DDS 6215 Analgesics_Mechanisms, Migraines, & Antirheumatics Burton Lecture Slides.pdf
Transcript
Analgesics: Mechanisms, Migraine Drugs, Antirheumatics 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 inf...
Analgesics: Mechanisms, Migraine Drugs, Antirheumatics 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 within these categories. Ø For DDS Exams: Be able to match a drug’s (and, for this lecture, an algesia or analgesia mechanism’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: Pain involves PNS, Spinal, & Brain Nociception in the forms of Local Algesia, Neuropathic Neuralgia (including Trigeminal Neuralgia & Migraines), and Inflammatory Algesia (including Hyperalgesia, Allodynia, & Autoimmune Inflammation), while Endogenous Analgesia is provided by Beta-Endorphin. Pharmacological analgesia is provided by NSAIDs, CNS prostaglandin blockers, neuroinhibitors, immunosuppressive antirheumatics, and opioids; Migraine drugs are neuroinhibitory (GABAergics or Antiglutamatergic Calcium or Sodium Channel Blockers, Botulinum toxin) and/or vasoactive (corrective systemic Vasoconstrictive Triptans, preventive systemic Vasodilating Alpha- or Beta-blockers, and preventive Meningeal-VasodilationBlocking huMAbs). 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] PAIN + ENDORPHIN CIRCUITRY Traite de l’Homme [Treatise of Man] by Renee Descartes: “A long fiber running from the foot to the cavity in the head is pulled by the heat and releases a fluid that makes the muscles contract.” Not too bad for 1664 CE, but... NOPE! What is “Pain”? PNS, SPINAL, BRAIN Nociception Activation of PNS Nociceptors (neurons that can sense injurious stimuli -can be polymodally gated by harmful thermal, chemical, mechanical &/or immune-inflammatory insults) Ascending Neurotransmission (afferent Glu & SubP toward & then up the spinal cord) Non-volitional Motor Reflex Response (extreme injury, or “nociceptor hyperactivation,” can trigger a direct spinal neuromuscular withdrawl reflex, prior to any afferent transmission to the brain) Brain perceptual, emotional, & cognitive processing (perceives nociception as “pain,” provides emotional context, processes & deliberates on it cognitively, then initiates a... Volitional Motor Response What “Good” is Pain? Warning System to Entrain Survival Behavior: People who feel no pain (e.g., SCN9A mutation eliminating nociceptorspecific NaV1.7 Na+ channel subunit, or FAAH-OUT mutation preventing anandamide metabolic removal), can die from serious injuries because they have no nociceptive warning system for aversive learning. Ensures Injury Protection & Physiological Healing: Sensitizes injured areas to even minor touch, to prevent further tissue damage. Releases cytokines, vasodilators, & wound repair effectors promoting blood supply, immune surveillance, & healing. ow? 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 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 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 non-specific (NSAID) or CNS-specific (acetaminophen) prostaglandin blockers, or autoimmune immunosuppressants like 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 and drugs of abuse like morphine LOCAL ALGESIA: “ ATORY” NOCICEPTOR CONDUCTION Local Anesthetic Adelta Fiber myelin Depolarization “leaps” (Latin:“saltare”) down cytoplasm between unmyelinated Nodes of Ranvier’s voltage-gated Na+ channels à super-fast (~20m/s)! Smaller diameter nociceptor fibers can’t depolarize (fire) if these channels are blocked, so no nociception occurs (and in LARGER local anesthetic doses capable of acting on LARGER-diameter axons of touch & motor neurons, no sensation or motion occurs, either!) NEUROPATHIC ALGESIAS (Neuralgias) SYMPTOM(S): Algesia (pain) Dysesthesia (abnormal excess sensation) CAUSE: Damage to Peripheral Nociceptors, Spinal Nerves, or Cranial Nerves (see Trigeminal Neuralgia). Can arise from... Pressure on nerves (from impacts [funny bone], spinal-disc or muscle compressions [sciatica], tumors, edema, surgical scarring, swollen joints & tendons [RA & OA, tendonitis], aneurysms, or abnormal vasodilation [migraine]) Aging Neurological Disorders (e.g., Fibromyalgia) Nerve-Demyelinating Diseases (e.g., Multiple Sclerosis [MS]) Inflammation (Infectious or Autoimmune) Amputation & consequent denervation-rebound supersensitization and/or somatosensory topographic redirection (or “remapping”) of denervated spinal cord & brain neurons [e.g., phantom-limb algesia or dysesthesia. (Alleviate by rubbing “mirrored” &/or “remapped” body area, e.g., rub left leg or right cheek to alleviate pain “felt by” right amputated limb]. TRIGEMINAL ALGESIAS TRIGEMINAL NEURALGIA (“Tic Douloureux”) Facial nociceptors’ dendrites extend up Cranial Nerve V (Trigeminal Nerve, innervating teeth, jaw, and face) to trigeminal ganglion near base of brain. Nerve pressure (e.g., aneurysms) or demyelination/scarring (e.g., age, multiple sclerosis) causes inappropriate firing, felt as jolts of tooth, jaw, &/or face pain. TRIGEMINAL GANGLIONIC MIGRAINES The trigeminal ganglion (root of Cranial Nerve V) at the base of the brain mediates migraine attacks & pain (4-72 hour throbbing headache, nausea, phono/photophobia, sometimes preceded by visual “aura”) by *sequentially releasing local vasoconstrictive 5-HT (causing auras) & later excitatory ACh & Substance P, triggering meningeal nerve release of meningeal blood vessel-vasodilating CGRP [Calcitonin Gene-Related Peptide] (causing headache). [*Sequence of events may (or may not?) be initiated or amplified by CNS “cortical spreading depression” (CSD)] INFLAMMATORY ALGESIA Damage PLA2 AA COX 1 and 2 CELL Prostaglandins Vasodilation & Edema Cytokine Release by Tissue & *T-cells (inflammation, fever) *Autoimmune T-cells can similarly cause inflammation/fever Peripheral Nociceptor Activation (pain conduction) [CNS has prostaglandins too -- increases central pain perception] INFLAMMATORY ALGESIAS NORMAL Inflammatory Algesia Mediated by damaged cells’ PLA2 [Phospholipase A2] conversion of membrane lipids to AA [Arachidonic Acid], from which COX1 & 2 [Cyclooxygenase 1 & 2] then synthesizes prostaglandins that diffuse from the damaged cells. The prostaglandins trigger local vasodilation, edema, & inflammatory & pyretic (feverinducing) cytokines, which act on local nociceptor neurons to both CAUSE nociceptor firing (algesia) and AGGRAVATE nociceptor firing severity (i.e., hyperalgesia & allodynia) AUTOIMMUNE Inflammatory Algesia Inflammation can arise NOT ONLY from damage & infection (e.g., immune cells appropriately attacking invading microbes and infected body cells) but ALSO from autoimmunity (e.g., immune cells inappropriately attacking normal body cells) HYPERALGESIA & ALLODYNIA Damaged Cell PLA2 OW! AA COX 1 and 2 Prostaglandins }-----}- }--}---}-------- Vasodilation Edema Cytokines wtf?... }---}------ }---}-------- }------ - HYPERALGESIA & ALLODYNIA Local vasodilation, edema, inflammation, & cytokines act BOTH on ADJACENT nociceptor neurons to cause supersensitization (“hyper-”) of their activation of painsignaling (“-algesia”), as well as on OTHER (“all-”) more distant nociceptors to induce pain (“-odynia”) even in response to normally NON-painful stimuli (such as a feather-touch) ENDORPHIN “ANALGESIA” MECHANISM: Neuroinhibitory Mu (µ), Kappa (κ) and delta (δ) opioid receptor [MOR, KOR, & DOR] binding by short-lived “endorphin” (“endogenous morphine”) agonists, Enkephalin [MOR, DOR], β-Endorphin [MOR], Dynorphin [KOR]). Main endorphin, & main analgesic target? βEndorphin, acting on neuroinhibitory Gi-coupled MORs (“Mu for MOR for MORPHINE”) CIRCUITS: “Endorphin” Euphoria & Pain Irrelevancy: Induced by locally released opioids within brain’s cortex, amygdala, & thalamus OW! “Endorphin” Analgesia: Induced in brainstem by descending brain hypothalamic arcuate nucleus endorphins suppressing brainstem PAG & medulla dorsal horn’s ascending pain transmission “Endorphin” Local Spinal Analgesia: Induced by these brainstem areas releasing 5-HT or NE to SC dorsal horn endorphin-releasing interneurons that then suppress nociceptor axons’ SubP release “Endorphin” Systemic Anti-Nociception: Pituitary gland endorphin secretion can also systemically calm nociceptors BENEFIT: Mediates temporary extreme analgesia, particularly upon emergency/bad wounding 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 Beta-Endorphin MECHANISM: Neuroinhibitory peptide cleaved from POMC (pro-opiomelanocortin) Strongest natural ligand (endogenous agonist) of the neuroinhibitory Mu opioid receptor (MOR) mediating CNS euphoria & analgesia, & spinal cord and PNS anti-nociception EFFECTS: Peaceful, calm euphoria (CNS) Analgesia (PNS) Pain irrelevancy (CNS) USES: Runners High; Nirvana (+anandamide, 5HT, DA) Detachment from extreme physical trauma, in emergency “fight or flight” situations (+NE & Adr ) MIGRAINE NEURALGIA Hieronymus Bosch, 1500 CE Mattias Grünewald, 1512 CE “The Temptation of St. Anthony” HISTORY OF MIGRAINES Trepanning (stone-age) Ergot Fungus (St. Anthony’s Fire): Bad rye caused hallucinations, and hands and feet to burn like fire and then drop off, gangrenous! -- Common and incurable from 200’s BC to recent times. Low Dose Ergot extract (Ergotamine): 3 sclerotia slowed bleeding & induced contractions during birth (Midwives, Middle Ages.) Ergotamine alleviated migraines (splitting headache +/- auras) via smooth muscle contraction in brain blood vessels (vasoconstriction) (1800’s). What Triggers a Migraine? Ganglia 5-HT! ACh, SubP! CGRP Vasodilation Vasoconstriction Meningeal Blood Vessel Time 1 Time 4 Time 2 Time 3 [------ AURA ------] OW! Pre-Migraine Auras Pre-Migraine Auras Migraine Drug CLASSES neuroinhibitory anticonvulsant & neuraglia drugs &/or vasoactive drugs Two Anticonvulsants as Migraine Preventives (Vasodilation Trigger-Block) 1. GABA Channel Activators: (topiramate) 2. Low-Threshold (T-type) Calcium Channel Blockers: (divalproex) 3. Calcium Channel Blockers 4. Synaptic Vesicle Blocker 5. Sodium Channel Blockers: (divalproex, topiramate) 6. Antiglutamatergic CB1 & Glycine Agonist, & Anandamide Clearance Blocker 7. GABA Clearance Blocker: (divalproex) 8. Glutamate AMPA Receptor Blocker: (topiramate) Other Migraine Preventives or Migraine Reversers 9. Migraine Preventive -- Vasodilation Trigger-Blocking Neurotoxin: (onabotulimtoxinA) 10. Migraine Preventive -- Direct Vasodilation-Blocking HuMAb: (erenumab) 11. Migraine Preventive -- Chronic Systemic Vasodilating Alpha- or Beta-Blockers: (amitriptyline [alpha], propranolol [beta]) 12. Migraine REVERSER – Vasodilation-Reversing Vasoconstrictive Triptan: (sumatriptan) Migraine Drugs’ Physiological Effects NSAID (& Related) Analgesics: Reduce CNS prostaglandins causing migraine pain. Don’t work great individually (migraines are pretty severe)! – NOT TESTED Cerebral Vasodilation Blockers: PREVENT neurotransmitter or neuromodulatory peptide triggers of migraine attack’s final meningeal vasodilation & pain (divalproex, topiramate, onabotulinumtoxinA, erenumab) Chronic Systemic Vasodilators: PREVENT migraine attack’s initial acute meningeal vasoconstriction &/or final acute meningeal vasodilation & pain (amitriptyline, propranolol) Cerebral Vasoconstrictors: REVERSE migraine attack’s final acute meningeal vasodilation & pain (sumatriptan) Divalproex [Valproic Acid] (DIE-val-PRO-ex) Drug class: Anticonvulsant, Migraine Preventive, Bipolar Antidepressant Mechanism/selectivity: Broad Spectrum: Promotes Increased Inhibitory GABA Levels (by Blocking GABA Transaminase & GABA Clearance); Blocks Excitatory Na+ Channels; Blocks Thalamic Excitatory Low Threshold T-Type Ca2+ Channels Underlying Absence Seizures Physiological effects exploited in medical settings Neuroinhibition “DIVALPROeX = DIstended Vessels, ALL Seizures, PRO ‘X’ (GABA)” Medical uses All Seizure Types Migraine Prevention (neuroinhibits meningeal vasodilation, preventing the distention of blood vessels triggering migraine pain) Bipolar Depression Side-Fx GI Upset (nausea) Teratogen (Fetal IQ Loss, neural tube defects) Lowers Vitamin D (impedes bone formation) Hepatotoxic (rare but potentially fatal) Drug Interactions (inhibits metabolic clearance of other drugs) US trade names (not testable): Depakote® DENTISTRY Nausea Impedes bone formation Topiramate (toe-PEER-ah-mate) Drug class: Anticonvulsant, Migraine Preventive Mechanism/selectivity: Blocks Voltage-Gated Na+ Channels; Blocks Glutamate AMPA Receptors; Enhances Inhibitory GABA Receptors “TOP of head = migraine” “TOPIRAM[P]ATE” Physiological effects exploited in medical settings Neuroinhibition Medical uses All Seizures OTHER than Status Epilepticus (most effective for Lennox-Gastaut syndrome and for partial-onset & primary generalized tonic-clonic seizures) Migraine Prevention (neuroinhibits meningeal vasodilation, preventing the distention of blood vessels triggering migraine pain) Alcoholism DENTISTRY Sedation (additive) Side-Fx Sedation, Slow speech, Slow cognition, Skinny, Sight damage (glaucoma), Stones (kidney) Teratogen (Cleft Palate) Drug Interactions (stimulates liver P450 CYP3A, inactivating steroid contraceptives) US trade names (not testable): Topamax® OnabotulinumtoxinA [Botulinum Toxin A] (OWN-ah-BOTCH-u-LINE-um-TOX-in-A) Drug class: Migraine Preventive TOXIN Mechanism/selectivity: Head Intramuscular-Injected Neurotoxin: Transported up Somatic Afferents of the Trigeminal Nerve to Trigeminal Ganglia, then Blocks SNAP-25 (SyNaptosomalAssociated Protein-25) Mediated Synaptic Release of Excitatory Neurotransmitter/Neuromodulator Meningeal-Vasoactive Triggers of Migraine “I’m not a roBOT” Physiological effects exploited in medical settings Neuroinhibition (peripherolytic anticholinergic) Muscle flaccid paralysis (neuromuscular junction anticholinergic) Medical uses Migraine Prevention (stops meningeal vasodilation trigger) Wrinkle Reduction (induced flaccid paralysis of muscles) Muscle Spasticity (paralyzes ACh neuromuscular junctions) Hyperhidrosis (paralyzes ACh input to sweat glands) Side-Fx Facial, Head, Glottis Paralysis (misplaced injection spreads to nearby muscles) Reduced facial expressiveness (excessive or misplaced injections) US trade names (not testable): Botox® Erenumab (eh-REN-you-mab) Drug class: Migraine Preventive HuMAb Mechanism/selectivity: Humanized Monoclonal Antibody (HuMAb): Prevents Brain Meningeal Vessel Final Vasodilation Step Underlying Migraine Pain (which is normally triggered by Trigeminal Ganglia-Release of Vasodilating Neuromodulatory Peptide “Calcitonin Gene-Related Peptide [CGRP]”) by Directly Blocking the CGRP Receptor on Meningeal Blood Vessels “ERE...MAb” = “Before...Migraine” Physiological effects exploited in medical settings Prevents meningeal blood vessel vasodilation Medical uses Migraine Prevention (periodic i.v. injection – reduces number of migraine days by 42%) US trade names (not testable): Aimovig® Amitriptyline (ay-mee-TRIP-tih-leen) Drug class: Tricyclic Antidepressant (TCA), Neuralgia Drug, Migraine Preventive Mechanism/selectivity: 1st Generation SNRI (inhibits brain 5HT & NE reuptake), but also nonselective strong anticholinergic, antiadrenergic, & Na+ Channel inhibitor “AMiTRI = AM a TRIcyclic” Physiological effects exploited in medical settings Elevates Mood (empathogenic & sympathomimetic stimulation from elevating CNS 5HT & NE levels) Peripheral Vasodilation (strong peripheral antiadrenergic [alpha-1 antagonist] effect) Neuroinhibition (CNS Na+ Channel inhibition) Sedation (strong anticholinergic CNS effect) Medical uses 1st Gen TCA SNRI, for Unipolar Depression – less safe (more non-SNRI effects) than later 2nd Gen SNRIs Treatment-Resistant Depression Anxiety DENTISTRY Chronic Headache & Migraine Prevention [Vasodilation + Neuroinhibition] Neuralgias (TMJ / Trigeminal, Migraine, Herpetic, Traumatic, Fibromyalgia) Treatments For TMJ neuralgic pain Side-Fx Antiadrenergic Risks Serotonin-syndrome interaction with MAO-Is, SNRIs, SSRIs & other drugs Faint while standing Orthostatic hypotension; reduces cardiac output Falls Cardiotoxic interaction if accidentally i.v. inject vasoconstricting anesthetics Cardiotoxic drug interaction Prolongs Heart QT Interval (PNS Na+ Channel inhibition) with vasoconstrictors CNS Sedation, Confusion, Hallucination Anticholinergic Risks PNS Tachycardia Dry Mouth PNS Anti-SLUDs (anti-Salivation, -Lacrimation, -Urination, -Defecation) Caries Potentiates other sedatives & anesthetics Sedation (additive) Coma/Death in OD US trade names (not testable): Elavil® (amitriptyline) Propranolol (pro-PRAN-uh-lol) Drug class: Migraine Preventive Mechanism/selectivity: Beta Blocker, non-selective vasodilating action (beta-1 & -2) “LOL prevents stress & migraine!” Physiological effects exploited in medical settings Hypotensive: Chronic systemic mild vasodilation includes vasodilating Brain Meningeal Blood Vessels, thus preventing later Acute Pathological Vasoconstriction-Then-Vasodilation sequence causing Migraine pain Calms Stress: Prevents Episodic Elevated BP that Triggers Migraine Sequence Other Central & Peripheral Sympatholytic Effects Medical uses Migraine Prevention Hypertension Stress, Anxiety, White-Coat Hypertension, Panic Disorders, Stage Fright, Golf Yips Cardiac Arrhythmias US trade names (not testable): Inderal® Sumatriptan (sue-muh-TRIP-tan) Drug class: Migraine Reverser Mechanism/selectivity: Serotonin 5HT1B,D Receptor Triptan-Type Agonist, Faster-Acting and More Brain-Selective Than Ergot Fungus-Derived 5HT1A Agonists: Directly Vasoconstricts Meningeal Blood Vessels (5HT1D), Inhibits Somatic Nociceptive PNS Nerves (5HT1B), and also Inhibits CNS Trigeminal Nerves (5HT1B,D) that Release Vasodilatory Triggers of Migraine Pain “Soo, MA TRIP was a number TeN headache! Hope to reverse my charges...” – Ted Cruz Physiological effects exploited in medical settings Vasoconstriction Reverses Meningeal Vasodilation Neuroinhibition of Discharging PNS & CNS Nerves May Also Suppress Neuronal Triggers of Meningeal Vasodilation Medical uses Migraine Reversal (short-half life: only acts for 2 hours, so migraine attack may return later) Other testable information Contraindicated for patients with coronary or peripheral artery disease (e.g., clogged arteries, angina, stent restenosis) Flushing Paresthesias (tingling) US trade names (not testable): Imitrex® HISTORY of IMMUNOSUPPRESSION Pien Ch'iao [Bian Que]: (300 BCE): Earliest known Chinese doctor, claimed to have performed a reciprocal heart transplant, with the two patients’ survival aided by a “numinous medicine”?... Saints Cosmas & Damian (300 CE): Arab twin doctors in Rome, attached a cadaver leg from a Moorish gladiator in place of a gangrenous cancerous leg of the sexton of their new Christian church. Élie Metchnikoff (1899 CE): 1908 Nobel with Paul Erlich for discovery of macrophages and cellmediated immunity: “Serum from guinea pigs previously injected with cells from mice’s lymph nodes, when injected back into normal mice, markedly deplete the mice’s circulating white blood cells.” So cool! WHY? HERE’S WHY!......Thomas Starzl & UMN’s John Najarian (1966 CE): “Monthly-donated plasma from guinea pigs horses injected with mouse human lymphocytes or T-lymphocytes prevent people from rejecting a transplanted kidney.” Anti-Thymocyte (Immuno)Globulin [ATG] Drug class: Immunosuppressant Antibody for Organ Transplant Recipients Mechanism/selectivity: Anti-Thymocyte serum injections inhibit T-cells & T-cell mediated immunity; ATG is more T-cell selective than earlier-developed ALG [Anti-Lymphocyte IgGImmunoglobulin], which additionally inhibited B-cells & B-cell mediated humoral immunity) Physiological effects exploited in medical settings Suppresses T-cell recognition of transplanted organs’ foreign HLA (human lymphocyte antigen) proteins. (HLA proteins are expressed on the outer surface of all body cells, which allows the body’s immune system, directed by T-cells, to recognize them as either “self” or “foreign” and to attack the foreign cells) Medical uses Prevents immune rejection of transplanted organs with non-identical HLA profiles. (A perfect HLA match in transplanted organs is rare outside of identical twins, while identical-twin transplants have a rare but unique risk of transplanting any cancer in the donor’s organ to the genetically-identical host) Side-Fx Impairs T-cell immunity to cancer and infections (viral, bacterial, fungal) DENTISTRY US trade names (not testable): Oral bacterial & fungal (candidiasis) infections Anti-D Immunoglobulin Drug class: Antibody Treatment for Rh(D)- Pregnant Moms to Inhibit Rh(D)+ Fetus Rejection Mechanism/selectivity: Injecting Anti-Rh+ Antibodies (purified from the blood plasma of Rhhumans exposed to Rh+ blood) into Rh- women carrying an Rh+ fetus prevents the moms from creating their own Anti-Rh+ antibody response (which would otherwise later cross her placenta to attack the blood cells of a second Rh(D)+ fetus) Physiological effects exploited in medical settings Prevents Rh(D)- mothers from mounting a transplacental immune response against fetal Rh(D)+ blood cells Medical uses Prevents fetal “Rh Disease” (formally called “Hemolytic Disease of the Fetus & Newborn [HDFN] Due to Anti-D Antibodies”) US trade names (not testable): WinRho® Cyclosporine (sigh-klo-SPORE-een) Drug class: Immunosuppressant Drug Mechanism/selectivity: Immunophilin ligand, blocks calcineurin-induced IL-2 in effector T-cells – it is a natural compound of a parasitic fungus of scarab beetles (!) “SPORe of scarabs, SPORe in mouth!” Physiological effects exploited in medical settings Immunosuppessant (oral) Medical uses Prevents transplanted organ rejection Prevents bone marrow Graft v. Host disease Also acts as a DMARD to prevent autoimmune disease symptoms in Rheumatoid Arthritis (RA) and Sjögren’s syndrome (including dry mouth & dry eye, psoriasis, eczema, ulcerative colitis, and oral lichen planus) Side-Fx Infections (viral, bacterial, fungal) Gum Hyperplasia Hirsutism DENTISTRY If Cyclosporine ISN’T working... Dry mouth Lichen planus If Cyclosporine IS working... Oral bacterial & fungal infections (oral candidiasis) Gum overgrowth US trade names (not testable): Sandimmune® Interferon-β (in-ter-FEAR-on bay-tuh) Drug class: Neuro-Immunosuppressant Drug Mechanism/selectivity: Immune Cytokine that Inhibits Autoimmune T-cells’ Brain Infiltration and Increases Release of Neuroinflammation-Suppressant Cytokines from NK-cells; Also Peripherally Triggers “Immune Storm” Attacks Upon Viruses (i.e., Interferon was discovered in 1957 CE because it was secreted by virus-infected cells and “interfered with further infection.”) Physiological effects exploited in medical settings Interferes with (suppresses) autoimmune destruction of neural tissue Interferes with (suppresses) viral infections Medical uses Prevents Initial Onset of Multiple Sclerosis (MS) Reduces MS relapses by a third (lengthens remission) in “Relapsing-Remitting MS” Antiviral drug (e.g., flu) Side-Fx 30% of MS patients are non-responders (many due to their making anti-interferon-β antibodies) Skin necrosis (5%) at i.m. injection site US trade names (not testable): Avonex® (Interferon-Beta 1a); Betaseron® (Interferon-Beta 1b) HISTORY of Rheumatoid Arthritis (RA) Ebers Papyrus (1550 BCE): 110 page (60-foot long) hieratic Egyptian scroll of medical & herbal treatments, includes the 1st Description of RA. (But also has anti-demon incantations, so its of “uneven” scientific quality...) Ebers scroll treatments still used today (e.g., for guinea-worms: “Pull from leg by twirling out on a stick.” But they had nada for any RA treatment) HISTORY of Rheumatoid Arthritis (RA) Hippocrates (400 BCE): Described “arthritis” (made no distinction between RA vs. nonautoimmune OA (osteoarthritis) Galen (130-200 CE): Coined term, “rheumatism[us]” Alfred Garrod (1858 CE): ID’d “RA” vs. “OA” vs. “Gout” HISTORY of DMARD Treatments for RA Bloodletting & Leeches (pre-1786 CE): Nuff said... Arsenic (psoriatic/RA, eczema): Fowlers’ Solution (1786 CE), or 1% Potassium Arsenite (KAsO2) -- used today ONLY for retinoid-refractory Acute Promyelocytic Leukemia, and for...RAT POISON! Gold Salts (1920 CE): Began as in vitro study to kill TB cultures by Robert Koch (father of modern bacteriology & 1905 Nobelist). People later assumed RA was a form of TB?! But it worked! The 1st Disease Modifying Anti-Rheumatic Drug, or DMARD! Modern DMARDS, by CLASS: “Transplant Rejection Drug” DMARDs (cyclosporine) “Gold Salt” DMARDs (auranofin) “Antimalarial” DMARDs (hydroxychloroquine) “Antimetabolite” DMARDs (methotrexate) “HuMAb Biological Response Modifier” DMARDs (adalimumab) Auranofin (are-AN-oh-fin) Drug class: “Gold Salt” DMARD (Disease Modifying Anti-Rheumatic Drug) Mechanism/selectivity: Immunosuppressant Gold-Conjugated Glucose – Functionally Impairs Metabolically-Active Cells “AU=Gold + R(heumatic) + FIN=End” Physiological effects exploited in medical settings Functionally impairs T-cells, which are more metabolically-active Action is delayed (due to need for gold particles to accumulate in the body) Medical uses Gold Salts were the 1st discovered DMARD for Rheumatoid Arthritis (RA) in 1920 CE -- shown to lessen RA symptoms Side-Fx Chrysiasis (accumulation of gold in skin cells, which after sun or laser-light exposure pigments the skin purple-brown/mauve, similar to Argyria after ingesting silver) Formerly kidney failure for original “gold salts” (but NOT a major side-effect of the weaker & gentler FDA-approved auranofin). US trade names (not testable): Ridaura® Hydroxychloroquine [HCQ] (hy-drox-ee-KLOR-oh-kwin) Drug class: “Antimalarial” DMARD (Disease Modifying Anti-Rheumatic Drug) Mechanism/selectivity: Suppresses T-cells’ inflammatory Toll-like Receptors Physiological effects exploited in medical settings T-Cell Immunosuppression “Drink HYDRO with QUINinE tablets for malaria (which takes its Toll)!” Medical uses Antimalarial Drug: Today used only on non-resistant P. falciparum. (Mass Rx of earlier antimalarials to U.S. Pacific Theater soldiers during WWII revealed the drugs ALSO were immunosuppressive, alleviating autoimmune symptoms in vets with RA [Rheumatoid arthritis] and lupus) Immunosuppressive DMARD to treat RA, lupus, & other autoimmune disorders (including Sjögren’s Disease, with symptoms including dry mouth and oral lichen planus) Not proven effective for COVID-19 DENTISTRY Side-Fx Retinal & cardiac toxicity (need eye-screens, strict dosing) Dry mouth Lichen planus Other testable information: Payne in 1895 CE advised using related drug quinine to treat lupus [“wolf-bite” face -- Rogerius (1100s CE)]. Baguall used related drug chloroquine for RA in 1957 CE US trade names (not testable): Plaquenil® Methotrexate (meth-oh-TREX-ate) Drug class: “Antimetabolite” DMARD (Disease Modifying Anti-Rheumatic Drug) Mechanism/selectivity: A folate [folic acid] antagonist (inactive analog, competes on folate-binding enzymes) -- suppresses DNA/protein synthesis Physiological effects exploited in medical settings Triggers T-cell apoptosis Releases adenosine, inhibiting inflammatory enzymes/cytokines/adhesins Stops cancer-cell division “TRiX folATE” Medical uses Most popular DMARD for RA (low doses) DMARD for other autoimmune diseases like Sjögren’s Disease (which includes dry mouth and oral lichen planus symptoms) (low doses) Cancer chemo treatment (high doses) DENTISTRY Side-Fx Birth defects Nausea Oral ulcers (alleviated by taking a folate pill after 24hr delay) Dry mouth Lichen planus Nausea Oral ulcers à instruct about folate Other testable information Methotrexate was created as an easier-to-manufacture analog of antifolate cancer drug aminopterin (used since 1948 for childhood leukemia). Was shown to be effective & safe for RA by 1962 CE, yet unused for 20 years (until the 1980s) -- doctors couldn’t believe a “cancer drug” would be safer & more effective than corticosteroids to treat their so-called “benign disease” (!) of RA US trade names (not testable): Rheumatrex® Adalimumab (ay-dah-LIM-you-mab) Drug class: “HuMAb” DMARD (Disease Modifying Anti-Rheumatic Drug) Mechanism/selectivity: Humanized Monoclonal Antibody “Biological Response Modifier (BRM)” DMARD that selectively inhibits the TNFα [tumor necrosis factor-alpha] inflammatory cytokine Physiological effects exploited in medical settings Immunosuppression of autoimmune diseases “LIMb HuMAb” Medical uses RA (Rheumatoid Arthritis) Psoriatic Arthritis Plaque Psoriasis Crohn’s Disease Eczema Side-Fx Cancer Otherwise rare viral, bacterial, and fungal infections (all consequences of immunosuppression) Other testable information Now a generic biologic, so new BRMs/Mabs and less painful injected formulations of this biologic are being developed & marketed aggressively for the same disorders DENTISTRY US trade names (not testable): Humira® Oral bacterial & fungal (candidiasis) infections Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #1 Which immunosuppressant drug is made from a parasitic scarab beetle fungus, prevents transplanted organ rejection and autoimmune disease symptoms, and weirdly causes gumhyperplasia? A. Adalimumab B. Auranofin C. Cyclosporine D. Methotrexate Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #1 CORRECT ANSWER Which immunosuppressant drug is made from a parasitic scarab beetle fungus, prevents transplanted organ rejection and autoimmune disease symptoms, and weirdly causes gumhyperplasia? A. Adalimumab – this is a humanized monoclonal antibody (“HuMAb”) DMARD drug that inhibits TNF-alpha inflammatory cytokine. Monoclonal antibodies are genetically engineered, rather than from natural sources like fungi that grow on scarab beetles B. Auranofin – this “gold-salt” DMARD is more precisely a gold-conjugated glucose molecule, and in addition to gradually building up in the body to inhibit immune cell over-reactivity, can react with light to pigment the skin and iris. It is not derived from scarab beetles or their natural fungi C. Cyclosporine – this parasitic scarab-beetle fungus-extract prevents transplanted organ rejection and autoimmune disease symptoms, and causes gum-overgrowth (as well as “wolfman” syndrome, or hirsutism, similarly to some of the multiple side-effects of the anticonvusant drug, phenytoin) D. Methotrexate – this “antimetabolite” DMARD is a folate antagonist that suppresses DNA and protein synthesis, triggering immune T cell self-destruction (apoptosis). It’s a manufactured inactive folate analog (a B vitamin derivative) rather than a fungal extract. Its side-Fx can include oral ulcers (drug induced Vitamin B deficiency), but not gum hyperplasia/overgrowth Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #2 Which autoimmunity drug is a “gold-salt” DMARD [Disease Modifying Anti-Rheumatic Drug] that causes the pigmentation side-effect of skin & eye chrysiasis upon the patient’s exposure to sun- or laser-light? A. Adalimumab B. Auranofin C. Cyclosporine D. Methotrexate Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #2 CORRECT ANSWER Which autoimmunity drug is a “gold-salt” DMARD [Disease Modifying Anti-Rheumatic Drug] that causes the pigmentation side-effect of skin & eye chrysiasis upon the patient’s exposure to sun- or laser-light? A. Adalimumab – this is a humanized monoclonal antibody (“HuMAb”) DMARD drug that inhibits TNF-alpha inflammatory cytokine. The only “gold” it provides is to its marketers -- because they made a new version of this generic drug that differs only in having a less acidic (less painful) injection solution, to allow them to now sell this generic drug again at high prices B. Auranofin – this “gold-salt” DMARD is more precisely a gold-conjugated glucose molecule, and in addition to gradually building up in the body to inhibit immune cell over-reactivity, can react with light to pigment the skin and iris C. Cyclosporine – this parasitic scarab-beetle fungus-extract prevents transplanted organ rejection and autoimmune disease symptoms. But the scarab beetle, in spite of being depicted by golden statues in ancient Egypt, is not a golden beetle -- it is commonly known today as the turd-ball pushing “dung beetle” D. Methotrexate – this “antimetabolite” DMARD is a folate antagonist that supresses DNA and protein synthesis, triggering iimmune T cells to self-destruct (apoptosis) Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #3 Beta-Endorphin is the primary endogenous (natural) agonist of which receptor? (This receptor also is the primary mediator of opioid drugs’ induced CNS euphoria & analgesia, and spinal cord & PNS anti-nociception.) A. DOR B. KOR C. MOR D. Anandamide Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #3 CORRECT ANSWER Beta-Endorphin is the primary endogenous (natural) agonist of which receptor? (This receptor also is the primary mediator of opioid drugs’ induced CNS euphoria & analgesia, and spinal cord & PNS anti-nociception.) A. DOR – the delta-opioid receptor primarily binds enkephalin (and DOR agonists are not used in humans) B. KOR – the kappa-opioid receptor primarily binds dynorphin. KOR agonists also induce CNS dysphoria, not euphoria (from “Drug Abuse & Addiction” lecture) C. MOR – the mu-opioid receptor primarily binds to beta-endorphin, and mediates opioids’ (MOR agonists’) induction of CNS euphoria and analgesia D. Anandamide – these receptors, also known as the CB1,2 cannabinoid receptors, are NOT opioid receptors, but do mediate euphoria and analgesia Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #4 “Tic Douloureaux” is another name for which of these algesic (pain) mechanisms gone bad (specifically leading to jolts of pain in the tooth, jaw, or face)? A. Allodynia B. Inflammatory Algesia C. Local Algesia D. Trigeminal Neuralgia Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #4 CORRECT ANSWER “Tic Douloureaux” is another name for which of these algesic (pain) mechanisms gone bad (specifically leading to jolts of pain in the tooth, jaw, or face)? A. Allodynia – this is pain perception at sites some distance away from the “hyperalgesic” direct injury, and is usually caused by local inflammation B. Inflammatory Algesia – this is pain perception caused by inflammation, mediated by cytokines C. Local Algesia – this is local pain nociception usually caused by an acute injury to nociceptors at a specific area, and can be blocked by local anesthetics D. Trigeminal Neuralgia – this is neuropathic pain caused by damage to nerves, in this case to the trigeminal nerve innervating the teeth, jaw, and face Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #5 CORRECT ANSWER The migraine drug sumatriptan (like its predecessor drug, ergotamine, and its predecessor, the Middle-Ages ergot fungus sclerotia causing side effects like anoxic hallucinations & limb gangrene), can act as a “migraine attack reverser” drug, due to its being in which Migraine Drug Class? A. Cerebral Vasoconstrictors B. Cerebral Vasodilators C. Cerebral Preventive of Vasoconstriction D. Cerebral Preventive of Vasodilation Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #5 CORRECT ANSWER The migraine drug sumatriptan (like its predecessor drug, ergotamine, and its predecessor, the Middle-Ages ergot fungus sclerotia causing side effects like anoxic hallucinations & limb gangrene), can act as a “migraine attack reverser” drug, due to its being in which Migraine Drug Class? A. Cerebral Vasoconstrictors – sumatriptan is the migraine “reverser” class drug, due to its meningeal blood vessel vasoconstricting serotonin 5HT1b,d receptor agonist activity (faster-acting & more brainselective than early ergot fungus-derived 5HT1a agonists). It ALSO may prevent brain triggers of cerebral vasodilation underlying migraine pain, but its short half-life means other drugs are better preventives B. Cerebral Vasodilators – this class of migraine drug are preventive systemic vasodilators (i.e., propranolol), which by causing chronic mild vasodilation of cerebral meningeal blood vessels prevents their later pathological excessive dilation underlying the migraine attack’s pain (Any idea how? Drug tolerance...?) C. Cerebral Preventive of Vasoconstriction – other than the above systemic cerebral vasodilators, no such migraine drugs have been developed to specifically prevent the initial painless (aura-stage) cerebral vasoconstriction step that’s later followed by the pathological vasodilation step causing pain -- but the below class of neuroinhibitory cerebral preventives of vasodilation may possibly also work at this earlier stage, too... D. Cerebral Preventive of Vasodilation – this class of migraine drug includes long-half life drugs such as neuroinhibitors also used as anticonvulsants and neuralgia drugs (e.g., divalproex, topiramate, onabotulinumtoxinA, erenumab). They all work to inhibit the brain’s and/or trigeminal ganglia’s neuronal or neuropeptide (e.g., CGRP) triggers of final cerebral meningeal blood vessel vasodilation that causes the migraine attack’s pain Analgesics / Mechanisms, Migraine Drugs, & Antirheumatics: PTQ #5 CORRECT ANSWER YOUR MAIN STUDY TIP? The migraine drug sumatriptan (like its predecessor drug, ergotamine, and its predecessor, the Middle-Ages ergot fungus sclerotia causing side effects likefirst anoxic hallucinations & limb gangrene), As mentioned in the slide can act as a “migraine attack reverser” drug, due to its being in which Migraine Drug Class? A. (“Session Objectives”), know the UNIQUE traits Cerebral Vasoconstrictors is the migraine “reverser” class drug, Side-Fx, due to its meningeal within the MOA,– sumatriptan Physiological Effects, Uses, & blood vessel vasoconstricting serotonin 5HT1b,d receptor agonist activity (faster-acting & more brainIssues of Each Drug Class & Each Drug: selectiveDentistry than early ergot fungus-derived 5HT1a agonists). It ALSO may prevent brain triggers of cerebral vasodilation underlyingDRUGS: migraine pain, but its short half-life means other drugs are bettererenumab, preventives MIGRAINE Divalproex, topiramate, onabotulinumtoxinA, amitriptyline, propranolol, sumatriptan... And also... DMARDs: Cyclosporine, auranofin, hydroxychloroquine, adalimumab B. Cerebral Vasodilators – this class of migraine drug are preventive methotrexate, systemic vasodilators (i.e., ALSO, know the UNIQUE identifying traits of these ALGESIC or ANALGESIC MECHANISMS: PNS, Spinal, & propranolol), which by causing chronic mild vasodilation of cerebral meningeal blood vessels prevents their later pathological excessive dilation underlying the migraine attack’s pain (Any idea how? Drug tolerance...?) Brain Nociception; Local Algesia; Neuropathic Algesia (Neuralgia); Trigeminal C. Cerebral Preventive of Vasoconstriction – other than the above systemic cerebralAllodynia; vasodilators, no Neuralgia; Trigeminal Migraines; Inflammatory Algesia; Hyperalgesia; such migraine drugsAnalgesia have been (including developed tothe specifically theits initial painless (aura-stage) cerebral Endorphin unique prevent traits of main endogenous opioid vasoconstriction step that’s later followed by the pathological vasodilation step causing pain -- but the below mediator, Beta-Endorphin) class of neuroinhibitory cerebral preventives of vasodilation may possibly also work at this earlier stage, too... D. WHY? So You Can Match the NAME of the Drug Class, Cerebral Preventive of or Vasodilation – this class of migraine drug includes long-half life drugs such as Drug, or Pain Analgesic Mechanism to Each TQ’s One neuroinhibitors also used as anticonvulsants and neuralgia drugs (e.g., divalproex, topiramate, (or More)erenumab). Provided UNIQUE Identifying Properties of or onabotulinumtoxinA, They all work to inhibit the brain’s and/or trigeminal ganglia’s neuronal neuropeptide (e.g., CGRP) triggers of final cerebral meningeal blood vessel vasodilation that causes the that NAME. migraine attack’s pain
