Lecture 14 Flashcards
What are the major targets for organ-selective toxicity
- Liver
- Kidney
- Respiratory system
- Nervous system
- Heart and vascular system
- Reproductive system
- Immune system
- Blood Skin
- Eye
What are the major categories of kidney function?
- Excretion of metabolic waste via urine
- Regulation of extracellular fluid volume
- Regulation of electrolyte composition
- Regulation of acid-base balance
- Synthesis and release of hormones
What is the nephron?
Functional unit of the kidney responsible for filtering blood and producing urine
Glomerulus
- Network of capillaries that are rseponsible for filtering blood as it passes through the kidney.
- Retention of cells and proteins
- Passage of smaller dissolved substances and water into the tubule
Tubule
Reabsorption of greater part of filtered liquid by transportation across tubule wall to reenter blood Fraction which is not resorbed remains in the terminal urine for excretion
High vulnerability of kidney to toxins is due to..?
- Large blood supply (high concentration of blood-borne chemicals)
- Concentration of urine (high concentration of waste and toxins)
- Metabolism (reactive intermediates)
- High oxygen demand (susceptible to hypoxia)
Give examples of environmetal chemicals, metals and drugs that can cause Nephrotoxicity
- Metals (cadmium, mercury, lead)
- Herbicides (paraquat)
- Organic solvents (toluene)
- Halogenated hydrocarbons (bromobenzene)
- Therapeutic agents (paracetamol)
What is acute renal failure?
- Abrupt decline in glomerular filtration rate
- Tubular effects - obsturction & backleak - decline in GFR
- Vascular effects - Decreased renal blood flow - decline in GFR
What causes permanent renal damage to occur?
- Toxic insults to kidney can interrupt any or all of its functions and thus have a devastating effect on overall body metabolism and homeostasis.
- If detoxification and compensatory mechanisms are overwhelmed, permanent renal damage can occur.
Paraquat
- 1,1ʹ-dimethyl-4,4ʹ-bipyridylium-dichloride
- Toxic to kidney, liver, heart and lungs
- Potent free radical generator
- Widely used broad-spectrum herbicide
- Banned in many countries
see slide 10
Mechanisms of paraquat toxicity
- Participation in cyclin reduction-oxidation reactions in biological systems
- Agent undergoes a single electron reduction in tissues, triggering formation of a free radical
Consequences of the redox cycling reaction
Generation of a superoxide anion radical, causing the formation of more toxic forms of reduced oxygen and hydrogen peroxide:
- Lipid peroxidation
- Membrane damage
- Inactivation of proteins
- Damage to DNA
Oxidation of cellular NADPH:
- Depletion of NADPH
- Disruption of crucial NADPH
- requiring biochemical processes, such as fatty acid synthesis
Oronasal breathers
- Humans
- Inhalation through nose and through the mouth
What is the driving force for ventilation?
- Driving force for ventilation is the pressure difference between the atmosphere and the intra-pulmoic pressure in the alveoli
Inspiration versus Expiration
- Inspiration - active process. Contraction of respiratory muscles. Increase of the volume of the chest. Lungs inflate
- Expiration - passive process. Lung volume decreases.
High vulnerability of lungs to toxins is due to…
- Large surface area - 100m2-300million alveoli
- Oxidative burden - Nitrogen dioxide, ozone and tobacco smoke
- Rich blood supply - Lungs exposed to circulating toxins and their metabolites
- Primary route of exposure - Inflation is a major route of entry in the human body for many potentially toxic substances
See slide 15
Pulmonary Fibrosis
- Disease process: Damaged alveolar epithelium is repaired by scare tissue, causing increased focal presence of collagen fibres in alveoli
- Decreased gaseous exchange mechanisms
- Representative substance: Paraquat (herbicide)
Emphysema
- Disease process: Loss of tissue and air trapping causes destruction of the gas-exchanging surface area.
- Hyper-inflated lungs do no longer effectively exchange O2 and CO2
- Representative substance: Tobacco smoke
Lung Cancer
- Disease process: Bronchogenic carcinoma (90% of all lung cancers) usually present with cough, weight loss and chest pain
- Tumor obstruction of airway
- Representative substance: Tobacco smoke
Vulnerability to neurotoxic insult
- Specialized metabolic requirement of the brain
- High energy demand of the brain
- Signal transmission across extracellular space
- Spatial extension of the nervous system
Neuronpathy - Neurotoxic Injury
- Representative Substance - Aluminium
- Neurological Sympthon - Dementia
Axonpathy - neurotoxic injury
- Representative substanc - Acrylamide
- Neurological Sympthom - Sensory neuropathy
Myelinopathy - Neurotoxic Injury
- Representative Substance - Hexachlorophen (antiseptic)
- Neurological Symptoms - Seizures
Transmission toxicity - neurotixic injury
- Representative Substance - Nicotine (overdose)
- Neurological Symptoms - Coma
Protection from potential neurotoxins
- Blood-Brain Barrier (BBB)
- Restricted interface between the blood and the nervous system (brain, spinal cord, retina, peripheral NS)
- Specialized endothelial cells in the brain’s microvasculature form the principal anatomical basis of the blood-brain barrier.
Heart and vacular system are susceptible to chemical or drug induced cardiac disorders of…
- Heart Rate
- Excitability
- Contractility
- Conductivity
Cardiotoxicity of pharmacological and indutrial agents
Slide 21
