Docstoc

Chemical Teratogenesis

Document Sample
Chemical Teratogenesis Powered By Docstoc
					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 – toxins react with airway proteins to form antigenic complexes e.g. toluene di-isocyanate dusts – cigarette smoke, asbestos, polycyclic aromatic hydrocarbons

• Stimulation of an Allergic Response

• Carcinogenesis

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% • 20% • 5% Unknown Transmission of known genetic defect 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


				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:31
posted:4/16/2008
language:English
pages:30