Pharmacology BIOAVAILABILITY :  It is the fraction of the unchanged drug reaching systemic circulation following administration by any route. Intravenous route – bioavailability is ~ 1 or 100%. For drugs administered orally, bioavailability may be less than 100% for two main reasons, incomplete absorption and first pass metabolism.

BIOAVAILABILITY & BIOEQUIVALENCE

Bioavailability of a drug Oral dose = Intravenous dose / F For example, the oral bioavailability (F) of digoxin (lanoxin) is 0.7 and i.v dose 175 ug. Oral dose of digoxin = 175 ug / 0.7 = 250 ug F

Pharmacology BIOEQUIVALENCE: For two drugs to be bioequivalent, they must have the same bioavailability and the same plasma profile, i.e. the curve must have the same shape. They must have the same Cmax and Tmax. Cmax: The maximum plasma concentration attained by a drug-administration. Tmax: The time at which maximum concentration is reached.

Pharmacology Volume of distribution : It is defined as the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration. The volume of distribution (Vd) of a drug is given by: D Vd = Loading Dose = Vd X C C D = Total amount of the drug in the body C = Drug concentration in plasma

Pharmacology 100 mg Drug dose Plasma concentration 100 mg/L 100 mg 10 mg/L Volume = 10 L Volume = 100 L 1 mg/L Volume 1L

Volume of distribution

Pharmacology VOLUME OF DISTRIBUTION Vd of about 4 L: Present mainly in the vascular compartment. e.g., Heparin. Vd of about 10 L: Present in extra cellular fluid, but are unable to penetrate cells. e.g., Mannitol. Vd of about 42 L: Drugs are able to pass most biologic barriers and are distributed in total body water (extra and intracellular) eg., Alcohol. Vd > 42 L: drugs are extensively stored within specific cells or tissues. e.g., Chloroquine Intracellular fluid 28L Plasma 4L Extracellular fluid 10L

Pharmacology PLASMA PROTEIN BINDING : Acidic drugs bind to albumin. Basic drugs bind to acid glycoprotein. Plasma protein bound drugs are restricted to the vascular compartment. Bound fraction (storage) is not available for action Sulfonamides when administered to a neonates can displace bilirubin from binding sites and can cause kernicterus. Sulfonamides competes with protein binding of warfarin and can result in increased free plasma concentration of warfarin leading to bleeding.

Pharmacology METABOLISM It renders the lipid soluble drug to water soluble. The primary sites for metabolism is liver, others include --- kidney, intestine, lungs and plasma It can be of two types: Phase I reactions – Microsomal - cytochrome P 450 Non-microsomal metabolism Phase II reactions – conjugation reactions.

Pharmacology

Biotransformation can leads to --- Inactivation Active metabolite from an inactive drug – Prodrug e.g. Levodopa  dopamine Enalapril  enalaprilat Active metabolite from an active drug e.g. Diazepam  oxazepam Imipramine  desipramine

Phase I reactions : Cytochrome P 450 enzyme system: 1. Oxidative dealkylations – Morphine, codeine 2. Deamination – Amphetamine, diazepam 3. Desulfuration - Thiopental Cytochrome P450-independent oxidations 1. Flavin mono-oxygenase – Chlorpromazine, amitriptyline 2. Dehydrogenases – Alcohol Reductions 1. Carbonyl reductions – Methadone, naloxone 2. Nitroreductions – Clonazepam Hydrolyses 1. Ester – Procaine, succinylcholine 2. Amides – Lidocaine, indomethacin

Drug metabolism

o INHIBITION OF CYP 450 DRUG METABOLISM : Eg : cimetidine, erythromycin, clarithromycin, grapefruit juice, SSRI o CYP 450 ENZYME INDUCTION : Eg : Chronic alcohol, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort. Lopinavir is co-formulated with Ritonavir in order to take advantage of P450 inhibition by Ritonavir which increases the beneficial effect of Lopinavir.

Illustrative Case 1 A 74-year-old woman with insulin-dependent (type 2) diabetes had been taking metoprolol and warfarin for atrial fibrillation and amitriptyline, 50 mg at bedtime, for diabetic neuropathy, for several years. On the death of her husband, she presented with symptoms of depression, and paroxetine was added to her medication regimen with the rationale that paroxetine would cause fewer side effects than an increase in the amitriptyline dosage. Three days after the initiation of paroxetine therapy, the woman was brought to the emergency department by her daughter, who had found her asleep at 11 a.m. On awakening, the patient complained of dry mouth and dizziness. The emergency department physician, noting that paroxetine had recently been added to the medication regimen, changed the patient to fluoxetine, which he thought would be less sedating. Three days later, the patient was still very sedated and dizzy, and complained of difficulty urinating. She was again brought to the emergency department, where bladder catheterization yielded two liters of dark urine. Her International Normalized Ratio (INR) was 4.0. On discussion with a colleague, the emergency department physician learned that both paroxetine and fluoxetine can inhibit cytochrome P450 enzymes (isoforms) responsible for the metabolism of the patient's other medications. This example illustrates the need to understand the cytochrome P450 isoforms responsible for drug metabolism and their inhibitors and inducers.

CYTOCHROME P D6  Absent in about 7% Caucasians  Hyperactive in about 30% East Africans  Catalyzes the metabolism of codeine, many TCAs and beta blockers  Inhibited by fluoxetine, paroxetine, quinidine Eg., Codeine is actually converted to morphine, a better analgesic. Codeine itself is much less active as an analgesic, but causes nausea and other adverse effects. The absence of cytochrome P450 2D6 in 7% of Caucasians means that these individuals cannot metabolize codeine to the active metabolite, morphine, and therefore will get little, if any, pain relief from codeine.

Pharmacology Phase II reactions : It is the conjugation of a drug to form a polar (ionized) drug which can be easily excreted. Glucuronide conjugation – diazepam, digoxin, morphine Glutathione conjugation - acetaminophen Sulfation conjugation – estrogens Acetylation – sulfonamides, INH Methylation – epinephrine, histamine

PHASE I REACTIONS PHASE II REACTIONS DRUG METABOLIZING ENZYME SYSTEM

Pharmacology EXCRETION Kidney : excretes all water soluble drugs. Lipid soluble drugs are reabsorbed. Changes in urinary pH affects the excretion of drugs acidic drugs are excreted in alkaline urine and urine made basic by agents like sodium bicarbonate (NaHCO 3 ), potassium citrate and acetazolamide. basic drugs are excreted in acidic urine and urine made acidic by ammonium chloride (NH 4 Cl), Vitamin-C, Cranberry juice.

Pharmacology P-GLYCOPROTEIN is a protein that play a protective role by preventing entry into body and promoting removal of foreign substances (drugs) from the body.  P-glycoprotein is expressed in intestinal mucosa, renal proximal tubules, blood-brain-barrier and in tumor cells (where it functions as a multi-drug resistance mechanism).  Induction of P-glycoprotein can result in decreased intestinal absorption, reduced entrance into the CNS and increased secretion of drugs into renal tubules.  Inducers of P-glycoprotein : Rifampin & St. John's wort  Inhibitors: Cimetidine & Grapefruit Juice.

Pharmacology FIRST ORDER KINETICS : The rate of elimination of the drugs is proportional to the plasma concentration. Constant fraction of the drug from the plasma is eliminated in unit time. 80mg  40mg  20mg  10mg  5mg Most of the drugs follow first order kinetics (within the therapeutic ranges).

Pharmacokinetics

Pharmacology SATURATION / ZERO ORDER KINETICS: The rate of the elimination of drug is constant irrespective of the plasma concentration. Constant amount of drug is eliminated in unit time. Eg : Phenytoin, Alcohol, Aspirin. 80mg  70mg  60mg  50mg  40mg

Pharmacology HALF LIFE : Plasma half life: It is the time required for the drug to reduce to half its original plasma value. Half life is a concept which is applied only to drugs following first order kinetics. The half ‑ life of a drug is given by: x Vd t½ = = Ke CL Ke = Elimination constant, is calculated by Ke = CL / Vd

Pharmacology Steady state is the state when the Rate in = Rate out. The time to reach the steady state is dependent only on half life of a drug and is independent of the dose size and the frequency of administration.  Exception : different doses as in loading dose and then maintenance dose.

Half life and steady state Half life % of steady state = 3.3 half life

Steady State Concentration A 1 B 2 C 3 D 4 E 5 F 6 G 7 Letters = doses; numbers = half-lives Plasma level, mg/dl % 75% 88% 94% 97% 99% 100%

Pharmacology Rate of Infusion : Irrespective of the rate of infusion, it takes the same amount of time to reach the steady state. If the rate of infusion is doubled, then the plasma level of the drug at steady state is doubled.

Steady state

Pharmacology CLEARANCE : It is the volume of the plasma from which the drug is completely removed in unit time. Rate of elimination Clearance = Plasma concentration

Pharmacology Drugs which follow a first ‑ order kinetics reach a steady state when the rate of input is equal to the rate of elimination. At the steady state : Rate of infusion = Rate of elimination Rate of elimination CL = Drug concentration

Pharmacokinetics At steady state Rate of infusion = Css X CL Dosing rate = Css X CL Maintenance dose (i.v) = Dosing rate x Dosing interval τ (hours) Maintenance Dose (Oral) = Css X CL X τ / F Dose X F Css = CL X τ

Steady state concentration Dose X F Css = CL X τ What will be the new steady state concentration, if the dose interval is reduced from every 8 hrs to every 4 hrs considering the dose and route of administered used are same in that individual? A. Increase 4 times B. Increase 2 times C. Remains same D. Decrease by half E. Decrease by 1/4

Pharmacology If a kinetic process is first-order, the clearance and the half ‑ life of the drug are constant and independent of the dose. If a kinetic process is zero-order, the clearance and the half ‑ life of the drug are not constant, but are dose-dependent. Rate of elimination Clearance = Plasma conc. Vd t½ = CL

Pharmacology Calculation of the loading dose When the desired plasma concentration is known. Loading dose = Vd X desired conc in plasma Patients CL Corrected dose = Average dose/day X Normal CL Q. A patient was taking gentamicin for the treatment of urinary tract infection at the dose of 80 mg 12th hourly with the normal kidney function. What is the best and the appropriate dose of the gentamicin in the patients with kidney function reduced to 50 %? A. 80mg 6th hourly B. 40mg every day C. 60mg 12th hourly D. 80mg every day E. 20 mg 8th hourly

Steady state plasma concentration