View source for Pharmacokinetics

{{review}}
{{toplink
|linkpage =WikiDrugs
|linktext =WikiDrugs
|sublink1 = Basic Concepts of Pharmacology
|subtext1 = Basic Concepts of Pharmacology
|pagetype = Drugs
}}
==Introduction==
'''Pharmacokinetics is the effect that the body has on drugs.'''
All aspects of pharmacokinetics can be covered by the acronym '''ADME''', which stands for:

*Absorption
*Distribution
*Metabolism
*Excretion

These underpin how a clinician chooses to use a drug and a good knowledge of a drug's pharmacokinetics will help one predict when therapeutic failure may occur and to enable one to safely use unliscensed products or multiple drugs on one patient. It must also be remembered that the the follwing factors also have an effect on a drug's pharmacokinetics:
* renal, hepatic and gastrointestinal disease
* multiple drug therapy
* species treated
* age
* drug formulation

==Absorption==
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 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:

===Properties of the Drug===
* 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 ionized or not?
* Molecular weight- lower molecular weight compounds are more readily absorbed than large M.W. compounds.
* Stability in the gastrointestinal tract- this only applies to orally administered drugs

===Physiological Variables===
* '''pH at site of absorption'''

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 ionization reaction of a weak acid is

 AH =<sup>'''Ka'''</sup> A<sup>-</sup> + H<sup>+</sup>

and its dissociation constant '''pK<sub>a</sub> is given by the Henderson-Hasselbach equation:

 pK<sub>a</sub> = pH + log<sub>10</sub> ([AH]/[A<sup>-</sup>])

The ionization reaction of a weak base is

 BH<sup>+</sup> =<sup>'''Ka'''</sup> B + H<sup>+</sup>

and its dissociation constant '''pK<sub>a</sub> is given by the Henderson-Hasselbach equation:

 pK<sub>a</sub> = pH + log<sub>10</sub> ([BH<sup>+</sup>]/[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 ionization of a drug (extent of absorption), depneds upon its '''pK<sub>a</sub>''' 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 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'''

'''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 larger the surface area for absorption the greater the absorption.
* '''Local Blood Flow'''
The greater the blood flow the greater the rate of absorption.

===Route of Adminstration===
Drugs can be given via a variety of routes. A choice of a specific route is determined by the following factors:
* the properties of the drug
* the therapeutic objective (eg speed on onset, length of duration)
* administration or restriction to a local site
Some of the route options are: oral, rectal, intravenous, intramuscular, sub-cutaneous, intra-articular, inhalation, transdermal patches, topical (eye, ear and nose drops), intramammary, intravaginal, epidural and sub-conjunctival.

'''Intravenous injections''' have the highest peak plasma concentrations after administration.

===Formulation===
For a drug to be absorbed it must be in an aqueous solution. Thus the rate of absorbtion of an injectable formulation is influenced by it's aqueous solubility.  As the solubility decreases the rate of absorbtion and thus its plasma concentration is lower. 

When considering formulations of drugs it is important to look at their Cmax and Tmax values.

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

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

====Oral Formulations====
Usually 75% of a drug is absorbed in 2-3 hours when given orally. The following factors affect their absorption:

* Tablet structure and size - this can be altered to change Tmax and Cmax
* Stomach enzymes - can breakdown the drug
* Stomach acidity - some drugs are unstable in such an acidic environment, others will be ion trapped
* Gastric motility - with increased motility there is less time for the drug to absorbed
* Damage to the epithelial barrier - either due to drugs or disease will result in reduced absorbtion
* Stability of the drug in the gastrointestinal tract
* Presence of food - it can delay drug absorption without changing the amount absorbed, it can delay the absorption and decrease the amount absorbed or it can increase the rate and amount absorbed.
* First Pass Metabolism - a drug can be extensively metabolised before reaching the systemic circulation. This can occur in the gastro-intestinal tract wall, in the portal circulation and in the liver.

====Bioavailability====
This is the fraction of the administered drug that actually reaches the systemic circulation in its active form.  It is expressed as a percentage of the total amount administered and is calculated using plasma drug concentrations.

To calculate bioavailability a curve of time against plasma concentration of a drug must be drawn in both it's intravenous form and then whichever form is underinvestigation, say intramuscular. Then use the following equation to calcute it:

Bioavailability = (Area Under Curve IM/Area under curve IV) x 100%

Products containing the same drug can be said to be '''bioequivalent''' if the rate and extent of absorption are the same; ie the AUC, Tmax and Cmax aren't significantly different.

==Distribution==
Once absorbed drugs can distribute to one of the major body compartments, these are:
* Plasma (5% of body weight)
* Interstitial Fluid (16%)
* Intracellular Fluid (35%)
* Transcellular Fluid (2%)
* Fat (20%)

Many drugs are bound to proteins with acidic drugs binding to albumin and basic drugs binding to globulin. The extent of the binding is dynamic and the bound drug and free drug exist in equilibrium. Normally only the free drug has the capability of crossing the vascular endothelium. Though if damage occurs protein-bound drugs can enter the circulations.

The '''Volume of Distribution (V<sub>d</sub>)''' is a measure of the volume of fluid needed to contain the total amount of drug at its plasma concentration. 

V<sub>d</sub> depends upon the ability of a drug to enter plamsa and interstitial fluid and to cross cell membranes and gives a good indication of the extent of drug distribution.

* Very low (0.005-0.1l/kg) - drug confined to plasma compartment
* Low (0.2l/kg) - drug confined to plasma and interstitial space
* Intermediate (0.6l/kg) - drug enters total body water
* 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 lipid-insoluble drugs are mainly contained in plasma and interstitial fluids; they are usually incapable of crossing the blood-brain barrier.

==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 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'''.

Drugs can be metabolised in a variety of sites including the blood, lungs, gastrointestinal tract wall and kidneys. But the main site of drug metabolism is in the '''liver'''.

===Drug Metabolism in the Liver===
For a drug to be metabolised in the liver it must be '''lipophilic''' as it must cross cell membranes to reach the enzymes in the liver microsomes. Metabolism here is a biphasic process.

'''Phase 1''' - involves mitochondrial mixed function oxidase (MFO) enzymes, or cytochrome P-450 enzymes. In phase 1 the reactions convert the molecules into more polar metabolites via oxidation, reduction and hydrolysis.

'''Phase 2''' - the metabolites are conjugated, adding groups such as glucuronic acid, glycine, sulphate and acetyl. This increases the metabolites polarity further and decreases it's lipophilicity and thus enhancing its excretion in urine.

Some species are deficient in certain aspects of this pathway. Cats lack glucuronidation, pigs lack sulphation and dogs lack acetylation. This will affect these animals ability to metabolise certain drugs. 

Some drugs a capable of either inducing or inhibiting metabolising liver enzymes. This can effect how long drugs will stay in the systemic circulation if concurrent therapy with another drug is used.

==Excretion==
Drugs are mainly excreted in either the urine or bile.

===Biliary Excretion and Enterohepatic Recycling===
Liver cells can transfer drugs from the hepatocytes and plasma into bile. Some drug conjugates (mainly glucuronides) are concentrated in the bile and transported to the intestines. Active drug is then released here, any free drug is then re-absorbed  and recirculates around the body. Eventually the drug will leave the body in faeces.

===Renal Excretion===
This is mainly a passive process and isn't very species specific. Though urine pH will greatly affect the extent of excretion of some drugs.

* The majority of drugs, unless protein bound, are filtered readily.
* Weak acids and bases are actively secreted into the renal tubule and are rapidly excreted.
* Lipid-soluble drugs are passively reabsorbed across the tubule and so aren't excreted readily by the urine.
* Due to ion trapping weak acids are more easily excreted in alkaline urine, and visa versa. 
* A lot of drugs are mainly excreted by renal excretion and so toxicity can result if a patient has renal disease.

==Quantative Pharmacokinetics==
Quantative Pharmacokinetic studies are used during drug development to standardise dosing regimens for a drug. The understanding of a drugs kinetics enables dosen adapatations for an individual, for example if an animal has renal failure. Knowing the '''half-life or T<sub>1/2</sub>''' of a drug is very useful in determining how long a drug will remain in the body. (Half-life is defined as the time taken for the plasma concentration of a drug to reduce by 50%.) The '''V<sub>d</sub>''' or Volume of Distribution of a drug helps determine the loading dose needed. 

===First Order Kinetics===
This is when the half-life doesn't depend on dose administered.
 Please insert appropriate drug clearance graphs

===Zero Order Kinetics===
This is when the elimination half-life depends on the dose administered.
 Please insert appropriate drug clearance graphs