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Final = examination + result score (100%) ( 80%) select question attendance and + experiment record respond in class (10%) sign in and respond in class (10%) sign in and experiment record Pharmacology Pharmacology 1. General Principles of Pharmacology (Yuan) 2. Peripheral Nervous Pharmacology (Cao) 3. Central Nervous Pharmacology (Liu) 4. Cardiovascular Pharmacology (Zang) 5. Splanchnic and Blood Pharmacology (Ma) 6. Endocrine Pharmacology (Zhao) 7. Chemotherapeutic Pharmacology (Lin) (7 sections ) PART 1 GENERAL PRINCIPLES OF PHARMACOLOGY Dr. Yuan Bing-Xiang Department of Pharmacology, Medical School, Xi’an Jiaotong University, Tel: 82657724, Email: [email protected] GENERAL PRINCIPLES Pharmacology CHAPTER 1 Introduction of Pharmacology Ⅰ CONCEPTION 1. Pharmacology can be defined as the science or course studying the interaction between drugs and bodies (living systems) including human being, animals and pathogens including pathogenic microorganisms (bacteria, virus, fungus…) , parasites and tumor cells… GENERAL PRINCIPLES Pharmacology Drugs are the chemicals beneficially altering biochemical and physiological states of body, applied to prevent, treat or diagnose diseases. Peripheral Nervous Pharmacology Central Nervous Pharmacology Systems Cardiovascular Pharmacology Drugs of bodies Splanchnic Pharmacology Act on Blood Pharmacology Bodies Endocrine Pharmacology Pathogens- Chemotherapeutic Pharmacology Antibacterial drugs; Antifungal drugs; Antivirus drugs; Antiparasitics Anticancer drugs GENERAL PRINCIPLES Pharmacology 2. Three aspects of pharmacology drug Pharmacodynamics, PD Pharmacokinetics, PK Impact factors body Pharmacology GENERAL PRINCIPLES 1) Pharmacodynamics (drug acts on body) Drugs actions Primary acting on the target effects Secondary Inducing effects in the organ or system effects * therapeutic effects * adverse reaction * dose-effect curves E └→PD parameters (KD, EMAX…) action(mechanism of effect) * Specific actions: drug-receptors; drug-ion channels; drug-enzymes; * Unspecific actions: drugs influence physical and chemical condition around cells (pH, osmosis …) D Pharmacology GENERAL PRINCIPLES 2) Pharmacokinetics (body acts on drug) Undergoing of drug in body C-T curves absorption transportation distribution excretion biotransformation drug blood Concentration-Time curves └→PD parameters from C-T curves: t1/2, Ka, Ke, F, Vd… C T Pharmacology GENERAL PRINCIPLES 3) Impact factors Drug Body Drug drug physico-chemical property dosage form batch number Medication dose and route time and interval course of treat association PK PD physiolopathopsychogenoliving habit …… body PHARMACOLOGIC PRINCIPLES CHAPTER 2 pharmacokinetics ( body Acts on drug ) Undergoing of drugs pharmacokinetics (sites of action) binding free (accumulation) free binding distribution drugs (plasma) (renal) absorption distribution Free drugs excretion po sc im binding drugs metabolites distribution transport transformation Metabolism (liver) out of body permeation across membranes pharmacokinetics Ⅰ.Drug permeation across membranes 1. Membrane The membranes with pore are composed of lipids and proteins in a ratio of 70:1. The liquid-form double-deck of membranes is formed a b c from lipid molecules; The d special proteins inserted into the double-deck are receptors, enzymes, ion channels, carriers…… e O< >O lipids O< >O O< >O O< >O pore O< >O O< >O O< >O carrier O< >O O< >O carrier ATP O< >O O< >O O< >O ion channels O< >O O< >O O< >O O< >O Lipid diffusion Filtration Facilitated transport Active transport Ion transport p a s s i v e permeation across membranes pharmacokinetics 2. Passive transport across membranes (down hill) A drug molecule moves from a side of membrane relatively high concentration to another side of low concentration without requiring energy, until an equilibrium has been achieved on both sides of the membrane. high ….. ….. ….. ….. ….. low .. ….. ….. ….. ….. ….. ….. ….. ….. ….. ….. ….. ….. … ….. ….. … equilibrium Lipid diffusion; Filtration; Facilitated transport permeation across membranes pharmacokinetics 1) Lipid diffusion ( Simple diffusion) The most important mechanism of drug transport Drug movement across membranes is driven by a concentration gradient after solution in the lipids of membranes. pH (pKa) ┐ Nonionized form pKa is pH when Ionized rate is 50% k1 k2 Ionized form more lipid soluble easy permeation less lipid soluble hard permeation ←less polar molecules polar molecules→ ion trapping Lipid diffusion HA (weak acids) HA k1 k2 H++A- k1 [H+][A-] Ka=──=───── k2 [HA] [A] pKa=pH-log ─── [HA] [A-] pH-pKa=log ─── [HA] [A-] ───=10pH-pKa [HA] pharmacokinetics B (weak bases) B+H+ k1 BH+ k2 k1 [H+][B] Ka=──= ──── k2 [BH+] [B] pKa=pH-log ─── [BH+] [B] pH-pKa=log ─── [BH+] [B] ───=10pH-pKa [BH+] Lipid diffusion [A-] ───=10pH-pKa pharmacokinetics [B] ───=10pH-pKa [HA] [BH+] weak acids weak bases ★ pH↑↓→[A-]↑↓→ ★ pH↑↓→[BH+]↓↑→ Degree of ionization↑↓ degree of ionization↓↑ →lipid solution↓↑ →lipid solution↑↓ →permeation↓↑ →permeation↑↓ Neither weak acids or weak bases are dissolved in same acid-base solution, the lipid solution↑, permeation↑; They are dissolved in opposite solution, the lipid solution↓, permeation↓. Lipid diffusion pharmacokinetics For example, Bicarbonate (NaHCO3) is very effective for treatment of acute toxication from weak acid drugs (like barbiturates). why? Lipid diffusion pharmacokinetics ① Alkalization of gastric juice →ionization↑ → permeation↓ →absorption ↓ pH ↑ > pH blood [A-]↑ > [A-] drug drug gastric juice Gastrolavage of NaHCO3 ② Alkalization of blood plasma → permeation↓→across blood-brain barrier↓ pH↑> pH Cerebrospinal fluid [A-]↑> [A-] drug drug blood Intravenous drop of NaHCO3 Lipid diffusion pharmacokinetics ③ Alkalization of humor (extra-cellular fluid) →ionization↑ →permeation↓ cell drug drug pH < pH↑ [A-] < [A-] ↑ ④ Alkalization of urine→ionization↑ →permeation↓→ drug tubular reabsorption↓→ excretion↑ blood urine pH ↑ drug [A-]↑ filtration pharmacokinetics ) Filtration (Aqueous diffusion): 2 Small molecules (<100-200 dalton) pass through aqueous pores without requiring energy driven by concentration gradient. * Water-soluble drugs with low molecular weight (Inc. some polar molecules) can diffuse through the aqueous pores of membrane. * A almost free drugs can be filtrated across large pores of capillaries from or to plasma. (like drug distribution, glomerular filtration and absorption following im or sc injection) facilitated transport 3) Facilitated transport (Carrier-mediated transport) The movement of a drug across the membrane could be facilitated by its special carrier and concentration gradient. In the carrier-mediated transport, the drug is released to another side of the membrane, and the carrier then returns to original side and state. pharmacokinetics facilitated transport pharmacokinetics The properties of facilitated transport are as follows: a. saturable process; b. special binding to the carrier c. cannot move against a concentration gradient without energy. Active transport pharmacokinetics 2. Active transport (up hill) A drug molecule moves from a side of membrane relatively low to one of high concentration with requiring energy and special carrier. a. saturable process b. special binding to the carrier c. transport against concentration gradient with consuming energy. Active transport pharmacokinetics For example: penicillin and probenecid Blood→tubule Blood→tubule penicillin probenecid Glomerular filtration (passive) H2O absorption Tubule high osmosis competitively inhibit tubular Secretion (active) Excretion of penicillin After glomerular filtration, penicillin undergoes tubular secretion (an active transport), having a very short halflife (t1/2=20~30 min); probenecid having the same active mechanism can competitively inhibit the tubular secretion of penicillin. The t1/2 & effects of penicillin are prolonged. Absorption pharmacokinetics Ⅱ.Absorption The transport of drugs from administration locale to bloodstream. Absorption pharmacokinetics 1. The routes of absorption 1) im or sc Absorption of drugs in solution through filtration from subcutaneous or intramuscular injection sites to blood is limited mainly by blood perfusion rate. im > sc (adrenalin), why? a. blood perfusion rate (im > sc) b. adrenalin ┌α↑→vesseel↑(subcutaniea) → perfusion↓ └β↑→vesseel↓(skeleton muscle) →perfusion ↑ Absorption 2) po (per oral) pharmacokinetics What about weak acids? Drugs are absorbed in gastrointestinal tract through lipid diffusion. The absorption takes place mainly in the upper small intestine. With oral administration of drugs, extensive gastrointestinal and hepatic metabolism may occur before the drugs are absorbed into systemic circulation and reach its site of action. This process is defined as the first-pass elimination. gastric mucosa small intestine mucosa Absorption pharmacokinetics 3) Sublingual or rectal administration Absorption properties of the administration a. incomplete and irregular absorption; b. without or less First-pass elimination. For example Nitroglycerin given sublingually bypasses liver and enters the superior vena cava and, in turn, perfuses the coronary circulation, therefore is immediately effective to relive patients with angina pectoris. Absorption pharmacokinetics 2. Bioavailability (F) F would be the extent and rate of drug absorption following extravascular administration (like orally). F could be the absolute rate of a drug, used for indicating the absorption amount (AUC) compared with that of intravenous administration, or relative rate of a pharmaceutical product, used for indicating the absorption amount (AUC) compared with that of standard preparation in the same administration (same route and dose). Absorption pharmacokinetics A (drug amounts in body) F (absolute) =───────────── ×100% D (administered dose) AUC (area under extravascular curve) F =────────────────── ×100% (absolute) AUC (area under intravenous curve) AUC (test pharmaceutics) F (relative) =──────────────×100% AUC (standard preparation) C C iv standard im test po T T Distribution pharmacokinetics pharmacokinetics Ⅲ.Distribution The transport of drugs from bloodstream to various organs and tissues, or to different physical compartments of body. Distribution pharmacokinetics 1. Compartments According to perfusion rate of drugs to various organs and tissues, body can abstractly be divided into one, two or more parts (one compartment model, two compartments model, three…). Distribution 1) One compartment model Drugs within the model are assumed to be distributed just to the organs or tissues with high blood flow and rapid uniform (brain, heart, liver, kidneys, lungs, active muscle, …). The C-T curve have one phase: elimination. The distribution is too rapid to be found in the C-T curve.. drug Ka Ke 。 。 T Distribution dC KC dt drug Ke C Co C C0 e 1/2 1/4 Ke 。 。 logC t1/2 logC0 t1/2 Kt T K logC logC 0 t 2.303 T Distribution pharmacokinetics 2) Two compartments model Drugs are not only distributed to the organs or tissues with rich blood perfusion (central compartment), but also to that with low blood flow (peripheral compartment: fat, skin, bone, resting muscle). The C-T curve have two phases: a. The distribution rate is known as the alpha half-life, t1/2α. b. The elimination rate is known as the beta half-life, t1/2β. Distribution pharmacokinetics central peripheral K1 Ka Ke K2 C α distribution α β β T 。 。 Ct=CAe-kαt+CBe-kβt elimination Distribution pharmacokinetics 2. Apparent volume of distribution (Vd) Vd is that drug in a plasma concentration should be solved in apparent volume of body fluid including the general circulation and the tissues. Vd is used for measuring distribution range, relating the amount in the body (A) to the concentration of drug (C ) in blood. total amount of drug in body, A(mg) Vd(L)=──────────────────── =── concentration of drug in plasma, C(mg/L) F.D C Distribution pharmacokinetics 3. Factors influencing distribution 1) Barrier: blood-brain barrier, placental barrier) a. less ionized drug & small particle→permeable b. inflammation→permeable 2) active transport→tissues concentration↑ active transport iodium thyroid 3) regional blood flow subcutaneous < intramuscular Distribution pharmacokinetics 4) Binding rate to plasma: binding ratio to plasma protein at the therapeutic dosage. moving balance free drug+plasma binding drug (active form) (inactive storage form) small particle of drug large particle of drug →rapid filtration → no filtration →rapid distribution → → no distribution → ┌ action ┌no action └elimination └no elimination (metabolism & excretion) Characters of binding to plasma a. saturability Dose↑→binding rate ↓→free drug ↑ Malnutrition liver function↓ Renal function↓ Plasmaalbumin↓ b. Unspecific competition competive combination binding binding rate↓ binding rate↓ free drug↑ free drug↑ warfarin A 98% (2%) ┅ ┅ ┅ ┅ ┅→96% (4%) →effect (toxicity)↑↑→bleeding 2%↓ B 92% (8%) ┅ ┅ ┅ ┅ ┅→90% (10%) →effect (toxicity) ↑ phenylbutazone Biotransformation pharmacokinetics Ⅳ.Biotransformation mainly in the liver hepatic microsomal mixed function oxidase system 1. two phases Phase 1 oxidation reduction hydrolysis Phase 2 conjugation with glycuronic acid Prodrugs drug activity↓ toxicity↓ binding rate↓ more polar activation Inactivation excretion↑ Biotransformation pharmacokinetics 2. Factors affecting drug metabolism 1) drugs activity of enzyme↑ enzyme inducer Chlorpromazine phenobarbital →tolerance (dosage↑) enzyme inhibiter phenylbutazone chloromycetin activity of enzyme↓ →hypersensitivity (dosage↓) Biotransformation pharmacokinetics 2) Pharmacogenetics hereditary variation in handling of drugs For example: * Deficiency in the activity of acetylase results peripheral neuritis from isoniazid; * Absence of glucose 6-phosphate dehydrogenase (G6PD) results hemolytic anemia from: sulfonamides vitamin K (antihemorrhagic) primaquine (antimalarial agent) phenacetin (antipyretic analgesic) broad beans. Biotransformation pharmacokinetics Glucose Oxidizing agent ATP G-6-P G6PD↓ 6-PG Acid ADP NADP NADPH↓ GSSG H2O2 ↑↑ GSH↓ H2O↓ Hemolytic anemia sulfonamides vitamin K Absence of G6PD + primaquine anminopyrine broad beans Biotransformation pharmacokinetics 3) Physiological and pathological condition Age 完善flaw elder liver function renal function newborn deficiency of drug elimination toxicity of drugs Less dosage For example: newborn chloromycetin gray syndrome elder numerous drugs toxicity↑ Circulatory failure Biotransformation pharmacokinetics Illness hepatic disease Renal dysfunction enzyme production↓ Plasma production↓ drug metabolism↓ Plasma binding↓ →free drug↑ Plasma loss↑ hypersensitivity Should dosage↓ pharmacokinetics Ⅴ.Excretion of drugs Drugs and their metabolites in circulation are excreted by kidneys, bile, milk, sweat and lungs. excretion pharmacokinetics 1. Renal excretion tubular secretion tubular reabsorption Plasma (Drug & metabolites) Bicarbonate? glomerular filtration Penicillin? Probenecid? tubular water reabsorption hyperosmotic in renal tubules lipid-solubility tubular reabsorption Drug excretion ↓ active diffusion tubular secretion Drug excretion ↑ excretion pharmacokinetics 2. Excretion in bile Plasma (drug) liver active transport bile Hepato-enteric circulation portal vein intestine prolongation of half-life high concentration in bile PO Beneficial for antiinflammatory of cholecystitis Excretion Exclusion excretion pharmacokinetics 3. Excretion in milk weak alkaline drugs (morphine, atropine) effects↑ If the mather is the addict, whai would be resulted? nursing mother concentrations in breast milk↑ reactions in infant lactiferous Ducts milk (low pH) reabsorption dissolved in the milk↑ fat-soluble drugs (sodium pentothal) Kinetics pharmacokinetics Ⅴ.Kinetics and rate process Kinetics model 2 compartment 1 compartment drug K12 drug K K Differental equation dC KC dt K 21 dCC KCC K 12C C K 21C P dt dC P K 21C P K 12C C dt Kinetics pharmacokinetics 1 compartment Exponent equation C C0 e 2 compartments C Ae Kt t α C C Be t β T T Linear equation logC logC Semi-logarithmic equation K logC logC 0 t 2.303 T A α β B T log(C - Be ) logA t 2.303 logC logB t 2.303 - .t Elimination pharmacokinetics 1. Elimination of drugs Drugs and their metabolites are eliminated from the body by excretion and metabolism with decrease of drug blood concentration. 1st-order 0-order 0 1 2 100 50 25 1000 900 800 3 4 5 …… 9 10 11 12 …… 100 50 25 12.5 12.5 6.25 3.125 700 600 500 Elimination pharmacokinetics 1) First-order kinetic All most drugs Blood concentration of drug is reduced in equal rate or in constant half-life (t1/2). The eliminated rate is direct ratio with blood concentration of a drug. C dC KC1 dt one compartment t1/2 T dC KC dt 2) Zero-order kinetic Blood concentration of drug is reduced in equal amount or eliminated in continuant shorten half-life (t1/2). C dC K 0 C 0 dt dC K 0 dt T 3) non-linear kinetics Low dose→ 1st order Overdose→ zero order salicylic acid, phenytoin, alcohol aspirin Low dose 1st order kinetics Large dose Urine pH↓→reabsorption↑ zero order T1/2=15-30 h kinetics C C first T1/2=2-3 h zero T T Elimination pharmacokinetics 4) Half-life of drug (t1/2) The half-life (t1/2) is the time required to decrease the drug plasma concentration by one-half (50%) during elimination. It is considered that drugs are almost (97%) eliminated after 5 t1/2. T1/2 is relates to drug character (lipid-solubility, size of particle, molecular structure, drug interaction) and body condition (function of kidneys and liver…), but generally not relates to drug blood concentration and the routes of administration (therapeutic dose). Elimination pharmacokinetics C C iv po T1/2 constant of a drug T T1/2 Relation to drug character t1/2 Individual variation No relation to Relation to body condition T1/2 T lipid-solubility, size of particle, molecular structure drug interaction Kidneys Liver …… concentration of drug (therapeutic dose) way of administration Steady state pharmacokinetics 2. Steady state concentration (Css) When given at a regular interval, a drug plasma concentration approximately could reach a plateau after 5 t1/2. 1) Level of Css relates to: * dose ↑→Css↑ * interval shorten → wave of Css ↓ intravenous drip → smooth concentration curves. (the most effective and safe administration) Steady state pharmacokinetics 2) Time to reach Css relates to: * When a drug is given at a regular interval, its Css could reached after 5 t1/2; * loading dose →reaching Css rapidly When the regular interval is t1/2 and loading dose is double , Css can be reached immediately in intravenous injection. Steady state C 2D-D pharmacokinetics C D ivd 93.8% 97% 87.5% 75% 50% T 1st-order T 0-order Steady state pharmacokinetics Steady state concentration T1/2 0 first -order 1 2 100 50 200 100 100 75 200 150 100 87.5 200 175 100 100 93.5 96.9… 100 200 200 187.5 193.8… 200 C. dose 200 amount zero -order 100 100 100 100 100 100 100 100 100 100 dose amount 100 50 100 100 100 150 100 200 100… 250… A. dose amount B. dose amount 100 200 100 3 4 5… n