Changes

===Absorption===

===Absorption===

The rate of absorption is dependent on the route of administration and the bioavailability of a substance.  

The rate of absorption is dependent on the '''route of administration''' and the '''bioavailability''' of a substance.  

The route of administration is significant because of the natural barriers that exist which may prevent or lessen a toxic effect by reducing the dose absorbed. Gastric acid and the low pH of the stomach are significant barriers to the absorption of swallowed substances, but conversely, substances that cause local irritation to the intestinal lining, where most absorption will occur, can enhance uptake as a result of this disruption to the gastrointestinal barrier. In addition, some drugs can increase absorption by utilising transport carrier systems present in the GI tract, and lipid soluble compounds will be more readily absorbed across the GI epithelium. Dermal absorption is more readily achieved in people where there is no fur and an increased vascularity in the dermis, but dermal absorption in animals is increased in areas where there are abrasions, waterlogged skin of exposure to organic solvents.

The route of administration is significant because of the natural barriers that exist which may prevent or lessen a toxic effect by reducing the dose absorbed. Gastric acid and the low pH of the stomach are significant barriers to the absorption of swallowed substances, but conversely, substances that cause local irritation to the intestinal lining, where most absorption will occur, can enhance uptake as a result of this disruption to the gastrointestinal barrier. In addition, some drugs can increase absorption by utilising transport carrier systems present in the GI tract, and lipid soluble compounds will be more readily absorbed across the GI epithelium. Dermal absorption is more readily achieved in people where there is no fur and an increased vascularity in the dermis, but dermal absorption in animals is increased in areas where there are abrasions, waterlogged skin of exposure to organic solvents.

===Distribution===

===Distribution===

The distribution of a toxic substance depends upon:

The distribution of a toxic substance depends upon:

*Blood flow to tissues

*'''Blood flow''' to tissues

*The affinity of the toxin to the tissue

*The '''affinity of the toxin''' to the tissue

*Lipid solubility of the toxin

*'''Lipid solubility''' of the toxin

*Protein binding capacity of the toxin.

*'''Protein binding capacity''' of the toxin.

Tissue affinity, lipid solubility and protein binding can lead to the '''accumulation''' of a toxin; examples include tetracycline, which accumulates in developing teeth/bones, organichlorides that accumulate in adipose tissues and paraquat which accumulates in the lungs.

Tissue affinity, lipid solubility and protein binding can lead to the '''accumulation''' of a toxin; examples include [[Tetracyclines|tetracycline]], which accumulates in developing teeth/bones, organochlorides that accumulate in adipose tissues and paraquat which accumulates in the lungs.

Blood flow explains the susceptibility of certain body organs to toxicity, such as the liver, kidney, brain and heart which are highly perfused, and bone which is relatively well protected because of poor blood perfusion. Toxins that are absorbed orally pass into the portal system into the liver - the periportal area is often where highest concentrations of toxins can be found.  

Blood flow explains the susceptibility of certain body organs to toxicity, such as the liver, kidney, brain and heart which are highly perfused, and bone which is relatively well protected because of poor blood perfusion. Toxins that are absorbed orally pass into the portal system into the liver - the periportal area is often where highest concentrations of toxins can be found.  

In some tissues there are additional barriers to compounds - the blood brain barrier protects the CNS from water soluble compounds and infectious agents. Lipid soluble substances can cross this barrier - other mechanisms for crossing natural barriers include cellular transport mechanisms (e.g.cyclosporin) or endocytosis (insulin accesses cells in this fashion).

In some tissues there are '''additional barriers''' to compounds - the blood brain barrier protects the CNS from water soluble compounds and infectious agents. Lipid soluble substances can cross this barrier - other mechanisms for crossing natural barriers include cellular transport mechanisms (e.g.cyclosporin) or endocytosis (insulin accesses cells in this fashion).

Protein binding can have a number of effects on a potential toxin. When bound to a protein a toxin is usually inactivated, but it cannot be excreted in this form so accumulation can occur. Toxicity can occur when protein levels are low (hypoprotinaemia) or when another substance competes for the protein binding site - Warfarin is 97% protein bound once absorbed, but can be displaced by NSAIDs and Sulphonamides.

Protein binding can have a number of effects on a potential toxin. When bound to a protein a toxin is usually inactivated, but it cannot be excreted in this form so accumulation can occur. Toxicity can occur when protein levels are low (hypoprotinaemia) or when another substance competes for the protein binding site - Warfarin is 97% protein bound once absorbed, but can be displaced by [[NSAIDs]] and [[Sulphonamides]].

===Metabolism===

===Metabolism===

Metabolism has two phases:

Metabolism has two phases:

*Phase 1 where the substance is broken down into smaller molecules - often mediated by the cytochrome P450 system

*Phase 1 where the '''substance is broken down into smaller molecules''' - often mediated by the cytochrome P450 system

*Phase 2 where molecules are conjugated to increase their solubility by the addition of glucuronide, sulphate, glutathione or acetyl/methyl groups prior to excretion.

*Phase 2 where molecules are '''conjugated''' to increase their solubility by the addition of glucuronide, sulphate, glutathione or acetyl/methyl groups prior to excretion.

 

Metabolism may create a toxic byproduct - this is the case with paracetamol and aflatoxin poisonings, or may reduce the toxicity of a substance e.g. Ivermectin metabolites demonstrate reduced toxicity. Alternatively, metabolism may make little difference to the toxic affects of a substance so this effect is specific to individual substances and drugs. Commonly, sites that undergo metabolism (usually ones that express cytochrome P450) are the targets of toxic effects - the liver is the main organ of metabolism, but the kidneys, lungs, nasal epithelium, eyes and GI tract are also targeted because of cytochrome P450 activity.

Metabolism may create a toxic byproduct - this is the case with paracetamol and aflatoxin poisonings, or may reduce the toxicity of a substance e.g. Ivermectin metabolites demonstrate reduced toxicity. Alternatively, metabolism may make little difference to the toxic affects of a substance so this effect is specific to individual substances and drugs. Commonly, sites that undergo metabolism (usually ones that express cytochrome P450) are the targets of toxic effects - the liver is the main organ of metabolism, but the kidneys, lungs, nasal epithelium, eyes and GI tract are also targeted because of cytochrome P450 activity.