Background

Levothyroxine is marketed as Synthroid (Abbvie Inc, North Chicago, IL) and is the most commonly prescribed drug in the United States, with 119.9 million prescriptions dispensed in 2014. Levothyroxine is a thyroid hormone supplement.

Pharmacology

The thyroid gland is responsible for synthesizing and releasing the hormones triiodothyronine and tetraiodothyronine (T4). Triiodothyronine is 10 times more potent than T4; however, 80% of triiodothyronine is actually formed by deiodination of T4 in peripheral tissues. Levothyroxine is a synthetic form of T4.

Thyroid hormones are believed to exert their physiologic effect by modulating DNA transcription and promoting protein synthesis. These proteins then act on their target organs to secrete hormones that regulate growth and metabolism.

Supplementing deficient thyroid hormones requires delicate titration because the therapeutic index of levothyroxine is narrow. Excessive thyroid hormone administration can precipitate symptoms of thyrotoxicosis that include adverse cardiac, respiratory, central nervous system, and gastrointestinal, hepatic, and musculoskeletal sequela.

Interactions with Dental Treatment

For the well-controlled hypothyroid patient taking a longstanding stable dose of levothyroxine, there are no specific interactions between levothyroxine and dental treatment. For patients who are recently diagnosed with hypothyroidism and are not yet euthyroid, elective treatment is best deferred and emergent treatment carried out with caution. The concern in the uncontrolled patient is that if the thyroid levels are too high then thyrotoxicosis can ensue. Hypothyroidism rarely results in an emergent situation; however, these patients are at risk for arrhythmias, heart failure, and myxedema coma if severely deficient.

Levothyroxine has several important relevant drugs interactions. Specifically, there are interactions with levothyroxine and warfarin, ketamine, and carbamazepine. Levothyroxine increase the International Normalized Ratio (INR) in patients taking warfarin. It is therefore important, especially when initiating levothyroxine, to monitor INR levels and adjust warfarin dosage until the INR is stable. Levothyroxine may increase the hypertension and tachycardia that occurs with administration of ketamine during parenteral sedation. Carbamazepine may increase thyroid hormone metabolism; thus, patients initiating these medications may need an adjustment of their levothyroxine dose.

Background

Levothyroxine is marketed as Synthroid (Abbvie Inc, North Chicago, IL) and is the most commonly prescribed drug in the United States, with 119.9 million prescriptions dispensed in 2014. Levothyroxine is a thyroid hormone supplement.

Pharmacology

The thyroid gland is responsible for synthesizing and releasing the hormones triiodothyronine and tetraiodothyronine (T4). Triiodothyronine is 10 times more potent than T4; however, 80% of triiodothyronine is actually formed by deiodination of T4 in peripheral tissues. Levothyroxine is a synthetic form of T4.

Thyroid hormones are believed to exert their physiologic effect by modulating DNA transcription and promoting protein synthesis. These proteins then act on their target organs to secrete hormones that regulate growth and metabolism.

Supplementing deficient thyroid hormones requires delicate titration because the therapeutic index of levothyroxine is narrow. Excessive thyroid hormone administration can precipitate symptoms of thyrotoxicosis that include adverse cardiac, respiratory, central nervous system, and gastrointestinal, hepatic, and musculoskeletal sequela.

Interactions with Dental Treatment

For the well-controlled hypothyroid patient taking a longstanding stable dose of levothyroxine, there are no specific interactions between levothyroxine and dental treatment. For patients who are recently diagnosed with hypothyroidism and are not yet euthyroid, elective treatment is best deferred and emergent treatment carried out with caution. The concern in the uncontrolled patient is that if the thyroid levels are too high then thyrotoxicosis can ensue. Hypothyroidism rarely results in an emergent situation; however, these patients are at risk for arrhythmias, heart failure, and myxedema coma if severely deficient.

Levothyroxine has several important relevant drugs interactions. Specifically, there are interactions with levothyroxine and warfarin, ketamine, and carbamazepine. Levothyroxine increase the International Normalized Ratio (INR) in patients taking warfarin. It is therefore important, especially when initiating levothyroxine, to monitor INR levels and adjust warfarin dosage until the INR is stable. Levothyroxine may increase the hypertension and tachycardia that occurs with administration of ketamine during parenteral sedation. Carbamazepine may increase thyroid hormone metabolism; thus, patients initiating these medications may need an adjustment of their levothyroxine dose.

Background

Opioids are central for pain management of the dental patient, especially when other medications such as nonsteroidal antiinflammatory drugs (NSAIDs) are inadequate. Hydrocodone with acetaminophen (hydrocodone/APAP) is marketed as Vicodin (Abbvie Inc, North Chicago, IL) and Lortab (UCB Inc, Smyrna, GA) and is the second most commonly prescribed drug in the United States, with 119.2 million prescriptions dispensed in 2014. Vicodin is a schedule II semisynthetic narcotic analgesic. All hydrocodone/APAP formulations contain 300 mg of acetaminophen; the hydrocodone contained in the tablet can be prescribed at 5, 7.5, or 10 mg.

Hydrocodone/APAP is an excellent analgesic; however, it is also a drug of abuse with approximately 97,000 drug-related emergency room visits in 2011. Owing to its abuse potential, the US Drug Enforcement Administration in 2014 rescheduled hydrocodone from a schedule III to a schedule II drug.

Pharmacology

Hydrocodone exerts its clinical effects by acting at the central nervous system opiate receptors and at smooth muscle. There are multiple subtypes of opioid receptors; the most commonly referenced are the μ-1, μ-2, δ, κ, and ORL-1 (nociceptin receptor). The clinically useful action of hydrocodone, that is, analgesia, occurs at the μ-1 receptor; however, the other opioid receptors are also activated by hydrocodone with μ-2 activation resulting in respiratory and cardiovascular depression, and constipation. The APAP component acts as an antipyretic by modulating hypothalamic heat regulating centers. The analgesic qualities of APAP are believed to be owing to prevention of prostaglandin synthesis. APAP is also a weak inhibitor of cyclooxygenase (COX)-1, COX-2, and possibly also COX-3. The combination of an opioid with acetaminophen improves the quality of pain relief when compared with APAP or an opioid alone.

Hydrocodone is metabolized by the liver and excreted in the urine. Hydrocodone has not been shown to have adverse effects in patients with renal failure ; however, some authors recommend using lower doses in moderate renal failure and longer time intervals in cases of severe renal failure. Acetaminophen has a plasma half-life of 1.25 to 3 hours and is increased in patients with liver damage. There is no ceiling dose with hydrocodone; however, owing to potentially dangerous side effects, particularly respiratory depression, the lowest functional dose should be used. The maximum acetaminophen dose in healthy patients should not exceed 4000 mg because of the risk of hepatotoxicity. Because one can approach toxic levels of APAP by taking opioids in combination with APAP, the US Food and Drug Administration (FDA) recommends discontinuing prescribing and dispensing of combination drugs containing more than 325 mg of APAP.

Interactions with Dental Treatment

There are no specific interactions between hydrocodone/APAP with dental procedures or local anesthetics. Because dentists will be prescribing opioids for perioperative pain management, we will present several pertinent scenarios warranting prudent prescribing of hydrocodone/APAP.

Patients on chronic opioids

Patients visiting the dentist may be taking hydrocodone/APAP for acute or chronic pain. Patients receiving chronic opioid therapy present a unique perioperative dilemma because they experience more severe acute pain and opioid-related complications than the opioid naive patient. It is believed that chronic opioid receptor activity induces a hyperalgesia, thereby decreasing a patient’s pain tolerance. When presenting for a procedure that may incur postoperative pain, patients should be encouraged to take their basal opioid the morning of the procedure. Then, using multimodal analgesia, nonopioid analgesics such as NSAIDs, APAP, COX-2 inhibitors, clonidine, and anticonvulsants such as gabapentin and pregabalin, may be added to the perioperative regimen. The use of anticonvulsants preoperatively may help to decrease the amount of postoperative opioid required without increasing the side effects of the opioid.

The dentist is cautioned against prescribing increased doses of opioids for patients on chronic opioids because the incidence of sedation is higher in the chronic opioid group and without frequent clinical monitoring it may be difficult to identify the appropriate postoperative opioid dose. The dentist is encouraged to consider the use of long acting local anesthetics, preemptive analgesia, and perioperative NSAIDs to mitigate the postoperative analgesic requirement required by the patient.

Patients with hepatic impairment

In patients with compromised liver function, peak plasma concentrations of hydrocodone can increase rapidly. The use of APAP in patients with compromised hepatic function is controversial. APAP toxicity has been reported to occur more easily with compromised hepatic function because these patients are more sensitive to the toxic metabolites of APAP and have compromised ability to eliminate the toxic metabolites. Contradictory reports suggest that the impaired liver maintains its capacity to metabolize and clear the toxic metabolites effectively and that APAP remains a safe drug when taken at recommended dosages.

It is recommended that patients with cirrhosis not exceed a daily limit of 2000 mg APAP. Practitioners should exercise caution when prescribing hydrocodone/APAP–containing medications to chronic alcoholics. In chronic alcoholics, the risk of hepatotoxicity actually increase if, owing to the APAP, the alcoholic stops their ethanol consumption. If they maintain their ethanol consumption, the risk of toxicity from APAP decreases but the central nervous system–depressing effects of ethanol and hydrocodone are additive.

Drug–drug interactions

Hydrocodone is metabolized to hydromorphone (active metabolite) by the hepatic cytochrome P450 system, specifically, the CYP2D6 enzyme. Therefore, other medications that a patient is taking that are inducers and inhibitors of CYP2D6 can alter the metabolism of hydrocodone. Patients who are poor metabolizers via CYP2D6 experience no analgesia from hydrocodone. Patients who are concomitantly taking other narcotics, antihistamines, anxiolytics, and other central nervous system depressants should use caution when taking hydrocodone, because the central nervous system depression is additive.

Background

Lisinopril is an antihypertensive drug marketed as Zestril (AstraZeneca, Wilmington, DE) and Prinivil (Merck, Whitehouse Station, NJ). It is the third most commonly prescribed drug with 103.7 million prescriptions dispensed in 2014. Lisinopril belongs to the class of antihypertensive agents called angiotensin-converting enzyme inhibitors (ACEi) and has extensive applications in the management of cardiovascular disease.

Pharmacology

The ACEi reduce blood pressure by modulating the hormones of the renin–angiotensin–aldosterone system. Renin is a hormone released by the juxtaglomerular cells of the kidney in response to decreased renal perfusion and increased sympathetic activity ; renin is also produced locally in tissues. Renin cleaves and activates angiotensin I. Angiotensin I is cleaved by the angiotensin-converting enzyme into angiotensin II. Angiotensin II acts centrally and peripherally to increase vascular tone thus elevating blood pressure. Angiotensin II also promotes sodium retention through it effects on aldosterone, and volume expansion through its effects on antidiuretic hormone. In summary, ACEi exhibit their effect by reducing systemic vascular resistance without increasing the heart rate effectively reducing blood pressure.

Interactions with Dental Treatment

Routine dental procedures under local anesthesia can proceed safely in patients taking ACEi. Perioperative modification of lisinopril in patients who are receiving general anesthesia is controversial. Most antihypertensive drugs are continued throughout the perioperative period; however, some data show that continuing ACEi perioperatively can exacerbate the hypotensive effect of anesthetics, whereas other data show no relation between continuing ACEi and intraoperative hypotension. Cumulative evidence recommends discontinuation of the ACEi the morning of surgery; however, modification of anesthetic induction technique may possibly ameliorate the hypotensive effects of concomitant ACEi use and anesthetics.

The side effects of ACEi are pertinent to the general dentist potentially affecting the process of care delivery. The specific side effects include postural hypotension, coughing, and angioedema, with angioedema potentially being life threatening.

Postural hypotension is a decrease in blood pressure that occurs when one rises from a supine position to an upright position; this can potentially lead to dizziness and syncope. To prevent issues related to postural hypotension, the patient should be uprighted from the supine position slowly.

Between 10% and 35% of patients taking ACEi develop a dry cough. This cough may impact the delivery of dental care. The cough is believed to arise from increase in bradykinin production that stimulates the release of prostaglandins. The cough usually develops within the first month and disappears within 1 week of cessation of the drug.

A rare and potentially life-threatening condition linked to ACEi is the development of angioedema. Oral or perioral angioedema describes a process of rapid swelling of the lips, tongue, mucosal, and submucosal surfaces. The incidence of ACEi induced angioedema is 0.1% to 0.2%. Angioedema can occur in any organ system and at anytime, but more commonly the head and neck are affected typically occurs within the first month of treatment. Patients of African descent are 3 times more likely to be affected. Patients with perioral swelling may present to their dentist thinking they have a tooth infection; therefore, the dentist should recognize the link between ACEi and angioedema, and refer the patient to emergency department for definitive management.

Drug–drug interactions

Patient on ACEi should not take NSAIDs for perioperative pain management for longer than 5 days because NSAIDs may decrease the effectiveness of the antihypertensive effects of the ACEi. It has also been shown that combining NSAIDs and ACEi in susceptible patients may precipitate renal failure and subsequent electrolyte abnormalities. Therefore, caution should be used when prescribing NSAIDs to patients taking ACEi, particularly the elderly, those with congestive heart failure, and those with preexisting renal disease.

Background

Metoprolol is marketed as Lopressor (Novartis, East Hanover, NJ) and is an antihypertensive, antiarrhythmic drug. It is the fourth most commonly prescribed drug with 83.3 million prescription dispensed in the United States in 2014. The indications for metoprolol include management of hypertension, angina pectoris, and to reduce mortality from myocardial infarction.

Pharmacology

Metoprolol is a beta-1 selective (cardioselective) beta-blocker. The beta-1 adrenergic receptor modulates heart rate; the beta-2 adrenergic receptor modulates smooth muscle relaxation. Beta-blockers are used to treat tachycardia and hypertension by blocking the activity of endogenous catecholamines at the cardiac beta-1 receptors and by inhibiting renin secretion by the kidneys. Beta-blockers are also used to treat angina pectoris. The mechanism of action is likely related to reductions in heart rate, myocardial contractility, and cardiac oxygen demand. Beta-blockers have also been shown to improve survival after myocardial infarction.

Beta-blockers may be nonselective and block both the beta-1 and beta-2 receptors or they may be beta-1 selective blockers. Beta-2 antagonism is not well-tolerated in asthmatics; therefore, selective beta-1 blockers are typically used when they are indicated in the asthmatic patient.

Interactions with Dental Treatment

Cardioselective beta-blockers have less dental-related interaction than nonselective beta-blockers. Nonselective beta-blockers can exacerbate bronchoconstriction in asthmatics, and cause hypertension and reflexive bradycardia (severe enough to require atropine) with epinephrine containing local anesthetics. As with ACEi, metoprolol can cause orthostatic hypotension; therefore, patients should be moved slowly from a supine to an upright position. Metoprolol may also cause xerostomia, dysgeusia, and oral lichenoid reactions. NSAIDs taken by those on metoprolol may reduce the antihypertensive effects of metoprolol.