Pharmacokinetics: It is the study of “what the body does to the drug”. This includes absorption, distribution, metabolism, excretion and elimination of the drug.
Drug absorption: Absorption of a drug is determined by route of administration and properties of the drug itself. Small, unionized, lipid-soluble drugs are absorbed easily. Weak acids will be unionized in an acidic environment and hence absorbed better in such an environment. Weak bases are unionized in an alkaline environment hence are absorbed better in an alkaline environment. For the same reason, excretion of weak acids like aspirin can be accelerated by alkalinizing the urine and vice versa. Most drugs are absorbed in the small intestines because of large surface area. Most drugs are absorbed by passive diffusion i.e. they move from an area of high concentration to an area of low concentration. Other drugs are absorbed by active transport, facilitated passive diffusion and pinocytosis.
Bioavailability is the proportion of a dose that reaches the systemic circulation. First pass effect is the metabolism of the drug to inactive forms leading to decreased bioavailability of the drug. It occurs in the liver, intestines etc. Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver, hence bioavailability of orally administered drugs is low. Bioavailability is affected by route of administration, age, sex, previous GI surgery, effect of food, physicochemical properties, gastric emptying rate, intestinal transit time, blood flow, GI flora and enzymes.
Less absorption = low bioavailability High first pass metabolism = low bioavailability
Drug distribution: Distribution of a drug is uneven in the body with some tissues having higher concentration of the drug than others. It is affected by solubility of the drug e.g. lipid soluble drugs like some anesthetics can easily enter the lipid rich brain; tissue binding e.g. warfarin stays mostly in the bloodstream as it binds to plasma albumin; blood supply as concentration of drug will rise more rapidly in richly perfused tissues compared to poorly vascular tissues; and total mass of the tissue. Acidic drugs are usually bound more extensively to albumin; basic drugs are usually bound more extensively to alpha-1 acid glycoprotein, lipoproteins or both. Tissue binding prolongs the duration of action of a drug.
Volume of distribution or Vd is the measure of distribution of a drug in the body.
Vd = Dose/plasma concentration
Drugs with a small Vd are confined to the blood while drugs with a large Vd are extensively distributed throughout the various body compartments and tissues. Drugs that have a large Vd will need to be given in higher doses to achieve a target concentration in the plasma and vice versa. Similarly, lipophilic drugs will have a larger Vd.
Drug metabolism: It occurs primarily in the liver. Other sites are kidney, lung, blood and intestines. Prodrugs are metabolized to form active drugs. Most drugs become inactive after metabolism. Some drugs may produce toxic products during their metabolism. An important part of metabolic reactions is to make the drug or it’s products more water soluble i.e. polar, so that it can be easily eliminated from the body.
| Phase 1 reactions (non-synthetic) | Phase 2 reactions (synthetic) |
| Converts drug to more polar or more reactive/active form | Make drug more water soluble, end product is inactive |
| Oxidation, reduction, deamination, hydrolysis | Conjugation with glucuronic acid, glycine, sulfate, glutathione etc. |
Drug metabolism rates vary among patients. In rapid metabolizers, effective blood and tissue levels of the drug may not be reached while in slow metabolizers, risk of adverse effects are higher. Rate of metabolism is affected by genetics, age, coexisting liver or other diseases and by concomitant use of drugs affecting metabolism.
Most oxidation reactions are carried out by cytochrome P450 enzymes located on the smooth endoplasmic reticulum of the liver, primarily. There are approximately 60 cytochrome P450 genes in humans. NADPH acts as electron donor to cyt P450 enzymes. Polymorphisms in cyt P450 enzymes affect drug metabolism. Major ones are CYP3A4 and CYP2D6.
| Inhibitors | Inducers |
| Cimetidine, amiodarone, erythromycin, ticlopidine, ciprofloxacin, omeprazole, fluconazole, bupropion, metoclopramide, quinidine, disulfiram, metronidazole, grapefruit juice, ritonavir, saquinavir | Carbamazepine, phenytoin, rifampin, phenobarbital, isoniazid, alcohol, tobacco, dexamethasone, prednisone, |
| Need to lower the dose of a drug given concomitantly with any drug (s) in this group | Need to increase the dose of a drug given concomitantly with any drug (s) in this group |
Glucuronidation is the most common conjugation reaction. Main site is the liver microsomal system. In glucuronidation, the enzyme UDP-glucuronosyltransferase conjugates the drug with glucuronic acid and converts it into hydrophilic and negatively charged glucuronides that can be easily excreted. This process is slower in newborns which puts them at risk of drug toxicity e.g. from chloramphenicol. Drugs like acetaminophen, diazepam, digoxin, morphine and sulfamethoxazole undergo glucuronidation.
Drug excretion: Excretion of most drugs is by the kidney. Inhaled anesthetics are mainly excreted by the lungs. Some drugs are excreted in bile and feces. Elimination is the conversion of a drug to an inactive metabolite. Elimination leads to termination of drug activity. Drugs undergo two types of elimination - first order and second order.
First order elimination is when rate of elimination is directly proportional to the remaining concentration of the drug i.e. a constant fraction of the drug is eliminated per unit time. Such drugs have a constant half life of elimination. They show an exponential decrease in plasma concentration when plasma concentration is plotted against time. Drug concentration will decrease by 50% for every half life. Most drugs follow first order kinetics.
Zero order elimination is when a constant quantity of the drug is eliminated per unit time. Drugs that saturate their elimination mechanisms show zero order kinetics. They show a linear decrease in plasma concentration when plasma concentration is plotted against time. They do not have a constant half life. Ethanol, aspirin, phenytoin at high doses, omeprazole, fluoxetine and cisplatin show zero order elimination.
Clearance of drug: It is given by the formula below
Clearance = Rate of elimination of the drug / Concentration of the drug in plasma
Clearance is constant for drugs that follow first order kinetics while it is not constant for drugs that follow zero order kinetics.
Half life of drug (t1/2): It is the time it takes for the concentration of a drug in the body to reduce by half e.g. if 5 hours are required to decrease the concentration of drug A from 100 mg/dl to 50 mg/dl then half life is 5 hours. It is given by the formula below.
t ½ = 0.693 X Vd/ Clearance
Vd is the volume of distribution
Any factor that affects the Vd or clearance will affect the half life. Age and renal failure (check creatinine clearance or GFR) are the most common factors that affect half life of a drug.
3 to 4 half lives are needed for a drug given by continuous infusion to reach steady state concentration (i.e. stable or constant plasma drug concentration).
Loading dose: It is calculated by the following formula
Ld = Vd X desired plasma concentration / bioavailability
Loading dose is not affected by clearance.
Maintenance dose: It is given by the following formula.
Md = Clearance X desired plasma concentration/ bioavailability
If the volume of distribution changes, the drug dose should be changed. If the elimination half-life of the drug changes, the dosing interval should be changed.
Therapeutic window: It is the safe range between the minimum therapeutic concentration and the minimum toxic concentration.
Therapeutic index (TI) or therapeutic ratio: It is the ratio of the dose that produces toxicity to the dose needed to produce the desired therapeutic response. It is given by the following formula. Drugs with a narrow TI need to be meticulously monitored as the difference between their therapeutic and toxic doses is very small.
TI = TD50/ED50, where TD50 is the toxic dose and ED50 is the effective dose for 50% of population tested. Higher the TI, safer is the drug.
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