Musculoskeletal System & Skin (Lecture 3) - Pharmacology - The Hashemite University PDF

Musculoskeletal System & Skin Six lectures: Pharmacology Lama Abualhaija 1: Drugs for Dermatological Disorders: Lectu...

Musculoskeletal System & Skin Six lectures: Pharmacology Lama Abualhaija 1: Drugs for Dermatological Disorders: Lecture 3 2+3: Drugs for Rheumatoid Arthritis and Osteoarthritis 4: Drugs for Gout 5+6: Neuromuscular Junction Pharmacology and Skeletal Muscle Relaxants Dr. Sofian Al Shboul Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 1  Anti-inflammatory Drugs In the end of (Rheumatoid Arthritis) the lecture Pharmacology and Toxicology ↓ Musculoskeletal System Summarizing tables for Third Year Medical Students rec(2 3) + Faculty of Medicine The Hashemite University Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 1  OUTLINGS: -> for (e2 2 + 3 ⑦ PROSTAGLANDINS & ASPIRIN/NSAIDS Antiinflammatory * ↳ - Mechanism of action Antipyretic Analgesic ~Anti-inflammatory/Analgesic - Anti-pyretic - Theraputic Uses ↳ I cardiovascular application External Application ~ Aspirin Pharmacokine tics -other NSAIDS - Gastrointestinal Adverse Effects - Bleeding W - - Drug 1 L onthe kinder a interactions other: (RS/CNS) - Toxicity/pregnancy - celecoxib ③ ACETAMINOPHEN Farmacokines AES methotrexate ⑪ DMARD S - Hydroxychloroquine - - W Leflunomide sulfasalazine/Glucocortecolds ④ ~Adalimumab Etanercept - NonTNf-a (Abatacept, Rituximab) B-DMAI2D S & - & Tofacitinib lin Golimumab fliximab  Aselectivity choice of drug depends on what is the clinical condition. Aspirin/NSAIDs val XG HEART X ~HEART dd Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 35  cical 8"for exi Aspirin/NSAIDs seziures what SAID would you N give him ? (NotAspirin) Drug interactions Salicylate is 80-90% protein- C Is for seizures Aspirin bound & & ⑧ GaAspirin Drugs that are highly G for Gout protein-bound can displace salicylate (and vice versa) Examples: warfarin, phenytoin, valproic acid…. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 36  Aspirin/NSAIDs ↳ crosses BBB Neurological St = S Toxicity O Mild salicylate toxicity (salicylism): nausea, vomiting, hyperventilation, headache, mental confusion, dizziness, and tinnitus. ⑧Severe salicylate toxicity: Restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death 10 g of aspirin can cause death in children Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 37  *Aspirin has a preventive effect againstcolon cancer. Aspirin/NSAIDs Imp Risks regarding the * I Benefits would A/B/c/D -> fetus and not the pregnant outweigh on Risks Pregnancy - & SES women thus guidlines now d changed to include both. First Trimester: CategoryO C Risk of Miscarriage Congenital Malformations: cardiovascular defects and gastroschisis Second Trimester: Category C NSAIDs are generally considered safer during this period compared to the first and third trimesters Third Trimester: CategoryGene D en NSAIDs should generally be avoided during the third trimester due to the following risks: Premature Closure of the Ductus Arteriosus Oligohydramnios Prolonged Labor or Delayed Onset of Labor Safer Alternatives During Pregnancy: Acetaminophen (Paracetamol) ↳ Almost100% Safe Pain killers Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 38  Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 3  Selective ses 5 8; 9;0 R Ul 5 COX20, COX1 ↳ Celecoxib w 1 85%I W W ; 05-21t Selective COX-2 inhibitor Minimal CON1 effect minimal - G1 Sts Results in reversible - inhibition of COX-2 CO Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 4  Celecoxib - Mosteffective - Stronger than Naproxen Therapeutic uses & effectagainst Dose E (water-sugar) Rheumatoid arthritis jointpain num people of ↑ Osteoarthritis Pain (similar efficacy to non- 0 selective NSAIDS) d Psychological C Pharmacokinetics O Effect 6 Oral s pain x I Half-life: 11 hours Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 5  Celecoxib Adverse effects Xfigure ❑Dyspepsia/diarrhea/abdominal pain C ❑LESS GI problems than non- C selective NSAIDS ❑Risk for cardiovascular disease Leonly know better than ↳ - 200 - - Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 6  Ex:Q:Which of the following NSAID has long half life? S - ⑧ Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 7  ⑧ upper al disturbance (20X1) -> Aspirin Gludomethacin ② No Antipyretic effect(xfever) -> Diflunisal ↓hel than Aspirin - 8 CNS disturbance/Very Patent->Indomethacin ④ Preisk of Mid Strokes (&coxal celecoxib limitation x (PCoxe ⑤ Half life - operoxicam & Meloxicam ⑥ Itoxicity -> ①Ibuprofen a Naproxen (safest) ③ Ketoprofen ⑦ Low cost/long history of Safety - Aspirin  Anti-inflammatory Drugs Prostaglandins Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Celecoxib Acetaminophen Traditional Disease-Modifying Antirheumatic Drugs (DMARDs) Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 8  In MCG avoid answers * with Always or Never 2,142 51js Acetaminophen /PARACETAMOL · ✓ Inhibits prostaglandin synthesis in CNS thus passes BBB (SES) - - -> ✓Antipyretic/analgesic ✓Minor effect on peripheral S: cyclooxygenase. Which means? 2 -- effect NSAIDSS Weak Anti-inflammatory I ✓Does not affect platelet function or increase bleeding time. ✓NOT considered an NSAID. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 9  Acetaminophen Therapeutic uses Fever Pain Useful in gastric/ complaints prolongation of bleeding time Preferable for children & pregnant. Blough ER and Wu M (2011) Acetaminophen: beyond pain and fever-relieving. Front. Pharmacol. 2:72. doi: 10.3389/fphar.2011.00072 Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 10  person can A have 1000mg Acetaminophen ↳ capills) 3-4 times a day. Pharmacokinetics ~ Adverse effects Shours IV/ oral/ rectal…. 5.5 hours Usually safe Rapidly absorbed from GI Be careful Hepatic necrosis ⑪ ⑳ conjugated in the&liverwith to patients form inactive glucuronidated with problems Patients with hepatic disease, viral severe 0 hepatitis, or a history of alcoholism liner 3 or sulfated metabolites A portion of acetaminophen are at higher risk of is hydroxylated to form N- acetaminophen- induced acetyl-p-benzoquinoneimine, hepatotoxicity. or NAPQI, a highly reactive G metabolite that can react with N-acetylcysteine is an antidote in sulfhydryl groups and cause cases of overdose liver damage. - - - Sofian Al Shboul ©  Anti- inflammatory Drugs Prostaglandins Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Acetaminophen Traditional Disease-Modifying Antirheumatic Drugs (DMARDs) Biologic Disease-Modifying Antirheumatic Drugs (B-DMARDs) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 12  s Inflammation “normal, protective response to a variety of noxious stimuli such as physical trauma, chemicals, or microbiologic agents in effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair” Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 13  - When Can Things Go Wrong? Rheumatoid Arthritis Chronic inflammatory disease affecting the joints. Middle ages (30-50 years) Aetiology still unknown; but environmental and genetic risk factors such as: smoking, obesity and vitamin D deficiency. Inappropriate activation of the immune system → inflammation → immune-mediated/autoimmune disease Activated immune cells secrete proinflammatory cytokines: TNF-α IL-1, IL-6 and IL-8 among others Transforming growth factor beta (TGF-ß) Fibroblast growth factor (FGF) Immunology.org Platelet-derived growth factor (PDGF) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 14  Iss's When Can Things Go Wrong? Rheumatoid Arthritis Most Imp (central) - - mediators thus they're ↑ targeted by drugs, Proinflammatory cytokines result in: 1. vascular permeability/cellular infiltration due to release of histamines, 0 kinins, and vasodilatory prostaglandins 2. increased hepatic production of C- reactive protein 3. increased production and release of proteolytic enzymes by chondrocytes → cartilage degeneration 4. increased osteoclast activity → focal bone erosions/osteoporosis 5. systemic manifestations: heart, lung. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 15  When Can Things Go Wrong? s Rheumatoid Arthritis Chronic inflammatory response can result in: progressive tissue injury Persistent polyarthritis (synovitis) functional disability significant pain Extra-articular manifestations Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 16  Traditional Disease-Modifying Antirheumatic Drugs (DMARDs) TRADITIONAL Advantages: They DON'T CUREbut G CNON-SELECTIVE) ⑦ Slow the course of the disease ↓ ⑳ Induce remission Methotrexate - ③ Prevent further tissue destruction - Hydroxychloroquine - Usually started as soon as Leflunomide - possible Before complete joint damage. -> Sulfasalazine - - Monotherapy is preferred; S combinational therapy for advanced or inadequate response. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 17  - wDoseAnti flammatory voteice -S asli, 8 ✓ inhibition of the binding of IL-1b 1 Methotrexate contraindication. ✓ inhibition of T cell activation and down-regulation of B cells MOA: folic acid antagonist ⑦ Actions: cytokine production and purine nucleotide biosynthesis → immunosuppression and anti- inflammatory Gree Mainstay in the treatment of RA ↳ Response: 3-6 weeks Monotherapy → inadequate - response? →combination Brown, P., Pratt, A. & Isaacs, J. Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol 12, 731–742 (2016). https://doi.org/10.1038/nrrheum.2016.175 - 3-6 weeks wegine NSAIDS During until the drug works. Sofian Al Shboul © to manage pain Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 18  Not1stchoice in: ①liver problems ② Pregnancy Methotrexate I & Adverse effect REMEMBER: dose used for RA is less than anticancer dose (given once weekly) ❑Cytopenias S Pregnancy? ❑Liver cirrhosis teratogenic effects: craniofacial abnormalities, ❑Acute pneumonia-like syndrome limb defects, and CNS defects Propose a solution to mitigate these adverse effects….. FOLIC ACID O de Since it's fA antagonist. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 19  oveined an- - 2 Hydroxychloroquine ⑰ Used for early-mild RA S Mechanism of action: unknown (for autoimmune diseases) Response: 6 weeks to 6 months Adverse effects: ocular toxicity, GI upset and skin discoloration - - we mentioned Methotrexate (M) is the 1stchoice each drug alone] Other uses: ankylosing spondylitis and psoriasis Same adverse effects Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 28  wired El Golimumab I neutralizes the biological activity of TNF-α by binding to it and blocking its interaction with cell surface receptors. ② Monotherapy or with methotrexate ③ SC-monthly Can be associated with hepatitis B reactivation Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 29  only 4 Infliximab [l The one not - used as a single mix of two diferentspecies (mine human) A (mouse) chimeric monoclonal antibody agains TNf-9 + v binds specifically to human TNF-α and S inhibits binding with its receptors W Approved for patients with inadequate C C response to methotrexate monotherapy C C di Not used as a single agent. Why? L Given IV infusion bi-monthly C C Similar adverse effect profile to the other TNF-α inhibitors the body may produce antibodies against it, reducing its effectiveness over time. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 30  a ⑤ Non-TNF-α inhibitors: Abatacept - a soluble recombinant fusion protein L Competes with CD28 for binding on CD80/CD86 protein, thereby preventing full T-cell activation (STEP II) ② Biological ⑪ For moderate to severe RA, no response to DMARDs or TNF-α inhibitors 9 g/dL to start begin with it tofacitinib (risk for anemia) Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 34  fesion Hodkinson B, Van Duuren E, Pettipher C, Kalla A; South African Rheumatism and Arthritis Association. South African recommendations for the management of rheumatoid arthritis: an algorithm for the standard of care in 2013. S Afr Med J. 2013 Jun 14;103(8 Pt 2):576-85. doi: 10.7196/samj.7047. PMID: 23885741. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 35 ⑦ PROSTAGLANDINS Aipoprostadil Lubiprostadio Misoprostol Bimatoprost Epoprostenol latanoprost iloprost PGE1 Analog: PGt1 PGE1 Plefza PGI2 Use: ⑧ Erectile constipation ① Protection opthalamology Pulmonary dysfunction of Gastric Arterial MucOSG HTN ②congenital & Induction Heart ds. of labor ② NSAIDS ASPIRIN other NSAIDS CELECOX1B Non selective cox) MOA i irreversible Reversible & CoX low dose (81) ⑤ Salicylic Acide Acne, corns deactylated ①oral Goral kinetics: O Oral - tosalicylate & Metabolism - Liver  ② Absorption:passive, ③ Elimination Renal upper small intesine ③ crosses BBB ④Metabolism:Liver ⑤ Elimination:Renal ⑥ Half life d Anti-inf. (49) same Ats: -> ⑧ Cl:albleeding + Ulcers ① less al ①Rey's syndrom (PG12/9Gt2/PGf2a) & Risk of CV. & Drug-Drug interact. ② Bleeding ③ with: ⑧ Kidney:(& vasoconstrictors) - probenecid (gont) =dienal Blood flow Phenytoin ④ avsaerecivecexispirin - valproic acid (seizures) ↳ Naproxin is least harmful, - Thyroxine Triodothyronine ⑤ Is: bronchospasm - Heparin ⑧ aNS: headache.. ③ 10g for children = DEATH ⑭ Toxicity - Brain coX2: Etodolac) Mam) oxib> aenac> Piroxicam cox1: Koolac) &in) flurbiprofan> Ketoprofin) Indomethacin) Nxen) rotin - ③ ACETOMINOPHEN ↳ MoA: Inhibits PG synthesis in S (VBBBS 6 & Antipyretic (fever)/Anlagesic (pain) ③ Weak Anti-inf. (Minor peripheral coxefect) ⑭ X & Bleed time X Plateletfunction XNSAIDS ↳ uses:Pain/fever/children/Pregnant Kinetics: QIV/oral/Rectal (62) ↳ & conjugate Liver/NAPQI in Ats:&& Risk for patients of:(hepaticds/Viral Inpatitis/ Alcoholism) ② Antidote:N-acetylcysteine,  Mainstay ⑭DMARDS for RA Glucocorticoids d Methotrexate Hydroxychloroquine Leflunomide Sulfasalazine MOA/ OFAantagonist ① for Early Mild RA. MOA: DHODH Response:1-3M Uses:a doseAnti-inf. & Response:6w-6m ① lymphocyte cell once weekly Arrest ③) & cytokine production ② Alt./comb with immunosuppressive = Methotrexate ④ Response;3-6 w. ⑤ Mono-combin AEs' Oliver cirrhosis - Weightloss ① leukopenia & Pregnancy; - cal Upset ⑧ hypokalemia Teratogenic ③ Hepatotoxic ③ WAEs: folic Acid -pregnancy ⑤ B-DMARDS ① clinical response seen within 2 weeks A) TNf-a inhibitors -> & employed when traditional DMARDS inadequate response = Aadilmumab Etanercept Golimumab infliximab Antibody against - - - - chimeric - monoclonal TNF Antibody (TNf) ① Moderate Severe- RA ① Mod-Severe RA OSC- monthy ① X Mono Resistance - & sc-weekly ② sc-weekly & Mono/cowb. @ IV-bimonthly with metho ③ Mono/comb. with ③ Mono/comb. methotrexate with metho. ③ Uses: - Psoriasis RA ⑭other: - - Psoriatic Arth. - psoriatic Arthritis - Ankylosing spond. - Ankylosing spondylitis - Ulcerative colitis - Crohn disease - Crohn's ds AC ↑ Risk of infections hepatitis B reactivation B) Non-TNfa inhibitors Uses: QMod-Sever RA (3rdline) Abatacept D28(D80/D86) inhibitors At i ② NoResponse to: DRAMDS/TNfa - ↑ Risk of with Methotrexate Rituximab CD20 use:Mod-Severe RA-- infections inhibitor of Tofacitinib -> Doral Janus kinases & Mod-Severe RA. Drugs for Alopecia: Trichogenic agents Best of Luck Minoxidil Indicated for the treatment of androgenic alopecia Originally an antihypertensive, but causes increased hair growth as a side effect When used topically, it does not cause hypotension Don’t forget to pray for Gaza MOA: unknown, shortening the rest phase of the hair cycle. Must be used continuously adverse effects: erythema and pruritus. Sofian Al Shboul © Copyright © 2018 Wolters Kluwer ٠ All Rights Reserved 41