Pharmacology MSK Flashcards

Question

What are spasms?’ Spasticity?

Answer 1

Painful, involuntary muscle contractions treated with antispasmodic agents Involuntary contraction of skeletal muscle causes stiffness that interferes with mobility and speech. Treated with spasmolytic agents Ex: Spasticity: MS, ALS, cerebral palsy, spinal injury.

Answer 2

Deficit in upper motor neuron. Signaling leaves lower motor neurons hyperexcitable. Deficit due to spinal cord injury or neurodegeneration. Ex: Cerebral palsy, MS, stroke. Dysregluation of the stretch reflex causes contraction response in the absence of stretch stimulus.

Answer 3

Lower motor neurons Interneurons in the reflex arc Skeletal muscle directly (Dantrolene) CNS active spasmolytics decrease alpha motor neuron activity by 1. Reducing activity of the excitatory interneurons 2. Enhancing activity of the inhibitory interneurons.

Answer 4

Glutamine Target AMPA receptors on the motor neuron and trigger an AP

Answer 5

They use GABA to target the excitatory interneurons and the motor neuron. They decrease cAMP and close Ca channels by targeting a2-adrenergic receptors and GABAb receptors. They inhibitors can upregulate GABAa Cl- channels or down regulate GABAb proteins.

Answer 6

Baclofen Diazepam

Answer 7

Tizanidine

Answer 8

Agents that cross the blood-brain-barrier (BBB) to affect the brain and spinal cord. So agonism of inhibitory receptors in the spinal cord to slow signals will also sedate the brain. This is common with spasmolytics and centrally active antispasmodics

Answer 9

Well known for their use as CNS-active sedatives and anxiolytics. They are positive allosteric modulator of GABAa receptors. -GABAa receptor has enhanced permeability to CL- which hyperpolarizes the neuron. This DOESN’T Administered orally and are nearly completely absorbed. Plasma protein bound! They can be short, intermediate or long acting

Answer 10

Diazepam: it is a long acting BZD.

Answer 11

Long-acting BZD. It has interactions with CYP3A4 substrates that increase apparent dose. (Ketoconazole, grapfruit juice, ritonavair) Interactions with CYP3A4 inducers decrease apparent dose (st. John’s wort, anticonvulsant) ``` Adverse drug response: Will cause sedation -daytime drowsiness -Rebound insomnia/anxiety -Anterograde amnesia -Coma and respiratory depression when used with CNS depressants like ALCOHOL ```

Answer 12

Flumazenil It is a benzodiazepine-binding site antagonist, not effective against barbiturates or alcohol. IV, rapid onset and short acting. (Needs to be readministered if large amount of BZD is consumed because it is plasma bound.) -side effects are agitation, confusion, dizziness, nausea.

Answer 13

It agonizes GABAb Receptor Often first choice for muscle spasticity due to MS or spinal cord injuries, if tolerated -Less sedation than diazepam. Short acting GABA analog and again agonizes GABAb and causes hyperpolarization. Reduces release of excitatory transmitters in the brain and spinal cord.

Answer 14

Rapid and complete oral absorption. T1/2: 3-4 hours. And most of the drug is eliminated renally and through biliary excretion. Nitrate also catheter of baclofen can control severe spasticity and muscle pain that is unresponsive to medication by other routes of administration. (Can be more dangerous by injecting it like this because it can’t cross the BBB to get out and can cause overdose.) ADR: Not tolerated well in all patients. -Can cause seizures in epileptic patients, can cause respiratory depression and coma. Abrupt discontinuation may cause seizures. Caution in pregnant women: animal studies suggest birth defects.

Answer 15

(Neurontin) Made to target GABA, but it doesn’t target GABA. It targets Ca channels at the presynaptic nerve terminal that trigger synaptic vesicles release. Treats shingles Causes less activation of post-synaptic GABA receptors. And reduces Gluatmetergic activity. Eliminated unchanged from the body. T1/2: 6 hrs. Well tolerated with adverse effects of sedation, somnolence, ataxia, fatigue.

Answer 16

(Zanaflex) A2-adrenergic agonist Agonism of a2-adrenergic receptors reduces firing rate of the presynaptic neuron. Inhibitory GPCR Not fully understood Used to treat spasms cause by MS, ALS, spastic diplegia, back pain, or other CNS injuries. Clinical trials with oral tizanidine report efficacy in relieving muscle spasm. As effective as baclofen, diazepam, and dantrolene. ADR: CNS-related: drowsiness, dizziness, Athenians A2-adrenergic receptors are expressend in ANS: hypotension, dry mouth. -CONTRAINDICATED for those with orthostatic hypotension. Can cause hepatotoxicity and acute liver failure. -Dosage must be adjusted in patients with renal and liver impairments. CYP1A2 inhibition raises the apparent dose. Induction of CYP1A2 by smoking will lower apparent dose!

Answer 17

Dantrolene and Botulinum Toxin

Answer 18

Botox Produced by clostridium botulinum. LD: 1.3-2.1 ng/kg intravenously or IM BTX enxymatically cleaves the SNARE proteins involved in vesicular release. -chemodenervation and local paralysis. Incontinence due to overactive bladder and chronic migraine.

Answer 19

An antispasmodic (Flexeril) Cyclobenzaprine: Centrally active agents that react peripheral muscle spasms by targeting the brain stem. Major interactions with other CNS-depressant drugs. -Strong antimuscarinic side effects, significant sedation, confusion and transient visual hallucinations, seizures, tachycardia, hypotension. Carisprodol is another that is metabolized to meprobamate, a schedule IV drug with sedative action and abuse liability.

Answer 20

Mediators of inflammation Histamine, bradykinin, serotonin, eicosanoids

Answer 21

They can relieve pain, reduce inflammation, and reduce fever which are both exasperated by prostaglandin.

Answer 22

Loss of articular cartilage and presents asymmetrically. It is related to weather, and duration of pain is less than 30 minutes. Pain is resolved with motion and recurs with rest. Only effects hands with Herberden nodes and Bouchard’s nodes, the knee, hips and spine.

Answer 23

Weight Management Physical Activity Insoles, and assistive devices Patient Education is crucial!!!!!!

Answer 24

Non-selective - Salicylates (aspirin) - Propionic Acid derivatives (ibuprofen) - Oxicam derivatives (piroxicam) - Acetaminopehn is not an NSAID, but has antipyretic and analgesic activity Selective: COX-2 inhibitors (Celecoxib, and Rofecoxib**** not on the market.)

Answer 25

Catalyze arachadonic acid to Prostaglandin COX-1 is housekeeping -maintains gut integrity, vascular tone, platelet aggregation, kidney function. COX-2 is induced by pro-inflammatory signals like cytokines -Cause inflammation, pain, regulate temp control, inhibit platelet aggregation

Answer 26

They inhibit both COX-1 and COX-2 Most are competitive, non-competitive or mixed reversible inhibitors.

Answer 27

Salicylate (Aspirin) -Inhibitor of COX1 and COX2. Inhibits prostaglandins and synthesis and platelet aggregation. 1/2 is 30 minutes Hydrolyze to salicylic acid. Indications: OA, RA, fever, pain, prophylaxis of stroke and MI. Salicylic acid is excreted in the breast milk and is category D in 3rd trimester Reduces TxA2 which reduces clotting. ADR: GI disturbance, can have allergic reactions.

Answer 28

Reversible non-selective inhibitor of COX1 and 2 (Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen) Ibuprofen is ok while breastfeeding, long 1/2 life of naproxen should be avoided. Black Box Warning: Increased risk of serious cardiovascular thrombotic event. Increased risk of serious GI event

Answer 29

Reversible inhibitors of COX 1 and 2. They have longer 1/2 lives which is better for more long term use. Ketorolac remains valuable alternative when opioid use is not an option. Not for fever treatment!!! Black Box Warning: Increase CV and GI event risk. Ketorolac Black Box Warning: Should be used for no more than 5 to 7 days to avoid renal and GI damage.

Answer 30

Non-selective reversible COX-1 and 2 inhibitor. 57 hour 1/2 life for piroxicam, and 20 hours for meloxicam. Much longer half life. Same Black box Warning of CV and GI events Oxicam analgesic is better than aspirin.

Answer 31

Centrally acting analgesic and antipyretic with minimal anti-inflammatory properties. Mechanism in reducing pain is the reversible inhibition of of the peroxidase site of COX1 and 2. Not anti-inflammatory! Black Box: Liver failure and acute hepatic damage needing transplant.******

Answer 32

COX1 is cytoprotective in gastric cells. Inhibition of COX-1 reduces both protective Prostaglandins and TxA2 that can lead to ulcers. TxA2 activates platelets so the inhibition of TxA2 will lead to bleeding ulcers. To stop this you can use combo therapy with omeprazole (20mg/once per day) protects upper GI

Answer 33

COX2 products regulate blood pressure and inhibit hemostasis (clotting) Selective COX2 inhibition decreases PGI2 (inhibits platelet aggregation) This increases total aggregation due to imbalance between TxA2.

Answer 34

COX-2 selective inhibitor NSAID 1/2 life of 11 hrs. Uses for pain, OA, and RA Causes HTN, GI disturbance (not GI bleeds, it is nausea/vomiting), headache Avoid for patients with heart failure or those taking ACE inhibitors. (Diuretic) BLACK BOX for increased risk of CV thrombotic event.

Answer 35

They are recommend not to use NSAIDs. Proton pump inhibitors should be used in conjunction when they need to be given.

Answer 36

Alternative analgesic to opioids that have addiction potential.

Answer 37

Disease-Modifying Antirheumatic Drugs Most common for RA Goal is to control inflammation

Answer 38

Inflamed synovium, symmetrical, extra-articular involvement, morning stiffness that lasts more than 30 minutes. Autoimmune disease No hip and back involvements.

Answer 39

PT, exercise, and rest NSAIDs for pain relief, but don’t slow the process. DMARDs will modify the disease immune response.

Answer 40

Slows the deterioration of tissue destructions Does not repair damage already done. Early diagnosis is needed.

Answer 41

Traditional - Antimetabolites - Corticosteroids - Aminoquinoline - 5-Aminosalicylate - Dihydroorotate Dehydrogenase inhibitor Biological - Tyrosine Kinase Inhibitor - TNFa inhibitor - IL-1 inhibitor - CD80/86 inhibitor

Answer 42

Prednisone, Methylprednisolone, triamcinolone Not a mono therapy usually. Inhibit numerous steps in the inflammatory response such as inhibition of antigen presentation to T cell, prostaglandin and leuktriene synthesis, and neutrophil and monocytes radical generation. 1/2 Prednisone 2-3 hrs - Others 18-36 hrs. ADR: Hypothalamic-pituitary-adrenal suppresion (Has to be tapered down). - Can lead to osteoporosis. - Glucose intolerance - Increased susceptibility to infections.

Answer 43

Methotrexate: Folate analogue that inhibits DHFR. This inhibits cytokines production, purine biosynthesis, and may stimulate adenosine release. 1/2: 3-10 hrs. Don’t use when pregnant!!! Can be used for cancer at higher doses. DMARD of choice for initial therapy. Results may be seen in 2-3 weeks and you can stay for 5-7 years. BLACK Box are bone marrow suppression and will cause fetal death or toxicity. Azothioprine: Imidazolyl derivative is an immunosuppressive antimetabolite that suppresses cell-mediated hypersensitivites and amuses alterations in antibody production 1/2 life: 5 hrs Serious: Leukopenia, hepatotoxicity. BLACK BOX: Chronic immunosuppression ADIVES PEOPLE to wear sunscreen!!!!!!

Answer 44

Hydroxychloroquine: Immunosuppressant, interferes with antigen presentation. 1/2: 172 hrs to 50 days Considered safe during pregnancy and breastfeeding. Can cause retinal disorders, hypoglycemia, and torsades de pointes May cause vision changes.

Answer 45

Sulfasalazine: Prodrug that is cleaved in the terminal lieu and colon that inhibits inflammation due to blockage of cyclooxygenase and prostaglandin synthesis in the colon. Inhibits IL-1 and TFNa production. Also Natural killer cells, and macrophages. 1/2: 7-14 hrs. Serious side effects due to sulfapyridine moiety. 40% of patients can’t tolerate it.****** Antibiotics reduce availability of active moiety And also may cause yellow-orange urine or skin

Answer 46

Leflunomide: Pyrimidine synthase inhibitor 1/2 life 14-16 days with loading dose. Teratogenic: May need Wash Out period before trying to conceive. Serious complication are Stevens-Johnson syndrome. Can cause liver toxicity by it is has efficacy similar to methotrexate.****** Avoid live vaccines during therapy!

Answer 47

Tofacitinib: JAK inhibitor. JAK is a tyrosine kinase protein that facilitiates STAT protein for expression of inflammatory genes. 1/2: 3-6 hrs Will Increase LDL and HDL levels******* BLACK box warning: serious infections leading to hospitalization or death. TB, viral Cholesterol should be monitored Don’t give with live vaccinations.

Answer 48

Biological Infliximab, etanercept, Adalimumab, golimumab, certolizumab. Monoclonal antibody with specific activity for TNFa 1/2 life is 14 days for all but etanercept which is 102 hrs. Increase risk of Hep B and cancer. Can get Autoimmune hepatitis. Don’t give with live vaccines Etanercept is less selective for TNFa also hits TNFb

Answer 49

Biological DMARD Anakinra: Competitive inhibitor of IL-1 binding Helps stop cartilage degradation 1/2: 4-6 hrs Can cause neutropenia Don’t give live vaccinations

Answer 50

Biological DMARD Tocilizumab: IL-6 receptor inhibitor that binds to IL-6 receptor to mediate signaling 1/2: 11-13 days Increased ALT/AST levels******** ADR: Neutropenia BLACK box of increased infection risk. Don’t give live vaccinations. More effective than adalimunab montherapy who can’t tolerate methotrexate.

Answer 51

Biological DMARD Abatacept: Downregulates T cell activation by binding to CD80/86 on the antigen presenting cell and prevents them from binding to CD28 1/2: 13-14 days Increases risk of infection. Can cause upper respiratory infection. Considerations: False high glucose readings may occur cause maltose is in the drug solution. May worsen COPD