Adverse Drug-Drug Interactions and Corticosteroids in Dentistry PDF

Adverse Drug-Drug Interactions Dental Pharmacology DDS 6215 Dr. Dan Skaar [email protected] Agenda Adverse drug interaction (DI) clinical risk Adverse DI mechanisms Select potential DIs in dentistry Summary Importance of Considering Your Patients’ Rx Medications Polypharamcy – Adult Rx use (2011-2012) 59% with any Rx drug 15% with ≥ 5 Rx drugs – Adult (≥65 y/o) use (2011-2012) 90% with any Rx drug 39% with ≥ 5 Rx drugs JAMA 2015 Adverse DI Clinical Risk Little agreement among drug compendia – Lack of standard terminology or severity rating systems Lack of reliable and timely data – Under reporting by practitioners Clinical relevance Adverse DI Risk Dental Profession on Record “..limited number of drugs routinely used in dental therapeutics: antibiotics, local anesthetics and vasoconstrictors, analgesics and sedative/anxiolytics. Consequently, most dental practitioners have a thorough knowledge of the indications for, contraindications of and precautions for the drugs they routinely use.” Moore et al JADA 1999 Adverse DI Reporting Product Circular Zithromax® Product circular Information overload (?) Adverse DI Reporting FDA Characteristics of Drugs Commonly Involved in Adverse DIs Major CYP450 enzyme substrates, inducers or inhibitors High protein binding Chronic use Narrow therapeutic Index (TI) – Cardiovascular drugs Digoxin Warfarin – Misc. drugs Cyclosporine Lithium carbonate Methotrexate Phenytoin Adverse DI Mechanisms Absorption – Antibiotic-cation complexes (antacids, Fe supplements, dairy products) Tetracycline – Alter gastric pH and GI bacteria Antacids Proton pump inhibitors Adverse DI Mechanisms Distribution – Alter plasma protein binding of highly bound drugs (>90%) Highly protein bound – Warfarin – Phenytoin – Sulfonylureas (glybride) Displacing drugs – NSAIDs Clinical relevance (?) Albumin major drug binding sites Adverse DI Mechanisms Metabolism – CYP450 enzymes – Drugs acting as Substrates Inducers Inhibitors Elimination – Change urinary pH – Inhibit renal excretion NSAIDs-lithium (low TI) – P-glycoprotein efflux pump Clarithromycin inhibits efflux of digoxin Potential Adverse DIs Drugs in Dentistry Vasoconstrictors Analgesics Antibiotics Sedatives Vasoconstrictor Interactions DI Mechanism Epi -TCAs amitriptyline, nortriptyline imipramine Block reuptake of neurotransmitters and adrenergic vasopressors Potentiate CV actions of vasopressors Inconclusive evidence Use epi with caution smallest effective dose(3< carpules 1/100,000) Epi - ↑ release and block reuptake of norepi and dopamine; Intensify postsynaptic response ↑ bp, angina, hypertension, arrythmias Avoid vasoconstrictors < 24-48 hrs after ingestion Monitor bp and HR -cocaine -methamphetamine Effect Importance Analgesic Interactions DI Mechanism Effect NSAIDs- EtOH COX-1 inhibition and EtOH stimulates gastric acid secretion ↑ risk of GI mucosa damage and bleeding Avoid EtOH consumption for 12 hrs Higher risk > 3 drinks daily NSAIDs-ACEIs, diuretics, Block renal PG ß-blockers vasodilation, Na+ and H2o retention mechanisms ↓ bp lowering effect Inconclusive Prescribe for < 5 days (exception may be elderly and severe CHF) NSAID ulcer gastric antrum Gastrolab Importance Analgesic Interactions DI Mechanism Effect Importance NSAIDs or ASA- warfarin GI mucosal damage; ↑ bleeding risk Platelet inhibition; CYP2C9 substrates; Protein displacement Avoid NSAIDs- SSRIs -citalopram (Celexa®) -sertraline (Zoloft®) -escitalopram(Lexapro®) Inhibit COX-1 and serotonin reuptake; Inhibit CYP2C9 NSAID GI mucosal damage Inhibit platelet aggregation and ↑ bleeding riskupper GI and post-op Short-term NSAID use low risk NSAIDs- low dose ASA Competitive COX-1 blocking ↓ ASA antiplatelet activity Avoid concomitant useNSAID > 8 hrs before or >30 min after ASA dose Studies needed Antibiotic Interactions DI Mechanism Effect Importance Tetracyclines- dairy products, -antacids, -vitamins Chelate di- and trivalent cations (Ca++, Fe++) ↓ absorption Doxycycline, minocycline not as affected Avoid Metronidazole- lithium ↓ renal excretion ↑ lithium plasma levels (low TI) Case reports Avoid Metronidazole- alcohol Inhibit acetaldehyde dehydrogenase → ↑ acetaldehyde Disulfiram rxnheadache, nausea Possible effect Avoid Antibiotic Interactions DI Mechanism Effect Importance Amoxicillin- warfarin Alter GI flora → ↓ vitamin K ↑ anticoagulation Inconclusive, Monitor Azithromycin- digoxin Clarithromycin- digoxin ↓ GI flora metabolism, ↑ digoxin plasma Inhibit p-glycoprotein levels (low TI) Case reports Avoid Antibiotics- OCs Alter GI flora Contraceptive failure (rifampin) Lack of studies Warn and recommend alternative methods ↓ enterohepatic recirculation of estrogens Anxiolytic Interactions DI Mechanism Effect Importance Benzodiazepines- CNS depressants Diazepam (Valium®) -alcohol ® Triazolam (Halcion ) -opioids Lorazepam (Ativan®) -antihistamines Alprazolam (Xanax®) Midazolam (Versed®) Additive depression Excessive sedation, respiratory depression Adjust dose, monitor, avoid ↑ sedation effect Use caution or avoid Benzodiazepines- -macrolide antibiotics Inhibit -protease inhibitors CYP3A4 metabolism Summary Severe adverse DIs rare for drugs prescribed in dentistry – Drugs in single doses or for short durations Longer duration therapies ↑ risk – Large margins for safety (wide TI) – Elective dental procedures can be postponed Prescribing decisions should account for potential drug interactions Corticosteroids— Systemic and Topical Dental Pharmacology DDS 6215 Reference: Pharmacology and Therapeutics for Dentistry Dowd et al., 2017 edition Chapters 30 Dr. Jill Siegfried [email protected] Outline Review Adrenal gland anatomy and physiology Corticosteroid regulation Corticosteroid physiologic actions Glucocorticoid drugs Glucocorticoids in dentistry Adrenal Gland Anatomy Located in the Extraperitoneal Space – Upper poles of each kidney Review: Adrenal Gland Regulation HPA axis: CRF/ACTH Adrenal cortex – Mineralocorticoid Aldosterone + and Feedback loops – Regulates salt and water balance (prior lecture) – Glucocorticoid Cortisol – Daily and stress secretion – Controls glucose, protein, lipid metabolism – Reduces inflammation – Heightens awareness – Androgen precursors Pharmacology 5th Ed LWW Review Cortisol Regulation Corticosteroid secretion (- and +) feedback loops Pharmacology 5th Ed LWW – Circadian release: highest in the morning – Limited Corticosteroid storage—need for functioning HPA axis – Necessary to respond to stress or changing temperatures and food availability Cortisol Regulation by three Mechanisms – CRF/ACTH via HPA axis Negative feedback loop controlled by circulating cortisol – CRF induced by Stress (physiologic and psychologic, neural signaling), increases ACTH – CRF/ACTH induced by inflammatory mediators from immune cells (interleukins like IL1, IL2, IL6) Corticosteriod Synthesis: Conversion from Cholesterol by CYP450 enzymes Chemically equivalent Glucocorticoid (cortisol) Physiologic Actions Complex and diverse actions – Cardiovascular: raises blood pressure – Anti-inflammatory and suppresses immune cell functions – Metabolic: mobilizes glucose from peripheral organs to make available to the brain and heart – Reduces bone and muscle formation Production abnormalities (covered previously) Excess cortisol – Cushing’s Syndrome Insufficient cortisol – Addison’s Disease Corticosteroid Metabolic Actions “Anti-insulin” effect Increases plasma glucose levels and gluconeogenesis Protein and fat catabolism Effect is to make amino acids and lipids available as sources of glucose production. This increases capacity for energy production in the brain and heart in response to stressors like cold temperatures. Glucocorticoid Cardiovascular Actions Increase blood pressure – Increase Na+ and water retention – Decrease glomerular filtration (GFR) – Constriction of blood vessels Indirect action: increase mineralocorticoid receptor numbers Direct activation: Glucocorticoid receptor (GR) found on blood vessels and cortisol activates mineralocorticoid receptors (shared structure with the GR) Corticosteroid Immune System Actions Anti-inflammatory – Reduces circulating lymphocytes, monocytes, eosinophils and basophils – Reduces chemotaxis of inflammatory cells – Reduces histamine release from mast cells – Suppresses cytokine and chemokine release Immunosuppressive – Decreases cytotoxic T cell lymphocyte proliferation Glucocorticoid Drugs Clinical Indications Epidemiology – ~5% of US adults chronically use corticosteroids Indications – Anti-inflammatory/ immune suppression – Cancer and organ transplantation – Replacement/ insufficiency – Primary: destruction of adrenal gland – Secondary: shut down of cortisol production Glucocorticoid Clinical Indications Anti-inflammatory – Pulmonary diseases Asthma/allergy – Rheumatic diseases Arthritis – Dermatologic diseases – Psoriasis – GI diseases – Colitis/Crohn’s Immunosuppressant – Organ transplants – Autoimmune diseases Lupus, Multiple Sclerosis Dowd Ch. 30 has extensive list of conditions treated with corticosteroids Glucocorticoid Clinical Indications Adrenal Insufficiency (AI) Primary – Adrenal cortex destruction Autoimmune and infection Addison’s disease – Reduces glucocorticoid and aldosterone levels Secondary – Hypothalamus and pituitary gland release no CRF/ACTH – Due to the normal negative feedback loop Induced by chronic use of exogenous corticosteroids 20-30 mg hydrocortisone (or equivalent) for 4 or more weeks Clinical Indications Adrenal Insufficiency → Crisis Medical emergency – Stress response – Due to lack of ACTH – Rare in dentistry Clinical manifestation - Response to acute illness, trauma, pain, anxiety, blood loss, surgery - Body’s demand for cortisol is not met Exacerbated symptoms – – – – – Weakness and fatigue Nausea and vomiting Severe hypotension Hypothermia Shock and cardiac arrest Medical management IV glucocorticoid, electrolytes, glucose, vasopressors Glucocorticoid Drugs MOA – Genomic actions Translocation into cell nuclei – Target gene expression – Timing is hours – Nongenomic actions Direct glucocorticoid receptor (GR) interactions – Rapid response – E.g. blood pressure Prednisone Glucocorticoid Drugs Dosage forms – Oral tablets and suspensions – Topical – IV, IM Dosing – Every other day in the A.M. mimics circadian cycle – Minimizes HPA axis suppression Glucocorticoid Drugs Absorption – Oral, mucous membranes and eye Distribution – Plasma protein binding carries corticosteroids throughout the circulation Metabolism – Liver conjugation and excretion in urine – Cortisol rapidly excreted Biologic t1/2 range 8 to 72 hrs. for cortisol analogs Properties of Glucocorticoid Drugs Compound AntiNa+inflammatory Retaining Potency* Potency* Halflife** (hrs) Duration of Action Formulation Hydrocortisone 1 1 8-12 short Oral tablet, Topical cream Prednisone 4 0.8 12-36 intermediate Oral tablet Prednisolone 4 0.8 12-36 intermediate Oral tablet Hydrocortisone acetate 1 1 8-12 short Topical paste Triamcinolone acetonide 5 0 12-36 intermediate Topical paste Dexamethasone 25 0 36-72 long Oral tablet *relative to hydrocortisone **biologic (suppression of HPA) Various other preparations are available for IV, IM, and intraarticular dosing Glucocorticoid Drugs General Adverse Effects – – – – – – – Infection resistance Muscle wasting GI: ulcers and hemorrhage Psychiatric: insomnia, agitation, mania Osteoporosis Acne and thinning mucosa Serious AEs Short-term use? More common with high intensity or long-term use Glucocorticoid Drugs Used for Dental Conditions Oral Ulcerations Topical pastes that adhere Carboxymethylcellulose resin (Orabase) Triancinolone acetonide or Hydrocortisone acetate Continuous exposure Lessen post-procedure sequelae Reduce edema and trismus Temporomandibular joint disorders (severe) Prednisolone or dexamethasone injected into the joint (intra-articular) Glucocorticoid Drug Use by Dental Patients Clinical implications – Decreased infection resistance – Candidiasis – Poorer wound healing – Friable mucosa (inflamed and prone to bleeding) – Mucosal atrophy – Suppression of HPA and dental stressors – Long-term use Management for Dental Patients taking Corticosteroids Pre-operative Patient evaluation Procedure type and duration Appt timing: morning Manage dental “stressors” with sedatives, general or local anesthesia, pain relief Monitor bp Supplementation if needed Medical consultation Post-operative Monitor – Wound healing – Infection – Candidiasis Medication prescribing – Analgesics – Antibiotics Glucocorticoid Supplementation for Dental Patients Guideline evolution – No standard of care Dosing and tapering post procedure Low risk of acute adrenal insufficiency – Consults needed before supplementation Routine nonsurgical procedures (negligible risk) – Daily dose Invasive/surgical procedures – Minor procedures (mild risk) Daily therapeutic dose to range of ~25 mg hydrocortisone Double usual dose day of procedure – Moderate and major procedures (higher risk) Double usual dose to range of ~ 50-150 mg hydrocortisone Day of and one to three days after Concepts and Drugs to Remember HPA: Hypothalamic-Pituitary Axis regulates hormone production in the adrenal gland ACTH: pituitary hormone that induces cortisol and aldosterone -induced by stress and by inflammatory mediators such as interleukins Cortisol: glucocorticoid produced in the adrenal medulla; required to respond to changes in the environment such as temperature, food availability, and stress; diurnal Aldosterone: mineralocorticoid produced in the adrenal medulla; regulates salt and water retention Major Actions of Cortisol: Controls glucose, protein, lipid metabolism, blocks inflammation, and heightens awareness. Overall effect is to break down protein and fat and produce more glucose. Also increases blood pressure. Major Corticosteroid Drugs: Hydrocortisone (equivalent of cortisol), Prednisone, Prednisolone, Triamcinolone acetonide, Dexamethasone Major Medical Uses: inflammatory conditions, autoimmune diseases, adrenal insufficiency, cancer, organ transplant Major Dental Uses: oral ulcerations, temporomandibular joint disorders, postoperative care, prevention of adrenal insufficiency Cushing’s Syndrome: overproduction of cortisol; Addison’s Disease: lack of cortisol Primary Adrenal Insufficiency: due to destruction of the adrenal glands Secondary Adrenal Insufficiency: shut down of HPA leads to no ACTH, no cortisol made Adrenal Crisis: Know the risks, symptoms, and treatment Practice Questions 1. Which of the following statements is FALSE about cortisol and/or its analogs: a. It increases gluconeogenesis b. Circulating levels show diurnal variation c. Cortisol has both genomic and nongenomic actions d. Long-term pharmacological use can lead to over-production of ACTH 2. Which of the following strategies would be best used to treat adrenal insufficiency in a patient prone to dental anxiety, currently taking a high dose corticosteroid, who is undergoing a major surgical dental procedure? Medical consultation has indicated a risk of an adrenal crisis. a. Avoid all corticosteroids to bring ACTH levels up b. Reduce dose of corticosteroid before the procedure c. Schedule the appointment for late afternoon d. Increase the dose of corticosteroid prior to surgery and taper a few days after the procedure Practice Questions 3. Which corticosteroid has the highest potency? a. Prednisone b. Hydrocortisone c. Dexamethasone d. Prednisolone 4. For which of the following conditions would a corticosteroid likely be prescribed? a. Cushing’s Syndrome b. Lupus c. Hypertension d. Osteoporosis Answers 1. 2. 3. 4. D D C B Anti-neoplastic and immune system activating drugs for cancer JILL SIEGFRIED, PHD DDS 6215 SPRING SEMESTER I have no conflicts of interest for this lecture; any mention of trade names is for educational purposes only Textbook: Dowd 2017 edition Chapter 36 OUTLINE Overview of cancer as a disease Strategies for cancer treatment Major Cancer Drug Classes Examples of Drugs from each Class Note: Dowd chapter 36 is very detailed, only drugs discussed in the lecture will be test material Oral Complications of Cancer Therapy Cancers of the Oral Cavity Practice Questions to go over on your own US Cancer statistics 1.7 million annual cases CA: A Cancer Journal for Clinicians,Volume: 68, Issue: 1, Pages: 7-30, First published: 04 January 2018, DOI: (10.3322/caac.21442) CURRENT TREATMENT OF CANCER - SURGERY, RADIATION, AND DRUG THERAPY SURGICAL REMOVAL FOLLOWED BY RADIATION IS COMMONLY USED, WITH LATER DRUG THERAPY DETECTION AND CURE DETECTION Even with the most sensitive diagnostic methods, at the time of diagnosis there will be 107 – 109 neoplastic cells present. Goal is to eliminate every cell! REMISSION A patient is ‘in remission’ when the number of cancer cells is below detectable levels. CURE A cancer is ‘cured’ when neoplastic cells cannot be detected and the patient is in remission for five years after completion of therapy. CANCER IS NOT A SINGLE DISEASE BUT A LARGE FAMILY OF DISEASES Carcinogenesis (Transformation) The process by which a normal cell is transformed into a cancer cell. It requires multiple mutations (genetic alterations) and can have a long latency period. Some mutations are drivers of specific types of cancers (like BRCA1 and BRCA2 in breast cancer), others are more general, like p53 (mutated in about 40% of all cancers). Types of Cancer Carcinoma - cancer arising from the epithelial cells Sarcoma - cancer arising from connective tissue Leukemia/Lymphoma/Myeloma - cancer arising from hemopoietic cells or immune cells ONCOGENES - Up-regulation or gain-of-function mutation of an oncogene induces transformation. - Initially identified as viral genes. Viruses that cause cancer carry a mutated version of a human oncogene. - Oncogenes are involved in promoting normal cellular function and growth. -However, gain-of-function mutations or over-expression through gene amplification of oncogenes causes cancer. Example: KRAS, involved in signaling from growth factor receptors. When mutated, becomes unregulated and over-stimulates growth. TUMOR SUPPRESSOR GENES - Loss-of-function mutations in these genes induce transformation. These genes normally are a brake on cell growth and loss of function removes the brake. Example: p53, involved in stopping a cell from entering DNA replication. SIX BASIC HALLMARKS OF CANCER TRAITS OR ‘HALLMARKS’ THAT GOVERN THE TRANSFORMATION OF NORMAL CELLS TO CANCER (MALIGNANT OR TUMOR) CELLS Imbalance in ratio of cells dividing vs. cells undergoing programmed cell death (apoptosis) “A wound that does not heal” Moving throughout body Creates new blood supply Telomeres (ends of chromosomes) don’t shorten Hanahan and Weinberg, Cell 100 (2000) 57–70 Cells die through an orderly process DNA damage Loss of growth signals Loss of oxygen supply Loss of nutrients Damaged cell goes through programmed cell death (apoptosis) Drugs target cancer by attacking the Cancer Hallmarks Blocking proliferative pathways 1. Antimetabolites and Platinum Agents shut down DNA Synthesis (S Phase of cell cycle) 2. Taxanes inhibit Mitosis (M phase of cell cycle) 3. Tyrosine Kinase Inhibitors block Growth Signals (G1 Phase of cell cycle) Blocking formation of new blood vessels Angiogenesis Inhibitors prevent tumors from increasing their blood supply Major Drug Classes for Cancer Therapy Chemotherapy Targeted Therapy Immunotherapy General toxicity to dividing cells Specific molecular targets in tumor cells Activates the normal immune system so it can reject cancer cells Cytotoxic Cytotoxic and cytostatic Neither cytotoxic not cytostatic More universal side effects among agents Side effects specific to the molecular targets Side effects due to over-activation of the immune system Often these drugs are given in combination, or sequentially, with cycles of therapy over time. Timing of cycles and intervals between cycles is designed to obtain maximal growth suppression of cancer cells while allowing normal tissues to recover from side effects. CANCER CHEMOTHERAPY: GOAL IS TO ERADICATE EVERY TUMOR CELL BUT WITHOUT DAMAGING NORMAL CELLS These drugs kill any cell that is dividing! Chemotherapy drugs exploit the fact that cancer cells are growing faster than normal cells (lack of selectivity). Chemotherapy drugs are often both cytotoxic and mutagenic (causes side effects). Side effects are most noticeable in faster dividing tissue, such as hair follicles, GI tract, and bone marrow, causing hair loss, nausea, and low white cell counts. Principal systematic adverse effects include: Bone marrow suppression and immune deficiency Susceptibility to additional cancers, especially blood cancers Elective dental treatments are not recommended during chemotherapy. Example of an Antimetabolite Chemotherapeutic METHOTREXATE (MTX): POISONS THE ENZYME DIHYDROFOLATE REDUCTASE (DHFR) Resembles folate (FH2) and competes for the enzyme’s active site. Blocks the production of tetra-hyrofolate (FH4), an essential cofactor for enzyme activity. Prevents purine (adenine and guanine) synthesis needed to form new RNA and DNA and thymidine synthesis needed to form new DNA. Commonly used for breast cancer, leukemia, lymphoma, bladder, and head and neck cancer. EXAMPLES OF CHEMOTHERAPEUTIC DRUGS PLATINUM AGENTS MECHANISM The platinum coordination complexes are DNA damaging agents because they and highly charged and react chemically with guanine to crosslink DNA This results in blocking of DNA polymerases at the cross-links, so DNA synthesis (replication) is halted. When the cell cannot divide, and cancer cells undergo programmed cell death (apoptosis). Nature Reviews Drug Discovery 4 (2005) 307-320 CLINICAL USE These drugs are often used to treat the testicles, bladder, ovaries, or lung cancers. CISPLATIN - the prototype of platinum coordination complexes Brand name: Platinol Chemical structure Taxane Chemotherapy Drugs Example: Docetaxel Brand name: Taxotere STRUCTURE Complex rings CLINICAL USE Often used for the treatment of ovarian, breast, lung, bladder, prostate, and other solid cancers MECHANISM:TARGETING MICROTUBULES They stabilize the microtubule polymer (alpha and beta tubulin subunits) and block its disassembly. This blocks the formation of new mitotic spindles, and mitosis is unable to progress to metaphase. or docetaxel Cell cannot divide because chromatids don’t separate, and prolonged activation of the mitotic checkpoint triggers apoptosis (programmed cell death). PDB ID:3J6G TARGETED THERAPY Therapeutic strategies that interfere with specific molecular targets involved in the growth, progression or spread of cancer. Goal is to eradicate the target in cancer cells without harming normal cells. The target is mutated or overactive in cancer, and the tumor is dependent on it for growth and survival. EXAMPLES OF TARGETED THERAPEUTICS 1. Hormone Therapy Tamoxifen—covered previously in hormone lecture Antagonist of the estrogen receptor, used for breast cancer 2. Tyrosine Kinase Inhibitors: block the kinase function of growth factor receptors The kinase causes enzymatic transfer of a phosphate group to tyrosine that activates the receptors, using ATP as the energy source. Kinase inhibitors block the ATP binding site in the kinase to prevent transfer. 3. Antibodies to growth factor receptors: contain “ab” in name Bind to growth factor receptors and block their ligand binding sites so they cannot be activated 4. Angiogenesis Inhibitors: block endothelial cell proliferation and development into blood vessels, starve tumors of oxygen and nutrient delivery from blood. IMATINIB (MARKETED AS GLEEVEC) (1) MECHANISM It is a tyrosine kinase inhibitor that specifically inhibits the kinase Bcr-Abl, which is created by translocation. Because Bcr-Abl is considered as a unique biomarker of chronic myeloid leukemia (CML), imatinib was a conceptual breakthrough in ʻtargeted therapy’. (FDA approval, 2001). (2) CLINICAL USE Chronic myeloid leukemia (CML) Acute lymphoblastic leukemia (ALL) CETUXIMAB (MARKETED AS ERBITUX) Antibody against the Epidermal Growth Factor Receptor (EGFR) EGFR normally binds its ligands and dimerizes to activate cell signaling that leads to proliferation Cetuximab both blocks EGFR signaling and causes the receptors to be internalized, where they are degraded Effective for head and neck cancers and colon cancers (both show dependence on EGFR signaling) EGFR Angiogenesis inhibitors for cancer therapy Growing tumors require formation of new blood vessels to supply oxygen and nutrients. New blood vessels (neoangiogenesis) are produced when endothelial cells migrate into tumors, multiply, and assemble into tubules to connect to the existing blood supply. Thalidomide is an old drug (an anti-nausea drug) that was taken off the market in the 1960’s because it produced severe birth defects (lack of limbs in newborns). Most likely this was due to truncation of blood vessel formation. Now very effective in multiple myeloma (cancer of the bone marrow) and is being studied for other cancers. Thalidomide Bone marrow has a high density of blood vessels compared to other organs, to promote renewal of bone marrow cells. Myeloma cells produce high amounts of angiogenetic factors to promote new blood vessels. Thalidomide blocks the AKT pathway in endothelial cells that respond to these angiogenic factors. Less severe side effects include sedation, rash, and neuropathy. More severe side effect is possibility of venous thrombosis (anti-coagulation therapy is needed during therapy with thalidomide). Potential for severe birth defects necessitates two forms of contraception during use. Patients and their physicians must enroll in a risk management program with the pharmaceutical company supplying the drug. IMMUNOTHERAPY HARNESSING THE IMMUNE SYSTEM TO DETECT AND DESTROY CANCER CELLS. HOW DO CANCER CELLS MODULATE IMMUNE RESPONSES? - Reduce the presentation of tumor antigens on cell surface. - Inhibit immune cell activation. - Induce cells in the tumor microenvironment to suppress immune responses. Tumors take advantage of normal mechanisms that keep the immune system from becoming over-active. Result: Cytotoxic T cells that infiltrate tumors either do not recognize them as foreign, or see them as foreign but do not activate the cytotoxic response IMPORTANT TYPE OF CANCER IMMUNOTHERAPY: Immune Checkpoint Blockers that overcome tumor-induced inhibition of immune cell function. T CELL RESPONSE TO CANCERS - T lymphocytes (T cells) are the major mediators of immune response against cancer cells. - Antigen-presenting cells (APCs) (e.g. dendritic cells) capture mutant/foreign proteins. - APCs present foreign antigens to naïve T cells in lymph nodes. - Mature Cytotoxic T cells recognize antigens on cancer cells, travel to tumors and exert cytotoxic effects. T CELL ACTIVATION AND INHIBITION Stimulatory signals: T cell receptors (TCR): bind antigens presented by the Major Histocompatibility Complex (MHC) on the tumor cell Co-Stimulatory CD28: binds to B7 ligand on dendritic cell Inhibitory signals (immune checkpoints): CTLA-4: binds to B7 to block CD28 PD-1: binds to it’s ligand PD-L1 The inhibitory signals keeps the T cell from becoming overactive http://img.medscapestatic.com/article/841/945/841945-fig2.jpg PD-1 (Programmed cell death protein 1) Transmembrane glycoprotein Primarily on mature T cells within tissues and tumors Ligand binding (PD-L1 and PD-L2) inhibits T cell activation Tumors express high level of PD-L1 or PD-L2 to inhibit T cells https://www.bio-rad-antibodies.com/immune-checkpoint-minireview.html Pembrolizumab (Keytruda) – monoclonal antibody against PD-1 - blocks the immune checkpoint (1) MECHANISM Binds to PD-1 and prevents ligands (PD-L1 and PD-L2) from binding to PD-1. Blocks the inhibitory PD-1 signaling. Boosts T cell activities at the effector phase (locally in tumors). Very effective for melanoma and lung cancer Modified from http://www.nzmu.co.nz/assets/images/treatment/pd-1inhibitors/anti-pd-1-inhibitors.jpg SIDE EFFECTS OF PEMBROLIZUMAB Autoimmune-like symptoms pneumonitis, hepatitis, colitis due to activation of the immune system against normal tissues results in inflammation of these organs Damage to normal tissues and organs (example muscle soreness) Rashes Diarrhea Oral Complications of Cancer Treatment Can interfere with quality of life, course of treatment, and can increase cost of cancer care High turnover rate of the oral mucosa makes it more susceptible to damage from chemotherapy agents that work by killing any fast-growing cell. Direct effects: toxicity of the drugs to oral tissues and salivary glands - dry mouth, oral blisters, pain - caused by factors such as salivary gland dysfunction, mucosal irritation, and neurotoxicity - taste dysfunction (high turnover of taste receptor cells) Indirect effects: cancer therapy causes changes in other organs that affect the oral cavity - opportunistic oral infections secondary to systemic immunosuppression - vomiting can cause acidic damage to the oral cavity Direct Toxicities to Oral Tissues Oral mucositis Salivary gland dysfunction Neurotoxicity Trigeminal nerve neuropathies Taste dysfunction Dentinal hypersensitivity Temporomandibular dysfunction Myofascial pain Temporomandibular joint dysfunction Dental and skeletal growth and development (pediatric patients) Abnormalities in dentition Changes in jaw development Indirect Toxicities that Cause Oral Complications Myelosuppression Neutropenia -immunosuppression Anemia Thrombocytopenia Infection -Viral (HSV, VZV, CMV, EBV, other) -Fungal (candida, aspergillus, other) -Bacterial Gastrointestinal mucositis Nutritional disturbances Nausea and vomiting Acidic damage to oral tissues Heightened gag reflexes Treatments of Oral Complications: Preventive cryotherapy using ice chips before and during chemotherapy, topical anesthetics, mucosal coating agents, systemic pain medication, and antifungal drugs or antibiotics if needed. CANCER THERAPY OF HEAD AND NECK CANCERS Can arise in the oral cavity (especially side of tongue and floor of mouth), the larynx, pharynx and hypopharynx, nasal cavity, or salivary glands Biology: 90% are squamous cell (arising from the epithelial cell lining), the other 10% are sarcomas, adenomas, or lymphomas Main risk factors are tobacco and alcohol use, especially in combination, sun exposure, HPV 16/18, radiation exposure, chewing betel quid or gutka, older age Main treatments: Surgery, radiation therapy, chemotherapy, targeted therapy, and immunotherapy; radiation is often combined with chemotherapy first DURING AND AFTER CHEMO OR RADIATION THERAPY Monitor the mouth every 4 to 8 weeks for 6 months after cancer treatment Oral hygiene should be reinforced Watch for demineralization and caries Radiation field (in the case of oral cancer) may cause muscle weakness or pain in the jaw area Elective oral surgery on irradiated bone is not advised and tooth extraction, if unavoidable, should be conservative Any invasive procedure requires checking of hematologic status if chemotherapy has been administered Check for oral source of infection in patients with fever of unknown origin during or after chemotherapy Mains Terms and Drugs to Remember Carcinogenesis: the process of a normal cell being transformed to a cancer cell Oncogene: a normal growth-promoting gene that becomes up-regulated in cancer Tumor suppressor gene: a normal growth-controlling gene that becomes down-regulated in cancer Types of Cancer: Carcinoma (Epithelial Cancers), Sarcoma (Connective tissue Cancers), Leukemia/Lymphoma/Myeloma (Blood Cancers) Types of Drug Therapy: Chemotherapy, Targeted Therapy, Immunotherapy Chemotherapy: kills any dividing cell Methotrexate: an anti-metabolite Cisplatin: a DNA damaging agent that cross-links DNA Docetaxel: blocks microtubule function during M phase so cells cannot divide Targeted Therapy: blocks specific functions in cancer cells Imatinib: tyrosine kinase inhibitor that blocks the oncogene BCR-ABL Cetuximab: monoclonal antibody that blocks the EGFR receptor Thalidomide: anti-angiogenic drug that inhibits new vasculature formation Immunotherapy (Immune Checkpoint Blockade): Re-activates T cells so they can attack cancer Pembrolizumab: Monoclonal antibody that blocks the PD-1protein and prevents its ligands from binding Practice Questions 1. Which ONE of the following is NOT a hallmark of cancer? 1. a. Activating metastasis b. Increasing proliferation c. Resisting cell death d. Suppressing angiogenesis 2. Which of the following is TRUE of cancer chemotherapy? a. A common side effect is a rash b. Chemotherapy is cytostatic, not cytotoxic c. Chemotherapy kills any dividing cell d. Chemotherapy selectively kills cancer cells 3. Which is the CORRECT mechanism of action for the cancer drug? a. Cetuximab (Erbitux): inhibits Bcr-Abl b. Imatinib: inhibits the Epidermal Growth Factor Receptor (EGFR) c. Methotrexate: inhibits angiogenesis d. Pembrolizumab (Keytruda): blocks Programmed Cell Death Protein 1 (PD-1) 4. Which of the following side effects is most likely to occur with Thalidomide? a. Symptoms of autoimmune disease b.Venous thrombosis c. Nausea d. Hair loss Answers to Practice Questions 1. 2. 3. 4. d c d b Gastrointestinal Drugs Jill M. Siegfried, Ph.D. Professor, Department of Pharmacology [email protected] DDS 6215 Spring Semester Reference: Pharmacology and Therapeutics for Dentistry, Dowd et al., 2017 edition, Chapter 28 1. Treating Stomach diseases a) Gastric hyperacidity - heartburn (pyrosis) burning sensation, lower chest upward to the neck most common symptom of gastro-esophageal reflux diseases (GERD) most common reason for primary care visits caused by abnormal reflux of gastric contents into esophagus acid in stomach promotes digestion b) Peptic ulcer disease (PUD) (gastric and duodenal) painful, but rarely fatal spontaneous healing and recurrence complication leading to hemorrhage – life threatening caused by – mucosal exposure to acid and pepsin H. pylori infection important causal factor, found in majority of ulcers (oral cavity can be a reservoir) Objectives for Treatment * Reduce acidity * Promote defense/protection (mucosal barrier) (PUD) * Eradicate infection (PUD) a) Reduce acidity - Regulation of acid secretion - from parietal cells - H+ released by a proton pump (H/K ATPase) -stimulated by parietal cell surface receptors for Gastrin (produced in stomach wall by G cell) Histamine (released from both Enterochromaffin-like cells and Mast cells) Muscarinic acetylcholine (Ach) (Vagus nerve) - Blocked by prostaglandin E2 (produced mainly by COX-1) G ce ll Drug target Prostaglandins (mucosa) Enterochromaffinlike cell (mast cell) vagus Drug target Drugs: i) Antacids (weak bases) – buffer the stomach acid Sodium bicarbonate - systemic antacid, Na+ overload, systemic alkalosis, short-term only Magnesium hydroxide – laxative effects Calcium carbonate – hypercalcemia, may be constipating ii) Proton Pump Inhibitors (PPIs) – most widely sold drugs, most potent Mechanism of action - irreversibly inhibits H+/K+ pump Longer action, most potent, taken on empty stomach Drugs – lansoprazole; dexlansoprazole (delayed release) Adverse effects – headache, diarrhea decreased Ca++ (risk of bone fracture) risk in developing Clostridium difficle infection with fever, diarrhea interferes with Vitamin B12 absorption increases risk of myocardial infarction Therefore, short term use only. (OTC can be abused) iii) Histamine H2 receptor antagonists Mechanism of action - competitively block histamine H2 receptors, thus reducing acid secretion. The first-line treatment for peptic ulcer (most selective) Drugs – Cimetidine (Tagamet) - first on market, but problems - Anti-androgenic at high doses (blocks androgen receptor), problem in men (impotence, gynecomastia) - Inhibits estradiol metabolism, galactorrhea (milky nipple discharge) in women - Inhibits hepatic CYP450s, thus reducing metabolism of other drugs - increases blood levels of diazepam and lidocaine Other H2 antagonists – example Ranitidine (Zantac) (no effect on sex steroids) iv) Prostaglandins – Mechanism of action – inhibits cAMP, which blocks proton pump Side effects – abdominal pain, diarrhea Drugs – misoprostol (synthetic prostaglandin E1) NSAIDs reduce prostaglandin production, results in higher action of proton pump, increased stomach irritation Other strategies for GERD/PUD: b) Enhance mucosal defense Chelates/foams – forming protective complexes Mechanism of action – salt/foaming complex protects stomach wall c) Eradicate infection – antibiotics (for H. pylori-associated ulcer) Clarithromycin and amoxicillin/metronidazole Triple regimen - Cornerstone therapy for H. pylori associated PUD 2 antibiotics* + 1 PPI *Antibiotics combination depends upon local situation of antibiotic resistance. Inhibitors of acetylcholine or gastrin for GERD/PUD are NOT practical. Dental implications of GERD/PUD 1. GERD patients may need to be kept at a 45 degree angle in dental chairs 2. Aspirin is contraindicated as an analgesic (use acetaminophen, or COX-2 selective inhibitors like celecoxib for acute pain) COX-2 inhibition is less likely to block prostaglandins in the stomach lining, but may still occur to lesser extent 3. Corticosteroids (used following oral surgery) - potential ulcerogenic Mechanism is reduced mucus production and reduced epithelial cell repair Usually promotes existing ulcerous damage rather than inducing new ulcers 4. Concerns for pre/post-operative sedatives Diazepam (anti-anxiety drug) PK may be altered by antacids and cimetidine or ranitidine inhibition of CYP metabolism of diazepam, increasing blood levels consider lower doses, especially in elderly patients 5. Antibiotic absorption affected by antacids - separate the time of administration 2. Anti-sialagogues Mechanism - Blocking muscarinic acetylcholine receptor, to control excessive salivation Drugs – atropine, and synthetic anti-cholinergics such as propantheline given at low oral dose so few CNS effects Dental implications – difficult swallowing contraindicated in glaucoma (obstructing aqueous humor outflow) prostate hypertrophy (causing dysuria) heart disease (increases heart rate) 3. Treatment for Nausea and Vomiting Mechanism – centrally controlled by chemoreceptor trigger zone (CTZ) VC Vomiting Center Brainstem peripherally controlled by visceral and vestibular (motion) CB Ach NK1 NK1 NK1 corticosteroid Neurochemical basis for anti-emetics: Antagonists to histamine (H1), acetylcholine (Ach), Dopamine (D2 R), seratonin (5-HT3 R), neurokinin 1 (NK1) Cannabinoid (CB) and corticosteroids Treatments Anti-emetics H1 histamine receptor antagonists – example Dimenhydrinate blocks H1 receptors in the vomiting center (brain) (H2 antagonist for stomach acidity control) Anti-cholinergic – Scopolamine (motion sickness) Dopamine (D2) antagonists Serotonin (5-HT3) antagonist – Ondansetron (potent, highly selective) NK1 antagonists Cannabinoids Corticosteroids– inhibit prostaglandin E production in vomiting center Emetics – emergency treatment of poison and intoxication activated charcoal adsorbent apomorphine – D2 Receptor agonist syrup of ipecac – less reliable Dental implications 1. Selective 5-HT3 antagonists are highly effective for postoperative nausea/vomiting 2. Cannabinoids – when conventional anti-emetics fail (THC, maybe CBDs) 3. Prophylactic application - combination of antiemetics, but consider drug interactions 4. Laxatives Laxatives, for constipation and preparation for bowel procedures Stimulants – increase motility and bring fluid into intestine lumen (bisacodyl) Adverse effects – abdominal pain Osmotic cathartics – increase intestinal fluid (such as Mg salt, PEG) can result in diarrhea Bulk forming agents – fibers, absorb water and expand in colon (methylcellulose) Softeners/lubricants (wetting) – detergent/surfactant effect, allows fluid to enter fecal mass Preparations - Docusate sodium, mineral oil Opioid receptor antagonists – reverses reduced GI motility produced by opioid use Adverse effects – nausea, stomach pain, dizziness short term treatment, restricted to use in hospitals For opioid-induced constipation (methylnaltrexone) General consideration – overuse/abuse of OTC laxatives! Summary of Laxatives Opioid Receptor antagonists Increases motility 5. Antidiarrheals Principles – remove excess water, decrease intestinal motility Diarrhea can be severe in young children and the elderly. Uses – To control acute diarrhea, but should be discontinued if diarrhea worsens. To control chronic diarrhea such as in Irritable Bowel Syndrome and inflammatory bowel disease (IBD) Drugs Kaolin – aluminum silicate, adsorbs fluids (non-selective) Bismuth Subsalicylate (Pepto-Bismol) – suspension of bismuth/ salicylate with magnesium aluminum silicate Action due to bismuth, which is not absorbed and remains in intestines anti-bacterial, toxin-binding (good for bacteria-induced diarrhea) reduces chloride secretion in bowel (less watery stool) Concerns – relatively safe, but cautious about patients also taking salicylate-containing drugs such as aspirin not recommended for young children Opioid agonist anti-diarrheal preparations – Action - GI inhibition (slows gut movement via the opioid mu receptor in the gut) Loperamide - most selective antidiarrheal opioid, little CNS effect, safe, OTC Diphenoxylate - schedule V, can be addictive Concerns – abdominal pain, cramps, constipation, dry mouth, drowsiness. Opposite effect of opioid antagonists 6. IBD/IBS A) Inflammatory bowel disease (IBD) a) Types/causes - ulcerative colitis, Crohn’s disease Ulcerative colitis - chronic inflammation (autoimmune) in the large intestine lining/rectum Crohn’s Disease – activated immune system (such as by infection) and genetics, any parts of GI lining b) Drugs – anti-inflammatory drugs – corticosteroids immune suppressors – cyclosporine, TNF-a inhibitors (antibodies) anti-diarrheals c) Dental implications – oral health affected by IBD and its medications Aphthous ulceration, angular cheilitis, mucosa abscess, lip edema B) Irritable bowel syndrome (IBS) – chronic abdominal pain, bloating, gas, diarrhea with or without constipation Causes – unclear, can be muscle, nervous system, inflammation, gut microbiome Chloride channel activators (Lubiprostone) for chronic constipation stimulates the chloride channel to bring chloride-rich fluid into the intestines increases intestinal motility and reduces transit time little systemic absorption with few side effects Adverse effects of dental medications in the GI - Opioid analgesics – constipation, nausea, vomiting - Aspirin analgesics – gastric distress, ulcer, blood loss - Antibiotics – may cause diarrhea, especially C. difficile-associated diarrhea, and in elderly - Dry mouth (Xerostomia) and oral lesions can be induced by numerous drugs Drugs to Remember for Heartburn, GERD, and PUD Class Drug Mechanism Pros Cons Antacids Sodium Bicarbonate Neutralize gastric acid (HCl) Works quickly Na+ overload systemic alkalosis Magnesium Hydroxide Works quickly, high capacity Laxative effect Calcium carbonate Prolonged neutralization May produce constipation Inhibits nocturnal acid secretion Anti-androgenic; decreases metabolism of lidocaine and diazepam H2 Receptor Blockers Cimetidine Reversible inhibitors of histamine decreases metabolism of lidocaine and diazepam Ranitidine Prostaglandin Analog Misoprostol Mimics Prostgl E to block acid secretion Prevent NSAIDinduced ulcers Causes abdominal pain and diarrhea Proton Pump Inhibitors Dexlansoprazole Irreversible blocker of H+/K+-activated ATPase Longest acting and most potent Increased risk of Clost. diff. infection; May interfere with absorption of Vitamin B12 Lansoprazole Other GI Drugs to Remember Class Drug Mechanism Clinical Considerations Anti-Sialagogue atropine Blocks muscarinic receptors Contraindications: glaucoma or heart disease Anti-Emetic Dimenhydrinate (Dramamine) H1 histamine Useful for motion sickness receptor blocker, also anticholinergic Anti-Emetic ondansetron Blocks serotonin at 5-HT3 receptors Useful for post-operative nausea/vomiting Anti-Emetic scopolamine Anti-cholinergic Transdermal patch preferred for motion sickness Laxative bisacodyl Intestinal stimulant Little systemic absorption Laxative methylcellulose Bulking agent Onset of action is slow Anti-diarrheal Bismuth subsalicylate Decreases fluid loss Also useful for reducing gastric distress Anti-diarrheal loperamide Activates the mu opioid receptor Does not enter the CNS, safe Antiflatulant simethicone Defoaming agent Safe and effective GI stimulant lubiprostone Activates chloride channels to increase intestinal secretions Useful in IBS with constipation Clinical Implications Example A dental patient in his mid-50’s has a history of rheumatoid arthritis and has been on long-term treatment with ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). He has been prescribed lansoprazole (a proton pump inhibitor) to treat stomach irritation associated with ibuprofen, and also regularly uses calcium carbonate antacids after meals. What are the considerations for using each of the following analgesic mediations after dental procedures? Aspirin: Acetaminophen: Codeine: Celecoxib: Prednisone: Clinical Implications Example A dental patient in his mid-50’s has a history of rheumatoid arthritis and has been on long-term treatment with ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). He has been prescribed lansoprasole (a proton pump inhibitor) to treat stomach irritation associated with ibuprofen, and also regularly uses calcium carbonate antacids after meals. What are the considerations for using each of the following analgesic mediations after dental procedures? Aspirin: causes stomach irritation so should be avoided Acetaminophen: safe alternative to aspirin or other NSAIDs to avoid stomach irritation Codeine: can be safely used in combination with acetaminophen to avoid stomach irritation Celecoxib: selective effects on COX2 reduces possibility of stomach irritation, but not completely Prednisone: corticosteroids can cause stomach irritation so should be avoided Practice Questions 1. Which of the following is NOT a characteristic of proton pump inhibitors? a. They are more effective than histamine H2-receptor antagonists b. They bind irreversibly to the proton pump c. They reduce both basal and stimulated acid secretion d. They reduce gastric pH Practice Questions 1. Which of the following is NOT a characteristic of proton pump inhibitors? a. They are more effective than histamine H2-receptor antagonists b. They bind irreversibly to the proton pump c. They reduce both basal and stimulated acid secretion d. *They reduce gastric pH By reducing H+ release in stomach they increase stomach pH 2. Which is the CORRECT mechanism of action of cimetidine? a. It blocks the action of prostaglandin b. It reduces H. pylori infection c. It neutralizes stomach acid d. It blocks the action of histamine in the GI tract 2. Which is the CORRECT mechanism of action of cimetidine? a. It blocks the action of prostaglandin b. It reduces H. pylori infection c. It neutralizes stomach acid d. *It blocks the action of histamine in the GI tract Blocking H2 histamine receptors will reduce production of stomach acid 3. Which of the following is CORRECT about use of antibiotics for peptic ulcer disease associated with H.pylori infection? a. They are generally used as a single agent b. They are generally used together with antacids for best effect c. They are generally used together with H2 receptor antihistamines for best effect d. They are generally used together with proton pump inhibitors for best effect 3. Which of the following is CORRECT about use of antibiotics for peptic ulcer disease associated with H.pylori infection? a. They are generally used as a single agent b. They are generally used together with antiacids for best effect c. They are generally used together with H2 receptor antihistamines for best effect d. *They are generally used together with proton pump inhibitors for best effect Two antibiotics plus a PPI is optimum 4. Which would be the best drug of choice for relieving pain in the oral cavity for a patient with gastroesophageal reflux disease? a. Acetaminophen b. Aspirin c. Celecoxib d. Prednisone 4. Which would be the best drug of choice for relieving pain in the oral cavity for a patient with gastroesophageal reflux disease? a. *Acetaminophen b. Aspirin c. Celecoxib d. Prednisone Aspirin, celecoxib and prednisone can all cause stomach irritation to different extents Prescribing Considerations for Special Populations: Pregnancy and Breast-feeding; Pediatric Patients Dental Pharmacology DDS 6215 Dr. Dan Skaar [email protected] Agenda and Objectives Prescribing during pregnancy – Recognize drug risks – Impact of drug pharmacokinetics – Changing FDA drug risk assessment – Prescribing decisions Understand prescribing issues for nursing patients Recognize pediatric prescribing considerations Adherence and compliance with prescribing medications Drug Risk During Pregnancy Drug-related birth defects uncommon – 3-5% of live births with birth defects 2-3% estimated drug-related Drug–related adverse fetal effects – Teratogenic → physical defects Structural abnormalities – E.g. cleft lip – Fetotoxicity → injury Late 1st trimester to birth – E.g. NSAIDs → renal dysfunction Timing of Teratogenic Effects Basic & Clin Pharmacol; 10 Ed Katzung Weeks 1 to 2 higher likelihood of “all or nothing” effect Weeks 3 to 8 structural organ abnormalities > week 8 growth and CNS abnormalities Drug Related Teratogenic Effects Thalidomide – One of biggest medical tragedies – Effects include Anti-inflammatory Antiangiogenic – Prescribed into early 1960s for morning sickness – “Rebirth” as FDA approved drug (Thalomid) Multiple myeloma Cutaneous leprosy lesions Drug Pharmacokinetics During Pregnancy Drug absorption – Delayed onset of action Stomach emptying time Motility pH Effect of concurrent antacids and supplement use Drug distribution – Potential for lower plasma [drug] ↑ plasma volume ↑ body fat may ↑ Vd for lipid soluble drugs – Potential for higher plasma [drug] ↓ maternal plasma [albumin] Drug Pharmacokinetics Drug metabolism – Potential for lower plasma [drug] Liver CYP450 enzyme activity ↑ liver blood flow Drug elimination – Potential for lower plasma [drug] Free drug delivery to kidney – ↓ albumin – ↑ in renal plasma flow – ↑ GFR Drug Pharmacokinetics Theoretical pharmacokinetic mechanisms – Value in prescribing decisions Competing pharmacokinetic actions Net impact of physiologic changes Drug Absorption Across Placenta Placenta is organ of exchange – Transport by week 5 (gestation) – Primary mechanism – Lipid solubility and low MW ↑ transfer Fetal [drug] ~50-100 % of maternal [drug] “Old” FDA Fetal Risk Classification Historic classification – Categories A-D, X Reliability and documentation – Lack of human studies – Difficulty extrapolating animal studies to potential human effects Categories based on risk and benefit not toxicity “Old” FDA Fetal Risk Categories A: Controlled studies in women failing to demonstrate fetal risk during pregnancy – Considered safe B: Animal reproduction studies fail to demonstrate fetal risk and no adequate studies in pregnant women – Considered safe C: Animal reproductive studies show fetal risk and no adequate studies in pregnant women – Benefit outweighs risks “Old” FDA Fetal Risk Categories D: Studies show evidence of human fetal risk – Benefits may outweigh risks X: Studies in animals or humans or both demonstrate studies demonstrate evidence of fetal abnormalities or adverse reaction risk – Fetal risk outweighs maternal benefits Changes in FDA Fetal Risk Guidance Historical classification – Ambiguous data – Lack guidance – Simplistic New FDA labeling requirements – New labeling effective June 2015 Drugs approved prior to 6-30-2001 – Not subject to ruling Drugs approved after 6-30-2001 – Gradual phase in New FDA Pregnancy and Lactation Drug Labeling New content and format changes – Summary of risks and benefits of use during pregnancy and lactation – Discussion of supporting data – Pregnancy exposure registry Managed by manufacturer List kept by FDA – Prescribing and counselling information New FDA Pregnancy and Lactation Drug Labeling Prescribing Considerations During Pregnancy Expected benefits exceed risks Special caution in 1st trimester Lowest therapeutic doses Shortest duration of therapy Avoid newly introduced drugs Drug Selection During Pregnancy Antibiotics to Use Use full doses and usual duration ß-lactam ring antibiotics DOC – Penicillins – Cephalosporins Chlorhexidine topical – Category (B) Antibiotics to Use (Penicillin Allergy) Macrolides – Azithromycin (B) – Clarithromycin (C) Use with caution Lincosamides – Clindamycin (B) Drug Selection Antibiotics to Generally Avoid Fluoroquinolones – Ciprofloxacin (C) Metronidazole (B) – Risks Carcinogenic in animal studies Clefting reported – Prescribing Avoid in first trimester Use with caution Antibiotics to Avoid Tetracycline, minocycline and doxycycline (D) – Risks Mineralized structures Enamel Drug Selection Antifungals Nystatin (A/C) DOC Clotrimazole (Mycelex) (B) DOC Fluconazole (C/D) Mycelex trouche Antifungals to Generally Avoid Ketoconazole (C) Drug Selection Antivirals Penciclovir (B) DOC Antivirals to Generally Avoid Acyclovir (B) – Lack of clinical research Drug Selection Nonopioid Analgesics Acetaminophen (B) – DOC ASA (C/D 3rd trimester) – Risks Premature constriction of ductus arteriosis Teratogenic effects – Avoid prescribing Nonopioid Analgesics Ibuprofen, naproxen, celicoxib – C/ D – Avoid 3rd trimester Premature closure of ductus arteriosis Prescribing – Use cautiously 1st - 2nd trimesters – Avoid 3rd trimester Lowest effective dose and limited duration Drug Selection Opioids Use with caution Category B/C (APAP combinations) – Oxycodone (Percocet®) (B/C) – Codeine 1st trimester teratogenicity (C) – Hydrocodone (Lorcet®, Lortab®, Vicodin®) (C) Opioids Risks – Multiple defects including heart, cleft lip and palate – Neonatal (prolonged use) Respiratory depression Withdrawal Prescribing – Oxycodone + APAP DOC – Lowest effective dose and limited duration Drug Selection Anxiolytics Fetal malformations and craniofacial defects(?) Single clinical dose likely to have less risk vs. longterm use Anxiolytics Benzodiazepines – Diazepam, lorazepam and alprazolam (D) – Triazolam (Halcion) Category __ Prescribing – Avoid use in pregnancy Nonbenzodiazepines – E.g. Zolpidem (C) Drug Selection Anxiolytics Nitrous oxide – Fetal [plasma] 80% of maternal – Use is controversial No FDA risk category Short-term exposure and lower doses minimize risk Anxiolytics Nitrous oxide – Avoid prolonged occupational exposure Decreased fertility Congenital abnormalities – Risks Unproven effects on pregnant woman and fetus Drug Selection Local Anesthetics Passive placenta diffusion LA considered safe for use – Lidocaine (B) DOC – Prilocaine (B) – Lidocaine (topical) (B) Local Anesthetics Vasoconstrictors – Epi considered safe for use Limit cartridges – Suggested 0.1 mg – 5 (1:100,000) cartridges – Levonordefrin No FDA classification Drug Selection Local Anesthetics LA to use with caution – – – – Articaine (C) Bupivacaine (C) Mepivacaine (C) Tetracaine and benzocaine (topical) Local Anesthetics Risks (high doses) – Fetal bradycardia – Uterine vasoconstriction – Methemoglobinemia Prescribing During Nursing Breast-feeding common for U.S. infants – 82% early post-partum – 61% six months after delivery Challenges assessing drug safety during lactation – Established prescribing guidelines are lacking Primarily animal studies – Milk composition varies among species Prescribing During Nursing Drugs crossing placenta are excreted to some extent into breast milk Recommend minimizing infant exposure – Timing of feeding vs drug ingestion – Consider pump-and-save then pump-and-discard strategy – Adjust dosing Resources – http://toxnet.nlm.nih.gov/ (LactMed) Prescribing During Nursing Dental Drugs Considered Safe Dental Drugs Considered Safe Local anesthetics – Lidocaine w/wo epi – Mepivacaine w/wo levonordefrin – Lidocaine (topical) – Dyclonine (topical) – Bupivacaine Analgesics – – – – APAP Ibuprofen Codeine Oxycodone with caution Antimicrobials – – – – – Penicillin VK Cephalexin Clindamycin Azithromycin Nystatin/clotrimazole Nitrous oxide Pediatric and Adolescent Patient Drug Pharmacokinetics Drug absorption – Oral Older children similar to adults Drug distribution – Protein binding reaches adult values CYP Drug metabolism – Elevated metabolism until puberty – Metabolism approaches adult function in teenage years Drug elimination – Renal function Pediatric and Adolescent Analgesic FDA Warning Codeine Black Box warning Metabolism risk Pediatric and Adolescent Patient Prescribing Dosage form – Liquid or chewable tablet – Children ( 1000 years Indications – Alzheimer’s and age related dementia Modest improvement MOA – Terpenoids and flavonoids Modulate neurotransmitter activity Vasodilator Inhibit platelet activating factor Dosing – 120 – 240 mg qd – Response in weeks Ginkgo biloba Ginkgo Adverse experiences – Dizziness, GI upset, headache, palpitations – Bleeding – Lower seizure threshold Drug interactions – CYP450 effects: 2C9 (strong inhibition) 3A4 (conflicting information) Dental/Misc – D/C prior to surgery (>36 hr) – Increased bleeding risk if taken with: Aspirin/NSAIDS Warfarin Garlic (Allium sativum) Indications – Hypertension ↓ BP vs. placebo: 7/5 mmHg (2-7%) – Hypercholesterolemia and atherosclerosis ↓ TC vs. placebo: 16-23 mg/dl (4-12%) MOA – Allicin (active) Antiplatelet (interferes with thromboxane synthesis) Inhibits HMG-CoA reductase Antibacterial, anti-inflammatory, antioxidant Dosing – Varies by raw, powder and extract forms Garlic Adverse experiences – GI irritation, heartburn – Breath & skin odor – Bleeding Drug Interactions – May induce CYP 3A4 – May ↑risk of bleeding with warfarin/ASA and antiplatelet drugs Dental/Misc. – D/C 7-14 days prior to dental sx Ginseng Indications – Stress and restores homeostasis – Lower postprandial glucose MOA – Ginsenosides with heterogenous effects Steroid-like actions Inhibit platelet aggregation Dosing – Varies by powder and extract – Limit use to 3 consecutive months Ginseng Adverse experiences – Hypoglycemia – Bleeding – Ginseng abuse syndrome Drug Interactions – Warfarin Dental/Misc. – D/C 7-14 days prior to dental sx Melatonin Indications – Insomnia and jet lag Reduce time to sleep Less evidence on sleep time and quality – Cancer and chemotherapy MOA – Regulate sleep cycle Dosing – 0.5- 5 mg (insomnia) Melatonin Adverse experiences – Dizziness – Headache Drug interactions – Sedatives Dental/Misc – Increase immune function Interfere w immunosuppressive therapy St. John’s Wort (Hypericum perforatum) Indications – Mild to moderate depression – Anxiety MOA – Hypericin and hyperforin Inhibits serotonin, norepi, dopamine reuptake Dosing – 600 - 1200 mg qd – Can have withdrawal reactions → taper dose – Comparable effectiveness to low doses of TCAs and SSRIs St. John’s Wort Adverse experiences – Photosensitivity – GI nausea, diarrhea – Confusion, drowsiness, dizziness, irritability – Xerostomia St. John’s Wort Drug Interactions – Increase metabolism of many drugs Potent CYP 3A4 inducer (double activity) – Alprazolam – CYP 2C9 inducer ↓ [ ] of NSAIDs (e.g. ibuprofen), warfarin – CYP 1A2 inducer (less than 3A4) – Induces P-glycoprotein transporter ↓ [digoxin] levels by 25% St. John’s Wort Dental/Misc. – Increases risk of serotonin syndrome and other CNS reactions Use with caution if taking psychotropic drugs (TCA, SSRI) – Avoid in pregnancy due to teratogenic risk Kava Indications – Anxiolysis and sedation MOA – Kavalactones Potentiate GABA inhibitory transmission Dosing – Max 250 mg qd Kava Adverse experiences – Kava dermopathy with heavy use Scaly cutaneous eruptions – Hepatotoxicity Drug interactions – Potentiate other sedatives Dental/Misc. – Caution if prescribing for anxiolysis D/C 1 -2 days Kava powder Echinacea (Echinacea purpura) Indications – Treatment of URIs and colds Est. 10-30% ↓ severity & duration – Prevention of viral respiratory infections (colds) Ineffective MOA – Immunomodulator (cell-mediated immunity) Dosing – Dose varies widely depending on the product 7-10 days starting with cold symptoms Long-term (< 8 weeks) Echinacea Adverse experiences – GI upset – Hepatotoxicity – Unpleasant taste Drug interactions (CYP3A4) – Avoid/caution with hepatotoxic drugs Acetaminophen – Avoid with immunosuppressant drugs Dental/Misc. – Immunosuppression with long term use (> 8 weeks) Risks Colloidal Silver FDA ruled ineffective and unsafe in 1997 Indications – Natural antibacterial Skin and respiratory infections Gum disease – Prevent colds and flu – Pregnancy MOA – Unknown function – Purported to strengthen immune system Inhibit bacterial enzymes Protein binding Colloidal Silver Dosing – Topical and oral administration Adverse experiences – Argyria Blue-gray skin and membrane discoloration – Irreversible – Kidney and liver Risk Natural tree native to SE Asia Used in tea to ease opioid withdrawal, fatigue, pain, cough and diarrhea MOA – Interaction with opioid receptors Contamination – Salmonella Risks Considerations Prior to Dental Procedures Increase Bleeding Risk Fish Oils Four “Gs” – – – – Gingko Garlic* (high doses) Ginger (> 1 gm qd) Ginseng* Other Risks Echinacea – Immunosuppressant Kava – Sedative effect – Hepatotoxicity (APAP) St. John’s Wort – Drug interactions – Hepatotoxicity (APAP) Feverfew* Evening Primrose (3 gm qd) Valerian – Sedative effect Vitamin E (> 400 IU qd) * Irreversible platelet inhibition Probiotics Formulations of living/vital microorganisms – Confer health benefit to host – Common use in U.S. Lactobacillus Bifidobacterium World market – $24 B sales (2011) lactobaccillus Probiotics Availability – Dairy foods – Beverages – Dietary supplements U.S. regulation – FDA Regulate as drug, dietary supplement or food No approved health claims Probiotics Uses – Gastrointestinal – Oral Mechanisms of effect – Influence mucosal integrity – Produce antimicrobial/ physiologic compounds – Immunomodulatory Probiotics Studies – Methodological limitations- early studies – Strong clinical evidence lacking – Safety data limited Long-term – Some formulations show promise science? Oral Probiotics Clinical uses – – – – – – Caries Gingivitis Periodontitis Reduce plaque Halitosis Teeth whitening – – – – Lozenge Mouthwash Mints Tablets Availability Oral Probiotics Mechanisms of effect – Compete for tooth and tissue adhesion sites – Modify local oral environment Alter pH – Produce antimicrobial compounds – Stimulate immune response Oral Probiotics Caries prevention – Bacteria adhere to tooth and integrate into biofilm Compete/antagonize cariogenic bacteria Lactobacilli S. mutans – Conclusive study results lacking Oral Probiotics Periodontal disease – Bacteria proposed to Inhibit periodontal pathogen growth Prevent superinfection Promote immune response Study results remain inconclusive Oral Probiotics Periodontal product – Proprietary mix of 3 bacteria S. viridans strains Dissolvable tablet – Bacteria release H2O2 – Bleaching effect Summary Dietary supplements including natural products widely used Government regulation of dietary supplements far less than for Rx drugs – DSHEA regulations – FDA role Clinical effects of natural products often have minimal evidence or are unproven Medication-Related Osteonecrosis of the Jaw (MRONJ) Dental Pharmacology DDS 6215 Dr. Dan Skaar [email protected] Agenda Osteoporosis – Epidemiology – Pathophysiology Osteoporosis drug therapies MRONJ Dental guidelines Osteoporosis Epidemiology Common, asymptomatic disease – Osteopenia Est. 47 MM (2020) – Osteoporosis Est. 14 MM (2020) Leading cause of fractures in older adults – Expected 3+ MM fractures annually Peak bone mass ~ age 30 Osteoporosis Pathophysiology Systemic skeletal metabolic disorder – Compromised bone strength Low bone mass and mineral density (BMD) Abnormalities in bone architecture Fracture risk Imbalance in bone remodeling Healthy Bone Remodeling Healthy Bone Remodeling Ono et al. Inflam and Regen 2020 RANKL: Receptor Activator of Nuclear Kappa-B Ligand RANK-RANKL interaction activates precursor osteoclast RANK receptor → osteoclast differentiation Systemic Bone Remodeling Regulation Ca++ regulation – Parathyroid homone (PTH) ↑ Bone resorption – Calcitonin Suppresses osteoclasts – Calcitrol (D3) ↑ Ca++ absorption – Skeletal support Feedback loop Osteoporosis Diagnosis Bone mineral density (BMD) measures w dual energy x-ray absorptiometry (DEXA) – Osteopenia Bone mineral density (BMD) lies between -1 and -2.5 (Tscore) – SDs below healthy – Osteoporosis Bone mineral density (BMD) lies ≥ -2.5 (T-score) – SDs below healthy Other risk factors Age, gender, hx of fracture Osteoporosis Signs and Symptoms Initially asymptomatic Fractures – Activity Pain Kyphosis Immobility Osteoporosis Fracture Risk Common fracture sites – Vertebrae, distal radius and proximal femur Risk factors – Low BMD Increasing age and postmenopause – ~40% of 50 y/o women will experience a osteoporotic fracture – ~10% of 50 y/o men will experience osteoporotic fracture – Smoking – Aging – Gender Osteoporosis Fracture Risk 50 y/o WF has 15% - 20% lifetime hip fracture risk – ~ 2/3 have diminished function – ~ 20% - 30% mortality by 6 months women age >70 y/o Osteoporosis Primary Secondary Postmenopausal women Systemic disease – Normal aging – Menopausal estrogen loss Male – Multifactorial Age most common contribution – Metastatic bone cancer – Hypercalcemia of malignancy Medication use – Glucocorticoid therapy Osteoporosis Therapies Goal: reduce fracture risk Therapies – Antiresorptive drugs ↓ rate of bone resorption – Pyrophosphate analogues » Bisphosphonates (BP) – RANKL ligand inhibitors (monoclonal antibody) – Sclerostin inhibitor – Selective estrogen receptor modulators (SERM) – Calcitonin – Anabolic Drugs Increase bone formation – Parathyroid peptide (PTH analogs) Antiresorptive Drugs Indications Osteoporosis prevention and treatment Paget’s disease Oncology – Hypercalcemia of malignancy – Bone metastases of solid tumors – Multiple myeloma Bisphosphonates (BP) First-line Therapy BP Pyrophosphate Analogues Bind to hydroxyapatite – R1 relates to binding affinity – R2 relates to efficacy and potency – Types Non N Linear N Ring N (high potency) Multiple dosage forms BP MOA Inhibits osteoclast activity – Decrease bone turnover – Increase bone density and formation – Long biologic half-lives~ 10yrs+ Rank Ligand (RANKL) Inhibitors Denosumab Brand names – Prolia and Xgeva MOA – Monoclonal IgG2 antibody – Blocks RANK-RANKL preosteoclast cell attachment ↓ osteoclast formation/activity – Increase BMD Indications – Postmenopausal women with high fracture risk Denosumab Comparison to BPs – Better tolerability – Lower nephrotoxicity – Shorter half-life (25 days) Dental considerations – Osteonecrosis of jaw reported – Bone remodeling effects diminish within six months Sclerostin Inhibitor Romosozumab-aqqg Brand name: Evenity MOA – Monoclonal IgG2 antibody – Dual effect Inhibits sclerostin (protein regulating bone metabolism) – RANK-RANKL – Wnt signaling pathways Stimulates osteoblasts Decreases bone resorption Indications – Postmenopausal women with high fracture risk Romosozumab-appq Dosing – Monthly injections x 1 yr – Followed by antiresorptive therapy Dental considerations – Osteonecrosis of the jaw Selective Estrogen Receptor Modulators (SERM) Brand names – Raloxifene (Evista) MOA – Increase BMD and decrease bone turnover Estrogen receptor partial agonist in bone Direct ligand binding reducing osteoclast activity Activate factor production decreasing osteoclast production and activity Anabolic Drugs Teriparatide (Forteo) – MOA Synthetic parathyroid hormone (PTH) Intermittent use increases osteoblast formation Stimulate new bone formation and increase BMD – Indications Men and postmenopausal women with osteoporosis and high fracture risk – Menopause, steroid use, gonadal failure – Dosing SQ daily dosing Osteoporosis Therapies MOA Overview Osteonecrosis of the Jaw (ONJ) Historical Perspective JP 1999 JP 2001 JOMS 2004 Minnesota Doctor of Dentistry 2009 Medication-related Osteonecrosis of the Jaw (MRONJ) Expansion beyond the bisphosphates Uncommon serious condition – Pathologic elevation of osteoclast bone resorption Etiology and pathology largely unknown – No universally accepted treatment algorithms Medication-related Osteonecrosis of the Jaw (MRONJ) Diagnosis – Exposure to antiresorptive and/or antiangiogenic agents – Exposed bone or fistula probable to bone in maxillofacial region > 8 weeks duration – No hx of radiation therapy to jaw or obvious metastatic disease AAOMS 2014 MRONJ Radiographic Findings Resorption and Apposition MRONJ Putative Risk Factors Patient factors – Systemic disease Osteoporosis Oncology – Corticosteroid use – Age, gender and smoking variably reported – Genetics (?) Oral factors – Pre-existing infection or inflammation Periodontitis – Dentures – Dentoalveolar surgery MRONJ Putative Risk Factors Medication factors – Types Antiresorptives Antiangiogenics – Bevacizumab (Avastin) – Duration of therapy ≤ 2+ years – Route of administration Higher dose/potency IV vs. oral Risk without dental procedures MRONJ Risk Challenges estimating frequency of uncommon diseases – Study design Sample sizes ONJ risk without medication exposure – Osteoporosis and cancer studies Placebo groups – Risk 0% - 0.02% (0-2 cases per 10,000 patients) MRONJ risk – 1%-10% w IV BP for metastatic disease – 0.001%-0.01% w oral BP for osteoporosis – Highest “reliable” study est. of 0.1% (2011) MRONJ Clinical Guidelines ADA (2011) International ONJ Task Force (2013) – National and international organizations AAOMS (2014 update) – Introduction of staging ADA Recommendations Antiresorptive Osteoporosis Therapy Inform patients of risks and benefits – Low risk but can’t be eliminated – Regular dental care and effective OH may reduce risk No diagnostic test to assess risk – Evidence for serum biomarker tests in insufficient – CTX D/C BP may not eliminate risk – Evidence for drug holiday is insufficient Obtain/document informed consent ADA Recommendations Antiresorptive Osteoporosis Therapy Generally should not modify routine dental care – Treating active dental disease likely lower risk Limited, sequential approach to surgeries Accelerate treatment for emergencies including infections ADA Summary Antiresorptive Therapy for Osteoporosis Risk of developing ONJ remains very low for oral BPs Regular dental care and optimal oral hygiene important to manage risk Recommendations are not a standard of care Health benefits of antiresorptive drugs outweigh small risk of ONJ MRONJ Summary Clinical value of antiresorptive drugs means dentistry will continue to face the risks of MRONJ Dental patient risk assessment continues to be challenging Treatment guidelines are without consensus and will continue to evolve NSAIDs (& Other Non-Opioid Analgesics) SESSION OBJECTIVES Ø For Future Clerkships & National Board Dental Exams: Know these traits of each listed drug (and its similar drugs): Name, class, mechanism of action, physiological effects, uses, major side-Fx, and the dentistry-relevant information (see green-colored text) within these categories. Ø For DDS Exams: Be able to match a drug’s provided name or class to one or more of its provided unique traits. Also be able to complete the below Key Concepts. Ø Key Concepts: NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) locally block the production of inflammatory prostaglandins, and block prostaglandin pain-signaling in both injured PNS tissue nociceptors and in pain-mediating CNS neurons. Acetaminophen is not an anti-inflammatory drug but is anti-pyretic (fever-reducing), and blocks prostaglandin pain signaling in pain-mediating CNS tissues, thus confers additive pain relief if combined with NSAIDs. Dr. Burton declares no conflict of interest regarding drugs discussed in this lecture Supplemental reading Pharmacology and Therapeutics for Dentistry (7th edition) Frank H. Burton, PhD Dept. of Pharmacology, UMN S3.220 HHRI-HCMC [email protected] HISTORY OF NSAIDs Willow Bark Extract (salicin) (Greece, Hippocrates, 400 BC) Buffered acetylsalicylic acid (aspirin) Germany, Charles Gerhardt (1853) & Felix Hoffman [Bayer Aspirin] (1899) Dental Pain Transmitted & Suppressed! Acetaminophen “Endorphin” [“ENDOgenous mORPHINe”] Euphoria & Pain-Irrelevancy (CNS) Big Brain Opioids NSAIDs Thalamus Neuroinhibitors OW! Brainstem PAG Pons CNS Neuroinhibitors PNS NSAIDs “Endorphin” “Endorphin” Analgesia Local (CNS) Pons Opioids Analgesia (CNS) Trigeminal Nerve Opioids Spinal cord Locals Antirheumatics Algesia (Pain) & Analgesia Mechanisms LOCAL ALGESIA: Mediated by nociceptor nerve axon conduction at voltage-gated Na+ channels along Nodes of Ranvier. Block channel & pain with local anesthetics like cocaine & derivatives NEUROPATHIC ALGESIA (NEURALGIA): Damage to peripheral nociceptors, or to spinal or cranial nerves. Lessen pain with neuroinhibitory analgesics, which include anticonvulsants TRIGEMINAL ALGESIAS: TRIGEMINAL NEURALGIA -- tooth, jaw, face pain jolts (Tic Douloureux) mediated by damaged PNS trigeminal nerve (cranial nerve V); & TRIGEMINALMEDIATED MIGRAINES. Lessen migraine pain or its neuronal & vasoactive triggers with neuroinhibitors &/or vasoactive drugs INFLAMMATORY ALGESIA, HYPERALGESIA, & ALLODYNIA: Damaged-cell prostaglandins cause local vasodilation, edema, & inflammatory cytokines that trigger supersensitized nociceptor (and CNS) activity for increased (“hyper-”) pain (“-algesia”) and also trigger other (“allo”) non-painful stimuli (e.g., light touches) to become painful (“-odynia”). Lessen inflammation-associated pain with non-specific PNS- + CNS- acting (NSAIDs) or specific CNS-acting (acetaminophen) prostaglandin blockers or autoimmune disease immunosuppressants like antirheumatics ENDORPHIN ANALGESIA: Endorphins (e.g., beta-endorphin, which binds the inhibitory Muopioid receptor [MOR]) lessen pain & make it irrelevant during Sympathetic Nervous System [SNS]-mediated “flight or fight” emergencies. This endogenous & short-term relief of pain can be reproduced long-term by opioid analgesics and illicit drugs like morphine NSAIDs Therapeutic Effects Hyperalgesia: Increased pain from a stimulus that should normally provoke pain. Damaged Cell PLA2 AA OW! COX 1 and 2 aspirin -- -}- }--} Prostaglandins (PGs) }----- ------} Vasodilation; Edema; Cytokine release (e.g., histamine, bradykinin, ATP); Local PNS Nociceptor & CNS Neurosensitization via G-protein-coupled Prostaglandin Receptors Allodynia: Pain from a stimulus that shouldn’t normally provoke pain. }---}------ }---- wtf?... }-------- }------ - NSAIDs Side-Fx (muck up COX1 makes: Gut & Kidney protective & upon injury proinflammatory Prostaglandin & Prostacyclin, and hemorrhagic Prostacyclin but ALSO thrombogenic Thromboxane ) Inflammatory COX2 makes: Upon injury proinflammatory Prostaglandin & Prostacyclin and hemorrhagic Prostacyclin but NO thrombogenic Thromboxane COX1 makes: Gut & Kidney protective & upon injury proinflammatory Prostaglandin & Prostacyclin, and hemorrhagic Prostacyclin but ALSO thrombogenic Thromboxane COX 1 COX 2 Aspirin (COX1,2 inhibitor, also irreversibly inhibits TXA in blood platelets) ibuprofen, naproxen (COX1,2 Inhibitors, naproxen longer half-life) Celecoxib (COX-2 inhibitor) Inflammatory COX2 makes: Upon injury proinflammatory Prostaglandin & Prostacyclin, and hemorrhagic Prostacyclin but NO thrombogenic Thromboxane INFLAMMATORY ALGESIAS (1) CELL DAMAGE-Induced Inflammatory Algesia Therapeutic Effect of NSAIDs: Inflammatory “algesia” (“pain”) is mediated by damaged cells’ PLA2 (Phospholipase A2) converting the cell’s bilayer outer-membrane wall’s bipolar phospholipids to the unipolar lipid-soluble long-chain fatty acid eicosanoid, AA (Arachidonic Acid), from which COX1 & 2 (Cyclooxygenase 1 & 2) then synthesize prostaglandins (PGs) such as PGE2 and PGI2 (“prostacyclin”) that diffuse from the damaged cells. These PGs then trigger local vasodilation, edema, & release of inflammatory & pyretic (fever-inducing) cytokines (like histamine, bradykinin, and ATP), and also, by binding neuronal excitatory G-protein coupled prostaglandin receptors, locally sensitize nearby PNS nociceptor neurons to pain signals & to the inflammatory cytokines (“peripheral sensitization”), and potentiate CNS spinal & brain pain circuits (“central sensitization”), which both increases firing of regional PNS nociceptors (i.e., hyperalgesia & allodynia) and increases CNS perception of pain. By blocking cell damage-induced COX1 & 2 production of local proinflammatory and pain-producing PGs, NSAIDs stop this process of inflammatory pain. NSAIDs also lessen pain from other sources (e.g., headache, arthritis) by inhibiting baseline- as well as nociception-induced- CNS (spine & brain) PG synthesis & signaling. Side-Effects of NSAIDs: Meanwhile, non-cell-damage-induced (i.e., normally-COX1 & 2-produced) prostacyclin (PGI2) and thromboxane (TXA2) normally maintain blood vessel homeostasis (prostacyclin vasodilates & stops platelet aggregation to allow blood to flow, while thromboxane does the opposite to cause blood clotting). Also, prostaglandin and prostacyclin normally protectively regulate kidney and stomach mucosal-wall homeostasis. But NSAIDs also block all these normal COX1 & 2-produced homeostatic organ effects, triggering the known Side-Fx (and *one alternate therapeutic use) of NSAIDs: stomach irritation & ulcers; kidney damage; *blood clotting inhibition & risk of hemorrhagic stroke; and, if the NSAID is more COX-2 selective, the side effects of blood clotting hyperactivation & risk of ischemic stroke or heart attack. INFLAMMATORY ALGESIAS (2) IMMUNE Damage-Induced Inflammatory Algesia Inflammation can arise NOT ONLY from the previously described direct cell damage (e.g., tissue injury, cartilage erosion & bone damage) but also from immunity (e.g., immune cells appropriately attacking invading microbes and infected body cells), and from autoimmunity (e.g., immune cells inappropriately attacking normal body cells). NSAIDs CAN alleviate inflammation & pain not only from physical injury and infection, but also from autoimmune Rheumatoid Arthritis (RA) and nonimmune Osteoarthritis (OA). But NSAIDs CANNOT prevent the autoimmune progression of RA (which CAN be prevented by immunosuppressants). Nor can NSAIDS prevent the chronic progression of the mechanical cartilage and bone destruction & deformation of OA (which cannot be prevented by any current drug therapies). NSAIDs are thus one of the only non-opioid treatments for OA, and only alleviate OA-associated regional inflammation & pain. NSAIDs by Chemical Class Will see again in Skaar’s clinical pharm course NSAIDs by % of COX1 vs. 2 Activity Will see again in Skaar’s clinical pharm course Aspirin [buffered acetylsalicylic acid] (ASP-uh-rin) Drug class: NSAID Analgesic Mechanism/selectivity: Non-specific but IRREVERSIBLE Cyclooxygenase (COX1) 1 & 2 INhibitor, prevents COX1 & 2 synthesis of proinflammatory prostanoids (prostagandins, prostacyclin, and thromboxane) from the long-chain fatty acid eicosanoid, Arachidonic Acid (AA) Physiological effects exploited in medical settings Analgesic (moderate-dose) Antiinflammatory (high-dose) Reduces COX1-dependent stomach mucosal wall cell protection (moderate-dose) Irreversibly inactivates (acetylates) COX1’s thromboxane synthesis in blood platelets (low dose) – platelets remain enucleated (DNA-free) during their 9-day lifetime and can’t synthesize new replacement COX1 “Unique Rx AS a Platelet IRreversible Inhibitor” Medical uses Alleviates mild to moderate pain Lessens inflammation & inflammatory pain Prevents ischemic heart attacks, pulmonary embolisms, strokes, and peripheral arterial disease & phlebitis – but don’t take with other NSAIDs, as they will block Aspirin’s irreversible COX1 inhibition and cardioprotection. Side-Fx Long-term use of NSAIDs of a given chemical class (e.g., salicylic, propionic, enolic acid) can allow resistance to the drug (switch to an NSAID of different chemical class) -- Aspirin’s chemical class is a salicylic acid. Stomach irritation leading to bleeding, ulcers, perforated stomach & abdominal sepsis (caused by loss of PGinduced loss of protective stomach lining) –> can be fatal Excessive bleeding and hemorrhagic strokes Large doses are zero-order metabolized (like alcohol), increasing risk of toxicity, kidney injury, & OD fatality US trade names (not testable): Aspirin is both generic & trade name due to early trademark lapse by Bayer Co. Ibuprofen (eye-byoo-PRO-fin) Drug class: NSAID Analgesic Mechanism/selectivity: Non-specific reversible Cyclooxygenase (COX1) 1 & 2 inhibitor, prevents COX1 & 2 synthesis of proinflammatory prostanoids (prostagandins, prostacyclin, and thromboxane) from the long-chain fatty acid eicosanoid, Arachidonic Acid (AA) Physiological effects exploited in medical settings Analgesic (moderate-dose) Antiinflammatory (high-dose) Reduces COX1-dependent stomach mucosal wall cell protection (moderate-dose) Fast oral absorption, short half-life, 90% plasma protein bound (few drug interactions) “PROstanoids FENd off” Medical uses Alleviates mild to moderate pain (fast-acting, short-lived, few drug interactions) Lessens inflammation & inflammatory pain Side-Fx Long-term use of NSAIDs of a given chemical class (e.g., salicylic, propionic, enolic acid) can allow resistance to the drug (switch to an NSAID of different chemical class) – Ibuprofen’s chemical class is a propionic acid. Stomach irritation leading to bleeding, ulcers, perforated stomach & abdominal sepsis (caused by loss of PGinduced protective stomach lining) –> can be fatal Risk of CV accidents (black-box warning on all NSAIDs) US trade names (not testable): Advil®, Motrin® Naproxen (nuh-PROX-in) Drug class: NSAID Analgesic Mechanism/selectivity: Non-specific reversible Cyclooxygenase (COX1) 1 & 2 inhibitor, prevents COX1 & 2 synthesis of proinflammatory prostanoids (prostagandins, prostacyclin, and thromboxane) from the long-chain fatty acid eicosanoid, Arachidonic Acid (AA) Physiological effects exploited in medical settings Analgesic (moderate-dose) Antiinflammatory (high-dose) Reduces COX1-dependent stomach mucosal wall cell protection (moderate-dose) Sodium salt form (e.g., naproxen sodium) faster absorbed for better analgesia than base form; but half-life (9-25hrs) for extended duration of action. “Can NAP because of long-half life” Medical uses Alleviates mild to moderate pain (fast-acting, long-lived) Lessens inflammation & inflammatory pain Side-Fx Long-term use of NSAIDs of a given chemical class (e.g., salicylic, propionic, enolic acid) can allow resistance to the drug (switch to an NSAID of different chemical class) – Naproxen is another propionic acid. Stomach irritation leading to bleeding, ulcers, perforated stomach & abdominal sepsis (caused by loss of PGinduced protective stomach lining) –> can be fatal Risk of CV accidents (black-box warning on all NSAIDs) US trade names (not testable): Aleve® Celecoxib (cell-uh-COX-ib) Drug class: NSAID Analgesic Mechanism/selectivity: Reversible COX2 > COX1 inhibitor, prevents COX2 synthesis of proinflammatory prostanoids (prostagandins, prostacyclin, but NOT thromboxane) from the longchain fatty acid eicosanoid, Arachidonic Acid (AA) Physiological effects exploited in medical settings Analgesic (moderate-dose) Antiinflammatory (high-dose) Prothrombotic (all doses), due to inhibiting COX2 production of vasodilating & hemorraghic prostacyclin while NOT inhibiting production of vasoconstricting and thrombogenic prostanoid thromboxane (TXA2) LESS reduction of COX1-dependent stomach mucosal wall cell protection (moderate-dose) “Hard Sell (CEL) this inhIBitor too (2)!” Medical uses Alleviates mild to moderate pain Lessens inflammation & inflammatory pain LOWER risk than from other NSAIDs of stomach irritation, ulcers, perforation, & abdominal sepsis Side-Fx Long-term use of NSAIDs of a given chemical class (e.g., salicylic, propionic, enolic acid) can allow resistance to the drug (switch to an NSAID of different chemical class) – Celecoxib is a pyrazole & COX2-specific inhibitor (slightly more COX-2 specific than the most COX-2 selective of older NSAIDs, diclofenac). HIGHER risk, compared to other NSAIDs and especially to irreversible platelet-thromboxane inhibitor Aspirin, of thrombus/blood clot-caused (i.e., ischemic) heart attacks, pulmonary embolisms, strokes, peripheral arterial disease & phlebitis US trade names (not testable): Celebrex® Acetaminophen (ah-SET-ah-MIN-o-fin) Drug class: Non-NSAID (Not Anti-Inflammatory) But Antipyretic CNS Analgesic Mechanism/selectivity: CNS-localized (Spine & Brain) Non-Specific Reversible Cyclooxygenase (COX1) 1 & 2 peroxide-site inhibitor, prevents synthesis of CNS pain-perception mediating prostanoids (prostagandins, prostacyclin) from the long-chain fatty acid eicosanoid, Arachidonic Acid (AA); also its liver-deacetylated and brain-Fatty Acid Acyl Hydrolase (FAAH)-synthesized active metabolite, AM404, inhibits the synaptic reuptake & metabolic degradation of pain-inhibiting AnandaMide (the brains’ endogenous cannabinoid agonist) Physiological effects exploited in medical settings Analgesic (moderate-dose) as CNS COX inhibitor, and (as active metabolite) an anandamide reuptake inhibitor LESS stomach COX1,2 inhibition than NSAIDs Fast oral absorption, short half-life Medical uses “ACETylcysteine cures OD” & “AM404” & “anti-INflammatory? Zero (O)!” P.S. “404” means “Riot” in police code... J Alleviates mild to moderate pain (fast-acting, short-lived) Lessens CNS perception of pain even more if combined with codeine or, even moreso, with ibuprofen or other NSAIDs (see next slide) Side-Fx Hepatotoxic (above 4000mg/day, or > eight 500mg extra-strength pills within 24hrs) in normal individuals à OD is lethal at >20g (day 1-2 gastric distress, day 3-4 death by liver necrosis); prevent lethal OD by early admin (within 8-16hr after lethal dose ingested) of n-acetylcysteine to increase glutathione (NAPQI-inactivator) Liver disease (Gilbert’s), fasting or malnutrition, CYP2E1 inducers or alcohol use/misuse (NAPQI [N-Acetyl-PbenzoQuinoneImine] metabolite causes mitochondrial death, O2 stress) increase hepatotoxicity at lower doses LOWER risk than NSAIDs of stomach irritation, bleeding, ulcers, perforated stomach & abdominal sepsis US trade names (not testable): Tylenol® Ibuprofen + Acetaminophen Drug class: Strongly Analgesic Non-Opioid 2-Drug Combination (FDA-approved) Mechanism/selectivity: PNS PLUS CNS reversible Cyclooxygenase COX1 & 2 inhibitor, PLUS Precursor of Brain AM404 (an Anandamide Reuptake Inhibitor [ARI]) Physiological effects exploited in medical settings Strong Analgesic (moderate-dose), due to ibuprofen’s NSAID inhibition of peripheral & central COX pain signaling plus acetaminophen’s inhibition of brain COX & also anandamide reuptake Ibuprofen-like antiinflammatory NSAID action (moderate-dose) Ibuprofen-like NSAID reduction of COX1-dependent stomach mucosal wall cell protection (moderate-dose) Acetaminophen-like hepatotoxic metabolites (in OD or with liver disease) Fast oral absorption, short half-life “OFEN + OPHEN” is the drug-drug combo! Medical uses Alleviates moderate to severe pain (fast-acting, short-lived) – analgesia reportedly synergistic, and superior to “opioid (codeine) + acetaminophen” for both inflammatory & acute (e.g., broken bone, tooth extraction) severe pain Lessens inflammation & inflammatory pain as an NSAID-containing drug-combo Side-Fx Ibuprofen-like risk of stomach irritation leading to bleeding, ulcers, perforated stomach & abdominal sepsis (caused by PG-induced loss of protective stomach lining) –> can be fatal Acetaminophen-like risk of hepatoxicity à can be fatal in OD US trade names (not testable): FDA approved Advil Dual Action® (with Ibuprofen), vs. Tylenol-4® (with codeine) NSAIDs: PTQ Any NSAID can in principle work with acetaminophen as a 2-drug combo to improve analgesia. But which one did a drug manufacturer get FDA approval to use? A. Aspirin B. Ibuprofen C. Naproxen D. Celecoxib NSAIDs: PTQ CORRECT ANSWER Any NSAID can in principle work with acetaminophen as a 2-drug combo to improve analgesia. But which one did a drug manufacturer get FDA approval to use? A. Aspirin -- Studies have shown aspirin and acetaminophen to work well, too; but Bayer didn’t seek FDA approval to market that combination preparation -- unlike Glaxo-Smith-Kline (GSK), the makers of Advil’s dual action combo of Ibuprofen + acetaminophen. B. Ibuprofen -- Ibuprofen + acetaminophen (“ofen + ophen”) is the FDA approved combination, but other studies have shown aspirin and acetaminophen to work as well (and both combos to work BETTER than opioid codeine + acetaminophen!) C. Naproxen -- This long-half life NSAID wasn’t chosen to be studied with short-half life acetaminophen. (If you don your scientist boots, you can guess why...That’s right! The dosing schedule would be “complicated.” You couldn’t always take both drugs at the same time!) D. Celecoxib – This COX-2 selective NSAID wasn’t chosen to be studied with acetaminophen either. Why do you think? Probably because 1) It barely got FDA approved by itself, and 2) both COX-1 inhibition and COX-2 inhibition mediate some aspects of peripheral sensitization and central sensitization of pain signaling, and you want your 2-drug combo to be as effective as possible, not just avoid stomach side-Fx. (Besides, acetaminophen does cause some stomach irritation. NSAIDs: PTQ YOUR MAIN STUDY TIP? Any NSAID can in principle work with acetaminophen as a 2-drug combo to improve analgesia. But which one did a drug manufacturer get FDA approval to use? A. B. As mentioned in the first slide (“Session Objectives”), Aspirin -- Studies have shown aspirin and acetaminophen to workknow well, too;the but Bayer didn’t seek FDA approval to market that combination preparation -- unlike Glaxo-Smith-Kline (GSK), the MOA, the makers of Advil’s UNIQUE dual action combotraits of Ibuprofenwithin + acetaminophen. Physiological Effects, Uses, Side-Fx & Ibuprofen -- Ibuprofen + acetaminophen (“ofen + ophen”) is the FDA approved combination, Dentistry-Relevant Info of Each Drug but other studies have shown aspirin and acetaminophen to work as well (and both combos to Class & Each Drug (also on Druglist): work BETTER than opioid codeine + acetaminophen!) Aspirin, Ibuprofen, Naproxen, Celecoxib, Acetaminophen, Ibuprofen+Acetaminophen C. Naproxen -- This long-half life NSAID wasn’t chosen to be studied with short-half life acetaminophen. (If you don your scientist boots, you can guess why...That’s right! The dosing schedule would be “complicated.” You couldn’t always take both drugs at the same time!) D. WHY? So You Can Match the NAME of the Drug Class or Drug to Each TQ’s One (orNSAID More) UNIQUE Celecoxib – This COX-2 selective wasn’tProvided chosen to be studied with acetaminophen either. Why do you think? Probably because 1) It barely got FDA approved by itself, and 2) both Identifying Properties of that Drug or COX-1 inhibition and COX-2 inhibition mediate some aspects of peripheral sensitization and central sensitization of pain signaling, and Drug you want your 2-drug combo to be as effective as Class. possible, not just avoid stomach side-Fx. (Besides, acetaminophen does cause some stomach irritation. Analgesics: Opioid Agonists & Antagonists SESSION OBJECTIVES Ø For Future Clerkships & National Board Dental Exams: Know these traits of each listed drug (and its similar drugs): Name, class, mechanism of action, physiological effects, uses, major side-Fx, and the dentistryrelevant information within these categories. Ø For DDS Exams: Be able to match a drug’s provided name or class to one or more of its provided unique traits. Also be able to complete the below Key Concepts. Ø Key Concepts: Opioid drugs act on the same target (MOR) but vary in potency, pharmacokinetic distribution, metabolism, & secondary properties; Pain Relief and Sedation conferred by Direct PNS & CNS neuroinhibition, while Euphoric Reward conferred by Indirect Dopaminergic Action. Dr. Burton declares no conflict of interest regarding drugs discussed in this lecture Supplemental reading Pharmacology and Therapeutics for Dentistry (7th edition) Frank H. Burton, PhD Dept. of Pharmacology, UMN S3.220 HHRI-HCMC [email protected] HISTORY OF OPIOIDS Opium: from asian poppy, the “Hul Gil,” or “Flower of Joy” à dried sap à morphine Morpheus, Greek God of Dreams, Son of Hypnus "Presently she cast a drug into the wine of which they drank to lull all pain and anger and bring forgetfulness of every sorrow." The Odyssey, Homer (900 BCE) HISTORY OF OPIOIDS Papaver somniferum – 1753 Linnaeus Morphine extracted in 1803 by Sertuner Followed by codeine and papavarine 1895 Bayer produces heroin as antitussive (cough). Assumed to be LESS addictive (!) 1905 US congress bans opium Pethidine/meperidine first synthetic opioid 1932, Methadone 1949 1960s methadone for addiction 1970s endogenous opioids identified 1990s opioid receptors cloned 2010s prescription opioids misused Today: Opioid OD death rate still increasing Dentists 5th highest Rx-ers of opioids Your PNS Nociceptor Nociceptor Afferent Fiber on MOR Gi é K+ channel Nociceptor soma ê cAMP MOR Synapse , Postsynaptic Dendrite in Spinal Cord via blood (intermediate pituitary) Gi Axon -releasing Spinal Cord Dorsal Horn Interneuron IN BRAIN?: Same. Endorphins dumped on pre- & postsynaptic MORs How is Pain Transmitted & Suppressed? Big Brain OW! CNS PNS “Endorphin” [“ENDOgenous mORPHINe”] Euphoria & Pain-Irrelevancy (CNS) Thalamus Brainstem PAG “Endorphin” Analgesia (CNS) “Endorphin” Local Spinal Spinal cord Analgesia (CNS) How is Pain Transmitted & Suppressed? Acetaminophen “Endorphin” [“ENDOgenous mORPHINe”] Euphoria & Pain-Irrelevancy (CNS) Big Brain Opioids NSAIDs Thalamus Neuroinhibitors OW! Brainstem PAG CNS Neuroinhibitors PNS NSAIDs Locals Antirheumatics “Endorphin” Analgesia (CNS) Opioids “Endorphin” Local Spinal Spinal cord Analgesia (CNS) Opioids Dental Pain Transmitted & Suppressed! Acetaminophen “Endorphin” [“ENDOgenous mORPHINe”] Euphoria & Pain-Irrelevancy (CNS) Big Brain Opioids NSAIDs Thalamus Neuroinhibitors OW! Brainstem PAG Pons CNS Neuroinhibitors PNS NSAIDs “Endorphin” “Endorphin” Analgesia Local (CNS) Pons Opioids Analgesia (CNS) Trigeminal Nerve Opioids Spinal cord Locals Antirheumatics Algesia (Pain) & Analgesia Mechanisms LOCAL ALGESIA: Mediated by nociceptor nerve axon conduction at voltage-gated Na+ channels along Nodes of Ranvier. Block channel & pain with local anesthetics like cocaine & its derivatives NEUROPATHIC ALGESIA (NEURALGIA): Damage to peripheral nociceptors, or to spinal or cranial nerves. Lessen pain with neuroinhibitory analgesics – which include many anticonvulsive drugs & THC or CBD containing pot TRIGEMINAL ALGESIAS: TRIGEMINAL NEURALGIA -- tooth, jaw, face pain jolts (Tic Douloureux) mediated by damaged PNS trigeminal nerve (cranial nerve V); & TRIGEMINALMEDIATED MIGRAINES. Lessen pain or its neuronal & vasoactive triggers with neuroinhibitors &/ or vasoactive drugs INFLAMMATORY ALGESIA, HYPERALGESIA, & ALLODYNIA: Damaged-cell prostaglandins cause local vasodilation, edema, & inflammatory cytokines that trigger supersensitized nociceptor activity for increased (“hyper-”) pain (“-algesia”) and also trigger other (“allo”) non-painful stimuli (e.g., light touches) to become painful (“-odynia”). Lessen pain with NSAIDs, CNS prostaglandin blockers (acetaminophen), or autoimmune immunosuppressants such as antirheumatics ENDORPHIN ANALGESIA: Endorphins (e.g., beta-endorphin, which binds the inhibitory Mu-opioid receptor [MOR]) lessen pain & make it irrelevant during Sympathetic Nervous System [SNS]-mediated “flight or fight” emergencies. This endogenous & short-term relief of pain can be reproduced long-term by opioid analgesics Mu OPIOIDS (DRUG CLASS) MECHANISM: Agonists of neuroinhibitory Mu Opioid Receptor (MOR) named for early discovery that it bound Morphine. Natural ligand is beta-endorphin (from POMC peptide) DRUG CHOICE: Consider affinity (agonist or partial agonist), potency (ED50), kinetics (half-life, CYP2D6 liver metabolism-rate polymorphisms, differentially analgesic or excitatory glucuronide metabolites, excretion by glomerular filtration with kidney complications); route (i.v. > i.m. > epidural > oral/coated > topical/mucosal for speed & clearance); cost (generic?); addictive potential with long-term use [>1week] (coated but highly potent? Oxycodone [Oxycontin®] Rxs increased 5x from ‘90s to 2010’s) MEDICAL USES [# tolerance (Fx lessen by scaling-up dose); *no tolerance (Fx worsen with dose)]: # Peaceful euphoria # Analgesia # Sedation (inhibits vasomotor center, activates parasympathetic vagus nerve, in high doses leading to bradycardia and hypotension) # Antitussive *Antidiarrheal SIDE-Fx [# tolerance; *no tolerance]: 3’ morphine # Nausea/Vomiting (Medulla CTZ) 6’ # Respiratory Suppression (Medulla); “NA to DOA!” (Can tolerate lethal doses only until addiction is broken) # CV Suppression (bradycardia, hypotension, including fainting when rising from dentist’s chair) # Pruritis & Urticaria (mast cell histamine respectively causes itching & hives; not an allergy – a MOR allele!) # Urinary retention (increased smooth muscle tone, reduced bladder constriction & fullness signaling) * Miosis [constricted pupils] * Constipation (inhibits peristalsis via ENS [Enteric Nervous System]), worsens to megacolon at high doses * Addictive (MOR agonists inhibit the VTA’s GABAergic interneurons, thus indirectly excite the VTA’s euphoric & rewarding dopamine [DA] release to the NAc) * Rebound withdrawal hyperalgesia & autonomic sympathetic effects * Mu opioid use (particularly chronically) also causes dry-mouth (xerostomia) by salivary gland neuroinhibiti

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