Musculoskeletal Flashcards
Tubocurarine
Induces muscle paralysis
A drug that blocks the acetylcholine at its receptor, preventing interaction and subsequent deplolarization.
Succinylcholine
A Phase I block depolarizing neuromuscular blocking drug.
Induces a depolarizing blockade by over-stimulation of Acetylcholine receptors.
Chemically, it is two acetylcholine molecules linked end-to-end
Short half life due to rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively.
“Dibucaine number” is used to test for genetic varients in esterases leading to prolonged action
Augmented by esterase inhibitors.
Can cause cardiac arrhythmias, cardiac arrest in burn patients, nerve damage, closed head injury, and other trauma; also may cause increased intraocular pressure and myalgia.
Neuromuscular Blocking Drugs
All neuromuscular blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally.
They all have presence of one or two quaternary nitrogens, limiting entry to CNS and cell membranes.
Characterized by a rapid initial distribution phase followed by a slow elimination phase.
Drugs eliminated by the kidneys have a longer half-life than those eliminated by the liver.
Vecuronium
An intermediate-acting steroid nondepolarizing muscle relaxant that depends on biliary excretion or hepatic metabolism for elimination.
More commonly used than longer acting pancuronium
Minimal cariac effects
Atracurium
An intermediate-acting isoquinoline nondepolarizing muscle relaxant.
Metabolized by the liver and naturally breaks down through Hofmann elimination.
Laudanosine is a breakdown product that in sufficient quantities can cross the BBB and induce seizures.
Cisatracurium is a more clinically used isomer
Cardiac effects (hypotension)
Mivacurium
Isoquinoline compound that has the shortest duration of action of all nondepolarizing muscle relaxants.
Onset is slower than succinylscholine.
Larger doses can lead to histamine release.
No longer in widespread clinical use
Pancuronium
80% eliminated by Kidney (thus long lasting)
Causes a moderate increase in heart rate and a smaller increase in cardiac output.
Reversal of Nondepolarizing Neuromuscular Blockade
Neostigmine and Pyridostigmine antagonize acetylcholinesterase, allowing more acetylcholine to be present at the synapse.
They also increase release from nerve terminal (unlike edrophonium)
Malignant Hyperthermia
Treated with dantrolene. It is a rare heritable disorder that can be triggered by a variety of stimuli including succinylcholine.
They have a hereditary alteration in Ca2+ channels leading to prolonged release. This leads to increased acidosis and body temperature
Diazepam
Acts at GABA-a synapses
Causes sedation
Dantrolene
interferes with the release of activator calcium through the ryanodine receptor channel by binding and blocking the channel’s opening.
Cardiac muscle and smooth muscle are not affected due to different isoforms
It is used as a spasmolytic drug, weakens skeletal muscle contraction
Can be used to treat malignant hyperplasia and Neuroleptic malignant syndrome.
Cyclobenzaprine
Work primarily at the brainstem
Structurally related to tricyclic antidepressants and produces antimuscarinic side effects.
Ineffective in treating muscle spasm due to cerebral palsy or spinal cord injury.
May cause serious sedation, confusion, visual hallucinations
Glucocorticoid
Prevent production of certain mediators of inflammatory reactions. Centered around phospholipase A2
This releases arachidonic acid, which is used to make prostaglandins, thromboxanes, leukotrienes, epoxides, and isoprostanes.
Glucocorticoids inhibit PLA2 on a nuclear scale (genetic)
COX I and II
COX I is constituitively expressed, COX II is expressed in platelets and inflammatory cell types when stimulated by cytokines and bradykinin.
COX I is thought to be expressed at a basal rate for everyday needs of the cell.
COX II is key player in inflammatory response.
In general, NSAIDs are nonselective, but there are some selective COX II inhibitors
Leukotrienes and Epoxides
Especially relevant in response to asthma
They are either 15, 12, or 5
Epoxides are made through Cytochrome p450s.
NSAIDs don’t affect lipoxygenases, epoxides, or isoprostane synthesis.
Glucocorticoids affect all of the above by hitting PLA2
Arachidonic Acid Pathway
Arachidonic acid is converted to PGH2 which is taken immediately to other prostaglandins or thromboxanes.
COX is the main enzyme to get to PGH2
The pathways are very cell specific, meaning one type of cell normally only has one end-product.
PGI2 is in vascular endothelium
Thromboxane A2 is in platelets
Biological Effects of Eicosanoids
PGE2, PGI2, and PGD2 are dilators, while PGF2alpha and TxA2 are constrictors
TxA2 induces platelet aggregation and constricts bronchial smooth muscle
PGI2 inhibits platelet aggregation and dilates bronchial smooth muscle
LTC4 and LTD4 dilate and create leaky capillaries to get cells to inflammator site
PGE2, PGI2, and LTB4 (chemotactic) are all algesics
PGE2 is synthesized by the OVLT to induce fever (local production in brain.
PGE2 and PGF2alpha contract uterus (don’t give NSAIDs to patients in labor)
PGE2, PGI2 decrease GI acid secretion, incerase mucus and bicarb secretion, and increase GI and renal blood flow, decreases chloride resporption in loop of Henle and ADH induced water reabsorption.
NSAID uses and side effects
general anti-inflammatory action
musculoskeletal disease
mechanical injury
rheumatoid arthritis
osteoarthritis
ankylosing spondylitis
analgesia: pain associated with inflammation and moderate pain of headache, myalgia dysmenorrhea
anti-pyretic
Side effects: GI discomfort and ulceration, decreased renal function in patients with compromised renal function, (Less common: dizziness, anxiety, drowsiness, skin rash)
Aspirin
Unique in that it is an irreversible inhibitor by acetylating a serine residue of COX-1 and COX-2
Has side effects of tinnitus and uncoupling of ox. phos.
Aspirin is used to target platelets, since they have no nucleus and cannot regenerate COX once it is covalently inactivated.
Aspirin can antagonize probenecid at low doses, uricosuric at high doses (Aspirin/salicylates are bad for gout)
Has some adjunct therapy in colon cancer
Other Salicylates
Mesalamine, sulfasalazine, and osalazine are all used for inflammatory bowel syndrome.
Sulfasalazine is mesalamine with an antibiotic sulfapyridine attached to it. It is used to treat rheumatoid arthritis as well.
Osalazine is a drug that consists of two mesalamine molecules linked together.
The linkages travel as an inert component until it gets to the bowel, where bacteria are able to break down the unique azole bond and activate the drugs
Diflunisal has poor CNS penetration and no anti-pyretic effect, but has potent anti-inflammatory action
Acetaminophen
Not a good anti-inflammatory drug
It is a good analgesic and anti-pyretic
Outside of the CNS, it doesn’t remain active.
Can cause liver toxicity that is fatal if untreated. Acetaminophen is either conjugated and excreted in the kidney, or metabolized by a p450 (liver) that leads to a reactive metabolite. When glutathione is around, the metabolite is reduced and there are no problems. With less glutathione, the metabolite reacts with protein sulfhydryl groups (overdose).
Treat overdose with N-acetylcysteine
Happens at about 4X recommended dose.
Infants have less of a conjugation reaction, more frequent overdoses.
Indomethacin
very potent COX inhibitor
high degree of side effects with chronic use (over half of patients who take long term have GI effects)
Ob/Gyn use: suppress uterine contractions
closure of patent ductus arteriosus (prostaglandins normally keep it open)
Can be used to treat acute gout
Sulindac
COX inhibitor
Unique: It’s a pro-drug, metabolically activated by the liver.
This has potential less GI side effects, because the form that hits the stomach is inactive.
Etodolac
Very potent anti-inflammatory with less GI side effects.
It is a slightly selective COX-2 inhibitor, which is responsible for sparing GI.
Mefenamic acid and meclofenamate
analgesic, treatment of arthritis
- not recommended as initial therapy
- may antagonize prostaglandin effects
Higher than normal toxicity, usually used when someone responds specifically to them.
They may also have some prostaglandin receptor antagnosim to them
Tolmetin
Studied a lot in pediatric populations, so it is used in pediatric populations
It is well-tolerated, and is used sometimes for juvenile arthritis
Ketorolac
Similar to acetomenaphen, but without the liver toxicity.
Doesn’t due anti-inflammatory
Used to treat post-op pain as alternative to opiates
Can be given IM
Diclofenac
very potent COX inhibitor
may reduce release and/or uptake of arachidonic acid
can be formulated with misoprostol to reduce GI toxicity
Misoprostol is a PGE analog, which is thought to be a GI protector. It hasn’t worked so well because this causes diarrhea.
Ibuprofen
Increasing popularity due to less GI side effects
Naproxen: more potency, same side effects
Ketoprofen: stabilized lysosomal membranes and antagonize bradykinin actions
Oxaprozin: long half life
Fenoprofen, fluribiprofen: similar to others
Piroxicam
in addition to being a COX inhibitor,
inhibits neutrophil activation in the presence of PGs
may inhibit proteoglycanase and collagenase in cartilage
long half-life - - 50 hrs
Must be careful with dose, as it is eliminated slowly
Meloxicam/Nabumetone
A semi-selective COX-2 inhibitor, was replaced by celecoxib.
Nambumetone is the same, but is a pro-drug
Most COX-2 inhibitors have been pulled from the market. The COX-2 inhibitors lead to big problems
Celecoxib
A COX-2 selective inhibitor that has no GI effects
It hits the kidney hard and can cause hypertension.
The COX-2 inhibitors don’t have an anti-platelet effect. This lead to increased MI’s, athersclerotic events, et c.
Other members of class had more problems than Celecoxib
Still a good drug for someone who needs chronic, long term NSAID use but who had GI trouble and who is not at risk for cardio or kidney disease
Glucocorticoids
-Means they are derived from cholesterol and are very lipophyllic. They go through membranes and find cytoplasmic receptors.
They effect gene transcription in a positive or negative manner depending on the cell/gene
They are also immunosuppressive (NSAIDs aren’t). Decrease IL-2,-4,-6, cell adhesion molecules (this can lead to minor increased WBC)
They hit two steps of Arachidonic acid pathway, COX-2 and PLA2
Most tissues are responsive to glucocorticoids, meaning their effects are wide-felt
Glucocorticoid Comparison
Cortisol has a short duration of action and a small anti-inflammatory effect (sodium retaining)
Prednisone has an intermediate duration and 4X the anti-inflammatory effect (sodium retaining) (prednisone requires liver activation)
Triamcinolone has an intermediate duration, has 5X the effect, and no sodium retaining potency
Betamethasone and Dexamthasone have a long duration, 25X the anti-inflammaroty effect, and no sodium retaining potency
Fludrocortisone is 125X more potent for sodium retention, used for patients lacking aldosterone (need sodium retention)
Colchicine
An acute gout drug
- Binds to tubulin and prevents polymerization into microtubules
- Interferes with mitotic spindle function
- Inhibits migration and phagocytic actions of granulocytes
- Inhibits neutrophil secretion of chemotactic factorscommon side effects:
nausea, vomiting, diarrhea, abdominal pain
affects rapidly proliferating epithelial cells in GI tract
Used when NSAIDs or glucocorticoids haven’t worked
NSAIDs for Gout
NSAIDs are used for gout. The heavy hitters are used because they won’t be used long term
Ibuprofen, naproxen, indomethacin, sulindac
DON’T USE ASPIRIN
Allopurinol
Chronic gout drug
parent drug and metabolite alloxanthine inhibit
xanthine oxidase, decreases uric acid synthesis
drug interaction: inhibits **metabolism** of azathioprine, 6-mercaptopurine (chemotherapeutics, need to back off the dose)
Gout often affects patients undergoing chemo for cancer
can be used with impaired renal function
Febuxostat
Chronic gout drug
Nonpurine xanthine oxidase inhibitor
Liver function abnormalities, diarrhea, nausea
Rasburicase
Chronic gout drug
Recombinant urate oxidase
Converts uric acid into soluble and inactive metabolite
Probenecid
Chronic gout drug
Uricosuric agent: means it blocks reabsorption of uric acid in kidney in tubules
Developed in WWII to inhibit secretion of penicillin (still blocks this, leading to increased penicillin doses)
Multiple drug interactions by blocking renal secretion of other drugs
Rheumatoid Arthritis
Previously, you would start by treating with NSAIDs, which relieve pain but don’t modify disease
Now, you try and modify the disease
Methotrexate
Used to treat rheumatoid arthritis
MOA is not extremely well known.
Adverse affects: nausea and mucosal ulcers, hepatotoxicity. Can use leucovorin rescue, but lowers effect. Hepatotoxicity is such a prominent side-effect, one needs to check liver biopsy samples every 5 years.
Cyclophosphamide
DMARD for RA
alkylating agents/cross link DNA
toxic effects of bone marrow suppression, infertility,
increased risk of infections and neoplasia
Sulfasalazine
Azo linkage of sulfapyridine and 5-aminosalicylic acid
Acts by scavenging free radicals and as COX inhibitor
and dihydrofolate reductase inhibitor
Abatacept
DMARD for RA
inhibits T-cell activation by binding to
CD80 and 86 (on APCs) and preventing
interaction with CD28 (on T cells)
given by IV infusion
increased risk of infection especially in combination
with anti-TNF agents
Rituximab
DMARD for RA
monoclonal antibody that targets CD20 (on B-cells)
depletion of B lymphocytes decreases antigen presentation to T lymphocytes
given by IV infusion, often combined with methotrexate
main use in treatment of rheumatoid arthritis refractory
to anti-TNF agents
rash in 30% patients with first treatment
Tocilizumab
IL-6 receptor antagonist
Used in RA when it hasn’t responded to other drugs
Anakinra
IL-1 receptor antagonist
RA drug
Used when response is lacking to other DMARD therapies
Anti TNF►alpha drugs
Anti- TNF-alpha drugs
Etanercept: recombinant fusion protein consisting of
two soluble TNF receptor regions linked to
Fc portion of human IgG
Infliximab: chimeric monoclonal antibody with
variable murine region linked to constant human region
specific against human TNF
Adalimumab: Recombinant human anti-TNF monoclonal antibody
Golimumab: Recombinant human anti-TNF monoclonal antibody
Certolizumab: Fab fragment conjugated to PEG, binds TNF
agents must given by injection
antibodies develop against these drugs
but don’t appear to alter efficacy
increase risk of macrophage dependent infections
screen for latent or active tuberculosis
Mycophenolate Mofetil
DMARD for RA
Inhibits inosine monophosphate dehydrogenase
Decreases de novo purine biosynthesis
T and B cell sensitive due to lack of salvage pathway
interferes with leukocyte adhesion by inhibition of E- and P-selectin expression
Azathioprine
DMARD for RA
converted to 6-mercaptopurine, inhibits de novo purine synthesis
primary targets T and B cells
toxicity - - any rapidly growing cell population
Leflunomide
DMARD of RA
Pro-drug that inhibits de novo ribonucleotide synthesis and triggers p53 translocation to nucleus arresting cells in G1 phase
Decreases T and B cell proliferation
Diarrhea as adverse effect in about 25% patients
Some liver toxicity
Cyclosporine
DMARD of RA
Inhibits calineurin phosphatase activity
Decreases transcription of cytokines in T-cells (IL-2)
Somewhat selective effect on T-cells, knocks out cytokine synthesis that activates T-cells
Causes: renal toxicity, does not cause bone marrow supression
Chloroquine and Hydroxychloroquine
DMARD of RA
Unclear mechanism of action in arthritis
May decrease T-cell response to mitogens
Decreases leukocyte chemotaxis
Stabilizes lysosomal membranes, traps free radicals
generally decreases DNA and RNA synthesis
Fairly well tolerated
Vitamin D analogs
Ergocalciferol- Vitamin D2-plant form that is cheap and works in humans
Cholecalciferol- Vitamin D3- the type made from cholesterol in mammals. The “-ols” have one hydroxyl group. The next one is put on in the liver
Calcifediol- already hydroxylated, so it doesn’t need to be activated by the liver.
Calcitriol- fully activated, but normally don’t start with this because there is no way to regulate. You would give this to a patient with kidney disease (especially ones that lead to bone trouble)
Calcitonin
Salmon and human forms, salmon more potent
Direct effect on osteoclast to decrease bone resorption
Decreases calcium and phosphate reabsorption in kidney
Don’t tend to have an allergic response to this
Estrogens
Used to treat osteoporosis
Act on osteoblasts to decrease osteoclast recruitment and activation
It’s used to upregulate osteoprotegerin, which inhibits RANKL
Menopause leads to decline in estrogen. Men’s androgen levels don’t decline until 80’s or 90’s
Estrogen can lead to certain cancers
Teriparatide
A.K.A. PTH; Drug stimulates bone deposition
Only the active part of the PTH
Used intermittantly, chased with a bisphosphonate
This is the only pharmacoligcal way we’ve discovered to help with bone reformation
Glucocorticoids (in relation to Vitamin D)
Antagonize Vitamin D stimulated intestinal calcium absorption
Stimulates renal calcium excretion
block bone collagen synthesis
increase PTH stimulated bone resorption
Denosumab
Can be used in women that have risk of estrogen driven cancers
mimics effect of OPG
Biphosphonates
etidronate, pamidronate, alendronate, risedronate, tiludronate, zoledronate, ibandronate (-onate = bisphosphonate)
retard formation and dissolution of hydroxyapatite
imbibed by osteoclasts, leads to decreased osteoclast function in structure, close to pyrophosphate
metabolized into ATP analog, accumulates in osteoclasts
impairs cell function and viability, induces apoptosis
(etidronate and tiludronate)
inhibition of protein prenylation important for
osteoclast function
(alendronate and ibandronate)
etidronate: side effect of inhibits bone mineralization
gastric irritation common with all except etidronate
some renal toxicity with zoledronate
Non-hormonal agents of bone regulation
calcium supplements:
IV-calcium chloride, gluconate, gluceptate
oral-calcium carbonate, citrate, lactate
thiazide diuretics:
reduce renal calcium excretion
useful to inhibit renal calcium stone formation
fluoride:
accumulates in bone and teeth
may stabilize hydroxyapatite
increases bone volume, may increase osteoblast activity
both acute and chronic toxicities limit use
No good way to distribute safely
Doxorubicin
Used after performing surgery and radiation. Primary agent used in treatment of soft tissue and bone sarcomas
Inhibits topo II
Free radicals, DNA strand breaks
Intercalates with DNA
Myelosuppression and cardiac toxicity (free radicals), give with iron kelator
Cisplatin
Used with doxorubicin to treat osteosarcoma (most common bone sarcoma)
Activates when water displaces chloride group
crosslinks with DNA and inhibits DNA replication
Intrastrand
Nephrotoxicity and ototoxicity, nausea and vomiting (worse of any chemo drug)
Ifosfamide
Alkylating agent
Used to treat soft tissue and osteosarcomas
Interstrand alkylator
Cyclophosphamide
Used to treat soft tissue and osteosarcomas
Cleaved into mustard phosphoramide and acrolein (toxic metabolites)
Interstrand
Dactinomycin
Treat soft tissue and bone sarcomas
Intercalates with DNA and blocks RNA polymerases
Hematopoietic suppression is most serious toxicity
Dacarbazine
Enhances remission duration, survival, and response rate in treatment of soft tissue sarcomas (used with doxorubicin)
Alkylating agent, spontaneous cleavage in target cell yields methyl diazonium ion (active alkylator)
Tumor cells that have a lot of demethylators result in resistance
Inactivated by liver CYP
Moderate myelosuppression
Etoposide
Forms ternary complex with topo II and DNA, blocks DNA replication
Cell cycle specific for S or G2 phases
Used with ifosfamide to treat osteosarcoma (they have different MOAs and no cross-reactivity)
Myelosuppression, nausea, and vomiting
Methotrexate
High-dose and leucovorin rescue to treat osteosarcoma
Inhibits DHFR –> indirectly inhibits thymidylate synthase and DNA synthesis
Leucovorin is converted to N5, N10-methylene-tetrahydrofolate, replenishes carbon donor pool for methylation of dUMP to from TMP by TS
Filgrastim
G-CSF
Increases neutrophil count during chemotherapy
Bleomycin
intercalates with DNA, reacts with oxygen and iron to from radicals –> fragmentation of DNA chain
Hydrolase inactivates bleomycin, present in many tissues but low in the lung –> *pulmonary toxicity
Used in combination therapy with dactinomycin and cyclophosphamide
Causes little suppression of bone marrow
Vincristine
Binds to tubulin, failure to form spindle and blocks mitosis
Causes little suppression of bone marrow function
Used in combination with dactinomycin and cyclophosphamide
Causes predictable neurotoxicity characterized by numbness of extremities leading to loss of motor function
Chemoprophylaxis
antimicrobial give before and during surgery
use beyond 24hrs bad b/c of inducing resistance
cephalosporins or vancomycin are drugs of choice
Superinfection
New infection during chemotheraphy of primary infection
Extended use of broad spectrum antibiotics alters natural flora, one species becomes dominant and invades
3rd-generation cephalosporins and tetracyclines cause superinfections
Superinfection from giving treatment for too long, developing resistance is from not taking treatment long enough
Delayed treatment of osteomyelitis
Debridement and resection of infected bone
Fixation with pins
Local antimicrobial therapy with antibiotic-impregnated polymethylmethacrylate beads, given bc of compromised blood supply to infected area
systemic antimicrobial therapy
Methicillin-resistance treatment
Organisms resistant to penicillins and cephalosporins (that are beta-lactamase-resistant)
Altered PBPs for methicillin resistance
Vancomycin is drug of choice to use against methicillin-resistant staphylococci (MRSA), monitor serum levels b/c of ototoxicity and nephrotoxicity
Rifampin used when foreign body (pin, prosthesis) used, induces P450
Resistance caused by vanA gene that modifies cell wall (cannot bind to d-ala-d-ala anymore)
Linezolid
Developed to overcome vancomycin resistance
Prevents formation of 70S ribosome complex by binding 23S subunit of 50S ribosome, blocks initiation of protein synthesis in gram (+)
Mutation in 2 or more copies of 23S rRNA required to induce resistance
Active against variety of resistant organisms
Well absorbed, can give orally
Quinupristin/dalfopristin
Used to overcome vancomycin resistance
Given with dalfopristin, combination therapy
Binds and changes conformation of 50S subunit in gram (+)
Good for vancomycin-resistant strains of enterococcus faecium (infections in urinary tract, blood, and soft tissue)
Inhibits P450 to slow metabolism of other drugs
Daptomycin
Aka Cubicin
Cyclic lipopeptide
Used for antibiotic resistant gram (+) bacteria
Binds to bacterial membranes and causes depolarization of membrane potential –> inhibition of protein, DNA, and RNA synthesis
Not well tolerated, hard to get correct dosing
Can cause severe peripheral neuropathy, directly damages nervous system
Used as last resort, resistance to all other drugs
Lyme disease treatment
First choice:
Oral- *doxycycline or amoxicillin for kids
IV- ceftriaxone for late phase
Metronidazole
IV
Treat C. tetani
Given 7-10 days to eradicate from wound
Chemically activated to form hydroxylamine which degrades DNA in anaerobic organisms
Some GI distress
Cannot take with alcohol
Treat C. bolulinum in GI
Metronidazole and Penicillin G to eliminate C. botulinum from GI tract
Diethylcarbamazine citrate
Most effective against microfilarial forms of filarial species
Treat W. bancrofti, B. malayi, and L. loa
Direct effect on W. bancrofti, causes organelle damage and apoptosis
Toxicity rare, can cause anorexia, nausea, headache, and vomiting at high doses
Most adverse effects result from destruction of parasites
Filariasis treatment
benzimidazole, albendazole, in combination with ivermectin
Benzimidazole and albendazole inhibit microtubule polymerization by binding to parasite beta-tubulin
Onchocerciasis treatment
Ivermectin, causes tonic paralysis of musculuture by activation glutamate Cl channels, well tolerated
Trichinosis treatment
Mebendazole or albendazole
Both inhibit microtubue polymerization by binding parasite beta-tubulin
Osteomyelitis Treatment
S. aureus
Give penicillin G
Nafcillin, oxacillin, dicloxacillin to penicillin-resistant
Vancomycin to methicillin-resistant
Nafcillin
Synthetic penicillin, resistant to beta-lactamase
Used for osteomyelitis (IM or IV)
Oxacillin
Synthetic penicillin, resistant to beta-lactamase
Used for osteomyelitis (IM or IV)
Dicloxacillin
Synthetic penicillin, resistant to beta-lactamase
Used for osteomyelitis (IM or IV)
Piperacillin-tazobactam
Piperacillin is very broad spectrum
Not beta-lactamase resistant so must be given with tazobactam which is beta-lactamase inhibitor
Imipenem
Very resistant to beta-lactamase
Has additional toxicities that other beta-lactams do not have (nausea, vomiting, possible seizures)
Used as last resort because of toxicities
Cefazolin
Cephalosporin
Cephalosporins used to treat infections of bones and joints, usually look to beta-lactamase resistant penicillins before cephalosporins
Others include cephalothin, cefuroxime, ceftriaxone
Septic arthritis cause/treatment
Caused by hematogenous spread
Usually caused by S. aureus and N. gonorrhoeae
Treat by joint drainage and system antibiotics for 3-4 weeks (nafcillin or oxacillin for S. aureus, vancomycin for MRSA)
Infectious arthritis cause/treatment
Gonococcal urethritis (N. gonorrhoeae)
Ceftriaxone, ciprofloxacin, ofloxacin, cefixime
Atropine
Muscarinic Cholinergic Antagonist
Tx: Antidote for organophosphate poisoning
MOA:
competitive (reversible) antagonist at all M receptors, thereby prevents release of IP3 & adenylyl cyclase
Eye: dilation (mydriasis), cycloplegia (paralysis of ciliary muscle = loss of accommodation), reduced lacrimation, tachycardia (M2 receptors), bronchodilation
Adv: Blind as a bat, mad as a hatter, red as a beet, hot as a hare, dry as a bone, the bowel and bladder lose their tone, and the heart runs alone –> Total PNS block.
Relatively safe for adults
Rapidly cleared in urine
*be careful of closed angle glaucoma
Scopolamine
Tertiary amine alkaloid (like atropine)
Muscarinic Cholinergic Antagonist (can also block H1 receptor and cause sedation)
Tx: Reduces vertigo, post-operative nausea, prevention of motion sickness (Transdermal patch)
MOA: M1 receptor
rapid onset and primarily CNS effects
Adv: Same effects as atropine + CNS: delirium , drowsiness, amnesia, excitement, hallucinations, coma
Acetylcholine
Choline Esters (charged; no CNS entry)
Muscarinic and Nicotinic receptor agonist
IV fusions of min. effective dose = vasodilation, ↓BP, reflex increase in HR
Larger doses produce bradycardia and ↓atrioventricular node conduction velocity in addition to hypotension
Active for 5-30secs (AChE hydrolyzed) and not well absorbed
Bethanechol
partial muscarinic receptor agonist [M2 (cardiac) and M3 (smooth muscle/ glands)]
used for postoperative and neurogenic ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and urinary retention
Longer duration of action than ACh (Active for 30 min to 2 hours)
Adv: Rule out GI and urinary obstruction before use (due to possible exacerbation of problem and may cause perforation as result of increased pressure). Excessive parasympathomimetic effects, esp. bronchospasm in asthmatics. Additive with other parasympathomimetics
Carbachol
Nonselective muscarinic (all M receptors) and nicotinic agonist
Tx: Glaucoma and the induction of miosis during surgery (can reverse ocular effects of atropine)
Bronchospasm in asthmatics
good resistance to cholinesterases
Muscarine
Parasympathomimetic alkaloid
Muscarinic receptor agonist. Binds irreversibly to AChE
Quaternary amine so it does not cross the BBB –> has more peripheral effects.
Tox: ↑ salivation, lacrimation, perspiration, abdominal pain, nausea, blurred vision
First source of muscarine: Amanita muscaria (mushroom). Interestingly, effects mimic atropine poisoning more than muscarine excess.
Muscarinic Receptor Types (M1-M5)
The M2 and M3 subtypes mediate muscarinic responses at peripheral autonomic tissues.
M1 and M4 subtypes are more abundant in brain and autonomic ganglia.
M1, M3, M5: Gq proteins to stimulate IP3 and DAG- increase Calcium
M2 M4: Gi proteins to inhibit adenylyl cyclase, which results in a decrease of intracellular concentration of cyclic adenosine monophosphate (cAMP)
Nicotine
Lipid soluble, so can be absorbed across the skin and crosses the BBB
Activates autonomic postganglionic neurons (sympathetic and parasympathetic) and somatic motor because of nicotinic receptors of skeletal muscle at neuromuscular junction
NM: Skeletal muscle - Na+/K+ depolarizing ion channel
NN: Postganglionic cell - Na+/K+ depolarizing ion channel
Lobeline
Tertiary Natural Cholinomimetic Alkaloid
Plant derivative similar to nicotine
Meth, Cocaine, Smoking cessation aid.
Pilocarpine
Partial Muscarinic agonist similar to Bethanechol
Tx: Glaucoma; dry mouth in Sjogrens syndrome
Decreases intraocular pressure by contracting ciliary body to allow outflow of aqueous humor.
Acetylcholinesterase
MOA: Acetylcholinesterase (AChE) splits ACh into choline and acetate.
Half life of ACh is short (fraction of a second)
AChE inhibitors cause ACh to accumulate in the vicinity of cholinergic nerve terminals and increase stimulation of cholinergic receptors
Butyrylcholinesterase
structurally related gene to AChE; synthesized in the liver and is primarily found in plasma.
MOA: Essentially the same as AChE
Under development as an antidote, to scavenge the AChE inhibitor in the plasma before it reaches peripheral and central tissue sites
Adv: Inhibited irreversibly by organophosphates
Malathion
Organophosphate insecticide AChE inhibitor
lipophilic (cross BBB)
Irreversibly bind to AchE by phosphorylating the active site of AchE.During “aging” the bond between the organophosphate and AchE strengthens.
Metabolized to inactive compounds. Safe for mammals and birds but toxic to insects and fish
Prodrug - must be converted to the -phosphor-derivative before it will have effects.
Parathion
Organophosphate insecticide AChE inhibitor
Similar MOA as Malathion
Adv: Not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is
not available for general public use in the USA
Sarin (“Nerve gas”)
Organophosphate
AChE inhibitor
Chemical warfare agent –> muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. CNS involvement (cognitive disturbances, convulsions, and coma)
follows rapidly + peripheral nicotinic effects, especially depolarizing neuromuscular blockade. Must maintain vital signs (esp. respiration), decontamination, and atropine parenterally in large doses (to control muscarinic excess), pralidoxime and benzodiazepines for seizures.
Echothiophate
Organophosphate insecticide
Not absorbed well by the skin like Malathion
“Aging” will occur with AChE and Echothiophate
Long duration of action with time (~100 hours)
Adv: Brow ache, uveitis, blurred vision
Edrophonium
Short-Acting AChE Inhibitor
“Tensilon Test”
Test for myasthenia gravis (will have improvement in muscle strength after injection), ileus, arrhythmias (rare)
An alcohol (doesn’t cross BBB) that electrostatically and by H bonds binds briefly to active site of AChE
Neostigmine
Intermediate-Acting AChE Inhibitor
Like edrophonium, but longer-acting
Tx: Myasthenia gravis; postoperative and neurogenic ileus and urinary retention
MOA: Forms covalent bond with AChE, but hydrolyzed and released
Physostigmine
Like neostigmine, but natural alkaloid tertiary amine; enters CNS
Intermediate-Acting AChE Inhibitor (Carbamate). Well absored and longer lasting (0.5-2 hours).
Tx: Myasthenia gravis (MG), acute angle-closure glaucoma (initial therapy with pilocarpine), postoperative and neurogenic ileus and urinary retention. Used to treat the CNS and PNS effects of atropine, scopolamine and other anticholinergic drug overdoses.
Adv: More toxic. Reverse effects with atropine.
Moderate doses: Modest bradycardia and ↑BP
High doses: marked bradycardia and hypotension
Pyridostigmine
Intermediate-Acting AChE Inhibitor (Carbamate)
Like neostigmine, but longer-acting (4-6 h)
Tx: Myasthenia Gravis
Ambenonium
Like neostigmine, but longer-acting (4-6 h).
Intermediate-Acting AChE Inhibitor (Carbamate)
Tx: Alternative to pyridostigmine for MG.
Carbaryl
AChE Inhibitor
Carbamate insecticide - very high lipid solubility –> CNS entry rapid
Pralidoxime
Acetylcholinesterase Regenerator
Tx: Organophosphate intoxication. Often given with atropine and diazepam. Does not cross BBB
MOA: Reactivates phosphorylated AcE. Drug has a higher affinity for the phosphorous than AchE because it is a strong nucleophile. Does not work if the enzyme is carbamylated. Must be given prior to “aging.”
Adv: Flushing, mydriasis, tachycardia, dryness of the mouth and nose if used with too much atropine
Triorthocresyl phosphate (TOCP)
Organophosphate AChE Inhibitor found in lubricating oils
Neurotoxic: Causes delayed neuropathy associated with demyelination of axons and intermediate syndrome (not related to cholinergic effects)
Pyrethrum
Pesticide made up of six known insecticidal esters:
Absorbed after inhalation or ingestion
the major site of toxic action is the CNS; excitation, convulsions, and tetanic paralysis can occur.
-Voltage-gated Na, Ca, and Cl channels are considered targets
Adv: Highly irritating to the eyes, skin, and respiratory tree –> irritant asthma and reactive airways dysfunction syndrome (RADS) and even anaphylaxis. Cutaneous paresthesias seen in workers spraying synthetic pyrethroids.
Rotenone
Pesticides derived from natural sources like nicotine
and pyrethrum
Clinical: The oral ingestion of rotenone produces gastrointestinal irritation. Conjunctivitis, dermatitis, pharyngitis, and rhinitis can also occur
Baclofen
spasmolytic
GABA/B agonist
induces hyperpolarization by increasing potassium efflux, reducing calcium influx and excitatory NT release in brain & spinal cord
less sedative effects than diazepam and
causes less reduction in muscle strength than dantrolene
Adv: increased seizure activity in epileptic patients, drowsiness but patients develop a tolerance
Diazepam
spasmolytic
acts at GABA/A synapses
Adv: sedation when given at high enough doses to reduce muscle tone
Benzodiazepines (midazolam, lorazepam, and diazepam)
Diazepam acts at GABA A synapses (causes sedation and reduces muscle spasm of almost any origin).
Tx: Sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant
Highly lipid-soluble benzodiazepines rapidly enter the CNS, which accounts for their rapid onset of action, followed by redistribution to inactive tissue sites and subsequent termination of the drug effect. Action can readily be terminated by administration
of their selective antagonist, flumazenil.
Botulinum Toxin
Produced from Clostridum Botulinum
Cosmetic uses for wrinkles
injecting overactive muscles with minute quantities of botulinum toxin type-A would result in decreased muscle activity by blocking the release of acetylcholine from the neuron by preventing the vesicle
salsalate
salicylate NSAID
azo link of mesalamine with sulfapyridine
Tx: IBS, rheumatoid arthritis
NSAIDs
Cyclooxygenase inhibitor
GI proglems (Unless COX2 selective)
Plicamycin
An antibiotic that can be used to inhibit osteoclast driven bone resorption
