Changes

Drugs are most usually small molecules (<1000 molecular weight) and thus can pass through cell membranes through '''passive diffusion''' and '''facilitated transport'''. For further information on these processes please look [[Transport Across Membranes - Physiology|here]].  To cross vascular endothelium drugs usually are able to squeeze through the gaps between the cells. The size of these gaps varies between different locations in the body; in the liver the gaps are large but in the central nervous system these gaps are tight junctions.

Drugs are most usually small molecules (<1000 molecular weight) and thus can pass through cell membranes through '''passive diffusion''' and '''facilitated transport'''. For further information on these processes please look [[Transport Across Membranes - Physiology|here]].  To cross vascular endothelium drugs usually are able to squeeze through the gaps between the cells. The size of these gaps varies between different locations in the body; in the liver the gaps are large but in the central nervous system these gaps are tight junctions.

The ability of a drug to cross the phospholipid bilayer not only infuences the rate and extent of its absorption but also the rate and extent of it's distribution, metabolism and elimination.

The ability of a drug to cross the phospholipid bilayer not only influences the rate and extent of its absorption but also the rate and extent of its distribution, metabolism and elimination.

Below are the main factors affecting absorption:

Below are the main factors affecting absorption:

===Properties of the Drug===

===Properties of the Drug===

* Lipid solubility - the more lipid soluble a drug the easier it is absorbed across the bilayer

* Lipid solubility - the more lipid soluble a drug the more readily it is absorbed across the bilayer

* Chemical nature - ie. Is it basic or acidic? Is it ionised or not?

* Chemical nature - ie. Is it basic or acidic? Is it ionized or not?

* Molecular weight

* Molecular weight- lower molecular weight compounds are more readily absorbed than large M.W. compounds.

* Stability in the gastro-intestinal tract - only applies to orally administered drugs

* Stability in the gastrointestinal tract- this only applies to orally administered drugs

===Physiological Variables===

===Physiological Variables===

* '''pH at site of absorption'''

* '''pH at site of absorption'''

Many drugs are either a '''weak base''' or a '''weak acid''' and so will exist in both an unionised and ionised form in the same solution. The ratio of the two forms is dependent upon the pH of the location of the drug. It must be remembered that ionised molecules don't pass easily through lipid membranes. Unionised molecules will diffuse easily as long as they are lipid soluble.

Many drugs are either a '''weak base''' or a '''weak acid''' and so will exist in both an non-ionized and ionized form in the same solution. The ratio of the two forms is dependent upon the pH of the location of the drug. It must be remembered that ionized molecules do not pass easily through lipid membranes. Unionized molecules will diffuse readily as long as they are lipid soluble.

The ionisation reaction of a weak acid is

The ionization reaction of a weak acid is

  AH =^'''Ka''' A^- + H⁺

  AH =^'''Ka''' A^- + H⁺

  pK_a = pH + log₁₀ ([AH]/[A^-])

  pK_a = pH + log₁₀ ([AH]/[A^-])

The ionisation reaction of a weak base is

The ionization reaction of a weak base is

  BH⁺ =^'''Ka''' B + H⁺

  BH⁺ =^'''Ka''' B + H⁺

  pK_a = pH + log₁₀ ([BH⁺]/[B])

  pK_a = pH + log₁₀ ([BH⁺]/[B])

The dissociaton constant allows one to measure the strength of an acid or base and to determine the charge on a molecule in any givem pH. Thus the extent of ionisation of a drug and so it's extent of absorbtion, depneds upon its '''pK_a''' and the pH within the body compartment.

The dissociaton constant allows one to measure the strength of an acid or base and to determine the charge on a molecule in any givem pH. Thus, the extent of ionization of a drug (extent of absorption), depneds upon its '''pK_a''' and the pH within the body compartment.

Due to the above drugs can become '''ion trapped''' in certain body compartments. If it is assumed that the ionised fraction is unable to cross cell membranes and the unionised fraction is; then a weak acid will become greatly concentrated in an environment with a high pH. This is because it will donate it's spare protons to the basic elements in the high pH environment and then will be unable to cross out of the environment as the drug is now ionised; it has been '''trapped'''.

Due to the above, drugs can become '''ion trapped''' in certain body compartments. If it is assumed that the ionized fraction is unable to cross cell membranes and the non-ionized fraction is, then a weak acid will become greatly concentrated in an environment with a high pH. This is because it will donate it's spare protons to the basic elements in the high pH environment and subsequently be unable to cross out of the environment as the drug is now ionized. The drug has now been '''trapped'''.

  '''Insert Diagram Here'''

  '''Insert Diagram Here'''

'''In summary a weakly acidic drug will become ion trapped in an environment with a high pH and a weakly basic drug will become ion trapped in an environment with a low pH.'''

'''In summary, a weakly acidic drug will become ion trapped in an environment with a high pH and a weakly basic drug will become ion trapped in an environment with a low pH.'''

* '''The Area of the absorbing surface'''

* '''The Area of the absorbing surface'''

The larger the surface area for absorption the greater the absorption.

The larger the surface area for absorption the greater the absorption.

'''Cmax''' = The maximum concentration that the drug will reach in that formulation in the body system.

'''Cmax''' = The maximum concentration that the drug will reach in that formulation in the body system.

'''Tmax''' = The time it takes to recah the Cmax.

'''Tmax''' = The time it takes to reach the Cmax.

====Oral Formulations====

====Oral Formulations====

* Very High (>1l/kg) - concentrated in a body fluid other than plasma and there may be bound residues eg fat

* Very High (>1l/kg) - concentrated in a body fluid other than plasma and there may be bound residues eg fat

Lipid-soluble drugs reach all compartments and can accumulate in fat. Whilst lipi-insoluble drugs are mainly contained in plasma and interstitial fluids; they are usually incapable of crossing the blood-brain barrier.

Lipid-soluble drugs reach all compartments and can accumulate in fat. Whilst lipid-insoluble drugs are mainly contained in plasma and interstitial fluids; they are usually incapable of crossing the blood-brain barrier.

==Metabolism==

==Metabolism==

For drugs to be eliminated from the body in a more water soluble form, most drugs require metabolism. The extent of metabolism varies between species and age. Herbivores metabolise drugs the most efficiently followed by dogs and then cats. This is due to the amount of metabolising enzymes present differ in each species. Old and neonatal animals show reduced hepatic metabolisma and renal excretion. Neonates also have greater absorption via the gastrointestinal tract and have an increased permeability of the blood brain barrier. This means that a neonate has higher plasma levels of a drug than an adult and so are at greater risk to drug toxicity.  

For drugs to be eliminated from the body in a more water soluble form, most drugs require metabolism. The extent of metabolism varies between species and age. Herbivores metabolise drugs the most efficiently followed by dogs and then cats. This is due to the amount of metabolising enzymes present differ in each species. Old and neonatal animals show reduced hepatic metabolism and renal excretion. Neonates also have greater absorption via the gastrointestinal tract and have an increased permeability of the blood brain barrier. This means that a neonate has higher plasma levels of a drug than an adult and so are at greater risk to drug toxicity.  

In certain drugs the metabolite is in fact the active form. The adminstered inactive form is called a '''pro-drug'''.

In certain drugs the metabolite is in fact the active form. The adminstered inactive form is called a '''pro-drug'''.