How do drugs work (Proceedings)

The science of how drugs work on the body (or the microorganism or parasite) is pharmacodymanics (its counterpart being pharmacokinetics, how the body works on the drug). In this section, the basic concepts of drug concentration and drug action are followed by a review of the mechanisms of action of the major drug groups used in food animal practice including NSAIDs, glucocorticoids, reproductive drugs, antimicrobials, and parasiticides.

We assume that drug concentration is correlated with drug action; in other words, higher concentrations of drug in the blood stream are correlated with increased pharmacological response. Of course, there are limits to the increase, and drug response has been demonstrated in the majority of cases to occur in a sigmoid fashion, as shown in the graph below. This graph demonstrates the typical line when the log of drug concentrations is graphed against percent of maximal response. Typical response curves include an area of steep slope, in which there is proportional increase in response with increases in drug concentration. At some point close to maximal response, increasing drug concentrations do not result in significantly increased action of the drug. The dose at which the response is 50% of maximal is designated the median effective dose or the ED50. The ED50 is a useful way to compare drugs, and a way to evaluate changes in drug response.

Typical Dose Response Curve: Represents Efficacy of a Drug

While this graph is a useful way to gauge response to different doses, it does not tell us what is causing the drug response. Drugs cause a response in the animal or the parasite in a number of ways, with the classical way being the receptor-mediated response. Other ways drugs can act include effects on enzymes (inhibiting or activating), effects on ion channels in cell walls (some of which are also "receptors" of some sort), and other non-specific actions (such as drugs that merely replace endogenous compounds or drugs that change osmolarity).

Drugs Acting on Animal Cells

Mechanisms of Autonomic Drugs

Drugs commonly used in food animals that act through receptors include many of the autonomic drugs, such as xylazine (an alpha-2 agonist) and epinephrine. When these types of drugs interact with the receptor, a cascade of events is generally activated in the cell, resulting eventually in the desired pharmacological action (such as the sedation associated with xylazine, or the reversal of sedation associated with tolazoline). Xylazine and other alpha-2 agonists act by interacting with alpha-2 receptors on post-synaptic membranes, which are associated with inhibition of neurotransmission. Epinephrine acts on pre-synaptic alpha and beta receptors non-specifically, and causes among other things vasoconstriction and tachycardia.

Mechanism of Ion Channel Blockers

Drugs commonly used in food animals that act on ion channels include lidocaine. Lidocaine is the major example of an ion-channel active drug used in food animals. Lidocaine blocks voltage-gated sodium ion channels in nerves and therefore blocks nerve impulses. In general, blockade appears to affect, in order from first to last, pain, warmth, touch, deep pressure, and motor function, although this can be altered in nerve trunks in which for example motor nerves are more peripheral and therefore more likely to be affected by locally infiltrated lidocaine.

Mechanisms of NSAIDs

Drugs commonly used in food animals that act by inhibiting enzymes include NSAIDS. Omeprazole is another example of a drug that inhibits an enzyme, although it is not commonly used in food animals. NSAIDs work by inhibiting the cyclooxygenase enzymes, including its isoforms COX-1 and COX-2. Arachidonic acid released from plasma membranes is the substrate for these enzymes, and the end-product is a number of prostaglandins and prostacyclins, depending on the substrate available in the cell. Prostaglandins are often produced in excess during inflammation and are also associated with fever. Therefore, the reduction of prostaglandins may result in decreased inflammation and fever. Prostaglandins are also associated with pain, and reduction in prostaglandin production can reduce the central integration of nociception known as pain.

Common discussions in the literature now include the appreciated of the differences in affinity of NSAIDs for COX-1 and COX-2 isoforms of the enzyme. COX-1 is generally thought to be expressed constitutively, meaning essentially all the time, and is associated with protective functions, such as regulation of kidney afferent blood flow and mucus production in the gastric and duodenal mucosa. COX-2 is generally thought to be expressed particularly under conditions of inflammation, and therefore, it has been believed that inhibition of COX-2 preferentially would provide a margin of safety. This has been shown to be true in some cases for some drugs, but not always. Allegedly COX-2 selective drugs have been associated with gastric perforation. Part of the issue is how drugs are designated COX-1 vs. COX-2 selective, since the assays to determine the inhibitory ratio for the two isoforms are generally performed in vitro, and the assay used has been shown to alter the ratio significantly. In addition, there are species differences in the specificity for enzyme isoform, so extrapolation from other species is not always accurate.

There appear to be no published data on plasma concentrations associated with efficacy, or pharmacokinetic parameters associated with efficacy.

Mechanisms of Glucocorticoids

Glucocorticoids are drugs which affect gene expression and transcription. Examples include dexamethasone and prednisone. They work in a number of ways, with the major mechanism typically described as the drug binding to cytosolic receptors that then translocate to the nucleus where the complex acts on so-called steroid-responsive elements on nuclear DNA. These elements then alter gene expression, including genes involved in the production of cytokines, chemokines, arachidonic acid metabolites, and adhesion molecules, all of which are associated with the inflammatory response. Other mechanisms associated with glucocorticoid action include binding nuclear transcription factors, as well as non-genomic mechanisms that are still being elucidated.

Mechanisms of Reproductive Drugs

Reproductive drugs such as prostaglandin F2-alpha and cystorelin act by mimicking endogenous compounds. Cystorelin acts like endogenous GnRH by increasing production of FSH and LH. PGF2-alpha acts by activation of protein kinase C, which shortens the lifespan of the corpus luteum, its intended action.

Antimicrobial Drug Action

Antimicrobials act by a number of different mechanisms, most of which can be divided in the major categories of inhibiting the production of cell wall components, inhibiting protein synthesis via ribosomes, and inhibiting nucleic acid synthesis via nucleic acid decoys or enzyme inhibition. There are some other miscellaneous mechanisms, such as perturbation of cell wall as occurs with polymyxins, but those are the main mechanisms, as in the table below.

Unlike some of the other drugs we use regularly, data have been gathered on the effect of concentration and time-course of concentrations of antimicrobials on efficacy. Dose does in fact matter, as does frequency, and dose and frequency can be related to the minimum inhibitory concentration of the drug in vitro against the pathogen being treated. These pharmacodynamics have been demonstrated experimentally in laboratory animals such as mice and rats as well as in retrospective studies in humans, during which drug concentrations are compared with MICs of pathogens.

As demonstrated in the table below, for example, the recommended dose for the beta lactam antimicrobials against most gram-positive infections is a dose that allows the drug concentration to remain above the MIC of the organism for 30-70% of the dosing interval. This parameter would not hold true for fluoroquinolones, which have been shown to depend on the ratio of the total area under the curve (AUC) to the MIC of the pathogen, with an optimal ratio being 100-250 in most cases. There are fewer data on the efficacy parameters associated with most of the protein synthesis inhibitors (with the exception of some specific newer drugs such as tigecycline, which has been shown to be more effective if AUC:MIC ratios are optimized).

Parasiticide Drug Action

Many of the parasiticides commonly used in food animal practice act by interfering with some form of neural transmission, resulting in paralysis of the nematode and subsequent expulsion. General mechanisms for the commonly used drug groups are presented in the table below.

Dosing and Impact on Efficacy

There appears to be little published in the literature on the pharmacodynamics of the anthelminthics along the lines of antimicrobial pharmacodynamics. While there are considerable pharmacokinetic data published, the correlation with efficacy or the correlation with a particular serum concentration of the drug with action in the parasite do not appear to have been addressed significantly in the literature. There are published data on days of persistent activity for the avermectins, which has been summarized in a USP monograph on macrocyclic lactones (monograph available at: http://www.aavpt.org/documents/macrocyclicLactones.pdf).

References available on request