Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Discovery and development of direct thrombin inhibitors wikipedia , lookup
Discovery and development of cyclooxygenase 2 inhibitors wikipedia , lookup
Discovery and development of cephalosporins wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Drug discovery wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Organ toxicity • Blood supply • Presence of specific enzyme or biochemical pathway • Function / position • Vulnerability to disruption / ability to repair Pulmonary Toxicity Influences: • Receives 100% of right heart output • Internal milieu in greatest contact with environment Pulmonary Toxicity Influences: • Receives 100% of right heart output • Internal milieu in greatest contact with environment • Designed to absorb and excrete gases • Major area for absorption and excretion of volatiles • Design encourages contact with aerosols and micro-particles • Defended by mucus and cilia against particles • Defended by mucus against aerosols and volatiles Pulmonary toxicity Types of Toxic Lung Injury: • Irritation to airways by water-soluble gases – e.g. ammonia, chlorine • Mucosal injury (water insoluble compounds) – e.g. petroleum, ozone, NO2 phosgene • Pulmonary fibrosis – mediated by macrophage uptake e.g. silica, asbestos • Stimulation of an Allergic Response – toxins react with airway proteins to form antigenic complexes e.g. toluene di-isocyanate dusts • Carcinogenesis – cigarette smoke, asbestos, polycyclic aromatic hydrocarbons Neurotoxicity cell damage – neuronopathy (trimethyltin) – axonopathy (hexane) – myelinopathy (hexachlorophene) neurotransmission interference • receptor blockade –(organophosphates) • ion channel blockade –(tetrodotoxin) –ciguatera Neurotoxicity Influences: Protective • CNS protection by blood-brain barrier • Little internal metabolism of potential toxins Vulnerable • Complex system • Poor regenerative ability Renal toxicity Influences: • Kidneys receive 25 % of cardiac output • Huge reserve capacity: – hence potential delay in recognising toxicity • Toxicity enhanced by tubular concentration – e.g. gentamycin, cephaloridine • Some protection from prior detoxication by liver Renal toxicity Types: • Ischaemia – eg NSAIDS (prostaglandin synthetase inhibition) • Tubular injury – cadmium, gentamycin, cephaloridine, lead • Glomerular injury – cadmium • Crystalluria – oxalate, sulphonamides • Allergic interstitial nephritis – penicillin, cephalosporins, sulphonamides Renal Toxicity Assessment / Detection Urine components – cells – proteins (tubular or glomerular) – small molecules normally fully absorbed (amino acids) – H+, Na+, K+, water Urine volume flow • Plasma components normally cleared – urea, creatinine, H+, phosphate • Dynamic function tests – inulin, CR-EDTA, creatinine clearances Hepatic Toxicity Hepatic Structure Hepatic Structure Hepatic Toxicity Types of injury: • necrosis • fat accumulation (steatosis) • cirrhosis • cholestasis • carcinogenesis Metabolism by Liver • drug or other foreign substance • reactive metabolite • conjugate or oxidise • excretion Metabolism by Liver P450 enzymes in the liver Hepatic Metabolism of Paracetamol (Acetaminophen) to Toxic Reactive Metabolite NABQI NABQI Poisoning occurs when • the quantity of paracetamol ingested exceeds the capacity of the high affinity glucuronidation and sulphation pathways, and • the flow through the P450 route uses up the liver’s stock of glutathione. NABQI is thus free to react with the next most ‘convenient’ substances, like protein and lipid. Hepatic Toxicity Evaluation: • Measurement of plasma enzyme activities – aminotransferases (AST ALT) alk phos, yGT • Hepatic functional performance – albumin, coagulation factors, bilirubin, lactate • Histology Hepatic Toxicity Cholestasis: toxicity to biliary epithelium • biliary dysfunction • intra-hepatic cholestasis • may sometimes have immunological basis – e.g. phenothiazines, some antibiotics, anabolic steroids, oestrogens erythromycin estolate, i.v. lipids • – Chemical Teratogenesis Teras = monster • 3 - 7% Human babies born with a malformation Aetiology • 65% Unknown • 20% Transmission of known genetic defect • 5% Chromosomal abnormality • 2 - 3% Infection Toxoplasma, Rubella, Cytomegalovirus, Herpes (TORCH) and Syphillis • 4% Maternal disease (diabetes, nutrition, addiction) • 1 - 2% Mechanical (uterine structure, cord wrap) • 1 - 5% Alcohol, drug abuse Teratogenesis Mechanisms • Mutation • Chromosomal aberrations • Mitotic interference • Nucleic acid metabolism / function alteration • Energy metabolism interference • substrate deficiency • pathway inhibition • Membrane alterations Teratogenesis Characteristics • Selectivity and Specificity • Genetic differences • Susceptibility and development stage • Manifestations • • • • death malformation growth retardation functional disorder Properties of the teratogen • Access to embryo & fetus • Dose–response effect • No effect level (NOEL) Chemical Teratogenesis Thalidomide Critical Periods: 21-22 days: absent external ears, cranial nerve disorders 24-27 days: phocomelia (especially arms) 27-28 days: phocomelia (especially lower limbs) 34-36 days: hypoplastic thumbs, anorectal stenosis • 10,000 infants born worldwide with defects • Withdrawn 1961, no new cases of these defects • Problems of anticipation from animal tests Chemical Teratogenesis Fetal Alcohol Syndrome Severe: • Microcephaly • Severe and mental retardation • Cardiac and renal abnormalities • Maxillary hypoplasia • Growth retardation Mild: • Growth retardation • Attention deficits with normal intelligence Chemical Teratogenesis Folic Acid Antaganists e.g. Aminopterin, methotrexate Critical Time: 8/40 - 10/40 (first 2 months) High rate of intrauterine death 20 - 30 % of surviving fetuses have malformations • • • • • • • hydrocephalus cleft palate meningomyelocoele absence of frontal bones craniosynostosis absent digits rib defects Note: Documented effect of (non-toxic origin) mild folate deficiency on incidence ofspina bifida Chemical Teratogenesis • Care in prescription to women of childbearing age and not just in pregnancy • Beware of self-medication / naturopathic preps • Beware of drug interactions with oral contraceptives