Organ toxicity

1. Organ toxicity • Blood supply • Presence of specific enzyme or biochemical pathway • Function / position • Vulnerability to disruption / ability to repair

2. Pulmonary Toxicity • Influences: • Receives 100% of right heart output • Internal milieu in greatest contact with environment

3. 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

4. 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

5. Neurotoxicity • cell damage • neuronopathy (trimethyltin) • axonopathy (hexane) • myelinopathy (hexachlorophene) • neurotransmission interference • receptor blockade • (organophosphates) • ionchannel blockade • (tetrodotoxin) • ciguatera

6. Neurotoxicity • Influences: • Protective • CNS protection by blood-brain barrier • Little internal metabolism of potential toxins • Vulnerable • Complex system • Poor regenerative ability

7. 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

8. 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

9. 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 • Dynamicfunction tests • inulin, CR-EDTA, creatinine clearances

10. Hepatic Toxicity

11. Hepatic Structure

12. Hepatic Structure

13. Hepatic Toxicity • Types of injury: • necrosis • fat accumulation (steatosis) • cirrhosis • cholestasis • carcinogenesis

14. Metabolism by Liver • drug or other foreign substance • reactivemetabolite • conjugate or oxidise • excretion

15. Metabolism by Liver P450 enzymes in the liver

16. Hepatic Metabolism of Paracetamol (Acetaminophen) to Toxic Reactive Metabolite NABQI NABQI

17. 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.

19. Hepatic Toxicity • Evaluation: • Measurement of plasma enzyme • activities • aminotransferases (AST ALT) alk phos, yGT • Hepatic functional performance • albumin, coagulation factors, bilirubin, lactate • Histology

20. 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

21. 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

25. Teratogenesis • Mechanisms • Mutation • Chromosomal aberrations • Mitotic interference • Nucleic acid metabolism / function alteration • Energy metabolism interference • substrate deficiency • pathway inhibition • Membrane alterations

26. 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)

27. 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

28. 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

29. 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

30. Chemical Teratogenesis • Care in prescription to women of childbearing ageand not just in pregnancy • Beware of self-medication / naturopathic preps • Beware of drug interactions with oral contraceptives