Drug Influence on Body and What the Body Does to the Drug

Drug Action

Pharmacokinetics explains the process by which a drug is absorbed, distributed, metabolized, and eliminated from the body. These processes are dependent on the amount of the drug administered, the method of administration (which affects the rate of absorption, biotransformation, and even excretion), and how the drug binds in the tissues. In essence, a drug's ability to transverse the cellular membranes depends on its solubility and molecular size and shape. The passive diffusion of the drug across cellular membranes depends on its lipid solubility as well as concentration gradients outside and inside the cellular membrane and the pH differences across the membrane. Active transport of the drug occurs when the drug is actually moved by components of the membrane. This can allow a drug move against concentration and electrochemical gradients but it requires energy, can be selective, and can be inhibited by similar molecules. The absorption rate is influenced by the drug concentration (with high concentrations being absorbed quicker than lower concentrations), the drug solubility, the circulation at the site of action, and the area of the absorbing surface. Absorption is also affected by the type of administration. For instance oral administration is affected by most of these aforementioned factors, whereas intravenous administration can bypass many factors involved in absorption and desired concentrations can be obtained immediately. However, with intravenous administration there are dangers of rapid and adverse concentrations being administered, there is little ability to reverse the action of the drug, and some drugs cannot be administered intravenously. Intravenous administrations can be subcutaneous or intramuscular, intro -- arteriole, etc. Other routes of administration such as pulmonary (sniffing), topical, etc. can also affect absorption rates.

Once absorbed into the body the blood flow typically determines the distribution of the drug and well-perfused organs are affected first followed by other areas. For example non- lipid soluble drugs are restricted in the distribution because they cannot pass the cell membranes as easily as soluble drugs. There are also other limitations of absorption such as the blood brain barrier limits entry of certain drugs into the CNS. In general, biotransformation reactions alter lipid soluble drugs into more hydrophilic metabolites. This occurs in two phases: Phase I biotransformation provides a functional group to increase the polarity of the metabolite (either oxidation, reduction, or hydrolysis), whereas phase II biotransformation increases water solubility and excretion of the metabolite from the body. The most important factor affecting biotransformation is genetic differences in people; however, environmental and physiological factors such as pollutants and age and gender can also affect biotransformation.

The elimination or excretion of drugs most commonly occurs as metabolites; however, sometimes excretion of the drug directly occurs. Metabolites are more easily excreted than lipid soluble compounds. The most important organ of excretion is the kidney (via urine). Other excretion mechanisms include the intestines via metabolites not reabsorbed from the intestinal tract (bile) and unabsorbed orally ingested drugs (feces), the lungs, and less commonly through breast milk and through the skin.

The pharmacokinetics of aspirin are as follows: Aspirin (salicylic acid) has a pKa of approximately 3.4 making it a weak acid. It is not soluble in the acidic environment of the stomach. The higher pH and larger surface area of the small intestine allows aspirin to be absorbed there, which allows it to be transferred to salicylate and to dissolve. Anywhere between 50 and 80% of salicylate in the bloodstream is protein bound and the remainder remains in an active ionized state. The pH of the blood stream is around 7.4, thus aspirin is the ionized avoiding diffusion back to the stomach. If binding sites are saturated this can lead to increased toxicity.

The volume of distribution is approximately 10% of body weight, but acidosis leads to increased volume of distribution due to enhanced tissue penetration. At smaller doses all pathways function via first order kinetics. Higher doses can saturate the pathways and lead to a longer half-life (typically the half-life is about four hours but can go up to 30 hours at high doses). Up to 80% of salicylic acid metabolized in the liver. Conjunction with glycine leads to the formation of Salicyl Uric acid and it forms a glucorinide with Glucoronic acid. Salicylic acid is mainly excreted by the kidneys as salicyluric acid but also as salicylic phenol (about 10%), free salicylic acid (also about 10%), and five percent as acyl glucuronides.

Pharmacodynamics is the study of the biochemical and physiological effects of drug actions. There are four levels of drug action; molecular, cellular, tissue, and system. Molecular targets for drugs are commonly receptors, ion channels, enzymes, and transport carrier molecules. Hormone and neurotransmitter receptors are very important molecular targets for drug actions. These are very selective and often the drug actions are also selective. These actions can be: (1) agonists that bind do a hormone and neurotransmitter receptor can mimic the effects of endogenous ligands; (2) antagonists that bind to the receptor but do not mimic -- interfere with agonist binding (competitive, noncompetitive, reversible, and irreversible antagonism); (3) partial agonists bind with receptors only partially; and (4) inverse agonists which stop productive independent reactivity of the receptor.

Ion channels are proteins in the transmembrane. When these are open they allow selective passage of specific ions via a specific configuration of the channel. Ion channels occur in four different states: (1) rested (here the channel is closed but stimulation can open it); (2) activated (open); (3) inactivated (closed and stimulation will not open it); and (4) transitioned between states.

Enzymes are important for regulatory and metabolic pathways. There are great many enzymes in cells and the bodily fluids of these are potential targets for drugs. Drugs either mimic enzyme substrate or inhibit enzyme activity. The drug action of enzymes occurs on the ligand -- recognition sites. For example, acetylcholinesterase degrades acetylcholine. There are two components to the substrate -- recognition site. Acetylcholine interaction with the site leads to acetylcholine hydrolysed choline and acetate. Some cholinester analogues can also bind to the site inhibiting hydrolysis of endogenous acetylcholine.

Transport molecules regulate cell contents using carrier molecules to facilitate passage of ions and molecules.

Cellular targets for drugs include molecular targets for drug action link to cellular response components (enzymes, ion channels, and so forth). This is accomplished via the transduction (second messenger systems). Receptors are classified according to the components they are linked to and include: (A) Receptor -- operated channels that are molecular targets and after ligand -- binding can have a role in transduction; (B) G -- protein -- linked receptors which are transduction components linked to a super -- family of receptors; (C) receptors that are enzymes such as Tyrosine kinases and Guanylyl cyclase; and (D) DNA linked receptors which are intracellular receptors that can interact with DNA.