DRUG INTERACTIONS: PHARMACOKINETICS AND PHARMACODYNAMICS

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Drug interaction is simply defined as the biological phenomenon in which the antimicrobial activity of a particular drug is influenced or affected by other substances (e.g., food, drinks or herb) or another medication. In drug interaction, the antimicrobial activity of a particular drug is either amplified or diminished. This phenomenon usually occurs when drugs are co-administered with other substances that produce similar or contradictory effect as the drug in vivo. The sole purpose of taking medications is to control the problematic activities of infectious disease agents (i.e., pathogenic microorganisms) either through prevention or curing. It is important that during drug administration that the medications not just reach their target tissues and/or pathogen but that therapeutic levels of the drug required to commence antimicrobial onslaught is available in vivo. It is also important that prior to antimicrobial administration that the antimicrobial susceptibility profile of the target pathogenic microorganism is known beforehand especially via susceptibility test results. This practice ensures that the most effective antimicrobial agent or drug is used to treat the disease or infection. And susceptibility test results also help to assuage the chances of selection of resistant pathogenic microorganism on or after antimicrobial therapy. It also helps to stop the emergence and dissemination of resistant strains of microbes through the administration of the correct therapy.

Drug interaction can be achieved clinically especially when the efficacy of two different drugs combined outweigh the effectiveness of the individual drugs especially when they are used separately. For example, some drugs when taken orally are easily excreted from the body even before they must have achieved their antimicrobial function in vivo. In such cases the easily excreted drug (in this case the primary drug) can be co-administered with another drug (the secondary drug) that reduces the excretion of the primary drug from the body. Drugs that are easily metabolized after administration and before they reach their target site in the body loses their therapeutic effectiveness. To prevent such development from happening, the drug can be co-administered with another medication that help to prevent its metabolism so that the primary drug can reach its target site in the body to unleash its antimicrobial potential. Such interactions between two or more different drugs are generally known as drug-drug interaction.

Drug-herb interactions and drug-food interactions are other types of drug interaction that can occur when a drug is used for treatment in combination with herbs or food. In such situations, the effectiveness of the chemotherapeutic agent may be undermined because the drug is reacting with a different chemical agent that may perhaps produce a new effect that adversely affect the recipient host or reduce the effectiveness of the drug. Therefore, it is critical to take drugs based on doctor’s prescription or guidelines to prevent adverse drug-drug interactions or drug-food and drug-herb interactions which are possible factors that may diminish the antimicrobial efficacy of the drug and probably allow resistant strains of pathogenic microorganisms to emerge and spread. Alterations in the pharmacokinetic and pharmacodynamic properties of a drug may also result in drug interactions. Drug interactions may be synergistic or antagonistic depending on the type of outcome that is expected from the combination of two or more drugs during antimicrobial therapy. Drug-herb interaction occurs when a drug reacts with an herb while drug-food interaction occurs when a drug reacts with a food to either produce synergistic or antagonistic effect.

In synergistic drug interaction, two or more drugs are combined to achieve a therapeutic effectiveness that is greater than the efficacy of the individual drugs added together. Some drugs especially those that target Mycobacterium tuberculosis (the causative agent of tuberculosis) and some viral agents such as human immunodeficiency virus (HIV) are usually combined clinically to achieve synergism. When two drugs (e.g., drug A and drug B) are combined in such a way that drug B for example reduces or blocks the therapeutic defectiveness of drug A, then antagonism is achieved. And antagonistic drug interaction can occur in scenarios in which a given drug interact and interfere with the absorption of another drug in the gastrointestinal tract (GIT) or in any other target site of the body. The therapeutic effectiveness of a drug apart from being amplified when two or more drugs are combined (as is obtainable in synergistic drug interaction) can also be potentiated (i.e., boosted). In drug interaction by potentiation, one drug enhances the therapeutic effectiveness of another drug when the two drugs are therapeutically combined.

To be clinically effective for the treatment of infectious diseases, every drug must reach a certain level of bioavailability in vivo. This is critical because drugs contain other constituents aside the actual portion of the medicine which is necessary to express antimicrobial action in the recipient host. The bioavailability of a drug is the actual portion of an administered drug that reaches the systemic or entire circulation of the recipient host in a chemically and effective unchanged form. It helps physicians or scientists to know the actual amount or concentration of the drug that was absorbed by the body after administration either parenterally or orally. Aside the actual fraction necessary for antimicrobial activity in vivo drugs also contain other additional constituents such as excipients (e.g., drug dispersing agents or delivering agents) which may directly or indirectly affect their bioavailability in the systemic circulation.

Excipients are substances added to drugs during their production to make them into pills (i.e., as capsules or tablets). The metabolic rate of the drug, its chemical instability in vivo as well as their solubility and mode of formulation are additional factors that affect the bioavailability of a drug. These factors must be considered and taken care of during the formulation or production of drugs to develop clinically effective medicines. Nevertheless, the absorption of a drug (i.e., the transfer of a drug from its initial site of administration to the bloodstream or general circulation) could also be slightly affected by their route of administration (either parenterally or orally); and as such a lower bioavailability of the drug will be experienced in such scenarios. This explains the reason why drugs administered parenterally often reach systemic circulation faster than orally administered medications because parenteral drugs are administered directly into the bloodstream (e.g. intravenously) while drugs taken orally first reaches the gastrointestinal tract (GIT) where it permeates or dissolves in the GIT fluids and then infiltrate the epithelial cells of the GIT for its distribution to the entire body or bloodstream. Some other factors such as food, the disease state of the individual and the co-administration of two different drugs may also affect the effectiveness of a primary drug. And this can cause drug interaction.

PHARMACOKINETICS

Pharmacokinetics is simply the study of how the body reacts to therapeutic agents or drugs over a period. It investigates what a therapeutic agent or drug does to the body after being administered. The pharmacokinetics of a particular drug describes alterations in the absorption, distribution, metabolism and the elimination or excretion of the drug from the body. After their administration either parenterally or orally, therapeutic agents are first broken down and absorbed by their target body sites and then metabolized or bio-transformed before it is finally excreted or eliminated from the body especially after the drug must have accomplished its restorative function in vivo.The pharmacokinetic properties of drugs are generally the mechanisms in which therapeutic agents are processed by the body. It describes what the body does to the drug.

Drugs after their administration must reach certain therapeutic levels in the bloodstream or plasma for it to be effective against a target pathogen or infection. Absorption, distribution, metabolism, and excretion are the main factors or pathways that control the circulation and modification of drug in the body prior to the expression of their authentic antimicrobial activity. An understanding of the pharmacokinetic properties of a drug (inclusive of drug absorption, drug distribution, drug metabolism and drug elimination or excretion) enables physicians and scientists alike to have basic knowledge of what drugs does to the body (aside their normal therapeutic property). This will go a long way in assisting clinicians to administer the most effective drug as per the differences that exist in individuals physiological and biochemical makeup.

  • Absorption: Absorption is the process by which a substance (e.g., a drug) is taken into the body. Drug absorption is usually the first pharmacokinetic property of a drug; and the absorption of drug from their initial site of administration allows the therapeutic agent to reach the bloodstream or blood plasma for further antimicrobial activity. However, the route of administration of a drug may affect the rate of its absorption by the body. While drugs administered parenterally may reach the bloodstream at a much faster rate than orally administered drugs; therapeutic agents administered orally take some time to reach the bloodstream because they have to be dissolved in the GIT fluid before proceeding to the bloodstream for distribution.    
  • Distribution: After their absorption into the body, it is critical that the absorbed drug becomes distributed across the body especially from the bloodstream to other body sites or fluids such as the intracellular fluids and interstitial tissues or extracellular fluids where their antimicrobial activity is expressed. The distribution of the drug allows it to reach the infected site of the body where restorative action is most wanted.
  • Metabolism: At this stage the drug is metabolized i.e., broken-down, or bio-transformed into substances that are easily excretable. This is mainly done by certain tissues of the body such as the liver or kidney and then processed for elimination from the body.
  • Excretion: Drugs are eliminated from the body in various ways. Both the drug and its metabolites are eliminated from the body in urine or feaces. Drugs can also be eliminated via milk in nursing mothers and via the intestines or skin.

PHARMACODYNAMICS

Pharmacodynamics is the study of the effects of drug on the body. It explains what therapeutic agents do to the body. The pharmacodynamic properties of a drug explore all the physiological and biochemical effects of therapeutic agents on not just the host taking the agent but, on the target, pathogenic organism in vivo. Antimicrobial agents particularly those that target pathogens in vivo interfere with some key metabolic processes of these infectious agents thereby inhibiting their infectious processes. However, in the process of expressing their antimicrobial effect, therapeutic agents can leave some untoward effects on the recipient host aside destroying their target pathogenic microorganisms. Both the pharmacokinetic and pharmacodynamic properties of therapeutic agents assist clinicians and physicians to effectively manage their patient’s disease process, and thus ensure that the best therapeutic regimens are always administered on case by case basis.   

ROUTES OF DRUG ADMINISTRATION

Therapeutic drugs are administered in various ways, and these include parenteral and oral administration. Other routes of drug administration include: sublingual administration (in which drugs are placed under the tongue), intranasal administration (in which the drug is administered through the nose), rectal administration (in which drugs are administered via the rectum), topical administration (in which drugs are applied topically i.e. on the skin surface), inhalation administration (in which drugs are administered via the respiratory tract) and transdermal and intraventricular administration in which drugs are administered to the skin via transdermal patch and directly into the cerebrospinal fluid (CSF) respectively. Parenteral and oral drug administration’s which are the two major routes of drug administration shall be highlighted in this section.

Parenteral drugs refer to therapeutic agents that are not given through the mouth (i.e., orally) but via injections. In parenteral drug administration, therapeutic agents are administered directly into the bloodstream where they assume systemic circulation. Drugs administered through parenteral routes are usually therapeutic agents that are poorly absorbed in the GIT. Therapeutic agents that are unstable in the gastric mucosa or fluid are also administered parenterally. Parenteral drug administration is usually the best route of administering therapeutic agents to critically ill patients. Drugs administered via this method assumes a high bioavailability because they do not have to be dissolved first in the GIT fluid before being transported or distributed to the bloodstream for systemic circulation in the body.

The major routes of parenteral drug administration include:

intravenous (IV) administration,

intramuscular (IM) administration, and

intraperitoneal or subcutaneous administration.

Most therapeutic agents are best administered orally i.e., through the mouth. Oral administration of therapeutic agents is often one of the commonest and versatile means of administering drugs; and the drugs can either be swallowed or chewed when administered via the mouth. Drugs administered orally passes through the digestive tract or GIT to the stomach where they are either absorbed or transported to the portal circulation or the liver from where they enter the systemic circulation.      

FURTHER READING

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India. 

Block S.S (2001). Disinfection, sterilization and preservation. 5th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.

Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2nd edition. Ellis Horwood Publishers, New York, USA.

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