Drug transport and disposition are influenced by a non-specific and reversible drug binding to plasma and tissues proteins. Albumin and al acid glycoprotein are the most important transport proteins of the blood. Albumin possesses specific sites for acidic and basic drug binding and can interact with them in the plasma since a third site is trapped only by digoxin. Diseases and stress conditions induce conformational changes either in plasma or in tissue proteins by the synthesis of endogenous substances which can strong interfere with the amount of the free pharmacological effective drug ratio. This may affect the binding of drugs in target molecules inducing significant pharmacokinetic alterations. Stress conditions are associated with FFA increase in serum playing an antagonistic role with other acidic molecules (e.g. ampicillin) to the same binding site. The bounded drug is displaced and freer ratio is available to interact with various organ receptors leading to pharmacological effect enhancement and therefore to side effects manifestation such as seizures. Furthermore conjunctive tissues diseases, ageing, prolonged bleeding, starvation or diseases affecting protein profile, characterized by reduced total plasma proteins, followed by albumin decrease and lessen binding sites lead to more free drug availability enhancing its pharmacological effect. Increased a1-acid glycoprotein the acute phase protein as by heart infraction or liver morbidities (e.g CCl4 intoxication) mainly occupied from basic substances, in the case of cationic drug treatment resulted to the enhancement of them and consequently to pronounced effectiveness. In addition, renal failure reduced free fractions of many acidic drugs. It may be concluded that by narrowed therapeutic index of a medicine, and when drug/drug or drug/disease interactions are anticipated, drug monitoring seems to be necessary for its dosage adjustment.

The use of intravenous bisphosphonates (pamidronate or zoledronic acid) is the cornerstone for the management of multiple myeloma-(MM-) related bone disease. However, osteonecrosis of the jaw (ONJ) is a rare, but sometimes difficult to manage, adverse effect of bisphosphonates therapy. A retrospective review of all MM patients who were treated with bisphosphonates in our department, from 2003 to 2013, and developed ONJ was performed. According to inclusion criteria, 38 patients were studied. All these patients were treated as conservatively as possible according to the American Association of Oral and Maxillofacial Surgeons criteria. Patients were managed with observation, oral antibacterial mouth rinse with chlorhexidine, oral antibiotics, pain control with analgesics, nonsurgical sequestrectomy with or without simultaneous administration of antibiotics, or major surgery with or without antibiotics. Healing of the lesions was achieved in 23 (60%) patients who were treated with conservative measures; the median time to healing was 12 months (95% CI: 4–21). The number of bisphosphonates infusions influenced the time to healing: the median time to healing for patients who received <16 infusions was 7 months and for those with >16 infusions was it 14 months (P = 0.017). We conclude that a primarily nonsurgical approach appears to be a successful management strategy for bisphosphonate-related ONJ.

Binding of drugs to plasma and tissue proteins is critically involved in their pharmacokinetics and pharmacodynamics. Stress affects drugs' protein binding via alterations in plasma proteins' levels and excessive increase of free fatty acids due to cortisol-induced fat mobilisation. Free fatty acids play a crucial antagonistic role to drugs for the binding sites on albumin, the major binding plasma protein, resulting in subtherapeutic or toxic levels of many medications' pharmacological classes (oral anticoagulants, beta-lactames, fluoroquinolones, local anaesthetics). Upon stress, changes in blood flow rate and vascular function are also important parameters that can alter drug distribution and pharmacokinetics. Many cases are reported where stress-induced pharmacokinetic alterations led to serious clinical consequences. However, the stress affected drug activity do not always deteriorate the clinical outcome, due to the adaptive and defensive mechanisms of healthy organism. Sensitive population as patients with serious underlying diseases or after trauma or surgery should be given special attention. Clinicians should be alert and monitor cases where stress-induced drugs' pharmacokinetic modifications can have negative impact on the clinical outcome.

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