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Pharmacology GENERAL PHARMACOLOGY PHARMACOKINETICS Anna Lorenc-Duda [email protected] Synonyms for drug medicinal drug medication medicine agent pharmacologic tool substance of abuse gr. pharmacon- drug; logos- word, science Drug any substance, other than food, used in the prevention, diagnosis, alleviation, treatment, or cure of disease John Jacob Abel (1859 – 1938) Drugs' names chemical name international name (nonproprietary, generic name) brand name (trade name) Groups of drugs analgesics antihistamine diuretics tranquillizers antipyretics anticoagulants laxatives antibiotics 1 Drug doses threshold (subtherapeuthic, minute) dose therapeutic dose initial loading dose toxic dose lethal dose Drug formulation - solid Suppositories : suppositories for application into the rectum, urethra, and vagina. Drug ingredients active ingredient(s) auxiliary substances: – disintegrants – binders – solvents etc. Drug formulation Drug formulation - solid Tablets : uncoated tablets, coated tablets, effervescent tablets, enteric (gastroresistant) tablets. Capsules : hard capsules, soft capsules, gastroresistant capsules. Drug formulation Parenteral preparations : injections, intravenous infusion. Ointments : lipophilic, water-emulsifying, or hydrophylic ointments, dermatological ointments, pastes, tooth pastes, creams, gels, (glicerol ointments). Medicinal solutions : aqueous solutions, alcoholic solutions, glycole solutions, paraffine solutions. Aerosols : aerosols for topical use, ophtalmic aerosols, aerosols for administration into the body cavities (rectum,vagina), aerosols for inhalations (administration via the respiratory system or nasal passages). Ophtalmic preparations : ophtalmic solutions, ophtalmic ointments. Transdermal systems 2 Compliance/non-compliance Rate of compliance Controlled-release preparations Extended-release, sustained-release, prolongedaction preparations Most appropriate for drugs with short half-lives Advantages: „Drugs don’t work if you don’t take them” ↓ the number of required dosing occasions will improve adherence to a prescribed dosage regiments – reduction in the frequency of administration of the drug – maintenance of a therapeutic effect overnight, – a decreased incidence and/or intensity of undesired effects Drawbacks: – interpatient variability – „dose-dumping” Principles of appropriate antibiotic use Michael S. Niederman* International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) Pharmacokinetics vs. pharmacodynamics Pharmacokinetics what the body does to the drug Pharmacodynamics what the drug does to the body Pharmacokinetics - overview • How drugs are absorbed, distributed, and eliminated Site of administration Urine, feces, bile Absorption Elimination Plasma Distribution Tissues Drug action Metabolism Absorption DEF: transfer of drug from site of administration to blood stream Determining factors: – lipid diffusion – blood flow to the absorption site (eg. intestine vs. stomach, epinephrine) – surface area (large in duodenum – microvilli, lungs – pulmonary alveoli) – contact time at the absorption surface (eg. diarrhea, constipation atropine) 3 is crucial for the absorption, distribution and excretion of a drug Bioavailability 120 100 80 Ionization state – key factor Passive diffusion Carrier-mediated processes – % of drug which reaches systemic circulation – for IV injection 100% C (mg/l) Drug diffusion across a lipid membrane Passage across membranes Absorption Bioavailability=AUCoral/AUCiv 60 40 20 – uncharged – lipid soluble (lipophilic) – (+) or (-) – lipid insoluble (hydrophilic) – facilitated diffusion – active transport Henderson-Hasselbach equation – log([XH]/[X]) = pKa - pH Through pores or ion channels By pinocitosis • XH – protonated form of the drug • X – unprotonated form of the drug • pKa – acid dissociation constant of the drug 0 0 2 4 6 8 10 time (h) – Important factors: first-pass effect, solubility, stability, formulation Drug diffusion across a lipid membrane The effect of pH on drug ionisation Henderson-Hasselbach equation – log([XH]/[X]) = pKa – pH Acid - Drug Protonated form Unprotonated form Acid HA H+ + A- Uncharged (lipophilic) (-) (hydrophilic) (+) (hydrophilic) Uncharged (lipophilic) Base BH+ B+H+ – Conclusion – for weak acids the lower the pH, the higher the lipid solubility (inversely for weak bases) Routes of drug administration Low pH (e.g. –COO- ) (e.g. –COO- ) Acid-H High pH (e.g. –COOH) High pH Base-H + (e.g. –NH3+ ) Ionised water-soluble form Base Low pH (e.g. –NH2 ) Enteral Parenteral Other – – – – – inhalation intranasal intrathecal/intraventricular topical transdermal Unionised lipid-soluble form 4 Enteral administration First-pass effect (metabolism) LIVER Oral – absorption: intestine (duodenum), stomach General circulation (much less) – high variability • • • • Metabolism degradation in the GI tract uneven absorption (food...) formulation, e.g. sustained-release preparations Portal circulation metabolism of a drug Metabolic barriers for drugs after oral administration Intestinal lumen Intestinal wall Liver Lung Drug administered intravenously (iv) enters directly into the systemic circulation and has direct access to the rest of the body. REST OF BODY Drugs administered orally are first exposed to liver and may be extensively metabolised before reaching the rest of the body. Factors affecting oral absorption Drug structure Formulation Gastric emptying Blood flow to the absorption site Examples of drugs undergoing substantial first-pass metabolism Glyceryl trinitrate Levodopa Lidocaine Morphine Propranolol Salbutamol Verapamil Enteral administration Sublingual – under the tongue – absorption through capillary network – lower variability • no first-pass effect • no degradation in the GI tract 5 Enteral administration Rectal – drug placed in the rectum – absorption through capillary network – lower variability • 50% of the drug bypasses portal circulation • no degradation in the GI tract – used for drugs which provoke vomiting, or for patients already vomiting – irregular and incomplete absorption – may be irritant Parenteral administration Intramuscular (IM) • requires absorption • Administration of larger volumes than s.c.; drug can be released slowly into the circulation, while some of it being stored in the muscle • Antibiotics usually given this way • often used as depot preparations (slow diffusion from lipid medium – e.g. haloperidol decanoate) Subcutaneous (SC) • • • • • requires absorption Advantage – injection not too deep and painful Disadvantage – only a small volume can be injected (max 2 ml) sometimes used with epinephrine to limit area of action used with solids (contraceptive capsules, insulin pumps) Intradermal Parenteral administration Avoids the GI tract Used for: – drugs poorly absorbed or unstable in the GI tract – unconscious patients – drugs requiring quick onset of action Advantages: – control over dose administered – no first-pass effect – quick onset of action Disadvantages: – disliked by many patients (painful) – usually requires qualified staff to administer – high cost Intradermal vs. subcutaneous injection Parenteral administration Types of parenteral administration: – Intravascular: Intravenous (IV) or intraarterial (IA; rarely) • Advantage - most control over dose administered (no absorption phase, no first-pass effect – bioavailability 100%) • Disadvantage – invasive, uncomfortable, risk of introducing bacteria, induction of hemolysis and other adverse effects Other administration routes Inhalation – Advantages: • rapid delivery – very large surface • quick onset of action (e.g. anesthetics) – used for patients with respiratory disorders Intranasal – absorbed through dense capillary network – used for desmopressin, calcitonin, and locally acting decongesting drugs, also for addictive drugs (cocaine, amphetamine) 6 Other administration routes Intrathecal/intraventricular – introduction of drugs directly into the cerebrospinal fluid (CSF) – e.g. methotrexate in acute lymphocytic leukemia – Advantages: no need to cross the BBB Topical – Mucous membranes, skin, eye – local effect (e.g. clotrimazole – antifungal) Transdermal (percutaneous) – systemic effect – application on the skin (patch) (e.g. nitroglycerin, nicotine for addicts) Distribution Volume of distribution (Vd) DEF: transfer of drug from blood stream to the tissues Steps: – dilution in blood – movement into extracellular fluid surrounding cells – uptake into cells Important factors: – – – – binding to proteins blood flow ability of the drug to cross cell membranes capillary permeability – D – total dose of drug administered – C – concentration of drug in the plasma • capillary structure (blood-brain barrier tight junctions vs. liver slit junctions) • drug structure – pH differences across membrane barriers The blood-brain barrier Junctions between endothelial cells in capillaries: – slit junctions large spaces, even proteins pass (liver, spleen) – tight junctions CNS cells virtually glued together BBB • additional barrier glial cells (astrocytes) surrounding capillaries • only lipophilic compounds pass (e.g., levodopa) Def: the volume of plasma that would contain the total body content of the drug at a concentration equal to that in plasma Vd=D/C Can be used to calculate the dose required to obtain desired plasma concentration The blood-brain barrier Typical Capillary Brain Capillary The blood-brain barrier Weaker: – – – – – – in fetuses and young children (<2 years of age) stress infection hypertension trauma aging Chemical trigger zone – area postrema toxic substances pass and trigger vomiting (dopaminergic system) 7 The placental „barrier” Drugs may cause congenital anomalies All drugs cross the placenta and enter breast milk!!! Binding to proteins Predominantly albumin – high affinity for weak acids and lipophilic drugs α1-acid glycoprotein (basic drugs) Metabolism Most frequently two phases – Phase I introduction of hydrophilic polar group (-OH, -NH2) – Phase II conjugation (glucuronidation, acetylation, sulfonylation, conjugation with amino acids) active/inactive D Phase I metabolism Most reactions depend on the Cytochrome P450 (CYP 450) system (microsomal mixed function oxidase) – important for metabolism of exogenous and endogenous compounds – many isozymes grouped into families • overlapping functions • induction/inhibition of CYP isozymes interactions Some reactions CYP-independent – amine oxidation (histamine), alcohol dehydrogenation (ethanol), hydrolysis (procainamide),… Contribution of the CYP isoforms in the metabolism of drugs CYP3A4, CYP3A5 – 50% of drugs CYP2C CYP2D6 active/inactive Ph I D -OH inactive Ph II D -O- C Phase II metabolism Conjugation – some drugs do not undergo this phase – some drugs enter Phase II directly – for some drugs Phase II and Phase I are reversed (isoniazid acetylation then hydrolysis) – neonates deficient in glucuronidation system increased toxicity of chloramphenicol 8 Factors affecting drug metabolism Genetic variation Environmental determinants Disease factors Age and sex Drug metabolism INHIBITORS cimetidine erythromycin grapefruit juice ketoconazole quinidine Routes of drug elimination kidney biliary system lungs external secretions – sweat – milk INDUCERS ethanol omeprazole phenobarbital rifampi(ci)n smoking Elimination Clearance – volume (of plasma presumably) per unit time that would be completely freed of the drug – CL = ve/[drug] = Vd/ke • ve – rate of drug elimination • Vd – volume of distribution • kel – elimination constant = ln2/t½ – Additive • CLt = CLrenal + CLhepatic + CLpulmonary + CLother Prodrugs Pharmacologically inactive compounds, designed to maximize the amount of the active species that reaches its site of action Examples: Cyclophosphamide Levodopa Valaciclovir Famciclovir Renal clearance Kidneys most important excretory organ Corellated with exogenous creatinin clearance or serum creatinin concentration Influencing factors: – Glomerular filtration binding to plasma proteins – Tubular secretion affinity for transporter mechanisms – Passive tubular reabsorption lipid solubility (eg. thiopental), pH, rate of urine flow 9 Hepatic clearance Drug elimination Excretion with bile intestine – some drugs deconjugated and reabsorbed enterohepatic circulation Various transporters in liver cells Conjugation • blood hepatocyte • hepatocyte bile duct Influencing factors: – – – – (Elimination) half-life (t1/2) – the time it takes for the plasma concentration, or the amount of drug in the body, to be reduced by 50%. Biliary duct molecular weight (+) genetic factors polarity (+) protein binding Pharmacokinetic parameters SUMMARY bioavailability volume of distribution clearance elimination half-life t1/2= 0.693 Vd / CLtotal Deconjugation Some drugs designed for biliary excretion Problems - examples Morphine has a pKa of about 8. Would you expect morphine to be mainly ionized or nonionized in the stomach pH? Drug X has a half life of 4 hours and is administered as an intravenous bolus dose to produce a concentration of 100 mcg/ml. How long after administration of the dose of Drug X will the concentration drop to 25 mcg/ml? 10