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IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Ppt
 

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IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Ppt

IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Ppt

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    IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Ppt IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Ppt Presentation Transcript

    • by Marc Imhotep Cray, M.D. Basic Medical Sciences Professor Companion Notes IVMS BASIC PHARM General Principles, Pharmacokinetics andPharmacodynamics Notes Chemotherapy drugs in vials and an IV bottle. (Bill Branson Photographer; image courtesy of National Cancer Institute Visuals Online.) 1
    • Pharmacokinetics “How the body handles a drug over time.” The Time-Dependent Roles of Drug Absorption, Distribution, and Elimination (Metabolism/Excretion) in Determining Drug Levels in Tissues.
    • Pharmacokinetics Locus of Tissue action reservoirs “receptors” Bound Free Bound Free Systemic circulationAbsorption Free drug Excretion Bound drug Metabolites Biotransformation 3
    • Important Properties Affecting Drug Absorption• Chemical properties • Physiologic variables – acid or base – gastric motility – degree of ionization – pH at the absorption site – polarity – area of absorbing surface – molecular weight – blood flow – lipid solubility or... – presystemic elimination – partition coefficient – ingestion w/wo food 4
    • Enteral Routes of Drug Administration
    • Oral Ingestion• Governed by: – surface area for absorption, blood flow, physical state of drug, concentration. – occurs via passive process. – In theory: weak acids optimally absorbed in stomach, weak bases in intestine. – In reality: the overall rate of absorption of drugs is always greater in the intestine (surface area, organ function). 6
    • Effect of Changing Rate of Gastric Emptying• Ingestion of a solid dosage form with a glass of cold water will accelerate gastric emptying: the accelerated presentation of the drug to the upper intestine will significantly increase absorption.• Ingestion with a fatty meal, acidic drink, or with another drug with anticholinergic properties, will retard gastric emptying. Sympathetic output (as in stress) also slows emptying. 7
    • Sublingual AdministrationAbsorption from the oral mucosa hasspecial significance for certain drugs despitethe small surface area.Nitroglycerin - nonionic, very lipid soluble.Because of venous drainage into thesuperior vena cava, this route “protects” itfrom first-pass liver metabolism. 8
    • Rectal AdministrationMay be useful when oral administration isprecluded by vomiting or when the patient isunconscious.Approximately 50% of the drug that isabsorbed from the rectum will bypass the liver,thus reducing the influence of first-passhepatic metabolism.-irregular and incomplete.-irritation. 9
    • Parenteral Routes of Administration
    • Subcutaneous• Slow and constant absorption.• Slow-release pellet may be implanted.• Drug must not be irritating. 11
    • Intramuscular• Rapid rate of absorption from aqueous solution, depending on the muscle.• Perfusion of particular muscle influences the rate of absorption: gluteus vs. deltoid.• Slow & constant absorption of drug when injected in an oil solution or suspension. 12
    • Intraarterial AdministrationOccasionally a drug is injected directly intoan artery to localize its effect to a particularorgan, e.g., for liver tumors, head/neckcancers.Requires great care and should be reservedfor experts. 13
    • Intrathecal AdministrationNecessary route of administration if theblood-brain barrier and blood-CSF barrierimpede entrance into the CNS.Injection into the spinal subarachnoidspace: used for local or rapid effects ofdrugs on the meninges or cerebrospinalaxis, as in spinal anesthesia or acute CNSinfections. 14
    • Intraperitoneal Administration• Peritoneal cavity offers a large absorbing surface area from which drug may enter the circulation rapidly.• Seldom used clinically.• Infection is always a concern. 15
    • Pulmonary AbsorptionInhaled gaseous and volatile drugs areabsorbed by the pulmonary epithelium andmucous membranes of respiratory tract.- almost instantaneous absorption- avoids first-pass metabolism- local application 16
    • Topical Application• mucous membranes Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, vagina, colon, urethra, and bladder for local effects. Systemic absorption may occur (antidiuretic hormone via nasal mucosa). 17
    • • Skin• Few drugs readily penetrate the skin.• Absorption is proportional to surface area.• More rapid through abraded, burned or denuded skin.• Inflammation increases cutaneous blood flow and, therefore, absorption.• Enhanced by suspension in oily vehicle and rubbing into skin. 18
    • • Eye - topically applied ophthalmic drugs are used mainly for their local effects. -systemic absorption that results from drainage through the nasolacrimal canal is usually undesirable; not subject to first-pass hepatic metabolism. 19
    • Physicochemical Factors In Transfer of Drugs Across Membranes • Cell Membranes • Passive Properties • Carrier-Mediated Transport 20
    • Fact...“The absorption, distribution,biotransformation, and excretion of a drugall involve its passage across cellmembranes.”Drugs generally pass through cells ratherthan between them. Thus, the plasmamembrane is the common barrier.Passive diffusion depends on movementdown a concentration gradient. 21
    • 1. Molecular SizeIn general, smaller molecules diffuse morereadily across membranes than larger ones(because the diffusion coefficient isinversely related to the sq. root of theMW). This applies to passive diffusion butNOT to specialized transport mechanisms(active transport, pinocytosis).tight junction: MW <200 for diffusion.large fenestrations in capillaries: MW 20K-30K. 22
    • 2. Lipid-Solubility Oil:Water Partition CoefficientThe greater the partition coefficient, thehigher the lipid-solubility of the drug, andthe greater its diffusion across membranes.A non-ionizable compound (or the non-ionized form of an acid or a base) will reachan equilibrium across the membrane that isproportional to its concentration gradient. 23
    • Absorbed from stomach in 50 580 1 hour (% of dose) 40 52 30 20 10 1Other things (MW, pKa) being equal,absorption of these drugs is 0 barbital secobarbital thiopentalproportional to lipid solubility. (pKa 7.8) (pKa 7.9) (pKa 7.6) 24
    • 3. IonizationMost drugs are small (MW < 1000) weakelectrolytes (acids/bases). This influencespassive diffusion since cell membranes arehydrophobic lipid bilayers that are muchmore permeable to the non-ionized formsof drugs.The fraction of drug that is non-ionizeddepends on its chemical nature, its pKa, andthe local biophase pH... 25
    • You can think of properties this way: ionized = polar = water-soluble non-ionized = less polar = more lipid-soluble _ Think of an acid as having a carboxyl: COOH / COO Think of a base as having an amino: NH3+ / NH2*For both acids and bases, pKa = acid dissociation constant, the pH at which 50% of the molecules are ionized. Example: weak acid = aspirin (pKa 3.5) weak base = morphine (pKa 8.0) 26
    • Weak acid Weak base H+ extracellular H+ pH B BH+HA A-HA A- B BH+ intracellular pH H+ H+ * The pH on each side of the membrane determines the equilibrium on each side 27
    • A Useful Concept...Drugs tend to exist in the ionized form when exposed to their “pH-opposite” chemical environment.Acids are increasingly ionized with increasing pH (basic environment), whereas…Bases are increasingly ionized with decreasing pH (acidic environment). 28
    • +HA acid base HB pH cromolyn sodium (2.0) diazepam (3.3) 2 furosemide (3.9) chlordiazepaxide (4.8) 4 sulfamethoxazole (6.0) 6 triamterene (6.1) phenobarbital (7.4) cimetidine (6.8) 7.4 phenytoin (8.3) morphine (8.0) 8A - chlorthalidone (9.4) 10 amantadine (10.1) B 29
    • Henderson-Hasselbalch Eqn. [protonated]log = pKa - pH [unprotonated] 30
    • 31
    • Problem: What percentage of phenobarbital (weak acid, pKa = 7.4) exists in the ionized form in urine at pH 6.4?pKa - pH = 7.4 - 6.4 = 1 take antilog of 1 to get the ratio between non-ionized (HA) and ionized (A-) antilog of 1 = 10 forms of the drug: if pH = pKa then HA = A- if pH < pKa, acid form (HA) will always predominate if pH > pKa, the basic form (A-) will always predominateRatio of HA/A- = 10/1% ionized = A- / A- + HA X100 = 1 / (1 + 10) X 100 = 9% ionized 32
    • Problem: What percentage of cocaine (weak base, pKa =8 .5) exists in the non-ionized form in the stomach at pH 2.5?pKa - pH = 8.5 - 2.5 = 6 take antilog of 6 to get the ratio between ionized (BH+) and non-ionizedantilog of 6 = 1,000,000 (B) formsof the drug: if pH = pKa then BH+ = B if pH < pKa, acid form (BH+) will always predominate if pH > pKa, the basic form (B) will always predominateRatio of BH+/B = 1,000,000/1% non-ionized = B/ (B + BH+) X100 = 1 X 10-4 % non-ionized or 0.0001% 33
    • In a Suspected Overdose... The most appropriate site for sampling to identify the drug depends on the drug’s chemical nature.Acidic drugs concentrate in plasma, whereas the stomach is a reasonable site for sampling basic drugs. Diffusion of basic drugs into the stomach results in almost complete ionization in that low- pH environment. 34
    • naproxen (weak acid, pKa 5.0) gastric juice plasma pH 2.0 pH 7.4 HA = 1.0 HA = 1.0 + + A- = 0.001 A- = 251 total totalHA + A- = 1.001 HA + A- = 252 morphine (weak base, pKa 8.0)small intestine plasma pH 5.3 pH 7.4 HB+ = 501 HB+ = 4 + + B = 1.0 B = 1.0 total total + +HB + B = 502 HB + B = 5 35
    • Other aspects….• amphetamine (weak base, pKa 10) – its actions can be prolonged by ingesting bicarbonate to alkalinize the urine... – this will increase the fraction of amphetamine in non-ionized form, which is readily reabsorbed across the luminal surface of the kidney nephron... – in overdose, you may acidify the urine to increase kidney clearance of amphetamine. 36
    • Certain compounds may exist as strongelectrolytes. This means they are ionized atall body pH values. They are poorly lipidsoluble.Ex:strong acid = glucuronic acid derivatives ofdrugs.strong base = quarternary ammoniumcompounds such as acetylcholine. 37
    • Membrane Transferpassive carrier-mediated endocytosisdiffusion active passive ATP ADP-Pi 38
    • Facilitated DiffusionThis is a carrier-mediated process that doesNOT require energy. In this process,movement of the substance can NOT beagainst its concentration gradient.Necessary for the transport of endogenouscompounds whose rate of movement acrossmembranes by simple diffusion would be tooslow. 39
    • Active Transport• Occurrence: - neuronal membranes, choroid plexus, renal tubule cells, hepatocytes• Characteristics - carrier-mediated - selectivity - competitive inhibition by congeners - *energy requirement - saturable - *movement against concentration gradient*differences from facilitated diffusion 40
    • Endocytosis, Exocytosis, InternalizationEndocytosis (or pinocytosis): a portion of the plasma membrane invaginates and then pinches off from the surface to form an intracellular vesicle.Ex: This is the mechanism by which thyroid follicular cells, in response to TSH, take up thyroglobulin (MW > 500,000). 41
    • Drug AbsorptionAbsorption describes the rate and extent atwhich a drug leaves its site of administration.Bioavailability (F) is the extent to which adrug reaches its site of action, or to abiological fluid (such as plasma) from whichthe drug has access to its site of action. 42
    • Pharmacokinetics Locus of Tissue action reservoirs “receptors” Bound Free Bound Free Systemic circulationAbsorption Free drug Excretion Bound drug Metabolites Biotransformation 43
    • AUC = area under the curve AUC oralplasma concentration of drug Bioavailability = X 100 AUC injected i.v. AUC injected I.v. AUC oral time 44
    • Factors Modifying Absorption • drug solubility (aqueous vs. lipid) • local conditions (pH) • local circulation (perfusion) • surface area 45
    • BioequivalenceDrugs are pharmaceutical equivalents if theycontain the same active ingredients and areidentical in dose (quantity of drug), dosage form(e.g., pill formulation), and route ofadministration.Bioequivalence exists between two suchproducts when the rates and extent ofbioavailability of their active ingredient are notsignificantly different. 46
    • DistributionOnce a drug is absorbed into thebloodstream, it may be distributed intointerstitial and cellular fluids. The actualpattern of drug distribution reflectsvarious physiological factors andphysicochemical properties of the drug. 47
    • Phases of Distribution• first phase – reflects cardiac output and regional blood flow. Thus, heart, liver, kidney & brain receive most of the drug during the first few minutes after absorption.• next phase – delivery to muscle, most viscera, skin and adipose is slower, and involves a far larger fraction of the body mass. 48
    • Pharmacokinetics Locus of Tissue action reservoirs “receptors” Bound Free Bound Free Systemic circulationAbsorption Free drug Excretion Bound drug Metabolites Biotransformation 49
    • Drug Reservoirs Body compartments where a drug can accumulate are reservoirs. They have dynamic effects on drug availability.• plasma proteins as reservoirs (bind drug)• cellular reservoirs – Adipose (lipophilic drugs) – Bone (crystal lattice) – Transcellular (ion trapping) 50
    • Protein BindingPassive movement of drugs across biologicalmembranes is influenced by proteinbinding. Binding may occur with plasmaproteins or with non-specific tissue proteinsin addition to the drug’s receptors.***Only drug that is not bound to proteins(i.e., free or unbound drug) can diffuseacross membranes. 51
    • Plasma Proteins• albumin - binds many acidic drugs• a1-acid glycoprotein for basic drugs The fraction of total drug in plasma that is bound is determined by its concentration, its binding affinity, and the number of binding sites. At low concentration, binding is a function of Kd; at high concentration it’s the # of sites. 52
    • Plasma Proteins• Thyroxine (thyroid hormone T4)• > 99% bound to plasma proteins.• The main carrier is the acidic glycoprotein thyroxine-binding globulin.• very slowly eliminated from the body, and has a very long half-life. 53
    • Drugs Binding Primarily to Albuminbarbiturate probenecidbenzodiazepines streptomycinbilirubin sulfonamidesdigotoxin tetracyclinefatty acids tolbutamidepenicillins valproic acidphenytoin warfarinphenylbutazone 54
    • Drugs Binding Primarily to a1-Acid Glycoproteinalprenolol lidocainebupivicaine methadonedesmethylperazine prazosindipyridamole propranololdisopyramide quinidineetidocaine verapamilimipramine 55
    • Drugs Binding Primarily to Lipoproteinsamitriptylinenortriptyline 56
    • Bone ReservoirTetracycline antibiotics (and other divalentmetal ion-chelating agents) and heavymetals may accumulate in bone. They areadsorbed onto the bone-crystal surface andeventually become incorporated into thecrystal lattice.Bone then can become a reservoir for slowrelease of toxic agents (e.g., lead, radium)into the blood. 57
    • Adipose ReservoirMany lipid-soluble drugs are stored in fat. In obesity, fat content may be as high as 50%, and in starvation it may still be only as low as 10% of body weight.70% of a thiopental dose may be found in fat 3 hr after administration. 58
    • Thiopental• A highly lipid-soluble i.v. anesthetic. Blood flow to the brain is high, so maximal brain concentrations brain are achieved in minutes and quickly decline. Plasma levels drop as diffusion into other tissues (muscle) occurs.• Onset and termination of anesthesia is rapid. The third phase represents accumulation in fat (70% after 3 h). Can store large amounts and maintain anesthesia. 59
    • Thiopental concentration (as percent of initial dose) 0 50 100 1 blood brain 10 minutes 100 muscle 1000 adipose60
    • GI Tract as ReservoirWeak bases are passively concentrated inthe stomach from the blood because of thelarge pH differential.Some drugs are excreted in the bile in activeform or as a conjugate that can behydrolyzed in the intestine and reabsorbed.In these cases, and when orallyadministered drugs are slowly absorbed, theGI tract serves as a reservoir. 61
    • RedistributionTermination of drug action is normally bybiotransformation/excretion, but mayalso occur as a result of redistributionbetween various compartments.Particularly true for lipid-soluble drugsthat affect brain and heart. 62
    • Placental TransferDrugs cross the placental barrier primarilyby simple passive diffusion. Lipid-soluble,nonionized drugs readily enter the fetalbloodstream from maternal circulation.Rates of drug movement across theplacenta tend to increase towards term asthe tissue layers between maternal bloodand fetal capillaries thin. 63
    • Clinical PharmacokineticsFundamental hypothesis: a relationship exists between the pharmacological or toxic response to a drug and the accessible concentration of the drug (e.g., in blood).• volume of distribution (Vd)• clearance (CL)• bioavailability (F) 64
    • Volume of Distribution Volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration of drug (C). **The apparent volume of distribution is a calculated space and does not always conform to any actual anatomic space.**Note: Vd is the fluid volume the drug would have to be distributed in if Cp were representative of the drug concentration throughout the body. 65
    • Total body water plasma volume extracellularplasma 3 litersinterstitialvolume interstitial volume 15 litersintracellularvolume intracellular 12 liters 42 liters 27 liters 66
    • At steady-state: total drug in body (mg) Vd = ------------------------------ plasma conc. (mg/ml) 67
    • Example of VdThe plasma volume of a 70-kg man ~ 3L, blood volume ~ 5.5L, extracellular fluid volume ~ 12L, and total body water ~ 42L.If 500 mg of digoxin were in his body, Cplasma would be ~ 0.7 ng/ml. Dividing 500 mg by 0.7 ng/ml yields a Vd of 700L, a value 10 times total body volume! Huh?Digoxin is hydrophobic and distributes preferentially to muscle and fat, leaving very little drug in plasma. The digoxin dose required therapeutically depends on body composition. 68
    • Clearance (CL)Clearance is the most important property toconsider when a rational regimen for long-term drug administration is designed. Theclinician usually wants to maintain steady-state drug concentrations known to bewithin the therapeutic range.CL = dosing rate / CssCL = rate of elimination / Css(volume/time) = (mass of drug/time) / (mass of drug/volume) 69
    • ClearanceClearance does not indicate how much drug is removed but, rather, the volume of blood that would have to be completely freed of drug to account for the elimination rate.CL is expressed as volume per unit time. 70
    • Sum of all process contributing to dis- appearance of drug from plasmaDrug in plasma at Drug concentrationconcentration of 2 mg/ml in plasma is less after each pass through elimination/metabolism process Drug molecules disappearing from plasma at rate of 400 mg/min 400 mg/min CL = = 200 ml/min 2 mg/ml 71
    • Example: cephalexin, CLplasma = 4.3 ml/min/kg• For a 70-kg man, CLp = 300 ml/min, with renal clearance accounting for 91% of this elimination.• So, the kidney is able to excrete cephalexin at a rate such that ~ 273 ml of plasma is cleared of drug per minute. Since clearance is usually assumed to remain constant in a stable patient, the total rate of elimination of cephalexin depends on the concentration of drug in plasma. 72
    • Example: propranolol, CLp = 12 ml/min/kg or 840 ml/min in a 70-kg man.The drug is cleared almost exclusively by the liver.Every minute, the liver is able to remove the amount of drug contained in 840 ml of plasma. 73
    • • Clearance of most drugs is constant over a range of concentrations.• This means that elimination is not saturated and its rate is directly proportional to the drug concentration: this is a description of 1st-order elimination. 74
    • CL in a given organ may be defined in terms of blood flow and [drug]. Q = blood flow to organ (volume/min) CA = arterial drug conc. (mass/volume) CV = venous drug conc.rate of elimination = (Q x CA) - (Q x CV) = Q (CA- CV) 75
    • Source: First Aid for the USMLE Step 1, 2012 pg.259-261 76
    • Source: First Aid for the USMLE Step 1, 2012 pg.259-261 77
    • Source: First Aid for the USMLE Step 1, 2012 pg.259-261 78
    • Source: First Aid for the USMLE Step 1, 2012 pg.259-261 79
    • Source: First Aid for the USMLE Step 1, 2012 pg.259-261 80
    • Source: First Aid for the USMLE Step 1, 2012 pg.259-261 81
    • FOR ADDITIONAL STUDY: PHARM2000 Medical Pharmacology and Disease-Based Integrated Instruction Programmed Study: Pharmacology Content, Practice Questions, Practice Exams Michael Gordon, Ph.D., site developer; email: Michael GordonChapter 1: General Principles--Introduction Practice question set #1 Practice question set #2 Practice question set #3 Practice question set #4Chapter 2: Pharmacokinetics Practice question set #1 Practice question set #2 Practice question set #3 Practice question set #4 Practice question set #5 Practice question set #6 Flashcards Problem set #1 Problem set #2 Practice Exam #1 Practice Exam #2Chapter 3: Pharmacodynamics Practice question set #1 Practice question set #2 Flashcards Practice Exam 1 http://www.pharmacology2000.com/Unit Practice Exam #1Unit Practice Exam #2Unit Practice Exam #3Unit Practice Exam #4 82