Week 2--Ethics and PHARMACOGENOMICS PDF

Ethical Issues and Best Practices in Psychopharmacology PRACTICING ETHICALLY In any kind of practice, it is essential to be sensitive to diversity Multicultural competence is an ethical imperative Develop a good understanding of our patient’s social, cultural, spiritual, s...

Ethical Issues and Best Practices in Psychopharmacology PRACTICING ETHICALLY In any kind of practice, it is essential to be sensitive to diversity Multicultural competence is an ethical imperative Develop a good understanding of our patient’s social, cultural, spiritual, sexual preference, and racial and ethnic backgrounds when interviewing, diagnosing and treatment planning. Consider all features that de ne a person in preparing them for pharmacotherapy A discrepancy between the practitioner’s style and patient’s assumptions may occur when a NP’s cultural background di ers from that of the patient Ex: highly expressive vs greater emotional restraint Beliefs and expectations Be aware of personal biases and decision-making style in challenging circumstances Consider how it is possible to misuse the power you have as a prescriber. Use an invitational style rather than a dictatorial style Self disclosure can be a positive experience but is not the main goal. Keep in mind prohibitions against self disclosure within certain ethnic and cultural groups Informed consent is not given in a single session but is an ongoing process. Maintaining con dentially is an important right and ethical issue. Prescribers need to frequently emphasize the importance and when it might be at risk ETHICAL QUESTIONS Is the risk of male cence greater when providers neglect to address psychopharmacological issues, including side e ects and noncompliance, during the counseling relationship? Should clients be informed of all available treatment methods, including psychopharmacology? When the diagnosis is not clear, the goals of treatment are not clear, or the practitioner is not con dent about what steps to take, consultation with someone with relevant expertise is prudent? PSYCHOTROPIC USE - DECISIONS Providers need to be mindful of subclinical pharmacotherapy The ethical practitioner should keep up-to-date with the e ects of somatic therapies, and their adverse e ects and contraindications Psychotropics should only be used when clearly indicated and there is a strong evidence base ETHICS CONT. Consider appropriateness of referrals—when, who, why Respect the client’s freedom of choice Right to refuse services and be advised of potential consequences and alternative treatments Inform client about possible side e ects, expected outcome, and follow up PSYCHOTROPIC USE - INFORMED CONSENT fi ff fi fi ff ff fi ff ff  The ethical practitioner should keep up-to-date with the e ects of somatic therapies, and their adverse e ects and contraindications Psychotropics should only be used when clearly indicated and there is a strong evidence base Ethical practitioners will have informed consent dialogues with their client SOCIAL DYNAMICS AND SOCIAL IDENTITIES CAN INFLUENCE MEDICATION MANAGEMENT Race Abilities Social Class Education Social Status Relational Equality Sexual Orientation Patriarchy Nation of Origin Family Dynamics Migration Power Dynamics Region E ects of Social Systems Gender Politics Age Capitalism Religion Social welfare MULTIPLE BELIEF SYSTEMS AFFECT MEDICATION ACCEPTANCE AND ADHERENCE Medical and therapeutic systems Religion Friends and family Media Self-help groups Alcohol and other substances New age beliefs Special foods Exotic substances Cultural remedies CULTURAL DIFFERENCES Attitudes about seeking help How roles and boundaries are perceived The importance of power in family relationships and therapy E ects of oppression and discrimination Class, Social Status, privilage, power systems, FACTORS INFLUENCING PERSONAL CHOICE OF TREATMENT Their experience of pain What they label as a symptom How they communicate about their pain or symptoms Their belief about its cause Their attitude toward helpers—nurses, doctors and therapists The treatment they desire or respect Responses to illness that di er from the dominate culture is likely to be labeled “abnormal” ASSUMPTIONS FOR PRACTICE ff ff ff ff ff  No one can ever fully understand another’s culture, but curiosity, humility and awareness of one’s own cultural values and history lead to sensitive interviewing and prescribing Clients from marginalized cultures may have internalized societies' prejudices about them—those from dominate cultural groups may internalize assumptions about their own superiority and right to be privileged in our society ETHICAL PRINCIPALS AND THEORIES ETHICAL PRINCIPALS: Autonomy Bene cence Nonmale cence Fidelity Justice Paternalism ETHICAL THEORIES: Ethical Relativism Feminist Theory Deontology Utilitarianism APPLICATION OF THE CODE OF ETHICS FOR NURSING PMHNPs provide care for the most vulnerable in society Face unique ethical dilemmas Nine provisions of the code of ethics for nurses include; Fundamental values and commitments Boundaries of loyalty and duty Duties beyond individual encounters with patients and health care consumers CODE OF ETHICS PROVISIONS 1. Respect for the Individual 2. Commitment to the Patient 3. Advocacy for the Health Care Consumer 4. Responsibility and Accountability for Practice 5. Duty to Self and Others 6. Contributions to Health Care Environments 7. Advancement of the Nursing Profession 8. Collaboration to Meet Health Needs 9. Promotion of the Nursing Profession PROVISIONS 1. Respect for the Individual—Compassion, instilling hope, advocate to overcome negative attitudes and beliefs related to PMH disorders 2. Commitment to the Patient—whether individual, family, group, community or population, awareness of boundary issues, balance human rights with safety and potential need for restrictive measures fi fi 3. Advocacy for the Health Care Consumer—promotes, advocates for and protects the rights and safety of the patient, monitors and carefully manages con dentiality, therapeutic self-disclosure and professional boundaries through all forms of interaction, understands the relationship between nurse and mental health patient is unbalanced 4. Responsibility and Accountability for Practice—authority, health promotion and patient care decision making, awareness of roles and scope of practice of other health care disciplines, able to articulate and demonstrate competence within own scope of practice 5. Duty to Self and Others—accord moral worth, respect and dignity to all human beings and self, preserve integrity, maintain competence and continue personal and professional growth with a commitment to practicing self-care 6. Contributions to Health Care Environments—recognize distress in the workplace, ethical obligation to report peer observations or concerns, moral obligation to help address problems faced by colleagues suggestive of mental distress and/or substance abuse 7. Advancement of the Nursing Profession—ethical obligation to be knowledgeable of evidence-based practice guidelines and apply them, seek continuing education and participate in health-related civic activities at all levels, provide mentoring to others and receive mentoring to continue growth 8. Collaboration to Meet Health Needs—collaborate with other nursing specialties, other health professionals, government agencies (SAMAHA, NIH), larger nursing community (APNA,ISPN), state and public to promote individual and social health and reduce disparities, address social determinates of health, bring attention to human rights violations and preserve rights of vulnerable populations 9. Promotion of the Nursing Profession—collectively articulate values, maintain integrity and integrate principals of social justice PHARMACOGENOMICS— And Psychiatric Medications PHARMACOGENOMICS: Pharmacogenomics is de ned as the study of how a person’s individual DNA a ects their response to medications Pharmacogenomics uses information about a person’s genetic makeup, or genome, to choose the drugs and drug doses that are likely to work best for that person. Pharmacogenomics is a “tool” to provide clinicians with personalized medication selection for each individual. PHARMACOKINETICS AND PHARMACODYNAMICS Pharmacokenetics—how much drug is in the system How the body a ects the drug Polymorphisms in pharmacokinetic (PK) genes (e.g. CYP450) can a ect drug blood levels Pharmacodynamics—how is the drug working when it gets to its target How the drug a ects the body Polymorphisms in pharmacodynamic (PD) genes can a ect drug action at its target (e.g. receptor binding). ff ff fi ff ff fi ff  GENES AND ALLELES A gene is a sequence of DNA that codes for a protein. An “allele” is the term that refers to the di erent versions of a gene. In most cases, we randomly inherit one copy of each gene from each parent. The combination of alleles (genotype) that we receive creates a certain physical presentation (phenotype). POLYMORPHISM The occurrence of two or more clearly di erent morphs or forms Polymorphism occurs when there are two or more possibilities of a trait on a gene THE CYP450 SYSTEM The CYP450 system is a family of about 57 enzymes responsible for drug metabolism, primarily in the liver. Multiple enzymes may be involved in the metabolism of a given drug. Family—P4501, P4502 Subfamily—P4501A, P4502D Single Gene or Protein P4501A2, P4502D6 P450 ENZYME ALLELES Variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities Variations contribute to alterations in drug clearance and impact patients' response to drug therapy CYP isoenzymes metabolize most of structurally diverse drugs and chemicals Individuals with unusual genes for these enzymes may experience diminished e cacy or increased toxicity in response to certain drugs Di erent levels of activities are associated with variant genotypes The frequency of variant alleles for drug-metabolizing enzymes often di ers among ethnic groups PHARMACOKINETICS AND PHARMACODYNAMICS Genes used for clinical pharmacogenetics are broken down into two groups: 1)Pharmacokinetics (i.e. “how much drug is in the system”) 2)Pharmacodynamics (i.e. how is the drug working when it gets to its target) ff ff ff ff ffi  Then walk them through this diagram from a medication being ingested to its clinical response and potential toxicity. Using di erent delivery mechanisms (e.g. IM, transdermal) does not compensate for variations in pharmacokinetic systems. While these mechanisms avoid rst pass metabolism, the medication will still eventually be metabolized in the liver. There are a number of well-studied genes in both groups. CYP450 METABOLIZER PHENOTYPES This is a summary slide of the data presented above. The key takeaway here is the phenotype frequency. Less than half of individuals are extensive metabolizers. A clinician can expect roughly 10% of his/her population to be poor metabolizers and 10% will be ultrarapid metabolizers. This means that 1 in 5 (20%) of his/her population may be signi cantly impacted by their CYP2D6 status. And this is only one gene of many that is important for medication selection/dosing. How does one know whether a patient is a poor or ultrarapid metabolizer other than to test them? Extensive : Designation given to an individual with the wild type or “normal” phenotype. Will metabolize a drug as desired Ultra Rapid : Designation given to an individual with increased expression of a metabolizing enzyme. Will metabolize a drug at a rapid rate, potentially unable to receive therapeutic serum levels of the medication. Intermediate : Designation given to an individual who possesses one semi-functional or non- functional allele coding for a metabolizing enzyme. Will metabolize a drug, but at a reduced rate Poor : Designation given to an individual with decreased or no expression of a metabolizing enzyme. Will metabolize a drug very slowly or not at all All of this variations in phenotype can make dosing and management of medications increasingly di cult. Given the prevalence of variation across multiple genes, putting all of this information together for one patient and all potential medications that patient may be tried on can get complex very quickly. One must have a thorough knowledge of the often multiple enzymes involved in each medication, the mechanism of action of each medication, and the genetic variation present in each of these genes. In fact, there are 1,728 possible combinations of the phenotypes from the 6 genes tested by GeneSight Psychotropic. fi ffi ff fi KEY PHARMACOGENOMIC GENES Analgesic Psychotropic ADHD MTHFR Pharmacokinetic Pharmacokinetic Pharmacokinetic Pharmacokinetic (PK) (PK) (PK) (PK) CYP2D6 CYP2D6 MTHFR CYP2D6 CYP2C19 (methyltetrahydro CYP2C19 CYP1A2 CYP2C9 CYP2B6 CYP1A2 CYP3A4 CYP2B6 CYP3A4 Pharmacodynamic (PD) Pharmacodynamic (PD) OPRM1 SLC6A4 (μ-opioid receptor) (serotonin transporter) 5HTR2A (serotonin 2A receptor) An introduction to the three GeneSight products. The key takeaway is that the products are personalized for the drug classes designed to treat each condition. For example, our antidepressant panel focuses on genes in the serotonin pathway, while the ADHD panel focuses on dopaminergic and noradrenergic genes. Transition: Let’s talk about the impact of genetic variation on these medications starting with the system that all share: liver metabolism. CYP2D6 A highly variable gene with 17 common, clinically relevant polymorphisms. Located at a site on chromosome 22. Duplications can occur. CYP2D6 is one of the most important liver enzymes and highly variable between individuals. It will be used as a model for the other CYP450 enzymes that work much in the same way. As discussed previously, this is a gene where gene duplications can occur so individuals may have more than the normal two copies of the gene.  Extensive Metabolizer Phenotype CYP2D6 EXPRESSION & PHENOTYPE An individual with two normally functioning copies of CYP2D6 is known as an extensive metabolizer. This term is often confused with ultrarapid, so emphasize that, in the case of the CYP450 genes, extensive is the “normal” phenotype. Individuals with one “good” copy and one “bad” copy of a gene are considered “intermediate” metabolizers. These individuals retain CYP2D6 function, but at a reduced capacity. In the example shown, the individual has one normal copy and one gene deletion, resulting in 50% of normal enzyme function. The individual may still be able to metabolize CYP2D6 substrates, but may need lower doses. Drug-drug interactions are of greater concern in these individuals due to their already compromised metabolic capacity. Genetic polymorphisms can also result in partially functional enzymes that create the intermediate metabolizer phenotype. Using the factory analogy, these individuals have the normal two factories but they are running at less than 100% capacity. Poor metabolizers are individuals with little to no enzyme function. This can be the result of gene deletions or alleles that produce nonfunctional enzymes (e.g. *4). As we will see, these individuals will have signi cant problems metabolizing CYP2D6 substrates. Signi cant dose adjustments or alternative therapies are likely necessary. The principles of Mendelian inheritance teach that these chromosomes are inherited independently, which means that there are a number of possible combinations of two alleles, based on which alleles the parents possess. This can result in a wide range of liver function. To simplify matters, researchers have collapsed these genotypic realities into “buckets” based on the ultimate result on liver function. The diagram here shows an individual with one normal chromosome and one chromosome that contains three copies of CYP2D6. This will result in twice the amount of CYP2D6 enzyme in the system, leading to an ultrarapid metabolizer phenotype. In the factory analogy, this individual has double the number of factories, each working at 100% capacity. Some genetic polymorphisms can increase the mRNA transcription rates, so even though the individual has the typical two copies of the gene, they are each working at above 100% capacity. This can also produce the ultrarapid metabolizer phenotype. fi fi THE FDA AND PHARMACOGENOMICS THE SEROTONIN TRANSPORTER The SLC6A4 promoter has two main variants: short (S) and long (L) The two variants are di erentiated by a 44 base pair insertion/deletion The short allele results in lower transcription rates, providing less active sites for SSRIs. The short allele is associated with lower rates of remission following SSRI treatment The promoter region is the “on/o switch” of the gene. It tells the gene to transcribe more or less mRNA. The 44bp deletion causes lower transcription rates, resulting in fewer transporters on the presynaptic neuron. This genotype is associated with lower response rates. It is not necessary to relate the following information, but some audience members may ask why S/S individuals respond less well to SSRIs, since the e ect of this genotype is similar to SSRIs (i.e. more serotonin in the synapse). Possible explanations may include less active sites for SSRIs, and down regulation of serotonin receptors due to more available serotonin. PHARMACODYNAMIC PHARMACOGENOMICS Serotonin Transporter (SLC6A4) The serotonin transporter is encoded by the SLC6A4 gene. It is responsible for reuptake of serotonin into the presynaptic neuron. Selective serotonin reuptake inhibitors (SSRIs) inhibit this process, allowing for more serotonin in the synaptic cleft. ff ff ff  ATOMOXETINE Atomoxetine (Strattera) is metabolized by CYP2D6. UMs are likely to experience reduced e cacy. PMs are have been shown to have higher rates of adverse events. FDA labeling information highlights this risk in CYP2D6 poor metabolizers and recommends dosing adjustment. THE FDA AND ATOMOXETINE “Poor metabolizers of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of Strattera compared with EMs… Laboratory tests are available to identify CYP2D6 PMs… The higher blood levels in PMs lead to a higher rate of some adverse effects of Strattera.” “In …CYP2D6 PMs, Strattera should be initiated at 0.5 mg/kg/day and only increased to the These are direct quotes from usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.” the atomoxetine package insert, showing the impact of CYP2D6 on atomoxetine levels, and provides speci c dosing information for patients known to be CYP2D6 poor metabolizers. CATECHOL-O-METHYL TRANSFERASE Catechol-O-methyltransferase (COMT) breaks down both norepinephrine and dopamine in the synapse COMT gene has a polymorphism (Val158Met) that results in an amino acid change – methionine (met) for valine (val) at codon 158 Met/Met homozygotes have 4-5x less COMT activity1 Met/Met carriers showed a reduced rate of response to stimulant medications2 Neurotransmitters that are released into the synapse are either recycled by transporters or degraded. Catechol-o-methyltransferase is an extracellular enzyme that degrades the catecholamines. A single SNP results in an amino acid substitution of a methionine for a valine at codon 158 in the amino acid chain. This results in signi cantly reduced activity of the enzyme. It’s been shown that Met/Met carriers show a reduced rate of response to stimulants as a result. Given the prevalence of variation across multiple genes, putting all this information together for one patient and all potential medications that patient may be tried on can get complex very quickly One must have a thorough knowledge of the often-multiple enzymes involved in each medication, the mechanism of action of each medication, and the genetic variation present in each of these genes fi ffi fi  Principles of Psychopharmacology PHARMACOKINETICS ▪ Time course of a drug ▪ Absorption ▪ Distribution ▪ Metabolism ▪ Excretion ▪ Drug transport to & from receptors ▪ What the body does to the drug PHARMACODYNAMICS ▪ Relationships between drug concentrations & responses ▪ Drug activity at receptors ▪ What the drug does to the body ABSORPTION & FIRST PASS METABOLISM Bioavailability = % of oral dose reaching circulation as compared to IV (F = % after absorption & rst pass metabolism, < 2% for p.o. asenapine) Amount a ected by Food ↑ ziprasidone, lurasidone, vilazodone absorption ↓ nefazodone absorption Enteric / hepatic metabolism Tyramine – MAO / Terfenadine - CYP3A4 Speed a ected by Enteric motility (↑ with metoclopramide, ↓ with TCAs) Formulation (solution > suspension > capsule > tab > enteric coated tab) EXCRETION Rate = ltration + secretion – reabsorption Filtration (glomerulus) A ected by binding interactions ↓ in renal disease Secretion (proximal tubule) Drugs compete for active transport Reabsorption (proximal > distal tubule) Passive (high for lipophilic drugs) Thiazides →↑ Li & Na reabsorption Acidifying urine →↓ base reabsorption ff fi ff ff fi  CYP 450 Overview SITE Present throughout the body Act primarily in the ER of the hepatocytes and the cells of the intestine Conditions that cause viral hepatitis or cirrhosis will a ect the e ciency of drug metabolism by the CYP enzymes P450 IN HUMANS Human CYPs are primarily membrane associated proteins located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells Some CYPs metabolize only one (or a very few) substrates, while others may metabolize multiple substrates Humans have 57 genes, and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 44 subfamilies DRUG METABOLISM CYP enzymes account for 75% of drug metabolism Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYPs to form their active compounds DRUG INTERACTION Many drugs may increase or decrease the activity of various CYP isozymes Inducing the biosynthesis of an isozyme (enzyme induction) Directly inhibiting the activity of the CYP (enzyme inhibition) This is a major source of adverse drug interactions If one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the CYP system Drug interactions are especially important when using drugs of vital importance to the patient, drugs with important side-e ects and drugs with small therapeutic windows DEFINITION: INDUCTION Induction is de ned as an increase in the amount and activity of a metabolizing enzyme CONSEQUENCES OF INDUCTION THERAPEUTIC IMPLICATIONS OF INDUCTION Most drugs can exhibit decreased e cacy due to rapid metabolism but drugs with active metabolites can display increased drug e ect and/or toxicity due to enzyme induction Dosing rates may need to be increased to maintain e ective plasma concentrations fi ff ff ffi ff ff ffi DEFINITION: INHIBITION Enzyme inhibition decreases the rate of drug metabolism, thereby increasing the systemic exposure of a substrate drug, leading to an increased propensity for side e ects and potential toxicity. CONSEQUENCES OF INHIBITION GENETIC VARIATION AND ITS IMPLICATION Wide variability in the response to drugs between individuals Consequences of such variation may be therapeutic failure Increase in the Reduction in or an adverse drug reaction plasma metabolite Genetic diversity is the rule rather than the exception with all concentration concentration of parent drug proteins, including drug metabolizing enzymes Exaggerated Increased and prolonged likelihood of pharmacologic drug-induced al effects toxicity CYP2D6 CYP2D6 is extensively studied, the gene for CYP2D6 is highly polymorphic Its expression leads to 3 phenotypes (phenotype is the expression of genetic make-up) Extensive metabolizers (EMs) have functional enzyme activity Intermediate metabolizers (IMs) have diminished enzyme activity Poor metabolizers (PMs) have little or no activity 5-10% of Caucasians 1-2% of Asians exhibit the PM phenotype CONCEPTS Substrate - An agent that is metabolized by an enzyme into a metabolic end product and eventually excreted Inhibitor - An agent which interferes with the ability of a given enzyme to metabolize a given substrate Competitive inhibition occurs when molecules very similar to the substrate molecules bind to the active site and prevent binding of the actual substrate. Allosteric inhibition is the slowing down of enzyme-catalzyed chemical reactions that occur in cells This leads to RAPID increase in levels of the substrate. Inducer - An agent which causes an increase in the production of the enzyme(s) responsible for metabolizing a given substrate. Leads to GRADUAL (1-3 weeks) decrease in blood level of substrate. ff  DRUG-DRUG INTERACTION PATTERNS Pattern 1 - An inhibitor is added to a substrate. Example: Paroxetine is added to nortriptyline, leading to an increase in the nortriptyline blood level. Pattern 2 - A substrate is added to an inhibitor. Example: Nortriptyline is added to paroxetine, leading to a higher-than-expected blood level of nortriptyline at a given dose. Pattern 3 : An inducer is added to a substrate. Example: Carbamazepine is added to haloperidol, leading to a decrease in the haloperidol blood level. Pattern 4: A substrate is added to an inducer. Example: Haloperidol is added to carbamazepine leading to a lower-than-expected blood level of haloperidol at a given dose. Pattern 5 : Reversal of inhibition. An inhibitor and a substrate have been stably co-- administered and then the inhibitor is discontinued. Example: Cimetidine is discontinued in the presence of nortriptyline, leading to a decrease in the nortriptyline blood level. Pattern 6 : Reversal of induction. An inducer and a substrate have been stably co-administered and then the inducer is discontinued. Example: A patient on clozapine abruptly discontinues smoking, leading to an increase in the clozapine blood level. THE ENZYMES 3A4 2D6 1A2 2C9 2C19 2A1 1ª4 3A4: NOTABLE SUBSTRATES 3A4:NOTABLE INHIBITORS azole antifungals cipro oxacin/nor oxacin uoxetine/ uvoxamine grapefruit juice HIV protease inhibitors macrolide antibiotics (except azithromycin) methadone nefazodone fl fl fl fl  3A4: NOTABLE INDUCERS ‹carbamazepine moda nil oxcarbazepine phenobarbital ‹phenytoin ritonavir topiramate St. Johns Wort barbiturates 2D6: NOTABLE SUBSTRATES 2D6: NOTABLE INHIBITORS cimetidine bupropion duloxetine uoxetine paroXetine quinidine ritonavir sertraline (>150 mg/d) TCAs 2D6 No known inducers – possibly dexamethasone and/or rifampin 1A2 :NOTABLE SUBSTRATES ca eine (and theophylline) clozapine cyclobenzaprine olanzapine probably several other typical antipsychotics 1A2: NOTABLE INHIBITORS ca eine cimetidine uoroquinolones uvoxamine grapefruit juice 1A2:NOTABLE INDUCERS Cruciferous vegetables (broccoli, brussels sprouts, cauli ower) carbamazepine moda nil rifampin TOBACCO smoking fl fl fl ff ff fi fi fl  2C9: NOTABLE SUBSTRATES glipizide/glyburide phenytoin warfarin THC 2C9: NOTABLE INHIBITORS cimetidine uconazole uoxetine/ uvoxamine/paroxetine metronidazole moda nil ritonavir sulfamethoxazole valproate 2C9:NOTABLE INDUCERS carbamazepine phenobarbital phenytoin rifampin 2C19: NOTABLE SUBSTRATES diazepam phenytoin tertiary amine TCAs 2C19: NOTABLE INHIBITORS carbamazepine cimetidine disul ram uoxetine uvoxamine omeprazole sertraline ritonavir topiramate 2C19: NOTABLE INDUCERS (SAME AS 2C9) carbamazepine phenobarbital phenytoin rifampin fl fl fl fl fi fi fl