1. PTP 546 Module 9 Pharmacology of Inflammation & Treatment of Skeletal Muscles Jayne Hansche Lobert, MS, RN, ACNS-BC, NP Lobert1

2. Pharmacology Skeletal Muscle Relaxants Treatment of Muscle Spasms – Benzodiazepines Diazepam (Valium) – Physical and psychological dependence – Polysynaptic Inhibitors Carisoprodol (Soma) Cyclobenzaprine (Flexeril) Methocarbamol (Robaxin) Lobert2

3. Pharmacology Skeletal Muscle Relaxants Benzodiazepines – Ex: Diazepam (Valium) – Action: potentiates the inhibitory effects of GABA – Therapeutic Effect: short term treatment of acute muscle spasms – Side Effects: sedation, psychomotor impairment, abrupt withdrawal  rebound symptoms anxiety, seizures, death Lobert3

4. Pharmacology Skeletal Muscle Relaxants Polysynaptic Inhibitors – Ex: Carisoprodol (Soma); Cyclobenzaprine (Flexeril); Methocarbamol (Robaxin); Chlorzoxazone(Paraflex) – Action: decrease reflex activity in the spinal cord & generalized reduction in CNS excitability – Therapeutic Effect: skeletal muscle relaxant – Side Effects: drowsiness, dizziness, ataxia, vertigo, potential for tolerance and physical dependence, should not drive – Note: typically used in combination with rest, physical therapy & NSAID’s-anti-imflaminatory Lobert4

5. Pharmacology Skeletal Muscle Relaxants Treatment of Spasticity – Traditional Agents Diazepam (Valium) Baclofen (Lioresal) Dantrolene (Dantrium) – Newer Agents Gabapentin (Neurotin)- also for diabetic neuropathy, seizures. Tizanidine (Zanaflex) Lobert5

6. Pharmacology Skeletal Muscle Relaxants Traditional Agent: Diazepam (Valium) – Action: potentiates the inhibitory effects of GABA – Therapeutic Effect: short term treatment of acute muscle spasms and spasticity from cord lesions – Side Effects: significant sedation, psychomotor impairment, abrupt withdrawal  rebound symptoms anxiety, seizures, death; physical and psychological dependence Lobert6

7. Pharmacology Skeletal Muscle Relaxants Traditional Agent: Baclofen (Lioresal) – Action: acts as a GABA agonist  inhibits transmission within the spinal cord; reduction of firing of the alpha motor neuron  relaxation of skeletal muscles – Therapeutic Effect: treatment of spasticity secondary to spinal cord injury and demyelination associated with multiple sclerosis – Side Effects: transient sedation; avoid sudden withdrawal  seizures, hallucinations – Note: intrathecal Baclofen is used for severe spasticity, rigidity and pain Lobert7

8. Pharmacology Skeletal Muscle Relaxants Traditional Agent: Dantrolene (Dantrium) – Action: inhibits calcium release in the muscle cell  inhibition of contractions & muscle relaxation – Therapeutic Effect: muscular relaxation; treatment of severe spasticity – Side Effects: generalized skeletal muscle weakness; hepatoxoicity Lobert8

9. Pharmacology Skeletal Muscle Relaxants Newer Agent: Gabapentin (Neurontin) – Action: GABA like inhibition in the spinal cord  reduces alpha motor neuron excitation  muscle relaxation – Therapeutic Effect: treatment of spasticity associated with MS and spinal cord injuries – Side Effects: sedation, fatigue, dizziness Lobert9

10. Pharmacology Skeletal Muscle Relaxants Newer Agent: Tizanidine (Zanaflex) – Action: alpha 2 adrenergic agonist: binds alpha receptors in the spinal cord and brain  pre and post synaptic inhibition – Therapeutic Effect: treatment of spasticity – Side Effects: sedation, dizziness, dry mouth Lobert10

11. Pharmacology Skeletal Muscle Relaxants Newer Agent: Botulinum Toxin(BoTox) – Action: reduces presynaptic acetycholine release  muscle paralysis – Therapeutic Effect: three month inhibition of local dystonias, (prevent Ach release to minimize muscle contractions very locally) – Side Effects: additive effects  paralysis Need an educated injector. – Note: dose limitations needed to avoid individual antibody production Does not work as well with repeated use. Lobert11

12. Pharmacology Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Prototype “gold standard” NSAID: Acetylsalicylic Acid(Aspirin) – Action: inhibits cyclooxygenase (COX 1 & 2) enzymes  inhibition of the prostaglandin production associated with pain, inflammation, thrombus formation & fever – Therapeutic Effect: antipyretic; anti-inflammatory; antiplatelet – Side Effects: gi effects  dyspepsia, gi bleed, ulcers; hearing effects  tinnitus, hearing difficulties; hypersensitivity – Note: avoid use in children with influenza to avoid Reyes Syndrome(Reye's Syndrome is a two-phase illness because it is almost always associated with a previous viral infection such as influenza (flu), cold, or chicken pox.)chicken pox – Note: preventative usefulness have been suggested in colorectal cancers, cv disease, ms, etc. (small amount in reduction of cancers (81mg-antiplatet, to decrease MI and CVA). Lobert12

13. Pharmacology Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Acetylsalicylic Acid (Aspirin) Diclofenac (Voltaren) Etodolac (Lodine) Indomethacin (Indocin) Flubiprofen (Anasaid) Ibuprofen (Motrin) Ketorolac (Toradol) Naproxen (Naprosyn) Piroxicam (Feldene) Ketoprofen (Orudis) Nabumetone (Relafen) Sulindac (Clinoril) Tolmetin (Tolectin) See table 15-2; page 207 Lobert13

14. Pharmacology Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen (Motrin) & Naproxen (Aleve) – Action: Inhibition of COX 1 and COX 2 – Therapeutic Effect: analgesic and anti-inflammatroy: treatment of pain and inflammation – Side Effect: fewer gi side effects than aspirin but still occurs in 15% of patients; long term use may contribute to renal impairment, Motrin is “hard on the gut”. – Note: monitor dosage, length of administration Can contribute to renal impairment Lobert14

15. Pharmacology Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) COX-2 Selective Drugs – Ex: Celecoxib (Celebrex) – Action: inhibition of COX 2 – Therapeutic Effect: suppression of inflammatory response – Side Effects: lack of inhibition of COX1  no gi side effects – Note: FDA removal of other COX 2 agents in 2004 secondary to MI and stroke risks Lobert15

16. Pharmacology Management of Rheumatoid Arthritis (RA) Treatment of RA – Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Ex: Aspirin (need large dose, and watch for GI bleeds); Dicofenac (Voltaren); Ibuprofen (Motrin) – Corticosteroids Ex: Hydrocortisone (Cortef); Methylprednisolone (Medrol) – Disease Modifying Antirheumatic Drugs (D-MARD) Antimalarials Ex: Hydroxychloroquine (Plaquenil) Gold Compounds Ex: Auranofin (Ridaura) Classic Immunosuppressants Ex: Azathioprine (Imuran) Tumor Necrosis Factor Inhibitors Ex: Adalimumab (Humira) Antimetabolite Ex: Methotrexate (Rheumatrex) Lobert16

17. Pharmacology Management of Rheumatoid Arthritis Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) – Ex: Aspirin; Dicofenac (Voltaren); Ibuprofen (Motrin) – Key Points: Side effects of aspirin (more gi bleeding, tinitus) versus Motrin Around the clock administration is important. Lobert17

18. Pharmacology Management of Rheumatoid Arthritis Corticosteroids – Ex: Hydrocortisone (Cortef); Methylprednisolone (Medrol) Acute: need a high dose, for anti-inflmmatory – Key Points: Side Effects: short term versus long term Tapering of Doses: to allow the adrenal to “kick-back- in” if not Addison’s disease, Lobert18

19. Pharmacology Management of Rheumatoid Arthritis Disease Modifying Antirheumatic Drugs – Classic Immunosuppressants Ex: Azathioprine (Imuran) Key Points: infection risk – Tumor Necrosis Factor Inhibitors Ex: Adalimumab (Humira) Key Points: SQ/IV meds that may retard the progression of joint inflammation; infection risk – Antimetabolite Ex: Methotrexate (Rheumatrex) Key Points: side effects are major limiters Lobert19

20. Pharmacology Management of Rheumatoid Arthritis Disease Modifying Antirheumatic Drugs – Antimalarials Ex: Hydroxychloroquine (Plaquenil) Action: decrease T cell stimulation Therapeutic Effect: treatment of RA (and malaria) Side Effects: retinal toxicity – Gold Compounds Ex: Auranofin (Ridaura) Action: inhibits T cells and phagocytes Therapeutic Effects: treatment of RA Side Effects: high incidence of se’s; diarrhea, indigestion, proteinuria, thombocytopenia -bleed out, leukopenia-bleed out and be infected. Lobert20

21. Pharmacology Management of Osteoarthritis Treatment of Osteoarthritis (OA) – Analgesics NSAID’s (ASA, Motrin) Acetaminophen (Tylenol) – Viscosupplementation Hyaluronan (Hyalgan, Synvisc) Glucosamine and Chondrotin Sulfate Lobert21

22. Pharmacology Management of Osteoarthritis Viscosupplementation – Hyaluronan (Synvisc, Hyalgan) Action: restore normal viscosity of synovial fluid Therapeutic Effect: reduces joint stress, limits progression of articular destruction; reduces pain Side Effects: pain with injection, localized inflammation Note: intrarticular injections 2-10 weeks of weekly injections; pain relief possible for 3-12 months Lobert22

23. Pharmacology Management of Osteoarthritis Viscosupplementation – Glucosamine and Chondroitin Sulfate Action: replacement or articular cartilage and synovial fluid components Therapeutic Effect: may slow the progression of joint degeneration Side Effects: rare gi intolerance Note: typically no effect for weeks to months; xrays have shown stabilization of joint spaces Lobert23