Mechanisms of toxicology Flashcards
What is exaggerated pharmacology and some examples
it is when non-pharmaceuticals can cause toxicity by interacting with pharmacological targets, or pharmaceuticals can cause toxic effects when used in above therapeutic doses.
e.g.,
NSAIDs renal failure
Ergot gangrene/limb loss
Eserine breathing difficulties, convulsions, nausea
TTX paralysis (cadmium blocks VGSCs too)
strychnine (glycine antagonism) paralysis
Depressants causing respiratory depression
Examples of enzyme inhibiton
Eserine, solanine, sarine and other nerve agents bloc AChE
The poison pea contains fluoroacetate which is converted to fluorocitrate causing acontiase inhibition - convulsions and cardiac failure/respirator arres
Cyanide causes cytochrome oxidase inhibition - respiratory failure
Reasons why certain organs are more susceptible to toxicity
Liver: hepatic portal vein directly feeds contents of GIT to the liver
Kidney sees concentrated amounts of the toxin
Lungs are an interface with the outside world
BBB can exclude toxins, however toxins that enter can be more dangerous as there is minimal antioxidant defence in the CNS.
Metabolic activation and toxicity mechanism and examples
Reactive metabolites can form (mostly from CYP and also prostaglandin-H-synthase AKA COX). reductive and oxidative metabolism by these causes the reactive metabolites with are associated with inflammation and tissue damage.
Rantidine (CYP inhibitor) was withdrawn as it decomposes into nitrosamine
Hydroxyurea decomposes into hydrogen cyanide
Cyclophosphamide toxicity mechanism
Metabolised by CYP enzymes and downstream turns into phosphor amide mustard (active metabolite for anti tumour effect) and acrolein (a toxic metabolite).
Acrolein is an unsaturated aldehyde.
COX involved in the metabolism of cyclophosphamide, and inhibition of COX reduces bladder and lung toxicity
Carbon tetrachloride toxicity and mechanisms and treatment
a dry cleaning fluid used as a model liver toxin.
It is metabolised into a trichlozomethyl radical which can then form covalent binding, as well as being metabolised into chloroform or phosgene downstream.
Causes hepatic necrosis
Vitamin E protects against the necrosis of this. inhibits lipid peroxidation and is a radical scavenger.
How events in one organ lead to toxicity elsewhere
Liver failure - ammonia accumulation - cerebral oedema.
toxic metabolites formed in liver can cause toxicity elsewhere, e.g., cyclophosphamide causing bladder and lung injury
E.g., in kidneys, CS-lyase converts glutathione conjugates to toxic cysteine conjugates.
Renal failure can present as cardiac problems due to electrolyte imbalance, e.g., QT prolongation.
Rhabdomyolysis from muscle breakdown can cause. renal failure from myoglobin.
Superoxide and vitamin K
Vitamin K is an essential blood clotting co-factor. menadione is a soluble injectable form of vitamin K used on newborns.
It can generate superoxide (oxygen radicals) in a similar mechanism to paraquat and MPTP. redox cycling
this can form hydrogen peroxide which causes toxicity through formation of hydroxyl radicals and through thiol oxidation
Neutrophils and macrophages utilise this however in antimicrobial defence.
Cellular defenses against oxidative stress
Glutathione (GSH)
Glutathione peroxidase - against H2O2
Glutathione-s-transferases catalyse conjugation between glutathione and reactive metabolites.
Metallothioneins chelate heavy metals. They can however inadvertently contribute to nephrotoxicity of cadmium
Antioxidant defenses in the body and why its important
Vitamin E for free radical scavenging and lipid peroxidase radicals destruction.
vitamin C maintains alpha tocopherol (prevents becoming radical) and scavenges alkoxy radicals. can also act as a pro oxidant by reducing Fe3+ to Fe2+
Oxidative stress causes organ malfunction, necrosis, apoptosis, ferroptosis, and autophagy.
Necrosis mechanism
Cell death where cellular integrity is lost and cell bursts.
Marked by mitochondrial dysfunction (loss of ATP), increase in ROS, high IC [Ca2+], defects in membrane permeability and inflammatory cells invade.
lactate dehydrogenase and increased potassium are biomarkers.
Apoptosis mechanism
Regulated cell death that requires protein synthesis.
Marked by loss of mitochondrial membrane potential and release of cytochrome C from mitochondria. this activates caspases leading to nuclear condensation and shrinking of the cell and its contents. then engulfed by macrophages
This reduces inflammation - opposite of necrosis.
Apoptosis can also be initiated by death receptors, where an adjacent cell signals for the elimination of self-reactive lymphocytes, e.g., TNF receptor
Ferroptosis mechanism
Regulated cell death marked by iron (Fe2+ mainly) dependence causing oxidatively damaged proteins.
Can be inhibited by iron chelators.
Role of macrophages and neutrophils in tissue injury and inflammation
neutrophils can initiate oxidative bursts, where oxygen radicals are formed.
M1 macrophages are proinflammatory forming oxygen radicals and reactive nitrogen species in response to inflammatory cytokines.
M2 macrophages are anti-inflammatory
Inflammation can lead to fibrosis (scar) formation - cirrhosis when in liver.
