Text books . Adam’s Veterinary Pharmacology and Therapeutics: 9° Ed., Jim E Riviere & Mark G Papich. Willy Blackwell. - Basic and Clinical Pharmacology 12" ed., Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor, McGrawHill - Goodman and Gilman’s “The Pharmacological Basis of Therapeutics” Brunton, McGrawHill Publication. . Veterinary Pharmacology and Toxicology. B.K.Roy, Kalyani Publishers, - Essentials of Medical Pharmacology. K.D. Tripathi, JAYPEEHistorical Trends In 1240 AD Frederick separated pharmacy from medicine. Valerius Cordus (German): first pharmacopoeia Paracelsus (1541) denounced humoral pathology, introduced new remedies. Von Hohenheim (swiss Physician): Tincture based therapy: Tr. Laudanum: tincture opium, inorganic chemicals in therapy Cinchona bark in treating malaria (1630): Spanish Explorer The first pharmacopeia was the French codex 1818 followed by 1820 US pharmacopeia.Historical Trends Edward Jenner: prophylactic immunization against small pox William Withering: digitalis for treatment of dropsy. Alexander Wood (1853): hypodermic syringe Friedrich Serturner (1783-1841): isolated narcotic alkaloid from opium and named morphine. Francois Magendie (1783-1855): studied effect of IV inj. Of drugs like ipecac, morphine, strychnine, quinine etc on animals Claude Bernard (1813-1873) and James Blake (1814-1893): gave the scientific basis of drugs effects, DRC, drug action, distribution and fate in the body and SAR.Historical Trends * Claude Bernard: Father of experimental medicine * Foundation of modern pharmacology: Credited to: Paul Ehrlich in late 19'' century, Langely, and Patan in early 20‘ century gave the concept of MOA of a drug and drug-receptor interaction. * Rudolph Buchheim (1820-1879): Father of modern Pharmacology.History of Pharmacology Morphine, isolated ae S from the opium poppy | ; bs P| (Papaver somniferum) 2 é q The anti-malarial compound quinine from the bark of cinchona tree (Cinchona officinalis).History of Pharmacology Purple foxglove, Digitalis purpurea, was one of twenty herbs used ina folk remedy to treat dropsy in 18" century England. Its leaves yielded the cardiac glycoside digitalis used in CHFHistory of Pharmacology Artemisia annua L. (wormwood}, used in China since antiquity to treat fevers, Source of the modem drug ginghaosu (artimicin): a modern anti-malarial compound.History of Pharmacology Paul Ehrlich described drug-receptor binding: “Corpora non agunt nisi fixate”. P Ehrlich (1908) (“Agents do not act unless they are bound”)History of Pharmacology * In 1897, Felix Hoffman, a research chemist (Bayer and Co.) synthesized acetylsalicylic acid. * In 1971 that Sir John Vane discovered the mechanism of action of aspirin, a feat that earned him the 1981 Nobel Prize for Medicine.History of Pharmacology The modern era These, and additional advances in the fields of chemistry and physiology, lead to the birth of modern pharmacology in the latter half of the 19** century. Thus, Materia Medica evolved into the experimental science of Human Smokers Have Increased pharmacology, which is Nicotinic Receptors in Prefrontal Cortex devoted to understanding the physiological action of these molecules.Human Smokers Have Increased Nicotinic Receptors in Prefrontal Cortex [ Pe)Hippocratic school (460-375Bc) Basis of treatment: Balance of Fire, Water, Air and Earth) Aristotle (384-322BC): Scientific basis of medicine Theophrastus (380-287BC): Classified medicinal herbs based on properties. Dioscorides (77): 18* Materia Medica: Herb, minerals, animal products as medicinal prepn. Galen (131-201): Polypharmacy/GalenicalsAncient Times Oldest Record: Medicinal Herb: Ayurveda (from Rigveda): 3000BC. (Herbs and Animal origin product). Basis: phlegm, pitta and yaau Charak, Shushruta, Bagbhat pioneered Ayurveda. Nakul: a man of Vety. and AHChina and Egypt * PenTaso: Chinese herbal Materia Medica by Emperor Shennung (2735-2700): Vegetable, metallic and animal product, * Egyptians: Kahan Papyrus ( 20008C) and Ebers Papyrus (15508C).Pharmacology: Basics Pharmacon (drug) and Logos (Science) It is the study of sources, properties (physical and chemical), administration, absorption, metabolism, and excretion; effects (physiological and biochemicals); uses and toxicity of drugs. Materia medica: refers to medicinal materials and includes study of sources, properties, compounding, dispensing, and uses of medicinal preparations for the treatment of diseases.Pharmacognosy: Study of sources and identification (origin) of the drugs. Pharmacometrics: Study of qualitative and quantitative aspects of drug effects in lab animals. It deals with the measurement of drug responses. Metrology: The science of weights and measures used in pharmacy. Pharmacy: It refers to identification, collection, compounding, standardization and dispensing of drug so as to render it fit for administration to animal patients.Pharmacology Divisions of Pharmacology * Pharmacokinetics * Pharmacodynamics * PharmacogenomicsPharmacokinetics * Is what the body does to the drug. * Absorption * Distribution * Metabolism * Elimination. Brand — original drug which is defended by patent and may be produced during patent term only by this pharmaceutical + _ Generic — when term of patent is discontinued the drug may be produced by different pharmaceutical companies under new product (trade) names but at the basis of original active substance (similar quantity, route of administration etc.) * All generics are much more cheaper compared to brands, that is the main reason — why they are so popular among the patientsPharmacokinetics OThe study of what the body does to a drug includes: OlAbsorbs — converts a drug into a form the body can use OMetabolizes — drug molecules are transformed into simpler products ODistributes — transporting a drug from Its site of administration to its site of action OExcretes —manner in which a drug is eliminated from the body. Pharmacokinetics Is what the body does to the drug. Absorption Distribution Metabolism EliminationPharmacokimeties * Based on the hypothesis that the action of a | drug requires presence of a_ certain concentration in the fluid bathing the | tissue. |* In other words, the magnitude of response | (good or bad) depends on concentration of the drug at the site of actionPharmacokinetics USTs ste * Distribution CW leelerebtsen ¢ EliminationDrug at site of “a administration Py Absorption (input) Qh eeete] a Drug in tissues [EE mecsvonsm | Metabolite(s) in tissues ya Elimination (output) Drug and/or metabolite(s) in urine, bile, tears, breast milk, saliva, sweat, or fecesDrugs movement across cellular barriers im their passage throughout the body PASSIVE TRANSPORT ACTIVE TRANSPORT A A Nf ~ Paracellular Diffusion Facilitated Drug transport diffusion transporters a v. “ a \ “ efo =) a eo e* The passive flux of molecules down conc" gradiant is ae a Ficks’ Law * Thickness=length of diffusion path * Incase of lipid diffusion, lipid to aqueous partition coeff. Is a major factor of mobility of drug. * This determines how readily the drug enters the lipid membrane from aqueous medium.Hendersan Hasalbalch Equation * Influence of pH * Most drugs: weak electrolyte: Ionization depends upon pH * Ionization of a weak acid HA is expressed asHenderson Hasselbalch equation ? pKa=-ve log of acidic dissociation constant ¢ Ifconc" of ionized and unionized drugs are equal Since log1= 0, so under this pH=pKa or when 50% ionization is there pH &pKa are numerically same. ° If pH is increased by one then Loot or Similarly when the pH is reduced by 1 then aeInfluence of pH on the distribution ota weak acid between plasma and gastric juice separated by a lipid bartier a —_ —_ = | Weak Acid HA A-+H* pk, =44 q B = [HA] + [Aq =[HA)+[A4GG weak acid Lipid membraneWeak base compartment =pH:pKa :lonization ; Unionization wet aod spin Pers Patadin thas bao Pika 86 shperaals Urine 948The distribution of a drug between its ionized and nonionized forms depends on the ambient pH and pKa of the drug When pHs lessthan pk, When pH Is greater than pk, the protonated forms atipoionted rst HAand BH" predominate, ‘rand B predominate, £\The interrelationship of the absorption. distribution, binding. metabolism, and exerction of a drug and its concentration at its sites of aetion.Study of [drug] over time Tpapaniet rat; Extravascular * Adnirisiration Toe | Absorption roite 4 J _ +z \\_liination Tissue *—, _ Distributi ‘Metabotsm Tissue Distribution __Syetaboism aa plus ftom oe >> Exeretion Effect-— Site of action The general slapes and their relationships in the life cycle ofa drug after administration.Bloavailability = __AUC oral x 100 AUC Iv 2 7a 3 3 5 2 8 z =How are [drug] measured? Invasive: blood, spinal fluid, biopsy Noninvasive: urine, feces, breath, saliva Most analytical methods designed for plasma analysis C-14, H-3A. Concentration data are plotted on a linear scale. B. Concentration data are plotted on a log sca Distribution Elimination phase phase 4 Most drugs show an exponential decrease in concentration with time during the elimination phase. g § 3 § § 5 3 é Ss = The half-life (the time it takes to reduce the pl Tug concentrationEffect of drug dose on the rate of metabolism. With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large. Therefore, the plasma drug concentration is much greater than Km, and drug metabolism is zero order, that 's, constant and independent of the i f i With most drugs the plasma drug concentration is less than Km, and drug elimination is first order, that is, proportional to the drug dose.Models of drug distribution and climination.Partition Coefficients: ratio of solubility of a drug in water or in an aqueous buffer to its solubility in a lipophilic, non-polar solvent ¢ pH and ionization: Jon TrappingBlood centration-time curves B 2 Ss £ > = 5 Ss < 5} £ = S 8 2 Ss oO [TTT] A: Drug rapidly and completely available B: Only half of availability of A but rate equal to A i Aarne: eneliietes seen: Mie ee or eeeMode of application and time course of drug concentration g 8 g a £ c g E € 8 6 3 D 2 oO: Drug concentration at time ¢Variation in the concentration of a drug with time in sample of (a) plasma and (b) urine after the administration of a single oral dose of a drug at time zero. a 1 c— \ Plasma Concentration / \ concentration in the excreted \ \ wie yee Therapeutic Window Useful range of concentration over which a drug is therapeutically beneficial. Therapeutic window may vary from patient to patient Drugs w/ narrow therapeutic windows require} smaller & more frequent doses or a different method of administration Drugs w/ slow elimination rates may rapidly | accumulate to toxic levels....can choose to give one large initial dose, following only with small | dosesTherapeutic window: Successively oral doses @ point X. Too high dose: Toxic, and Too low is ineffectiveShape: The variation of concentration of a drug in plasma (Cp) with time when admd by (a) quick single IV injection, (b) IV infusionDistribution ¢ Rate & Extent depend upon TO To ievece in Rom eles — Rate of blood flow — Ease of transport through membrane — Binding of drug to proteins in blood — Elimination processesExamples of apparent Vd’s for ROO) CORI la tea) | Drug OA a4 L/70 kg Sulfisoxazole 0.16 “ilo? Phenytoin 0.63 44.4 Phenobarbital ORL} Sieie) | Diazepam va 168 Digoxin uf 490PRINCIPLE: Vd Following absorption, drugs enter in to systemic circulation, then distributed in to interstitial and HTilaesCee) LTT Ta ath CO The vol. of body fluid that would accommodate the entire drug (D), if its concentration through out the body was the same as in plasma (Cp); is termed as apparent vol. of distribution (V4). Vd = D/C,p (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with a concentration equal to its plasma concentration(Sources & Composition of Drugs) » Term derived from the Greek word pharmakon - drug and gnosis - means knowledge. * It is a branch of pharmacology which deals with the study of sources of drugs derived from microbes, plants, animals and_ their physical/ chemical properties._ - Currently most drugs used in therapeutics are | synthetic in nature (70 %). ‘| i © Natural sources are still resource for obtaining : some drugs mainly because their synthesis is ficult or uneconomical.Classification of drugs (Nature of origin) A)- Natural sources of drugs (basis of chemical nature) Organic ip nature ¥ Animal sourees ¥ Microbial sources v Vegetable sources Inorganic in nature ¥ Metallic OUTCCS, ¥ Non-metallic sources B)- Semi-synthetic C)- Biosynthetic D)- Synthetic sources of drugsNatural sources is *» Small amount of active principles of drugs are present in crude form (leaf, root, bark, flower, etc). * To increase their effectiveness these active Principles are concentrated by various techniques or by pharmaceutical processes.Organic drugs Animal sources: Some important drugs are obtained from. animal sources “» Hormones: Insulin (Pork). Thyroxin, Gonadotropins (GNRH, PGF,,). Lanolin *» Vitamins: Cod liver oil (Vitamin A. B,,). Fish oil Heparin (leech) | | %& Vaccines or Sera: = \ Antileabies vaceine, ATS (anti-tetanic serum), anti-shalte Sct anti-diphtheria serum. cte mya” NL iaMicrobial sources Microorganisms also served as important sources of drugs b Bacteria Bacitracin - Bacillus subtilis Fungi Penicillin - Penicillium notatum Gentamicin - Micromonospora purpueria Griseofulvin - Pencillin grisofullivum Molds Streptomycin - Steptomyces griseus Chloramphenicol - Streptomyces venezuelace Neomycin - Streptoniyces fradiaeEe Vegetable sources Ee See “Very old and i important source of drugs bark, leaves, fruits, etc) of the plants are still used for ‘ ** Substances obtained from different parts (roots, stem, obtaining several important drugs. “Still number of drug candidates are discovered from the plant sourcesAction / Clinical use Drug (s) Plant Source Atropine Atwopa helladoma Anti-cholinergic Codeine / Papaver somniferum Anti-tussive, Morphine analgesic Cynarin ‘vnara seolymus Cholerectic Digitoxin Digitalis purpurea Cardio-tonic Oubain Strophanthus kombe Cardio-tonic I phedrine lphedra vulgaris SympathomimeticPlant Source Hvosevamus niger Anti-cholinergic Nicotiana tabacunm Insecticide Physostigmine Physosigma venenosum Achl Inhibitor ») Podophyllotoxin Podephyllum peltatum Cinchona ledgeriana Theabroma eacao Anti-neoplastic Anti-arrhyhmic Diuretics Chondradendron tomentosim Skeletal muscleAction / Clinical use | Vincristine Carharauthaus roseus Anti-neoplastic hi ) Yohimbine Pausinystalia yohimbe “adrenergic-blocker # Reserpine Rauwlfia serpantina | Adrenergic agonist i Cocaine Enythroxylum coca Local anesthetic Camptotheca acummata \nti-neoplastic Capsicum spp. Tropical algesic at oODrug (s) Colchicine Plant Source Colehroum autumnale Action / Clinical use Anti-gout Emetine =| Galanthamine Cephaelis ipecacnanha Lencajum aestivum Anti-amoebic Ach? inhibitor Pilocarpine Pilocarpus jaborandi Cholinomimetic Artemisinin Artemisia annna Anti-malarial | Taxol Taxus brevi Anti-neoplastic Zinkgolide B Zinkgo biloba PAF R Antagonistme (s) | a Plant source Clinical Use , Eugenol Clove Local anesthetic. jj Senegrin Senna Purgative Strychnine = | Strychmismix-vomica Rodenticide Squill Urginea Emetic | Gingcr oil Ginger |Carminative Sandal wood oil Ry Sandal wood Urinary antisepticPhysical and Chemical Properties of DrugsAlkaloids ++ Nitrogenous heterocyclic bases - active principles of plants and animals * Organic compound consists of C, H,O and N ** When combines with acids to from crystalline salts without water production * Mostly obtained from plants and also from animals & * Alkaloids + heavy metals/Tannic acid inactive products“+ They are readily soluble in alcohol but sparingly soluble in water, but their salts are frecly soluble in water. * They are bitter in taste and are often poisonous (in higher concentrations) * Their names mostly ends with ine.— Natural alkaloids Cicnplitl (Gree a iar2 itp) Pry se Coy uta Orisa el Orse ta sty Caffeine, Sirychnine CoH TUL ta (eOsE Ce Te) Arccholine, Nicotine —Semi-synthetic alkaloids Apomorphine, Homatropme ty — Animal alkaloids Pie a eilint is hee bere diet:‘cosides 5 Combination of sugar moiety with non-sugar moiety Pune To utantsaial ey em eeCse eo aceess (Cp Mm ineletste Sugar moicty (glycone) is responsible for the phannacokinctic properhies of the glycoside Phinnscolowien! wetivity resides im the mon-saar mien that iv called qulvcope Lo gent)iS ~ Neutral in reaction and do not combine with acids to form salts * On hydrolysis yield sugar (glycone) and non-sugar moiety (aglycone)Digitoxin Oubain Dioxin Nerm Strophanthrin Allicm Botanical source Digitalis purpurea Strophanthus komkge Digitalis janata Nerium oleaniler Strophanthus kombe Altium sativum Clinical applications Congestive heart failure Congestive heart failure Cardiac glycoside Cardiotoxic¢ Congestive heart failure Hypertension, AntibacterialSaponins (sapo — soap) SUC CCRC area property of frothing - Toxiesaponins are called sapotoxinsName of saponins Botanical source — Clinical a Pplications Glyeyirhizin Giveyirhica glabra Sweetener Senegin Polvgala senegad Hypoglycemic activity Quill A Quillaja saponaria Adjuvant in vaccines Sarsaparilla Smilax ornata Rheumatism, Syphilis Diosein roscored bulbijera Steroidal conwaceptivesResins = Solid substance produced by some plants or secretions of plant tissue (resin ducts). = Oxidative products of volatile oils or polymerization of volatile oils » Resins are amorphous solids, bitter in taste and are soluble in alkalis forming non-detergent resin soaps. » Resins are insoluble in water, but soluble in organic solvents alcohol and ether.Name of resins Resin of jalap Gamboge Podophyllum Canada balsam Asafetida Botanical source Ipomea jalapa Gareinia cambodia * Podophyllum peltatum Ahies balsamea Ferula assa-foetida Clinical applications Laxative and Purgative Antioxidant irritant purgative Solvent kxpectorant, AsthmaTannins or Tannic acid Complex non-nitrogenous phenolic derivatives or mixture of esters of gallic acid with glucose Tannie acid is obtained from oak galls, nut galls and is used for treating burns haemostatic and diarrhea Characterized by their astringent action on the mucous membrane, precipitate proteins to forms a_ protective coating over il Pyrogallol tannins are glycosides of glucose that oceur in oak galls. Pyrocatechol tannins are present in catechu, cinchona & eucalyptusName of tannins Oak Tannic acid ) Epicatechin Tannins Botanical source Quercus spp Punica granatum Camellia sinensis Red & white color beans Clinical applications Chronic dermatitis, Astringent (Clarifying agent in alcoholic drinks ‘Taste and flavor, Anticancer Rheumatism, SyphilisGums + Gums are complex polysaccharides and secretary products of plants, yield simple sugars on hydrolysis. * Pharmacologically inert, amorphous, colloidal, and when dissolve in water forming viscid adhesive fluid known as mucilage. e.g. Gum Acacia, Gum tragacanth. * On ingestion adsorb water to increase the volume of intestinal contents to serve as evacuants.Name of gums Psyllium gum Guar gum Rubber latex Gum ghatti Neem Botanical source Plantago spp Cyamopsis tetragonolobus Hevea brasiliensis Anogeissus latifolia Azadirachta indica Clinical applications Bulk purgatives Hydrophilic colloids Irritant purgative Emulsifier, Stabilizer AntimicrobialsWaxes — Waxes are esters of higher fatty acids deposited in the form of a plastic substance by insects or obtained from plants. — Insoluble in water and soluble in organic solvents — Petroleum and firmer in consistency and have higher melting points — They can be sapanified by alcoholic alkali e.g. yellow and white bees wax.Name of waxes Wax of honeybee Fatty acid esters Fatty acid esters Pyrethrins Lanolin (wool wax) Source Apis mellifera Trogopterus xanthipes Feces Trogopterus Chrysanthemum spp Sheep sebaceous glands Clinical applications Cosmetic, pharmacy Potent anticoagulant Amenorrhea. Menses pain Rmulsifier, Stabilizer Cosmetic & dermatologyOils Oils are Glycerides of higher fatty acids, Solid at room temperature-Fats Liquid at room temperature-Oils Oils are obtained from v Vegetable-Clove oil, mustered oil ¥ Animal -— Cod liver oil Y Mineral sources — Kerosene oil, Paraffin** Essential/aromatic/ Volatile oils * Fixed oils ** Mineral oils& > > Essential oils / Volatile oils On exposure to air and light or prolonged stay they tend to oxidize, evaporate and turn rancid —Rancification (foul smell)They are frequently used as carminatives and EISb eben Pebsiteahyoteoit - Carminative, » Clove oil - Anodyne » Oilof wintergreen -Counter irritant « + Peppermint oi! —lPlayoring oil olid volatile oil — * camphor, Menthol, ThymolName of oils Peppermint oil Clove oil Eucalyptus oil Ginger oil Turpentine oil Camphor Source Menthe piperita -gium aromaticum Eucalyptus globulus Zingiber officinale Distillation of resin obtained from pines Cinnamomum camphora Clinical applications Breath freshener, Analgesic Toothache, Cough, Asthma. Antispasmodic, Decongestant, Antiseptic Expectorant, Antiseptic, Analgesic Arthritis, Cosmetics . Decongestant, Anti-inflammatoryFixed oils I olete and palmitic dete « They are obtained from the seeds that are present within the cells as crystals or droplets. They are non-volatile and leave greasy stains on evaporation and liquid at ordinary temperature = They have caloric or food value. = They form soaps with alkalies. + On prolonged) stay, they become rancidOtic hike High caloric value = Sunflower, groundnut and coconut Pharmacological value = Plant origin- Castor oil, croton oil, Olive oil WTEC Te Ke} = b 3 Animal otigin= cod liver oil, fish oll, Shark liver ‘oll.Fixed oils Castor oil Pea nut oil Olive oil Linseed oil Sesame oil Corn oil Neem oil Source Ricinus communis Arachis hypogaea Olea europoea Linum usitatissimum Sesamum indicum Zea mays Azadirachta indica Clinical applications Cathartic, lubrication Liniments, plasters Emollient, soothing agent Lotions and liniments Laxative, demulcent Solvent for injection Antiviral. antibacterialMineral oils Obtained by boring the carth and extracted by fractional distillation. Mineral Oils are mostly petroleum products and re mixtures of hydrocarbons of the methane and related aliphatic series. S No food value These are extracted in various consistencies - hard paraffin, soft paraffin and liquid paraffinSome have pharmacological important e.g: liquid paraffin (lubricant, laxative), Vaseline (mon absorbable ointment), kerosene oil, petroleum + Hard and soft paraffin’s are used as vehicles for preparation of ointments / creams while liquid paraffin is employed as a purgative.Inorganic Drugs Drugs obtained from inorganic sources and classified into — Metals — Non-metals Metalloids show intermediate properties usually add with metals.Metals Avent Clinical Use Magnesium sulphate -Purgative Calcium carbonate -Astringent Copper sulphate -Emetic Ferrous sulphate -Ha Chive caliphate = Ashiiieget Aluminum hydroxide /Sod. bicarbonate -Antacid Aluminum si te (Kaolin) -Adsorbent: Potassium bromide -Sedatives Silver nitrate - Caustics Sulphur - Acaricide Lead acetate, Bismuth sub nitrate - Antisepticaesaetals Todipe or KI er Olay Bromine or KBr -Sedative Lithiurn -Anith janie \ \ rhOy pu piss Sutle Sulphur sea disinfectant penal) ane ahh: ah oo a aSemi-synthetic Sources Semi-synthetic processes are used to prepare drugs when the synthesis of drugs (complex molecules) may be difficult. expensive and uneconomical or when the natural sources may yield impure compounds Some examples are semi-synthetie human insulin and 6- amunopenicillanic acid derivatives.Biosynthetic drugs * Relatively new field which is being developed by mixing discoveries from molecular _ biology. recombinant DNA technology, DNA alteration, gene splicing and immunology. Some of the recent developments are genetically engineered novel vaccines (Recombinex HB - a hepatitis-B vaccine), recombinant DNA engineered insulin’s (Humulin- human insulin) for diabetes.Synthetic sources of drugs * Synthetic drugs are prepared in laboratory with the help of inorganic and organic drugs and today majority of drugs are obtained synthetically * Numerous drugs which were ongmally obtamed trom plants are now prepared synthetically Sas esac Ly tanaeacrtuler est ble eacnnat acceso iho as Ele tiseAdvantages of synthetic drugs: O Dhev wtechenvieally pmae- QO The process of preparing them is easier and cheaper. QO Control on the quality of the drug is excellent. _Q Since the pharmacological activity of a drug depends on its chemical structure and physical properties, more effective and safer drugs can be prepared by modifying the chemical structure of the prototype drug.The enterohepatic shunt+ Rate & Extent depend upon SOL enintec IR tanwiariccaa ats (Uris — Ratc of blood flaw peecee uate tens ua mines simulates te SEH riterrerMeimeraT SM CMU CeCe Tens) ert] = Elimination processes* Partition Coefficients: ratio of solubility of a drug in water or tn an aqueous bulTer to its solubility in a lipophilic, non-polar solvent * pH and ionization: fon TrappingElimination Se eRe CRITE ete nec Tuk emcee a a La eI CRS Tae T CO Sc eCA ECT ERIM sie Caer ei UL an eliminated per unit time. RoR MEO y moar Celi ETE ie ae weA Zero Lone placmna Deus Copdsahabron “Te frkeace pt af prepress ice. 8 i abeibruliorS] Ptr « ¢ hos A L ‘ Reon. . Ploomea c) org Cone inbereag het 2F% bine of -CLimriredtron 2€e r mse Conatet-+ \ aye! ence he E more ; as Paraben =p ackon a at Time Cbd Concantroon tire pf? offen eI 23>Physical volumes (in L/kg body weight) of some body compartments into which drugs may be distributed. Compartment and Volume Water Total body water (0.6 L/kg') Extracellular water (0.2 L/kg) Blood (0.08 L/kg); plasma (0.04 L/kg) Fat (0.2-0.35 L/kg) Examples of Drugs Small water-soluble molecules: eg, ethanol Larger water-soluble molecules: eg, gentamicin Strongly plasma protein-bound molecules and very large molecules: eg, heparin Highly lipid-soluble molecules: eg, DDT4 Extrapolation to time zero gives Co, the hypothetical drug concentration Distribution Elimination phase phase 4 Most drugs show an exponential decrease In concentration with time during the elimination phase. Plasma concentration (Cp) Plasma concentration predicted If the distribution had been achieved instantly. Co=t 0.5 o4 0.3 0.2 The half-life (the time It takes to reduce the plasma drug concentration by half) Is equal to 0.693 V4/CL.Blood concentration-time curves Concentration of drug in blood Time A: Drug rapidly and completely available B: Only half of availability of A but rate equal to A I 1 GC: Drua completely available but rate onlv half of AFirst Order Elimination = Bo} rs 3 iS coy 5 (5) oO (= n & aPRINCIPLE TERMI MU baeAMiRO mA CMO hG usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (K,,).First Order Elimination PO reco ROME MO Crea meruetet seommeletimatvetcy Clearance = Rate of elimination + plasma conc. ¢ Half-life of elimination: time for plasma conc. to decrease by half. Useful in estimating: Sabet COB cor( Mt eHCeh ME Tcm ee elaoelneTeCOe - time for plasma concentration to fall after dosing is stopped.Rate of eliminationyicney Rate of elimination < Rate of elimination Cc otherRate of elimination = K, x Amount in body Rate of elimination = CL x Plasma Concentration BUtocotecen Kx Amount = CL x Concentration Pt 0.693/t1/2 = CL/V,ath (ela aD The half-life of elimination of a drug (and its residence in the body) depends on its clearance and its volume of distribution t1/2 is proportional to V, t1/2 is inversely proportional to CL t1/2 = 0.693 x V,/CLMultiple dosing * Oncontinuous steady administration of a drug, VEULR oO RENE mlm NOC slowly and reach a plateau, where: ee em rR ROE LEC ie. steady state is reached. * Therefore, at steady state: Dose (Rate of Administration) = clearance x plasma conc. Or If you aim at a target plasma level and you know the clearance, you can calculate the dose required.Constant Rate of Administration (i.v.) 30 —~ 20 a = Es Cp(ss) is a O10 0 0 10 20 30Plasma Concentration Single dose — 7 Loading dose o Therapeutic level ne m Repeated doses — Maintenance dose Time20 a Cp (mg/L) o 6 12 18 24 Time (hour)First-Order Kinetics = Ss 338 Lorreguacuc wuUselg12 18 Time (hour)Pharmacokinetic parameters Get equation of regression line; from it get Ky, Cy , and AUC * Volume of distribution V,= DOSE / C, par Oucka cella Cl=K,.Vq BEB ESE MICO lic t1/2= 0.693 / K,, Sa eRe TIEL TT ag (AUC), / (AUC),,iE 80 3 fe 60 dC/dt = CLxC 2 8 dC =CLxCxdt 5 20 Oo 0 0 2 4 6 8 10 Time (hour) But C x dt = small area under the curve. For total amount eliminated (which is the t EVM Ab Yo OMe amiate)Bioavailability Stee = 2) ce o £ as Ss © o = fe} ° i] (ss a & alPRINCIPLE BU y HI RCICaM lear ee-Ticel RCO eMC ar Teme Lele ho h similar in all individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually and doses adjusted accordingly.The Compartment Model * WE can generally think of the body as a series of interconnected well- Se RCUMRED Nao KMRL git Cl the [drug] remains fairly constant. ¢ BUT movement BETWEEN Cee va Carta Tae 1 determining when and for how long a ChAT Me atom MOLI heModels of drug distribution and climination.WON ea nel eT CMe tiie TimePartitioning into body fat and other tissues A large, nonpolar compartment. *Fat has low blood supply—less than 2% of cardiac output, so drugs are delivered to fat ortho nary Ons bu *For practical purposes: partition into body fat is important following acute dosing only for a few highly lipid-soluble drugs and environmental contaminants which are poorly metabolized and remain in body for long period of timeIMPORTANT EFFECTS OF pH PARTITIONING Oe Urinary acidification will accelerate the excretion of weak bases and retard that of weak acids; alkalination has the opposite effects Oe Increasing plasma pH (by addition of NaHCO,) will cause weakly acidic drugs to be extracted BGrosomielem OU hom telco Maetom o)c-tyeute « Reducing plasma pH (by administering a carbonic anhydrase inhibitor) will cause weakly pln putes a Le concentrated in the CNS,Renal Elimination Glomerular filtration: molecules below 20 kDa pass into filtrate. Drug must be free, not protein bound Tubular secretion/reabsorption: Active transport. Followed by passive & active. DP=D +P. As D transported, shift in equilibrium to release more free D. Drugs with high lipid solubility are reabsorbed passively & therefore slowly excreted. Idea of ion trapping can be used to increase excretion rate---traps drug in filtrate.Plasma Proteins that Bind Drugs ¢ albumin: binds many acidic drugs and a few basic drugs MUS Melee moar a Mr hee aucol! have also been found to bind certain basic drugsImportance of Sema seca fo intensity andA bound drug has no effect! ¢ Amount bound depends on: ¢ 1) free drug concentration ¢ 2) the protein concentration ¢ 3) affinity for binding sites % bound: __[bound drug x 100 [bound drug] + [free drug]% Bound ¢ Renal failure, inflammation, fasting, malnutrition can have effect on plasma protein binding. « Competition from other drugs can also affect % bound.FaWiWa>.<-100} ee ° warfarin (anticoagulant) protein bound ~98% « Therefore, for a 5 mg dose, only 0.1 mg of drug is free in the body to work! + Ifpt takes normal dose of aspirin at same time (normally occupies 50% of binding sites), the aspirin displaces warfarin so that 96% of the warfarin dose is protein-bound; thus, 0.2 mg warfarin free; thus, doubles the injested doseAYN CRIM DIOR a UO TTACiy I - C= DN, — V,is the apparent volume of distribution — C=Cone of drug in plasma at some time — D= Total cone of drug in system. V4 gives one as estimate of how well the drug is distributed. Value < 0.071 L/kg indicate the drug Ter b as mUCRe TCH CTO R ANIC T me flee 0.071 L/kg indicate the drug has gotten into specific tissues. iVs. time plots Zero order, slope = -k First order, slope = -k Cc log. C First order Time t ———+ Time t - {a) (b) (a) Zero- and first-order concentration-time plots and (b) first-order log, congentration-time plots NSComparison * First Order Elimination + Zero Order Elimination — [drug] decreases — [drug] decreases linearly reesei MA ME LBUte) SGU embreaTe Rate of elimination is BRET cmo Mel neh Te COT proportional to [drug] Cees See amo eee (eutel nod — Rate of elimination is In[drug] vs. time are independent of [drug] linear ONC tee a — ty, is constant regardless of [drug]Use of t 1. & ky data ¢ Ifdrug has short duration of action, design drug with larger t ,. & smaller ky + Ifdrug too toxic, design drug with smaller t ,. & larger kyClearance * Volume of blood in a defined region of the body that is cleared of a drug in a unit time. * Clearance is a more useful concept in reality than t 1) or k, since it takes into account blood flow rate * Clearance varies with body weight * Also varies with degree of protein binding U3Not imp in ug level Clearance Rate of climination =k, D, — Remembering that C= D/V, — And therefore D= C Vd — Rate of elimination =k, C V4 * Rate of elimination for whole body = CL; C Combining the two, CL; C =k, C Vj and simplifying gives: Or ae