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AUC (F.O) / AUC (F.Iv) PHARMACOKINETIC The aim of the pharmacokinetic study? 12 Provides the knowledge to 10 TOXIC RANGE determine the dosage and the 8 6 THERAPEUTIC RANGE necessary adaptation of plasma 4 2 SUB-THERAPEUTIC Plasma Concentration Plasma concentrations in order to 0 0 1 2 3 4 5 6 7 8 9 optimize the effect of a drug: Dose 2 PHARMACOKINETIC PHARMACODYNAMIC 3 Plasma Site of Dosage Effects Concen. Action Pharmacokinetics Pharmacodynamics 4 Introduction to Pharmacy Drug’s effect is correlated to its concentration near to the receptor, in general effect is correlated to plasma concentration 5 4 steps determine the pharmacokinetic profile Absorption à partir du site 1. Absorption d’administration 2. Distribution Distribution Effets 3. Metabolism [ ] 4. Elimination Métabolisme Elimination ADME steps –occur in the same time –it is not necessary to have all the steps for all the drugs 6 PHARMACOKINETICS Relation PK / PD Pharmacokinetic Pharmacodynamic study Correlation between [C] = f (t) Effect according to C [C] these processes and effect their effects on drug [C] concentrations ( C ) at Time pharmacologically relevant sites. PK/PD Effetc/time effect Time Introduction to Pharmacy 7 Drug Absorption and Distribution General route of administration: Drug must pass through the blood to reach its target Local application for local effect 8 The fate of the drug in human body 9 Pharmaceutical forms according to the route of administration 1. Oral administration (per os): Tablet, capsules… Liquid forms: syrup, oral solution 10 Pharmaceutical Forms 11 Excipients 12 Excipient properties/role To facilitate the manufacture of the dosage form: diluent, binder, lubricant in a tablet, emulsifier, ... capsule shell Facilitate the use of medicines (disintegrant for tablets, solvents, flavors, sweeteners, colors ...) Adapt the pharmacokinetic profile of the active ingredient (accelerated release: effervescent form, delayed release: enteric- coated form, slow release: LP form) Ensure the conservation of the drug (antiseptic, antifungal, antioxidant, chelating buffer substance ...) 13 Composition of a drug: Gardenal Principe Actif (D.C.I.) ex : phénobarbital + Excipient(s) (amidon, dextrine, stéarate Mg, carbonate Ca) Conditionnement Primaire (blister, tube … ) Conditionnement Secondaire (Boîte + R.C.P.) Criteria to choose excipients: Safety Inertia with respect to active ingredient Inertness to packaging (no interaction between container/content) Inertness to the body (neither clean nor toxicity share) 14 Route of administration Percutaneous route Local route SUBLINGUAL INHALER NASAL VAGINAL INTRASPINAL 15 Pharmaceutical Forms Rectal Administration: Suppositories Local application: ointment, cream, Eye drops 16 Parenteral Administration with syringe and needle Intravenous Injection: intra-arterial Injection Subcutaneous Injection Intradermal Injection Intramuscular Injection 17 Oral route: Anatomy Absorption is the process by which the unchanged drug is excreted from its site of administration to the systemic circulation (measurement site) 18 Different barriers in oral absorption Mouth: rapid absorption without first pass hepatic effect; dissolution in saliva Stomach (1m² area): Few drugs are absorbed, secretion of pepsinogen and HCl. Small intestine + colon (200-300m ² area): duodenum: Site digestion jejunum, ileum and colon: absorption sites very large exchange surface (Micro-vili the small intestine) Different secretion: mucus, digestive enzymes (such as lipase, amylase, esterase), trypsinogen, chymotrypsinogen, etc ... bicarbonate Pancreas: no absorption Gallbladder: secret synthesized which contains electrolytes bile and bile acids that help emulsify fat and increase the solubility of the fatty acids 19 Oral route: different barriers and different milieu (2) 20 Factors related to the GI tract Digestive pH The rate of gastric emptying and intestinal motility Food Co-administration of drugs Age Other variations : pregnancy, physical exercise Co-morbidity factors : heart failure, severe hypotension, inflammatory process 21 Oral Bioavailability Bio-availability: amount of the dose who reaches the blood circulation. 22 Drug resorption depends on: Drug molecule cross the natural barrier (cytoplasm membrane). The rate of absorption depends on : 1. Physico-chemical properties which control the balance Hydrosolubility/ liposolubility (hydrophilicity/lipophilicity) 2. Chemical Nature (Size and morphology), pKa and degree of ionization. 3. Partition Coefficient (solubility nOctanol/water) 4. Morphology and crystallization form : micronized powder of Theophyllin 5. Pharmaceutical Form : controls the dissolution rate in the GI tract 23 How to cross biological barriers Enterocytes show tight gap with microvillosity. Several process are involved 1. Passive diffusion : 2. Active transport 3. Facilitated diffusion 4. Filtration (like renal elimination) 24 PASSIVE DIFFUSION Transmembrane cross with Fick equation: Rate of diffusion = DKsS (Cm-Cf)/E D: constante of diffusion S: surface (area )of exchange Ks: Partition Coefficient Cm - Cf : différence de concentration ; E = épaisseur (thickness) Diffusion depends on concentration gradient. It is a non-saturable process with no specificity. Passive diffusion depends on balance hydro/liposolubility and the amount of the non-ionic form. 25 Drug ionization degree is related to gastro-intestinal pH 26 Active transport of drugs Specific Transporter of a given substance or substance type Transporter can be saturated, Possibility of competition between similar drugs Energy is required Against concentration gradient 27 Examples of active Transport 1. Endogenous carriers enable transport of ionized molecules, high molecular weight or of low lipophilicity. 2. This is the case of the system LNA (large neutral amino acids) that allows the entry of certain amino acids and structurally similar drugs such as L-Dopa, melphalan, Gabapentin. 3. The levodopa, Baclofen (Lioresal ®) which is a central muscle relaxant and phosphonoformate (antiviral) use the same carrier. 4. We can also mention the Glut-1 glucose transporter non-insulin-dependent, which can also carry certain glycopeptides. 28 FACILITATED DIFFUSION Facilitated Diffusion ≠ passive diffusion : Rate of absorption is > concentration gradient Possible Transporter 29 P Glycoprotein or P-Gp Efflux Protein, belongs to ABC transporters (« ATP Binding Cassette proteins ») : ex. P-Gp (glycoprotéine P = ABCB1) 30 12/12/2014 31 Oral route is forbidden 1. If the molecule is destroyed in gastric juice Penicillin G 2. Peptide like structure : Insulin 3. Drugs extensively metabolized 4. Unconscious patients 32 Oral Bioavailability Bioavailability is the amount of drug who reach the blood (percentage of blood level/ administered dose) Determined by comparison to IV administration (IV = 100% of bioavailability) F= AUC (f.o) / AUC (f.iv) 33 Pharmacokinetic II DISTRIBUTION 34 2nd step: Distribution 35 DISTRIBUTION The whole body can be considered as set of organs (aqueous compartments) separated by cell membranes (Phospholipid). The passage of the drug from one compartment to another depends on its physicochemical properties (lipophilicity, pK ...). Thus, the drug must be soluble in the aqueous phase to stay while to spread from one compartment to another, it must be soluble. For example for a body weight of 70 kg = approximately 42 liters of total water of the body which is = 60%. 36 Apparent Volume of distribution Volume of distribution is virtual (imaginary) volume wherein all of the drug is distributed in the same concentration as in plasma. It helps to calculate the dose in order to obtain the appropriate concentration at the site of action. When VD is large, there is a significant tissue distribution. When VD is small, the distribution is preferably plasma 37 Dose 10 mg Volume réel 500 ml Sans charbon Avec charbon Concentration 20 mg/l Concentration 2 mg/l Volume apparent 500 ml Volume apparent 5000 ml VD > 0,6 L.kg-1 forte diffusion VD < 0,3 L.kg-1 faible diffusion 38 Examples VD values ​​do not correspond to a physiological entity 39 How does the drug circulate in the blood? Liaison drug-protein is REVERSIBLE Unbound fraction + plasma protein Protein Bound fraction (Unbound fraction fu) (Bound Fraction) Active Form (pharmacology) Inactive Form (pharmacology), (no tissue diffusion) Loi d’action de masse: Médicament libre + protéine plasmatique Médicament lié à la protéine 40 Plasma proteins involved: -Albumin -α1glycoprotein acid -Lipoproteins -γ globulin -Transcortin 41 Drug-Drug Interactions : consequence of binding-unbinding plasma protein on distribution volume. 42 Factors modifying VD Obese patients : increase VD for very lipophilic drugs: Diazepam, Thiopental Hydro-electrolytic disturbances, elderly patients Modifications of natural barriers : placenta, blood-brain barrier 43 Natural Barrier 44 Blood-Brain Barrier 45 Distribution in the CNS The brain capillary membrane is lined with a fabric of glial astrocytes support, thus creating a double barrier - glial membrane and capillary endothelium – very few hydrophilic molecules can cross BBB. The cerebral capillaries are formed of closely contiguous endothelial cells, devoid of intercellular pores and fully covered with cellular elements, mainly of astrocytes. The transcellular penetration appears to be the most plausible The flow of cerebrospinal fluid is the only limiting factor for the diffusion of lipophilic molecule 46 Placenta barrier Placenta = organ of exchange of substances between mother and fetus. The placental diffusion
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