Pharmacology
Overview
Two biochemical factors play an important role in both the choice and use of pharmacological agents in sedation: pharmacokinetics and plasma protein binding and passage across memberanes.
Pharmacokinetics
Pharmacokinetics involves the characteristic interactions of a drug and the body in terms of its absorption, distribution, biotransformational metabolism, and excretion. Absorption or uptake is determined by both the route of administration and the amount given. For example, if a drug is administered intravenously as, the peak affect will be seen more rapidly than it would if it were given orally. If the drug is administered intravenously as a bolus, the effect will occur more rapidly than if it is titrated in.
The technique that we use today and the one that's being advocated in this module is one of titration, where small, incremental amounts of agent are given until the patient receives the desired affect in which the patient is a bit somnolent but responds readily to commands.
One technique which was popular many years ago involved the use of intravenous valium; a syringe of 10 mg of diazepam (Valium) would be cannulated into a vein in the antecubital fascia, the practitioner would pull back on the plunger, and then bolus in the 10 mg of valium. This provided a very high concentration of drug in a very small volume of blood which would travel to the brain, and the diazepam would flow from an area of high concentration to low concentration and a peak affect would be reached very quickly and the patient would be rendered somnolent.]
Absorption is also determined by the blood flow to target organs. We know that the brain receives a large amount of blood flow, there also has to be equilibration across membranes, and remember membranes are a phospholipid bilayer, and therefore the lipid solubility of the drug is extremely important.
The liver plays a very important role in biotransformation and metabolism of pharmacologic agents. The liver plays a very important role in pharmokinetics. The liver is also responsible for the production of plasma proteins, such as albumin, and the microglobulins important for binding drugs
Plasma protein binding is also important. Drugs circulate either as a free or bound drug, and it is the free drug that is free to diffuse across membranes. For instance diazepam is 97% protein bound. In an elderly patient, who is perhaps making less protein plasmas in the liver may only be able to bind 94%. That will result in an effective doubling of the dose of the amount of diazepam that you give. So plasma protein binding is very important, especially for drugs that are highly protein bound.
Remember that there is a first pass effect with drugs that are given by mouth. The blood flow from the G.I. tract is to the liver first, before it goes back into the systemic circulation, where toxins can be detoxified and metabolized to protect the organism. Some metabolites are active, such as the metabolites of diazepam, while other metabolites are inactive, such as those of medazalam.
There are several specific properties of drugs that are especially important, including
- lipid solubility
- molecular size of the agent
- the pKa
The pKa, or ionization, is the pH at which the chemical amount of ionized drug equals that of non-ionized drug). Recall from general chemistry that weak acids are ionized at a high pH and weak bases at a low pH, and the pKa is the pH at which the amount of unionized drug equals the amount of ionized drug, and it is the non-ionized drug which will diffuse through a lipid membrane.
This becomes important when considering , for instance, in a drug like aspirin, which has a pKa ~ 3, which is about the pH of the stomach; therefore, aspirin is absorbed through the stomach and not through the small intestine because of the pKa of the aspirin. Biotransformation is performed mostly in the liver by the hepatic microsomal system. This system of enzymes will convert the drug to a more polar compound, making it less lipid soluble, and will also conjugate the molecule to an acid, again, significantly decreasing its lipid solubility and allowing it to be excreted.
Plasma Protein Binding
Recall the fluid mosaic model of the phospholipid bilayer, which allows bulk flow via intracellular pores, as well as receptor binding of certain agents on cell surfaces, especially in the brain and the central nervous system. It is the non-ionized lipid-soluble form of the drug that is free to act, and it is unbound drug, i.e., drug that's not bound to plasma proteins, that is also free to diffuse through membranes and act.
Half-Life
The half-life is generally the time required for half the agent to either be redistributed or eliminated. There are several factors that increase the half-life of a drug, and with that, increase the effect of the drug, including:
- decreased renal blood flow
- liver disease
- addition of a second drug that displaces the first from plasma proteins
- decreased metabolism (due to liver disease or to the presence of other drugs)
A Note About Renal Disease
Excretion is performed via the kidney, and remember with renal disease, we may need to alter the dose of the agent. The blood brain/brain barrier contains tight junctions between cells, therefore there are no pores, and it is only highly lipid-soluble drugs such as brevatol, alcohol, nicotine, that can diffuse very readily through the blood/brain barrier.