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General Pharmacology:

General Pharmacology Drug Pharmacokinetics Pharmacodynamics

Pharmacology:

Pharmacology SOURCE OF DRUGS Plants - Morphine Animals - Insulin Human - Growth hormone Mineral - Iron Microbes - Penicillin Synthetic - Ciprofloxacin

Pharmacology:

Pharmacology ROUTES OF DRUG ADMINISTRATION: Oral Sublingual Rectal Transdermal Respiratory Parenteral Topical / Vaginal

Pharmacology:

Pharmacology ORAL Merits : commonest, convenient and noninvasive. Demerits : cannot be used during vomiting. Certain drugs are destroyed by the gastric juices or not absorbed e.g., Aminoglycosides . Extensive first pass metabolism

Pharmacology:

Pharmacology First pass metabolism

Enterohepatic circulation:

Enterohepatic circulation

Pharmacology:

Pharmacology The first-pass metabolism or presystemic metabolism is the fraction of drug which is lost in liver and gut wall. Thus the concentration of a drug is greatly reduced before it reaches the systemic circulation. E.g., Lidocaine, nitroglycerine .

Pharmacology:

Pharmacology SUBLINGUAL: No first pass metabolism Example ., NTG and nifedipine RECTAL: Relatively less first pass metabolism. Examples ., Diazepam and acetaminophen

Pharmacology:

Pharmacology TRANSDERMAL DELIVERY SYSTEM Smooth plasma concentration. Less inter-individual variation. No first pass metabolism. Convenient – better compliance. E.g., NTG, scopolamine, ortho-evra and nicotine

Pharmacology:

Pharmacology RESPIRATORY Alveolar epithelium offers good surface area for lipid soluble drugs Rapid action Dose required is less Eg : Volatile anesthetics, albuterol , beclomethasone

Pharmacology:

Pharmacology PARENTERAL ROUTES OF DRUG ADMINISTRATION : Intravenous Intramuscular Subcutaneous Intraarticular Intrathecal

Pharmacology:

Pharmacology PARENTERAL – INTRAVENOUS Immediate action Useful in emergencies Avoids gastric acid / liver metabolism Can be used in unconscious patients Irritating drugs can be given Demerits Thrombopheblitis Expertise required

Pharmacology:

Pharmacology INTRAMUSCULAR Mild irritant drugs can be given Absorption is quick Volume injected is max.10 ml INTRADERMAL BCG, allergy testing. INTRAARTICULAR Steroids in Rheumatoid arthritis INTRAOSSEOUS Pediatric emergencies

Pharmacology:

Pharmacology SUBCUTANEOUS Self administration possible - Insulin Pellet implantation – drug released over weeks. Eg : testosterone. INTRATHECAL / EPIDURAL Strict aseptic precautions Spinal anesthesia Opioid analgesics TOPICAL Used in treatment of skin, eye and vagina.

Slide 15:

Intramuscular Subcutaneous Intravenous

Slide 16:

INTRAOSSEOUS INTRAOSSEOUS

Slide 17:

PHARMACOKINETICS Absorption Distribution Metabolism Excretion

Pharmacology:

Pharmacology FACTORS AFFECTING ORAL DRUG ABSORPTION: GASTRIC EMPTYING TIME PARTICLE SIZE pH SURFACE AREA FOOD

Pharmacokinetics:

Pharmacokinetics Effect of pH on absorption of a drug : HA  ------  H + + A - --------- Acid BH + ------  H + + B ---------- Base Non-ionized forms like HA and B are lipid soluble and cross the cell membrane. Ionized forms like A - and BH + are water soluble and do not cross the membrane.

Ionized or non-ionized determines the cell membrane permeability:

Ionized or non-ionized determines the cell membrane permeability I Ionized Molecule NI Non-Ionized Molecule

LOGARITHM:

LOGARITHM x x y 1/1000 10 -3 -3 1/100 10 -2 -2 1/10 10 -1 -1 1 10 0 0 10 10 1 1 100 10 2 2 1000 10 3 3

PHARMACOKINETICS :

PHARMACOKINETICS Effect of pH on ionization of weak acid: HA ------------  H + + A - ------ Acidic drug { A- or ionized or Unprotonated } pH – pKa = log --------------------------------------- { HA or non ionized or Protonated } { ionized } 10 pH-pKa = ---------------------- { non-ionized }

PHARMACOKINETICS:

PHARMACOKINETICS Effect of pH on ionization of weak base: BH + --------  B + H+ ----------- Basic drug {B or non ionized or Unprotonated } pH – pKa = log ------------------------------------------------- { BH+ or ionized or Protonated } { non ionized } 10 pH-pKa = --------------------- { ionized }

PHARMACOKINETICS:

PHARMACOKINETICS HENDERSON-HESSELBACH EQUATION: { ionized } 10 pH-pKa = --------------------- Acidic drug { non-ionized } {ionized } 10 pKa-pH = --------------------- Basic drug { non-ionized }

Slide 25:

HENDERSON-HESSELBACH EQUATION: { ionized } 10 pH-pKa = --------------------- Acidic drug { non-ionized } { non ionized } 10 pH-pKa = --------------------- Basic drug { ionized } { UNPROTONATED } 10 pH-pKa = ------------------------------------- Acidic or basic drug { PROTONATED }

Practice Questions:

Practice Questions The pKa of a basic drug Meperidine is 8.00. What percentage of the drug is in an absorbable form at the pH of 6.00? A.0.1% B.1% C.10% D.90% E.99%

Practice Questions:

Practice Questions pKa = 8.00 basic drug Meperidine pH = 6.00 pH - pKa = log (Unprotonated / Protonated) -2 = log (Nonionized / Ionized) 10 -2 = Nonionized / ionized 1/100 = Non-ionized / ionized Therefore, the ratio is 1: 100 and in terms of %, the nonionized is 1% and ionized is 99%. Non ionized (absorbable lipid soluble) form is around 1%

Practice questions:

Practice questions A pharmacologist is determining the PK parameters of a novel antibiotic in order to determine the proper dosage. The drug is a weak acid with a pKa of 5 .0 . Assuming a pH of 8.0 in the urine, approximately what percent of the drug will be in a form that can be rapidly excreted? A. 0.1 B. 1 C. 90 D. 99 E. 99.9

Practice questions:

Practice questions D rug is a weakly acid pKa of acidic drug is 5.0 pH of the surroundings 8.0 in the urine pH-pKa = 3 { ionized} 10 pH-pKa = ---------------------- for an Acidic drug { non-ionized } 1000 { ionized } ---------- = ------------------ for an Acidic drug 1 { non-ionized }

PHARMACOKINETICS:

PHARMACOKINETICS

Slide 31:

EFFECT OF PH ON IONIZATION OF A DRUG Weak acids become highly ionized as pH increases or pH-pKa becomes more positive. Weak bases become highly ionized as pH decreases or pH-pKa becomes more negative.

Slide 32:

Ionization FACTORS REQUIRED TO predict whether majority of drug is in the ionized form or non-ionized form OR state whether majority of drug is in the hydrophilic form or lipophilic form Acid / Base nature of the drug pKa of a drug pH of the surrounding

Pharmacology:

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.

Pharmacology:

Pharmacology BIOAVAILABILITY : The systemic bioavailability of the drug (F) can be predicted from the extent of absorption ( fg ) and the extraction ratio (ER). Bioavailability (F) = fraction absorbed( fg ) X fraction escaping first pass metabolism ( Fh ) Fraction escaping first pass metabolism ( Fh ) = 1- ER F = fg X ( 1 - ER)

Slide 36:

Bioavailability of a drug CL (Liver) Extraction ratio = ---------------- Q ( blood flow) Oral dose = Intravenous dose / F For example the oral bioavailability (F) of digoxin ( lanoxin ) is 0.7 ; For digoxin 175 ug given intravenously, the effective oral dose = 175 ug / 0.7 = 250 ug

Pharmacology:

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.

Slide 38:

BIOAVAILABILITY & BIOEQUIVALENCE

Pharmacology:

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 D Vd = --------- Co = -------- Co Vd D = Total amount of the drug in the body C = Drug concentration in plasma at zero time

Pharmacology:

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

Volume of distribution:

Volume of distribution http://www.icp.org.nz/icp_t3.html

Pharmacology:

Pharmacology Volume of distribution of a drug Vd of about 3 L: Present mainly in the vascular compartment. e.g., Heparin. Vd of about 11 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 3L Extracellular fluid 11L

Pharmacology:

Pharmacology PLASMA PROTEIN BINDING : Acidic drugs bind to albumin Basic drugs bind to glycoprotein Plasma protein bound drugs are restricted to the vascular compartment Bound fraction is not available for action, metabolism and excretion. Sulfonamides when administered to a neonates can displace bilirubin from binding sites and can cause kernicterus .

Pharmacology:

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:

Pharmacology

Pharmacology:

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. Codeine  morphine Imipramine  desipramine

Drug metabolism:

Drug metabolism Phase I reactions : Cytochrome P 450 enzyme system. Oxidation reactions – carried by cytochrome P 450 system. e.g. : barbiturates, acetaminophen, benzodiazepines Reduction reactions – carried by cytochrome P 450 system. e.g. : chloramphenicol , methadone

Drug metabolizing enzyme system:

Drug metabolizing enzyme system PHASE I REACTIONS PHASE II REACTIONS

Drug metabolism:

Drug metabolism

Drug metabolism:

Drug metabolism INHIBITION OF CYP 450 DRUG METABOLISM : Eg : Acute alcohol, cimetidine , erythromycin, clarithromycin , grapefruit juice. CYP 450 ENZYME INDUCTION : Eg : Chronic alcohol, carbamazepine, phenobarbitone, phenytoin, rifampin, St. John’s wort.

Slide 51:

CYTOCHROME P 450 2 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 a pro-drug that is 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:

Pharmacology NON-MICROSOMAL METABOLISM: Alcohol and aldehyde dehydrogenase for alcohol Xanthine oxidase for allopurinol. Monoamine oxidase (MAO) for dopamine, serotonin and norepinephrine. Esterases for procaine

Pharmacology:

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 – adrenaline, histamine

Pharmacology:

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:

Pharmacology EXCRETION Feces : purgatives – liquid paraffin Exhaled air : volatile anesthetics, alcohol Saliva and sweat : Rifampin, iodides Milk : Metronidazole, Phenytoin

Pharmacology:

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

Pharmacokinetics:

Pharmacokinetics

Slide 59:

F irst order kinetics

Pharmacology:

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

Slide 63:

First order kinetics Zero order kinetics

Pharmacology:

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: 0.693 t½ = ------------ Ke Ke = Elimination constant, is calculated by Ke = CL / Vd

Pharmacology:

Pharmacology The half-life can also be calculated as follows: Vd t½ = 0.693 ---------- CL

Pharmacology:

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 and steady state Half life 1 2 3 4 5 6 7 8

Steady State Concentration:

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 50 100 150 200 250 300 50% 75% 88% 94% 97% 99% 100%

Steady State Concentration:

Steady State Concentration Time and the steady state : 100% steady state = ~ 7 half life 96.85% of the steady state = 5 half life 93.75% of steady state = 4 half life 90% of steady state = 3.3 half life 87.5% of steady state = 3 half life 75% of the steady state = 2 half life 50% of steady state = 1 half life

Pharmacology:

Pharmacology 0 1 2 3 3.3 4 5 6 7 8 Half life 100 90 75 50 25 93.75 87.50

Pharmacology:

Pharmacology

Pharmacology:

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.

Slide 75:

Steady state

Pharmacology:

Pharmacology

Pharmacology:

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

Pharmacology:

Pharmacology

Pharmacology:

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

Pharmacology:

Pharmacology 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 Css = Dose X F / CL X τ

Slide 81:

Dose X F Css = ------------------ CL X τ

Steady state concentration:

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? Increase 4 times Increase 2 times Remains same Decrease by half Decrease by 1/4

Pharmacology:

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 = 0.693 -------- CL

Pharmacology:

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 25 %? A. 80mg 6th hourly B. 40mg 12th hourly C. 40mg 8th hourly D. 40mg every day E. 20 mg 6th hourly

Slide 85:

Loading dose

Pharmacokinetics:

Pharmacokinetics Q. The half life of digoxin is 36 hrs. It is administered at maintenance dose of 0.25 mg every 24 hrs. What will be the loading dose of digoxin? Accumulation factor = 1/ 0.33 = 3.0 Loading dose = 0.25 x 3 = 0.75mg

Pharmacodynamics:

Pharmacodynamics RECEPTOR Receptors are the macromolecular component of the cell to which a drug bind to produce its effect. Functions of the receptors : Propagation of signal from outside to inside the cell. Amplify the signal. Adapt to short and long term changes.

Pharmacology:

Pharmacology Affinity : It is the ability of the drug to bind to the receptors Intrinsic activity : It is the ability of a drug to activate the receptor and produce the response. AGONIST : It binds to the receptors and it will activate the receptor. It has both affinity and intrinsic activity. Eg : morphine, epinephrine INVERSE AGONIST: It binds to the receptors and it will activate the receptor in a manner opposite of agonist.

Pharmacology:

Pharmacology ANTAGONIST : It binds to the receptor but it will not activate the receptor. It has affinity but no intrinsic activity Eg : atenolol , metoprolol , prazosin PARTIAL AGONIST : It activates the receptor and produce sub maximal response. It antagonizes the action of pure agonist. Eg : buprenorphine

Slide 90:

Pharmacodynamics Inverse agonist

Slide 91:

Partial agonist Partial agonist act as competitive antagonist in presence of an agonist

Pharmacology:

Pharmacology RECEPTOR FAMILIES CHANNEL LINKED (IONOTROPIC) G PROTEIN LINKED (METABOTROPIC) ENZYME LINKED INTRACELLULAR RECEPTOR

Pharmacodynamics:

Pharmacodynamics Eg., Nicotinic Ach receptor Eg., Insulin ANP Eg., Steroids Adrenergic receptors

Pharmacology:

Pharmacology Graded Dose Response Curve (DRC) : Potency : It refers to the amount of drug needed to produce the response. The position of the curve on the dose axis is an index of drug potency. The dose required to produce half the maximum response is used as an index to determine the potency.

Pharmacology:

Pharmacology Efficacy : It refers to the maximum response of the drug. The upper limit of the drug response curve is an index of efficacy of the drug. Steepness of the curve indicates the dose range – steep slope indicates that a small increase in the dose markedly increase the response. Slope of the curve is related to the mechanism of action of a drug.

Graded dose response curve:

Graded dose response curve GRADED DOSE RESPONSE CURVE

Pharmacology:

Pharmacology Therapeutic index is the ratio of median lethal dose (LD 50) and the median effective dose (ED 50). It indicates the safety of the drug. Quantal (Cumulative) DRC plots % of population responding to specific drug effect versus dose, is useful in determining therapeutic index.

Quantal Dose-Response Curves:

Quantal Dose-Response Curves Frequency of distribution % population responding to drug A 1 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg) % population responding Frequency of distribution % population responding to drug A Dose (mg/kg) log scale % population responding ED10 ED50 ED90 1 10 100 Cumulative distribution of population responding to drug A

Quantal Dose Response Curve:

Quantal Dose Response Curve Cumulative or Quantal dose response curve

Pharmacology:

Pharmacology Drug receptor antagonism : Competitive/Reversible antagonist : Antagonist and agonist compete to bind to the same receptor. Parallel shift of DRC to the right side Decrease the potency not efficacy Eg : Acetylcholine and atropine, Epinephrine and prazosin

Pharmacology:

Pharmacology Noncompetitive/irreversible antagonist : The antagonist binds irreversibly or to site other than that of agonist. Non parallel shift of DRC to right side. It decrease the efficacy. Eg : Phenoxybenzamine and epinephrine

Slide 104:

Competitive drug antagonism Non-competitive drug antagonism Fig. 3

Competitive drug antagonism Irreversible drug antagonism:

Competitive drug antagonism Irreversible drug antagonism

Pharmacology:

Pharmacology FACTORS MODIFYING DRUG ACTION: Age Sex Race/genetics Psychological/pathological factors Other drugs Tolerance: It is the requirement of higher dose than usual dose to produce the effect

Pharmacology:

Pharmacology Natural : Individual is inherently less sensitive to the drug Eg : Certain race are tolerant to mydriatics Acquired : repeated use of drug in an individual who was responsive initially results in less response later on. Tachyphylaxis : When a drug is repeated in very quick succession, it results in marked reduction in response. Usually seen with indirectly acting drugs like ephedrine

TACHYPHYLAXIS:

TACHYPHYLAXIS

Receptor Regulation:

Receptor Regulation Sensitization or Up-regulation Prolonged/continuous use of receptor blocker e. g., Beta blocker in angina pectoris Desensitization or Down-regulation Prolonged/continuous use of agonist e.g., Albuterol in bronchial asthma.

Drug development:

Drug development All drugs have a potential to produce harmful and beneficial effects. All substance are poisons; there is none which is not a poison. It is the dose which differentiates poison from remedy. The FDA regulates both the efficacy and safety of drugs but not of foods, nutritional supplements, and herbal remedies.

Drug development:

Drug development Experimental animal studies : Preclinical testing: The new drug is thoroughly investigated in at least two different animal species before administered to human beings. The studies in animals ascertain -- beneficial / harmful effects on vital organs -- elucidate the mechanism of action -- determine the pharmacokinetics

Drug development:

Drug development Animal testing : Acute toxicity Chronic toxicity Tests for teratogenicity and mutagenicity are also done on the animals. Anti-cancer drugs and drugs for HIV/AIDS can go through accelerated development and approval. Investigational New Drug Application (IND) : The FDA must approve an application for investigational new drug (IND) before the drug can be distributed for conducting clinical studies in human subjects.

Drug development:

Drug development Clinical trials : Phase I : It consists of careful evaluation of safety in a small number of volunteers ~ 25. Phase II : It involves evaluation of a drug in a moderate number of patients ~200 with the target disease. The goal is determine the desired therapeutic effect at the doses that are tolerated by the patients. Phase III : It consists of large design involving many patients ~ 5000 in a manner proposed for its ultimate use. The goal is to compare efficacy and safety with older drugs, explore spectrum of beneficial effects of new drug and to discover toxicity.

Drug development:

Drug development Teratogenicity: It is based on the animal studies and, when available human studies. Category Description of Risk Examples A Studies show no risk Folic acid B No evidence of risk in humans Zidovudine C Risk cannot be ruled out Aspirin D Positive human evidence of fetal risk Phenytoin X Contraindicated in pregnancy Thalidomide

Controlled substance act:

Controlled substance act Schedule Potential for abuse I High; Heroin, LSD No accepted medical use; Only research II High; Morphine, Methadone, Amphetamine Accepted medical use; Severe dependence III < I or II; Codeine, Nandrolone High / moderate potential for dependence IV < III; Pentazocine, Alprazolam Limited potential for dependence V < IV; Buprenorphine Limited dependence possible

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