of diffusion)
- Lipoid diffusion (weak acids and weak bases) (follows Henderson-Hasselbalch equation)
- Filtration: (through aqueous pores): Usually in capillaries
- Specialized transport
- Carrier-mediated transport
- Active transport: (Primary or secondary) (Needs energy)
- Pinocytosis (Endocytosis or exocytosis)
Enumerate the factors modifying drug effect/drug action.
Factors modifying drug action
A. Patient- related factors
- Body weight/body size
- Diet / food
- Species / Race
- Environmental factors/occupation
- Genetic factors
- Presence of disease
- Psychological factors – Placebo
- Psychological factors – Patient compliance
B. Drug- related factors
- Route of administration
- Time of administration
- Drug dependence
- Drug interactions