Lecture ‘Symptomatic/Anti-inflammatory Pharmacology (Drugs Used in Inflammation) dr. Agung Nova Mahendra, M.Sc. Abstract Pain and inflammation in dentistry has unique features. Pain not only signals tissue injury, but it also acts as an impediment to most dental procedures, delays resumption of normal daily activities following dental surgical procedures, and lessens the likelihood of patients seeking dental procedures in the future. While pain during therapy is usually adequately controlled by local anesthesia, post-operative pain control is often inadequate, because of either insufficient relief of pain or unacceptable side-effects such as nausea, vomiting, and upper Gl tract bleeding. In addition, inadequate control of pain during the immediate post-operative period may lead to development of hyperalgesia. These considerations indicate that optimal analgesic and anti- inflammatory therapy for ambulatory dental patients should be efficacious, with a minimum incidence of side effects. Clinical Vignette ‘A male patient, 67 years-old, presents to a dental clinic for treatment of acutely painful tooth. After a sequence of examinations, the patient was then indicated to have a tooth extraction procedure because the tooth is non-reparable. To control immediate post- operative pain, the dentist prescribes an anti-inflammatory drug (mefenamic acid) that must be taken PO TID or as needed (PRN). Three days later, the patient revisits the clinic and complaining of nausea and vomiting after taking six doses of this drug in 2 days. The patient is also under the therapy of antihypertension (hydrochlorothiazide tablets), with daily baseline systolic blood pressure of + 130 mmHg. He denies history of drug allergy, gastric, hepatic and renal disease.Learning Tasks 1. Explain the pharmacokinetics and pharmacodynamics of the drug used in the management of post-operative pain in this case? PK: A: Rapid absorption (PO) D: Vo 1.06 U/kg (N healthy adults [18-45 yr}); protein binding 90% M: Hepatic (phase 1> oxidation by CYP2C [metabolites activities has not been studied]; phase 2 > direct glucuronidation) E: elimination half-life about 2 hrs; fecal (up to 20%) & primarily renal excretion PD: An anthranilic derivative (a fenamate NSAID); inhibits PG synthetase (COXs} Reference: www.drugbank.ca 2. Why does this patient exhibit nausea and vomiting? Explain the pathomechanism! NA PG inhibits gastric aci 2011). COX-1 inhibition by mefenamic ion (Mi acid reduces gastric PG and mucosal protection against gastric acid & the mefenamic acid per se. Oversecreted gastric acid may undergo reflux > sour taste > stimulations of brain regions involved in nausea and vomiting > NIV 3. What is (are) the potential drug-drug interaction(s) (ODIs) of mefenamic acid and antihypertensive drugs, such as hydrochlorothiazide? Co-administration of mefenamic acid & HCT may lead to reduced antihypertensive effect of HCT (reduced effectiveness of blood pressure control). 4, Explain the mechanism of DDIs between NSAIDs and antihypertensive drug! Mefenamic acid inhibits both COX isoforms > + reduced refial-based vasodilation (mediated by COX-1 inhibition in glomeruli & afferent arterioles), and+ reduced diuresis & natriuresis (mediated by COX-2 inhibition in afferent arterioles, podocytes, & macula densa) Reference: www.medscape.com Reduced renal vasodilation > activation of RAAS Reduced diuresis & natriuresis > salt & water retention All of these effects ultimately lead to increased vascular filling & systemic vascular resistance > increased blood pressure Key Reference Katzung, BG, Trevor AJ. 2015. Basic and Clinical Pharmacology Thirteenth Edition. McGraw-Hill Education: New York.