drugs that may bind to an alternate site on a given receptor along with the primary effector, producing different clinical effects (Kat- zung, 2018, p. 21). Receptors also come in various forms, such as receptor proteins, enzymes, transport proteins and structural proteins. Receptor proteins control endogenous chemical signals and constitute the most well-established pharmaceutical recep- tors. Enzymes accelerate chemical reactions by converting sub- strates into products, which then alter the biologic activity of said product compound. Transport proteins facilitate drug reactions by moving specific molecules across biologic membranes. Structural proteins are typically fibrous, and compose arrangements such as our muscles, fingernails, hair, cartilage, ligaments, etc. A receptor’s attraction, or affinity, to a given pharmaceutical, along with the physical number of present receptors, largely de- termines the concentration requirement to achieve a desired ef- fect. While low doses of a drug are often associated with effects in direct proportion, increasing dosage will inevitably lead to a point of saturation. This is known as a concentration-effect curve , a hyperbolic mathematical representation that factors in drug- binding affinity as well (Katzung, 2018, p. 21). Competitive and noncompetitive agonists also affect concentration/effect ratios. While competitive agonists vie for open receptors with agonists, non-competitive antagonists generally form strong, often irrevers- ible, receptor bonds, thereby depleting the percentage of avail- able receptors for a given agonist. Agonists can also be catego- rized as partial or full. Partial agonists produce relatively reduced physiologic reactions at full receptor occupancy when compared to full agonists. Partial agonists compete with full agonists for re- ceptor occupancy, which reduces the physiologic effects more so than if the full agonist alone maintained full receptor occupancy (Katzung, 2018). Using the example of opioids, a partial agonist is often safer because they do not reduce respiratory depression to the same degree as full opioid agonists. As well, a partial opi- oid agonist may hasten opioid withdrawal symptoms for pertinent patient populations. Antagonists may produce physiologic reaction without direct at- tachment to a receptor. Chemical antagonists may form bonds with drug molecules, which in turn may prohibit the target drug from binding to a target receptor. Physiologic antagonists may obstruct a physiologic process and reduce individual hormone production. Receptor-specific pharmaceutical agonists are often easier to control and more exclusive in term of effects when com- pared to a physiologic antagonist. Five fundamental pharmacotherapeutic mechanisms for drug ac- tion at the site of a biological membrane must be considered: 1. Lipid-soluble ligands cross the membrane directly and bind to an intracellular receptor. 2. Ligands allosterically bind to the outer face of transmembrane receptor proteins (receptors located within the membrane), producing an enzymatic activity inside the cell. 3. Ligands bind to transmembrane receptors, stimulating intracellular tyrosine kinase. 4. Transmembrane ion channels are provoked to open by a ligand binding externally. 5. Transmembrane receptors activate G proteins (aka GTP- binding signal transducer proteins), which control production of an intracellular second messenger (Katzung, 2018, p. 26). The goal of clinical dosage is to produce maximum clinical benefit with minimal toxicity. Potency is a relative quality of a drug’s abil- ity to produce 50 percent of the maximum effect when compared to other pharmaceuticals. Potency is dependent upon a drug’s comparative affinity to a given receptor, as well as relative efficacy of physiologic effect. Potency may be described in terms of thera- peutic dosages, dosage rates and ratio against multiple drugs. Maximal efficacy is the highest point of physiologic response and is an important clinical marker to establish therapeutic dosage. Therapeutic window refers to the relationship between minimum therapeutic dose and minimum toxic dose (Katzung 2018, p. 37). This clinical term is used when prescribing pharmaceutical man-
present in plasma. Plasma protein availability may be affected by present pathologies, age, malnutrition and/or trauma. Protein- binding forms protein reservoirs. As the unbound drug is elimi- nated from the body, thermodynamics enact and the reservoir re- leases more of the given molecule to increase the concentration and re-establish equilibrium. In some cases, a second pharmaceu- tical compound may be presented, which possesses a higher af- finity for a given receptor. This can lead to prolonged presence of a protein-bound drug in the body, and unfortunately may result in toxic physiologic effects. A common example of this pharmaceuti- cal risk includes Coumadin, which may be displaced by secondary drugs, such as non-steroidal anti-inflammatory agents, and cause dangerous toxicity due to large protein-binding (Amiji, 2014, p. 130). Pharmaceuticals are therefore most permeable in unionized forms. Drug excretion occurs primarily in the kidneys and mimics the pro- cess of absorption. If the drug is not bound to a protein, the kid- ney may filter it out of the blood where it can be excreted in urine. A drug that remains protein-bound may be excreted in its entirety. A drug compound may also be actively secreted into the proximal tubules by way of efflux transporters. A third course of excretion includes passive reabsorption. Compounds that are more polar or ionized tend to be excreted due to their remaining presence in glomerular filtrate, while nonpolar lipophilic compounds are more likely to be reabsorbed. In addition, excretion may also take place in the biliary calculi, alongside the process of absorption. Large molecules can be transported to the intestines via active efflux transporters. Of these compounds, some will be eliminated in fe- ces, while others may be reabsorbed. Additional sites of excretion include saliva, tears, breath, sweat and breast milk. These sites typically excrete weak acid and weak base drugs in non-ionized forms via passive diffusion. Electrolytes An electrolyte is an acid, base or salt that ionizes to form posi- tive cations and negative anions in aqueous solution. A common example references sodium chloride dissolving into positive so- dium cations and negative chloride anions. When compared to nonelectrolytes, electrolytes are dependent upon concentration in solute as opposed to chemical identity, can conduct electricity, and demonstrate rapid chemical reactions (Amiji, 2014, p. 61). Chemical strength of an electrolyte reflects relative tendency to ionize in aqueous solution. Strong electrolytes, such as hydro- chloric acid, may completely ionize in water depending on the solution’s pH. Weak electrolytes, such as ammonia, ionize to a significantly lesser extent on a relative scale of 1 to 10 percent. Nonelectrolytes, such as sucrose, do not ionize in water and thus do not conduct electricity in solution (Amiji, 2014, p. 61). The ma- jority of ingredients in pharmaceuticals are weak electrolytes. The body exhibits buffer systems to maintain relative pH values at 7.4; values that vary greatly from this normative are contrary to or- ganic life. Common blood buffers include hemoglobin, bicarbon- ate, plasma proteins and phosphate (Amiji, 2014, p. 74). Biologic tissue inflammation is significantly related to variance between the pH of a physiologic solution and that of a given pharmaceuti- cal solution. Pharmacodynamics Actions of a drug upon the body are termed pharmacodynamics . Pharmacodynamic processes usually involve multi-step coupled reactions that conclude with an effector mechanism to produce the intended pharmaceutical action. While agonists activate re- ceptors to directly or indirectly bring about an effect, antagonists are pharmaceuticals or biologic molecules that fasten to a recep- tor and may prohibit or inversely affect a mechanism that would otherwise take place. Additional drugs mimic agonists by bind- ing to receptors, which normally terminate a given physiologic process, thereby enhancing and continuing a desired physiologic effect. A receptor is the element of a cell or organism that interacts with a drug, leading to a chain of events and resultant physiologic effects. In addition to agonists and antagonists, allosteric modulators are
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