Introduction to Pharmacokinetics Notes

Pharmacokinetics

Pharmacokinetics is derived from two words: Pharmacon meaning drug and kinesis meaning movement. In short, it is ‘what the body does to the drug’. It includes absorption (A), distribution (D), metabolism (M) and excretion (E) of a drug. All these processes involve the movement of the drug molecule through various biological membranes.

All biological membranes are made up of lipid bilayers. Drugs cross various biological membranes by the following mechanisms:

1. Passive diffusion: It is a bidirectional process. The drug molecules move from a region of higher concentration to a lower concentration until equilibrium is attained. The rate of diffusion is directly proportional to the concentration gradient across the membrane. Lipid-soluble drugs are transported across the membrane by passive diffusion. It does not require energy, and this is the process by which the majority of the drugs are absorbed.
2. Active transport: The drug molecules move from a region of lower to higher concentration against the concentration gradient. It requires energy, for example transport of sympathomimetic amines into neural tissue, transport of choline into cholinergic neurons and absorption of levodopa from the intestine. In primary active transport, energy is obtained by hydrolysis of ATP. In secondary active transport, energy is derived from the transport of another substrate (either symport or antiport).
3. Facilitated diffusion: This is a type of carrier-mediated transport and does not require energy. The drug attaches to a carrier in the membrane, which facilitates its diffusion across the membrane. The transport of molecules is from the region of higher to lower concentration, for example, the transport of glucose across the muscle cell membrane by a transporter GLUT4.
4. Filtration: Filtration depends on the molecular size and weight of the drug. If the drug molecules are smaller than the pores, they are filtered easily through the membrane.
5. Endocytosis: The drug is taken up by the cell through vesicle formation. Absorption of vitamin B12–intrinsic factor complex in the gut is by endocytosis.

Read And Learn More: Pharmacology for Dentistry Notes

Drug Absorption

The movement of a drug from the site of administration into the bloodstream is known as absorption.

• Factors influencing drug absorption

1. Physicochemical properties of the drug:
   • Physical state: The liquid form of the drug is better absorbed than solid formulations.
   • The lipid-soluble and unionized form of the drug is better absorbed than the water-soluble and ionized form.
   • Particle size: Drugs with smaller particle sizes are absorbed better than larger ones, for example, microfine aspirin, digoxin and griseofulvin are well absorbed from the gut and produce better effects. Some of the anthelmintics have larger particle sizes. They are poorly absorbed through the gastrointestinal (GI) tract and hence produce a better effect on gut helminths.
   • Disintegration time: It is the time taken for the formulation (tablet or capsule) to break up into small particles and its variation may affect the bioavailability.
   • Dissolution time: It is the time taken for the particles to go into solution. The shorter the time, the better the absorption.
   • Formulations: Pharmacologically inert substances like lactose, starch, calcium sulfate and gum are added to formulations as binding agents. These are not totally inert and may affect the absorption of drugs, example calcium reduces the absorption of tetracyclines.
2. Route of drug administration: A drug administered by intravenous route bypasses the process of absorption, as it directly enters the circulation. Some drugs are highly polar compounds, ionize in solution and are not absorbed through the GI tract; hence, they are given parenterally, for example, gentamicin. Drugs like insulin are administered parenterally because they are degraded in the GI tract during oral administration.
3. pH and ionization: Strongly acidic (heparin) and strongly basic (aminoglycosides) drugs usually remain ionized at all pH; hence they are poorly absorbed.
4. Food: The presence of food in the stomach can affect the absorption of some of the drugs. Food decreases the absorption of rifampicin, levodopa, etc.; hence they should be taken on an empty stomach for better effect. Milk and milk products decrease the absorption of tetracyclines. Fatty meal increases the absorption of griseofulvin.
5. Presence of other drugs: Concurrent administration of two or more drugs may affect their absorption, e.g. ascorbic acid increases the absorption of oral iron. Antacids reduce the absorption of tetracyclines.
6. Area of the absorbing surface: Normally, drugs are better absorbed in the small intestine because of a larger surface area. Resection of the gut decreases the absorption of drugs due to a reduced surface area.
7. Gastrointestinal and other diseases: In gastroenteritis, there is increased peristaltic movement that reduces drug absorption. In achlorhydria, the absorption of iron from the gut is reduced. In congestive cardiac failure (CCF), there is GI mucosal oedema that reduces the absorption of drugs.

Bioavailability

It is the fraction of a drug that reaches the systemic circulation from a given dose. The intravenous route of drug administration gives 100% bioavailability, as it directly enters the circulation. The term bioavailability is commonly used for drugs given by oral route.

If two formulations of the same drug produce equal bioavailability, they are said to be bioequivalent. If formulations differ in their bioavailability, they are said to be bioequivalent.

• Factors affecting bioavailability

The factors that affect drug absorption (physicochemical properties of the drug, route of drug administration, pH and ionization, food, presence of other drugs, pharmacogenetic factors, area of absorbing surface, gastrointestinal and other diseases) also affect the bioavailability of a drug.

Other factors that affect the bioavailability of a drug are discussed as follows:

1. First-pass metabolism (First-pass effect, systemic elimination): When drugs are administered orally, they have to pass via the gut wall → portal vein → liver → systemic circulation. During this passage, certain drugs get metabolized and are removed or inactivated before they reach the systemic circulation. This process is known as first-pass metabolism. The net result is a decreased bioavailability of the drug and diminished therapeutic response. Drugs are lignocaine (liver), isoprenaline (gut wall), etc.
   • Consequences of high first-pass metabolism:
     • Drugs that undergo extensive first-pass metabolism are administered parenterally, for example, lignocaine is administered intravenously in ventricular arrhythmias.
     • The dose of a drug required for oral administration is more than that given by other systemic routes, for example, nitroglycerin.
2. Hepatic diseases: They result in a decrease in drug metabolism; thus increasing the bioavailability of drugs that undergo first-pass metabolism, for example, propranolol and lignocaine.
3. Enterohepatic cycling: Some drugs are excreted via bile but after reaching the intestine they are reabsorbed → liver → bile → intestine, and the cycle is repeated – such recycling is called enterohepatic circulation and it increases bioavailability as well as the duration of action of the drug, example morphine and doxycycline.

Drug Distribution

Distribution is defined as the reversible transfer of drugs between body fluid compartments. After absorption, a drug enters the systemic circulation and is distributed in the body fluids. Various body fluid compartments for a 70-kg person can be depicted as:

Apparent Volume Of Distribution

The apparent volume of distribution (aV_d) is defined as the hypothetical volume of body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma, assuming the body to be a single compartment.

• Drugs with high molecular weight (for example heparin) or extensively bound to plasma protein (for example warfarin) are largely restricted to the vascular compartment; hence their aV d is low.
• If the aV_d of a drug is about 14–16 L, it indicates that the drug is distributed in the ECF, for example, gentamicin, streptomycin, etc.
• Small water-soluble molecules like ethanol are distributed in total body water— aV_d is approximately 42 L.
• Drugs that accumulate in tissues have a volume of distribution that exceeds total body water, e.g. chloroquine (13,000 L) and digoxin (500 L). Haemodialysis is not useful for the removal of drugs with large aV_d in case of overdosage.
• In CCF, V_d of some drugs can increase due to an increase in ECF volume (e.g. alcohol) or decrease because of reduced perfusion of tissues.
• In uraemia, the total body water can increase, which increases V_d of small, water-soluble drugs. Toxins that accumulate can displace drugs from plasma protein-binding sites resulting in increased concentration of free form of drug that can leave the vascular compartment leading to an increase in Vd.
• Fat: lean body mass ratio— highly lipid-soluble drugs get distributed to the adipose tissue. If the ratio is high, the volume of distribution for such a drug will be higher; fat acts as a reservoir for such drugs.

1. Redistribution Highly lipid-soluble drug, such as thiopentone, on intravenous administration immediately gets distributed to areas of high blood flow such as the brain and cause general anaesthesia. Immediately within a few minutes, it diffuses across the blood-brain barrier (BBB) into the blood and then to the less-perfused tissues such as muscle and adipose tissue. This is called redistribution, which results in the termination of drug action. Thiopentone has a rapid onset of action and is used for induction of general anaesthesia.
2. Drug reservoirs or tissue storage Some drugs are concentrated or accumulated in tissues or some organs of the body, which can lead to toxicity during chronic use. For example, tetracyclines— bones and teeth; thiopentone and DDT – adipose tissue; chloroquine – liver and retina; digoxin – heart.
3. Blood-brain barrier The capillary boundary that is present between the blood and brain is called blood–blood-brain barrier (BBB). In the brain capillaries, the endothelial cells are joined by tight junctions. Only the lipid-soluble and unionized form of drugs can pass through BBB and reach the brain, For Example. barbiturates, diazepam, volatile anaesthetics, amphetamine, etc. Lipid-insoluble and ionized particles do not cross the BBB, For Example. dopamine and aminoglycosides. Pathological states like meningitis and encephalitis increase the permeability of the BBB and allow the normally impermeable substances to enter the brain. For example, penicillin G in normal conditions has poor penetration through BBB, but its penetrability increases during meningitis and encephalitis.
4. Placental barrier Drugs administered to a pregnant woman can cross the placenta and reach the foetus. Passage across the placenta is affected by lipid solubility, degree of plasma protein binding, presence of transporters, etc. Quaternary ammonium compounds, for example, d-tubocurarine (d-TC) and substances with high molecular weight like insulin cannot cross the placental barrier.
5. Plasma protein binding Many drugs bind to plasma proteins like albumin, α1 acid glycoprotein, etc.

• Clinical importance of plasma protein binding

1. Drugs that are highly bound to plasma proteins have a low volume of distribution.
2. Plasma protein binding delays the metabolism of drugs.
3. Bound form is not available for filtration at the glomeruli; hence excretion of highly plasma-protein-bound drugs is delayed.
4. Highly protein-bound drugs have a longer duration of action, example sulfadiazine is less plasma protein bound and has a duration of action of 6 h, whereas sulfadoxine is highly plasma protein bound and has a duration of action of 1 week.
5. In case of poisoning, highly plasma-protein-bound drugs are difficult to remove by haemodialysis.
6. In disease states like anaemia, renal failure, chronic liver diseases, etc., plasma albumin levels are low. So there will be an increase in the free form of the drug, which can lead to drug toxicity.
7. Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site on plasma protein. The drug with higher affinity will displace the one having lower affinity and may result in a sudden increase in the free concentration of the drug with lower affinity.

Biotransformation (Drug Metabolism)

Chemical alteration of the drug in a living organism is called biotransformation. The metabolism of a drug usually converts the lipid-soluble and unionized compounds into water-soluble and ionized compounds; hence, they are not reabsorbed in the renal tubules and are excreted. If the parent drug is highly polar (ionized), it may not get metabolized and is excreted as such.

Sites: The liver is the main site for drug metabolism; other sites are the GI tract, kidney, lungs, blood, skin and placenta. The end result of drug metabolism is inactivation, but sometimes a compound with pharmacological activity may be formed as shown below:

1. Active drug to inactive metabolite: This is the most common type of metabolic transformation.
   • Phenobarbitone → Hydroxyphenobarbitone
   • Phenytoin → p-Hydroxyphenytoin
2. Active drug to active metabolite:
   • Codeine → Morphine
   • Diazepam → Oxazepam
3. Inactive drug (prodrug) to active metabolite:

• • Levodopa → Dopamine
  • Prednisone → Prednisolone

1. Prodrug It is an inactive form of a drug that is converted to an active form after metabolism.
   • Uses of prodrug (advantages)
     • To improve the bioavailability: Parkinsonism is due to a deficiency of dopamine. Dopamine itself cannot be used since it does not cross the BBB. So it is given in the form of a prodrug— levodopa. Levodopa crosses the BBB and is then converted into dopamine.
     • To prolong the duration of action: Phenothiazines have a short duration of action, whereas esters of phenothiazine (fluphenazine) have a longer duration of action.
     • To improve the taste: Clindamycin has a bitter taste; so clindamycin palmitate suspension has been developed for paediatric use to improve the taste.
     • For site-specific drug delivery:
2. Pathways of drug metabolism Drug metabolic reactions are grouped into two phases. They are phase 1 or nonsynthetic reactions and phase 2 or synthetic reactions.
   • Phase 1 reactions
     • Oxidation: The addition of oxygen or removal of hydrogen is called oxidation. It is the most important and common metabolic reaction.
       1. Oxidation reactions are mainly carried out by cytochrome P450, cytochrome P450 reductase, molecular O₂ and NADPH.
       2. There are several cytochrome P450 isoenzymes.
       3. More than 50% of drugs undergo biotransformation reactions by CYP3A4/5. Other enzymes include CYP2D6, CYP2C9, CYP2E1 and CYP2C19
     • Reduction: Removal of oxygen or addition of hydrogen is known as reduction.
     • Hydrolysis: The breakdown of the compound by the addition of water is called hydrolysis. This is common among esters and amides.
     • Cyclization: Conversion of a straight-chain compound into a ring structure.
     • Cyclization: Breaking up of the ring structure of the drug
       • At the end of phase I, the metabolite may be active or inactive.
   • Phase 2 reactions Phase 2 consists of conjugation reactions. If the phase I metabolite is polar, it is excreted in urine or bile. However, many metabolites are lipophilic and undergo subsequent conjugation with an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid or amino acid. These conjugates are polar, usually water soluble and inactive.
     • Not all drugs undergo phase 1 and phase 2 reactions in that order. In the case of isoniazid (INH), the phase 2 reaction precedes the phase 1 reaction.
3. Drug-metabolizing enzymes They are broadly divided into two groups— microsomal and nonmicrosomal enzyme systems.
   • Microsomal and Nonmicrosomal Enzymes
     
     
     
     • Hofmann elimination: Drugs can be inactivated without the need for enzymes— this is known as Hofmann elimination. Atracurium— a skeletal muscle relaxant undergoes Hofmann elimination.
       • Enzyme induction Repeated administration of certain drugs increases the synthesis of microsomal enzymes. This is known as enzyme induction. The drug is referred to as an enzyme inducer, for example, rifampicin, phenytoin, barbiturates, carbamazepine and griseofulvin.

• • • Clinical importance of microsomal enzyme induction

1. 1. • 1. Enzyme induction may accelerate the metabolism of drugs; thus reducing the duration and intensity of drug action, which leads to therapeutic failure, for example, rifampicin and oral contraceptives. Rifampicin induces the drug-metabolizing enzyme of oral contraceptives; thus enhancing its metabolism and leading to contraceptive failure.
        2. Autoinduction may lead to the development of drug tolerance, for example, carbamazepine, enhances its own metabolism.
        3. Enzyme induction can lead to drug toxicity, for example, increased incidence of hepatotoxicity with paracetamol in alcoholics is due to overproduction of toxic metabolite of paracetamol.
        4. Prolonged phenytoin therapy may produce osteomalacia due to enhanced metabolism of vitamin D
        5. Enzyme inducers, for example, barbiturates, can precipitate porphyria due to overproduction of porphobilinogen.
        6. Enzyme induction can also be beneficial, for example. phenobarbitone in neonatal jaundice— phenobarbitone induces glucuronyl transferase enzyme; hence bilirubin is conjugated and jaundice is resolved.
      • Enzyme inhibition Certain drugs example chloramphenicol, ciprofloxacin, erythromycin, etc. inhibit the activity of drug-metabolizing enzymes and are known as enzyme inhibitors. Inhibition of the metabolism of one drug by another can occur when both are metabolized by the same enzyme. Enzyme inhibition is a rapid process as compared to enzyme induction.
        • Clinical relevance of enzyme inhibition: Enzyme inhibition can result in drug toxicity, for example, increased incidence of bleeding with warfarin, due to concomitant administration of erythromycin or chloramphenicol. These drugs inhibit the drug-metabolizing enzyme of warfarin, resulting in increased plasma concentration of warfarin and enhanced anticoagulant effect (bleeding). Toxicity following inhibition of metabolism is significant for those drugs which have saturation kinetics of metabolism. Enzyme inhibition can be beneficial, for example boosted protease inhibitor regimen used for the treatment of HIV infection.

Drug Excretion

Removal of the drug and its metabolite from the body is known as drug excretion. The main channel of excretion of drugs is the kidney; others include the lungs, bile, faeces, sweat, saliva, tears, milk, etc.

1. Kidney: The processes involved in the excretion of drugs via the kidney are glomerular filtration, passive tubular reabsorption and active tubular secretion. Glomerular filtration and active tubular secretion facilitate drug excretion whereas tubular reabsorption decreases drug excretion.
   • Rate of renal excretion = (Rate of filtration + Rate of secretion) − Rate of reabsorption
     • Glomerular filtration: Drugs with smaller molecular sizes are more readily filtered. The extent of filtration is directly proportional to the glomerular filtration rate (GFR) and to the fraction of the unbound drug in plasma.
     • Passive tubular reabsorption: The main factor affecting passive reabsorption is the pH of the renal tubular fluid and the degree of ionization. Strongly acidic and strongly basic drugs remain in the ionized form at any pH of urine and hence are excreted in the urine.
       1. Weakly acidic drugs (for example salicylates, barbiturates) in acidic urine remain mainly in ‘unionized’ form; so they are reabsorbed into the circulation. If the pH of urine is made alkaline by sodium bicarbonate, the weakly acidic drugs get ‘ionized’ and are excreted easily.
       2. Similarly, weakly basic drugs (for example morphine, amphetamine, etc.) in alkaline urine remain in ‘unionized’ form, and hence are reabsorbed. If the pH of urine is made acidic by vitamin C (ascorbic acid), the basic drugs get ‘ionized’ and are excreted easily.
     • Active tubular secretion: It is a carrier-mediated active transport that requires energy. Active secretion is unaffected by changes in the pH of urine and protein binding. Most of the acidic drugs (for example penicillin, diuretics, probenecid, sulfonamides) and basic drugs (for example quinine, procaine, morphine) are secreted by the renal tubules. The carrier system is relatively nonselective and therefore drugs having similar physicochemical properties compete for the same carrier system. For example, probenecid competitively inhibits the tubular secretion of penicillins/cephalosporins, thereby increasing the duration of action as well as the plasma half-life and effectiveness of penicillins/cephalosporins in the treatment of diseases such as gonococcal infections.
2. Lungs: Alcohol and volatile general anaesthetics such as ether, halothane, enflurane and isoflurane are excreted via the lungs.
3. Faeces: Drugs that are not completely absorbed from the GI tract are excreted in faeces, for example, purgatives like senna, cascara, etc.
4. Bile: Some drugs are secreted in bile. They are reabsorbed in the gut while a small portion is excreted in faeces, for example, tetracyclines.
5. Skin: Metals like arsenic and mercury are excreted through the skin.
6. Saliva: Certain drugs like potassium iodide, phenytoin, metronidazole and lithium are excreted in saliva. Salivary estimation of lithium may be used for noninvasive monitoring of lithium therapy. Metronidazole is highly effective in acute ulcerative gingivitis (AUG), as it is secreted in saliva.
7. Milk: Drugs taken by lactating women may appear in the milk. They may or may not adversely affect the breastfed infant. Drugs like penicillins and erythromycin are safe for use, but chloramphenicol should be avoided by mothers during breastfeeding.

Pharmacokinetic Parameters

The important pharmacokinetic parameters are bioavailability, volume of distribution, plasma half-life and clearance (CL).

1. Plasma half-life (t_1/2) It is the time required for the plasma concentration of the drug to decrease by 50% of its original value. The plasma half-life of lignocaine is 1 hour and that of aspirin is 4 hours.
   • Clinical importance of plasma half-life: It helps to:
     • Determine the duration of drug action.
     • Determine the frequency of drug administration.
     • Estimate the time required to reach the steady state. At a steady state, the amount of drug administrated is equal to the amount of drug eliminated in the dosing interval. It takes approximately four to five half-lives to reach a steady state during repeated administration of the drug. A drug is almost completely eliminated in four to five half-lives after a single administration.
2. The clearance (CL) of a drug is defined as the volume of plasma from which the drug is removed in a unit of time.
   1. First-order kinetics: A constant fraction of the drug in the body is eliminated per unit time. For example, assume a drug ‘A’ with a plasma t_1/2 of 1 hour following first-order kinetics of elimination having an initial plasma concentration of 100 mcg/mL. The rate of drug elimination is directly proportional to its plasma concentration. The t_1/2 of the drugs following first-order kinetics will always remain constant. The drug will be almost completely eliminated in four to five plasma half-lives if administered at a constant rate at each half-life. Most of the drugs follow first-order kinetics.
   2. Zero-order kinetics: A constant amount of a drug in the body is eliminated per unit time. For example, ethanol is eliminated from the body at the rate of about 10 mL/h. Assume that a drug ‘B’ with an initial plasma concentration of 200 mcg/mL is eliminated at a constant amount of 10 mcg per unit time. The concentration will be 190 mcg/mL after 1 hour and 100 mcg/mL after 10 hours. So, the half-life is 10 hours. If its concentration is increased to 300 mcg/mL, the concentration will be 290 mcg/mL after 1 hour (as a constant amount of 10 mcg per unit time is eliminated) and 150 mcg/mL after 15 hours. The half-life increases to 15 hours. Thus, the t1/2 of the drug following zero-order kinetics is never constant. The rate of elimination is independent of the plasma drug concentration.
3. Steady-state concentration If a constant dose of a drug is given at constant intervals at its t_1/2, the plasma concentration of the drug increases due to its absorption and falls due to elimination in each dosing interval. Finally, the amount of drug eliminated will equal the amount of drug administered in the dosing interval. The drug is said to have reached a steady state or plateau level. It is attained after approximately four to five half-lives.

Target-level Strategy

The dosage of the drug is calculated to achieve the desired plasma steady-state concentration of the drug which produces a therapeutic effect with minimal side effects.

1. Loading dose: Initially, a large dose or series of doses of a drug is given with the aim of rapidly attaining the target level in plasma. This is known as the loading dose. A loading dose is administered if the time taken to reach a steady state is relatively more as compared to the patient’s condition, e.g. the half-life of lignocaine is more than 1 h, so it takes more than 4–6 h to reach the target concentration at a steady state. When a patient has life-threatening ventricular arrhythmias after myocardial infarction, initially a large dose of lignocaine has to be given to achieve the desired plasma concentration quickly. Once it is achieved, it is maintained by giving the drug as an intravenous infusion.
2. Maintenance dose: The dose of a drug that is repeated at fixed intervals or given as a continuous infusion to maintain steady-state concentration is known as the maintenance dose. The dose administered is equal to the dose eliminated in a dosing interval.

Therapeutic drug monitoring

Monitoring drug therapy by measuring the plasma concentration of a drug is known as therapeutic drug monitoring (TDM).

1. Indications of TDM
   • Drugs with narrow therapeutic index, for example, phenytoin, lithium, digoxin, aminoglycosides, etc.
   • Drugs showing wide interindividual variations, for example, tricyclic antidepressants.
   • To ascertain patient compliance.
   • For drugs whose toxicity is increased in the presence of renal failure, for example, aminoglycosides.
   • To check the bioavailability.
   • In patients who do not respond to therapy without any known reason.
   • In drug poisoning, an estimation of plasma drug concentration is done.
2. TDM is not required in the following situations
   • When clinical and biochemical parameters are available to assess response:
     • Blood pressure measurement for antihypertensives.
     • Blood sugar estimation for antidiabetic agents.
     • Prothrombin time, activated partial thromboplastin time (aPTT) and International Normalized Ratio (INR) for anticoagulants.
   • Drugs producing tolerance, for example opioids.
   • Drugs whose effect persists longer than the drug itself, for example, omeprazole.

Fixed-dose combinations (FDCs; fixed-dose ratio combinations)

It is the combination of two or more drugs in a fixed-dose ratio in a single formulation.

Some examples of WHO-approved FDCs are:

1. Amoxicillin + clavulanic acid in augmentin.
2. Sulfamethoxazole + trimethoprim for cotrimoxazole.
3. Ferrous sulfate + folic acid for anaemia of pregnancy.
4. Isoniazid + rifampicin + pyrazinamide for tuberculosis.
5. Levodopa + carbidopa for parkinsonism.
6. Oestrogen + progesterone as oral contraceptive.

The advantages and disadvantages of FDCs are explained in Table.

Methods To Prolong The Duration Of Drug Action

Prolongation of action of a drug helps:

1. To reduce the frequency of drug administration.
2. To improve patient compliance.
3. To minimize fluctuations in plasma concentration.

Various methods to prolong the duration of drug action are

1. By retarding drug absorption:
   • For orally administered drugs:
     • Using sustained-release/controlled-release preparation: Sustained-release preparation consists of drug particles, which have different coatings that dissolve at different intervals of time. It prolongs the duration of action of the drug, reduces the frequency of administration and improves patient compliance, example tab. diclofenac has a duration of action of 12 hours, whereas diclofenac sustained-release preparation has a duration of action of 24 hours.
   • For parenterally administered drugs:
     • By decreasing the vascularity of the absorbing surface: This is achieved by adding a vasoconstrictor to the drug, for example, adrenaline with local anaesthetics. When adrenaline is added to a local anaesthetic, the vasoconstriction produced by adrenaline will delay the removal of the local anaesthetic from the site of administration and prolong the duration of its action. It also reduces the systemic toxicity of the local anaesthetic and minimizes bleeding in the operative field. Combined preparation of adrenaline with a local anaesthetic should be avoided in patients with hypertension, CCF, cardiac arrhythmias, ischaemic heart disease and uncontrolled thyrotoxicosis because of its dangerous side effects on the heart.
     • By decreasing the solubility of the drug: By combining it with a water-insoluble compound. For example,
       1. Injection penicillin G has a duration of action of 4–6 hours.
       2. Injection procaine penicillin G: It has a duration of action of 12–24 hours.
       3. Injection benzathine penicillin G: It has a duration of action of 3–4 weeks.
     • By combining the drug with a protein, for example, protamine zinc insulin– the complexed insulin is released slowly from the site of administration, thus prolonging its action.
     • By esterification: Esters of testosterone, for example, testosterone propionate and testosterone enanthate are slowly absorbed following intramuscular administration resulting in prolonged action.
     • Injecting the drug in an oily solution, for example, depot progestins (depot medroxyprogesterone acetate).
     • Pellet implantation: for example Norplant for contraception.
     • Transdermal patch
   • By increasing the plasma protein binding of the drug, for example, sulfadiazine is less bound to plasma proteins and has a duration of action of 6 h. Sulfadoxine is highly protein-bound and so has a duration of action of 1 week.
   • By inhibiting drug metabolism: For example, allopurinol + 6- mercaptopurine (6-MP). 6-MP is metabolized by xanthine oxidase. Allopurinol (xanthine oxidase inhibitor) → inhibits the metabolism of 6-MP → prolongs the action of 6-MP.
   • By delaying renal excretion of the drug, for example, penicillin/cephalosporins with probenecid.