Prime Drug Interplay in Dental Practice

Drug interaction is a negative representation of pharmacotherapy. In order to provide the best patient care possible, a thorough knowledge of how the drug interactions occur is needed for proper application in practice. Possible interactions among current medication and drugs being prescribed should be considered always. A thorough understanding of the mechanism of interactions among drugs is a must for the health care practitioner. Considering the astounding number of drugs patients may be taking, this task seems discouraging. The count of possible interactions in dental practice are less due to few number of drugs utilized and brief period of therapy, but still notable number are to be considered. The aim of present preview is to consider the manifold and multiplex nature of pharmacological drug-drug interaction in the general dental practice setting.

In order to optimize desirable pharmacological responses to medications and minimizing the risk of adverse reactions to them, prediction and prevention of drug interplay is prime. Professor Bottiger stated: drug treatment has become more complicated with prescription of medicines with narrow therapeutic window, given concomitantly with many drugs, for longer periods, increasing the risk for drug interactions and also the patients are getting older. As a result the responsibility for drug treatment on doctors has increased [1]. The statement holds more relevance today, even after 39 years. The usage of drugs by patient is increasing continuously and so is the risk of drug interactions [2], which is an emerging concern for all fields of patient care.

Now, talking about the patient population of different age groups, Polypharmacy in geriatric dental population is the norm [3], due to increase in this population and presence of multiple disease states. Compound procedures involving restorative, periodontal, and implant over complete or partial dentures, is the treatment opted by many of these patients [4]. As a result, the need for local anaesthesia /vasoconstrictors, analgesics, anxiolytics, and antibiotics, on occasion could lead to adverse interactions with an array of drugs they are on. The intake of certain prescription medications, especially within the cardiovascular classes of drugs, among young to middle-aged adults, is on the rise. The unique physiology and anatomy of paediatric dental patients, make them vulnerable to drug interactions, mainly multiple central nervous system depressant drugs [5].

The aim of the present paper is to lay emphasis on those potential adverse drug interactions that are clinically relevant to the general dentist. The paper also provides an insight into the understanding of the general mechanisms behind such interactions, thereby aiding the clinician in identifying them before they occur.

Mechanisms of Drug Interactions: Alteration of one drug by either another drug or food items or environmental chemical agent is referred as an interaction [6]. Drugs interact in unique ways with each other, but in this paper, we have discussed about different interaction mechanism that is encountered repeatedly [Table/Fig-1].

Pharmacokinetic Interactions: It involves the ability to alter the absorption, distribution, metabolism and excretion of one drug by another [6] (the so-called ADME interactions).

Drug absorption interactions: These involve drug administration via oral route involving more than two drugs or a drug along with food product. The effectiveness and blood levels of the drug are reduced due to the impairment of its ability caused by food product or other drug to cross mucous membrane in the stomach and intestine. Well known example of this type interaction to dental practitioners is chelation ability of systemic tetracycline and quinolone antibiotics to drugs and dairy products containing divalent and trivalent cations [7,8].

Drug displacement (protein-binding) interactions-[Table/Fig-2]: Drugs on absorption are rapidly distributed via circulation around the body. Some being completely dissolved in plasma water, but many others are transported in solution and rest are bound to plasma proteins, mainly albumins. The unbound portion of drug is pharmacologically active and free to interact with its receptors. Clinically significant interactions can occur when two extremely protein-bound drugs (usually >90%) are given concurrently and fight for receptor sites, due to the availability of finite number of protein-binding sites. So, one of the highly protein-bound drugs exhibit a rather low therapeutic index and is dislodged from plasma protein-binding sites by a so called extremely protein-bound displacer drug [9]. At supratherapeutic blood levels, the displaced drug, free in the plasma, likely results in a situation similar to an overdose of the displaced drug. NSAIDs, diazepam & chloral hydrate are probable displacer drugs used in dentistry.

It involves the chemical alteration of the drug to either less lipid soluble or inactive form for easy excretion via kidney. The principal organ involved in the process is liver along with other tissues in the body, including the kidney, small intestine, bloodstream, and neuronal tissue. Drugs with a high first-pass effect, pre-hepatic metabolism in the small intestine is known to be an important site for metabolic drug interactions [11].

Well recognized biochemical target is the cytochrome P450 system for vast majority of drug metabolic interactions [12], a group of heme-containing enzymes embedded in the smooth endoplasmic reticulum of hepatocytes and enterocytes of liver and small intestine respectively. Cytochrome P450 isoenzymes known so far, are more than 30; CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 being the significant ones. The isoform mostly concerned with greater number of metabolism of drugs and adverse interaction is CYP3A4. [13]. Two basic processes affecting metabolic enzymes in drug interactions are enzyme induction causing diminished drug effect and enzyme inhibition causing exaggerated effect due to overdose [Table/Fig-3].

With respect to drugs employed in dentistry, several benzodiazepines and narcotic analgesics come under substrate listings, while several commonly in use antimicrobial agents appear as enzyme inhibitors. When a cytochrome P450 substrate and a corresponding cytochrome P450-inducing or -inhibiting drug are administered on chronic basis, these types of interactions become most significant.

Drug excretion interactions-[Table/Fig-4]: The primary organ of drug elimination is kidney. The retention of supratherapeutic blood levels of the drug occurs due to the capability of one drug to weaken the renal elimination of another drug [Table/Fig-5].

These interactions without altering drug’s concentration in tissue fluid revise its pharmacological effect [18]. Classification of these interactions is less easy than those of a pharmacokinetic type.

The rest of this review will condense about the significant drug interactions as they relate to dental practice, especially dealing with the drugs prescribed in common medical conditions [19] like hypertension, hypercholesterolaemia, CVD, haematological condition and depression.

Analgesic Agents: The use of analgesics is widespread, in dental or periodontal practice. Due to short-term duration of therapy and the relative low doses that are prescribed, serious adverse drug interactions involving them are rarely reported [11,20].

Non-Steroidal Anti-Inflammatory Drugs: With the ability to interfere with arachidonic acid metabolism & inhibit inflammatory process, the most commonly employed NSAIDs in dental practice includes of aspirin, ibuprofen, ketoprofen, naproxen, diclofenac, meloxicam and celecoxib. The recommended daily dosage is maximum of 2 g acetaminophen for alcoholics [Table/Fig-6,7]. If the dose remains in the therapeutic range there are little chances of toxicity [26]. The chances of enhanced gastrointestinal toxicity occur, if one consumes 3 or more drinks per day [20]. The recommendation is that consumption of aspirin and alcohol be separated by at least 12 hours [27]. The effect of interaction with antihypertensive drugs is observed when NSAIDs are taken for more than 5 days. Antihypertensive drugs like β-adrenergic blocking agents, ACE inhibitors and diuretics effects is dependent on prostaglandins [28]. By blocking the synthesis of the prostaglandins in the kidneys NSAIDs lower the antihypertensive effect [29–30].

[Table/Fig-6]:

Metabolism of paracetamol and ethanol [14].

When NSAIDs are administered concomitantly with high dose of methotrexate [31], decrease in prostaglandin-dependent renal perfusion and consequent elimination of methotrexate results. The combination of NSAIDs with Selective Serotonin Reuptake Inhibitors must be avoided where ever possible. According to a meta-analysis, the risk of upper gastrointestinal haemorrhage is serious, due to SSRIs impaired vasoconstrictive potential and NSAIDs risk of gastric damage [32]. Impairment of thromboprophylactic action of aspirin [33] is seen when administered with other NSAIDs. Theoretically, when both aspirin and a NSAIDs are involved all at once, drugs like ibuprofen could vie with aspirin for the cyclooxygenase-1 binding site in the platelet [34]. As a result the synthesis of thrombaxane A2 may resume after subsequent removal of NSAID.

Narcotic Analgesic Agents: Patients managed with opioid analgesics following treatment to manage post-procedural pain, are at risk of serious drug interactions. The metabolism of most of the opioid analgesics is by CYP2D6. In the case of codeine, the active demethylated metabolite morphine & the parent molecule, in case of tramadol, appears to possess analgesic activity by enhancing noradrenergic and serotonergic activity in the central nervous system [35]. Their analgesic effect is eradicated, on administration of antiarrhythymic agent quinidine, a known CYP2D6 inhibitor [36].

Normeperidine effects are worsened due to deactivation of neurotoxic meperidine metabolite by monoamine oxidase inhibitors. Life-threatening episodes have been reported in monoamine oxidase inhibitor consumers with therapeutic doses of meperidine. Similarly, other opioids in the phenylpiperidine series, including tramadol and propoxyphene, have their own intrinsic serotonergic activity, which may bring into being a serotonin-like syndrome when taken at the same time with monoamine oxidase inhibitors [37].

Behaviour Modifying Agents [Table/Fig-8]: Orally administered behaviour modifying agents, for patient relaxation and release of anxiety, are valuable additions to a dentist’s pain control armamentarium. Signs of excessive central nervous system depression: lethargy, prolonged sedation, loss of consciousness, and/or respiratory depression, is the most significant systemic adverse drug reactions related with these agents. CYP3A4 isoenzymes are inhibited by drugs like calcium-channel blockers verapamil and diltiazem [38], cimetidine [39] and protease inhibitors [40]. Due to its inhibition the metabolism of benzodiazepine like triazolam, oral midazolam, alprazolam is altered resulting in their 2-3 fold increase in blood. Antimicrobials like erythromycin, clarithromycin, ciprofloxacin, and the azole antifungals are potential inhibitors of enzymes needed for the triazolam and oral midazolam’s metabolism [41]. Hepatic enzymes required for the oxidative metabolism of certain benzodiazepines: alprazolam, triazolam, and midazolam; are induced by rifampin [42] and carbamazepine [6].

Barbiturates are less specific with dental procedures, compared to the currently available benzodiazepines. In order to maintain therapeutic prothrombin times, an increment of 30% in warfarin doses is needed when administered in patients on chronic barbiturate therapy. Chloral Hydrate is the most commonly used oral sedative in paediatric dentistry. It is found to be involved in a variety of drug interactions. Combination with alcohol results in supraadditive interaction due to alteration of alcohol metabolism.

Local Anaesthetics [Table/Fig-9]: They are all central nervous system depressants and function by inhibiting neuronal functions [43]. The greatest concern to general practitioners and specialists, are the drug interactions that supplement the severity of central nervous system depression. For adults, the maximum number of 1.8-ml cartridges that can be used of 2% lidocaine with 1:100,000 epinephrine and of 3% mepivacaine are 14 and 7 respectively [44]. A summation drug interaction predicts that the maximum dose of grouping of these agents would be seen with seven cartridges of 2% lidocaine with epinephrine and 3.5 cartridges of mepivacaine.

Amide local anaesthetics metabolism is inhibited by certain drugs. Cimetidine (H2-histamine antagonist) a known inhibitor of hepatic oxidative enzymes is required for the biotransformation of many drugs including lidocaine. A 50% increase in blood concentration following steady-state infusion occurs, thereby slowing the elimination of lidocaine [45]. Reduction in clearance of lidocaine occurs by β-adrenergic blocker propranol, by 40% [46]. When treating paediatric dental patients, systemic depressant effects of local anaesthetics are most apparent due to possible interactions with other central nervous system depressants. One-third the dose of a 150-lb (68-kg) adult for a child of 50-lb (23-kg) is the maximum recommended safe dose. Opioids usage has been correlated with local anaesthetic toxicity reactions [47]. The mechanism for this interaction is probably many-sided. In part, when excessive doses are administered, synthetic opioids, such as meperidine, have convulsant properties [48]. There is decrease in protein binding of local anaesthetics on opioid administration, resulting in distribution of more unbound drug to the central nervous system.

Theoretically, there may be reduction in sulphonamide antibacterial activity following use of ester local anaesthetics [49]. Sulphonamide inhibition is antagonized by an increase in concentration of p-amino benzoic acid available to bacteria due to metabolism of ester local anaesthetics. Development of drug-induced methemoglobinaemia is associated when excessive doses of dental anaesthetics like prilocaine and benzocaine (and rarely lidocaine and articaine) is administered. Methemoglobin production results due to concomitant drug therapy with various nitrite preparations, antimicrobials dapsone and sulphonamides and the analgesic phenacetin [50]. It is recommended that local anaesthetic dose be calculated carefully and that the weight-based maximum safe dosage recommendations not exceeded.

Vasoconstrictors [Table/Fig-9]: Of all the drugs prescribed in dentistry, vasoconstrictors are of most worry due to potential adverse drug interactions with them. Non- selective β-adrenergic blocking agents on interaction with epinephrine block the β2 vasodilatory effects of epinephrine, allowing the α1 vasoconstrictive effects to function unopposed. Case reports of patients on non-selective β-adrenergic blockers have demonstrated serious sequel injections of local anaesthetic volumes equivalent to two cartridges of 2% lidocaine plus 1:50,000 epinephrine [51]. It is recommended that individuals on non-selective β-adrenergic blocking agents receive an initial test dose of no more than 0.04 mg epinephrine or 0.2 mg levonordefrin (two cartridges of a 1:100,000 epinephrine solution or two cartridges of a 1:20,000 levonordefrin solution) and then be monitored for increase in blood pressure before additional local anaesthetic is administered [52].

Tricyclic antidepressant’s potential to block the non-adrenergic reuptake pump, the accumulation of epinephrine and levonordefrin in the vicinity of postsynaptic α- and β-adrenergic receptors could result, leading to enhanced cardiovascular activity. Epinephrine dosages should not exceed 0.054 mg and levonordefrin and norepinephrine should be avoided. Cocaine possesses tricyclic antidepressant-like activity and may also enhance adrenergic neurotransmitter release and postsynaptic responses to epinephrine-like drugs. After the last dose of cocaine, for at least 48 hours the use of vasoconstrictors should be suspended [52]. Norepinephrine reuptake inhibitor atomoxetine and amphetamine or amphetamine-like stimulants (Attention Deficit Hyperactivity Disorder Drugs) are the commonly employed drugs [53], resulting in increased release of norepinephrine and other catecholamines and also blocking their reuptake [54]. These dosage of epinephrine (0.04–0.054 mg) or levonordefrin (0.2 mg) can be used in children and adults with normal blood pressures and heart rates.

Recently introduced drugs as adjuncts to levodopa/carbidopa, in the management of Parkinson’s disease are tolcapone and entacapone (Catechol-O-Methyltransferase Inhibitors). They reversibly block catechol-O-methyltransferase, inhibiting levodopa inactivation in the periphery [55]. Inactivation of epinephrine and levonordefrin enclosed in a local anaesthetic solution is also inhibited by them. It has been recommended that no more than the equivalent of one cartridge of lidocaine with 1:100,000 epinephrine be administered initially and to monitor the patient’s blood pressure and heart rate before administering any additional local anaesthetic with vasoconstrictor [55]. Adrenergic neuronal-blocking agents, guanethidine and guanadrel both deplete and inhibit the release of norepinephrine from adrenergic nerve terminals. Subjects pretreated with guanethidine that received norepinephrine infusions, showed significant increase in press or response with more frequent cardiac arrhythmias [56]. Recommended epinephrine dose not exceeding 0.054 mg and careful aspirating technique is advised. For population on digitalis glycosides, cautious use of dental vasoconstrictors is recommended, due to induction of additive dysrhythmogenic activity.

Antibiotic/Antifungal Agents: Duration of drug therapy with antimicrobial agents is more long-lasting than other drug classes used in dental practice, which increases the hazard of adverse drug interactions compared to other drug classes. Possibility of adverse drug interactions in dentistry is increased due to four commonly employed antibiotics (clarithromycin, erythromycin, ciprofloxacin, and metronidazole), which are potent inhibitors of various cytochrome P450 isoforms. Ciprofloxacin and erythromycin are CYP1A2 isoenzyme inhibitors, which reduce the biotransformation and raise the blood levels of CYP1A2 substrate drugs. Example of such drugs are (Fluvoxamine, imipramine); (Theophylline); (Clozapine, Halperidol) and (Tacrine) [57]. Most clinically relevant interactions for practicing dentists is the ability of metronidazole & fluconazole to significantly increase the blood concentrations and half- life of the anticoagulant warfarin [58] & antiepileptic phenytoin [59], which are CYP2C9 substrates. CYP3A4 metabolizes the greatest number of drug substrates and correspondingly is involved in the greatest number of possible metabolic drug interactions, of all the cytochrome P450 isoenzymes {[Table/Fig-10] lists such interactions}.

Metronidazole, like disulfiram, in the ethanol degradation pathway inhibits the enzyme acetaldehyde dehydrogenase, resulting in an accumulation of acetaldehyde in the bloodstream. Avoidance of alcohol consumption is needed during metronidazole therapy and for at least 3 days after that. Due to low therapeutic index of digoxin, antibiotics like clarithromycin, erythromycin, and azithromycin should be avoided in patients on digoxin therapy. Its the ability of these antibiotics to inhibit P-glycoprotein, contributing to the swift increase in digoxin blood levels in patients ensuing in classic digitalis toxicity [60]. One of the most debated interactions is the reported capability of commonly prescribed antibiotic agents to lower blood levels and efficacy of oral contraceptive agents [61]. Oral contraceptive failure reports have appeared in literature, following therapy with certain antibiotics like tetracyclines, penicillins, erythromycin, metronidazole and cephalosporins [62]. Plausible mechanism is that the enterohepatic recirculation of the estrogen steroid component of the pill is inhibited by common antibiotics [62].

Drug interactions are an avoidable cause of patient harm. With the continued introduction of new therapeutic classes of drugs, the number of potential adverse drug interactions will continue to grow. Drug interactions should be considered both in the differential diagnosis of symptoms and when prescription changes are made. In order to prevent drug interactions, the sound place to start is with patient’s current medical history and medication intake. Vigilance regarding recognition and prevention of such interactions is needed by dental clinician.

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