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Pharmacology > Musculoskeletal > Flashcards

Musculoskeletal Flashcards

1
Q

Tubocurarine

A

Induces muscle paralysis

A drug that blocks the acetylcholine at its receptor, preventing interaction and subsequent deplolarization.

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2
Q

Succinylcholine

A

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.

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3
Q

Neuromuscular Blocking Drugs

A

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.

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4
Q

Vecuronium

A

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

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5
Q

Atracurium

A

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)

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6
Q

Mivacurium

A

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

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7
Q

Pancuronium

A

80% eliminated by Kidney (thus long lasting)

Causes a moderate increase in heart rate and a smaller increase in cardiac output.

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8
Q

Reversal of Nondepolarizing Neuromuscular Blockade

A

Neostigmine and Pyridostigmine antagonize acetylcholinesterase, allowing more acetylcholine to be present at the synapse.

They also increase release from nerve terminal (unlike edrophonium)

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9
Q

Malignant Hyperthermia

A

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

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10
Q

Diazepam

A

Acts at GABA-a synapses

Causes sedation

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11
Q

Dantrolene

A

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.

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12
Q

Cyclobenzaprine

A

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

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13
Q

Glucocorticoid

A

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)

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14
Q

COX I and II

A

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

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15
Q

Leukotrienes and Epoxides

A

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

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16
Q

Arachidonic Acid Pathway

A

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

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17
Q

Biological Effects of Eicosanoids

A

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.

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18
Q

NSAID uses and side effects

A

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)

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19
Q

Aspirin

A

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

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20
Q

Other Salicylates

A

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

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21
Q

Acetaminophen

A

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.

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22
Q

Indomethacin

A

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

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23
Q

Sulindac

A

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.

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24
Q

Etodolac

A

Very potent anti-inflammatory with less GI side effects.

It is a slightly selective COX-2 inhibitor, which is responsible for sparing GI.

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25
Q

Mefenamic acid and meclofenamate

A

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

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26
Q

Tolmetin

A

Studied a lot in pediatric populations, so it is used in pediatric populations

It is well-tolerated, and is used sometimes for juvenile arthritis

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27
Q

Ketorolac

A

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

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28
Q

Diclofenac

A

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.

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29
Q

Ibuprofen

A

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

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30
Q

Piroxicam

A

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

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31
Q

Meloxicam/Nabumetone

A

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

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32
Q

Celecoxib

A

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

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33
Q

Glucocorticoids

A

-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

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34
Q

Glucocorticoid Comparison

A

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)

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35
Q

Colchicine

A

An acute gout drug

  1. Binds to tubulin and prevents polymerization into microtubules
  2. Interferes with mitotic spindle function
  3. Inhibits migration and phagocytic actions of granulocytes
  4. 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

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36
Q

NSAIDs for Gout

A

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

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37
Q

Allopurinol

A

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
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38
Q

Febuxostat

A

Chronic gout drug

Nonpurine xanthine oxidase inhibitor

Liver function abnormalities, diarrhea, nausea

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39
Q

Rasburicase

A

Chronic gout drug

Recombinant urate oxidase

Converts uric acid into soluble and inactive metabolite

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40
Q

Probenecid

A

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

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41
Q

Rheumatoid Arthritis

A

Previously, you would start by treating with NSAIDs, which relieve pain but don’t modify disease

Now, you try and modify the disease

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42
Q

Methotrexate

A

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.

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43
Q

Cyclophosphamide

A

DMARD for RA

alkylating agents/cross link DNA

toxic effects of bone marrow suppression, infertility,
increased risk of infections and neoplasia

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44
Q

Sulfasalazine

A

Azo linkage of sulfapyridine and 5-aminosalicylic acid

Acts by scavenging free radicals and as COX inhibitor
and dihydrofolate reductase inhibitor

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45
Q

Abatacept

A

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

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46
Q

Rituximab

A

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

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47
Q

Tocilizumab

A

IL-6 receptor antagonist

Used in RA when it hasn’t responded to other drugs

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48
Q

Anakinra

A

IL-1 receptor antagonist

RA drug

Used when response is lacking to other DMARD therapies

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49
Q

Anti TNF►alpha drugs

A

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

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50
Q

Mycophenolate Mofetil

A

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

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51
Q

Azathioprine

A

DMARD for RA

converted to 6-mercaptopurine, inhibits de novo purine synthesis

primary targets T and B cells

toxicity - - any rapidly growing cell population

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52
Q

Leflunomide

A

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

53
Q

Cyclosporine

A

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

54
Q

Chloroquine and Hydroxychloroquine

A

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

55
Q

Vitamin D analogs

A

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)

56
Q

Calcitonin

A

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

57
Q

Estrogens

A

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

58
Q

Teriparatide

A

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

59
Q

Glucocorticoids (in relation to Vitamin D)

A

Antagonize Vitamin D stimulated intestinal calcium absorption

Stimulates renal calcium excretion

block bone collagen synthesis
increase PTH stimulated bone resorption

60
Q

Denosumab

A

Can be used in women that have risk of estrogen driven cancers

mimics effect of OPG

61
Q

Biphosphonates

A

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

62
Q

Non-hormonal agents of bone regulation

A

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

63
Q

Doxorubicin

A

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

64
Q

Cisplatin

A

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)

65
Q

Ifosfamide

A

Alkylating agent

Used to treat soft tissue and osteosarcomas

Interstrand alkylator

66
Q

Cyclophosphamide

A

Used to treat soft tissue and osteosarcomas

Cleaved into mustard phosphoramide and acrolein (toxic metabolites)

Interstrand

67
Q

Dactinomycin

A

Treat soft tissue and bone sarcomas

Intercalates with DNA and blocks RNA polymerases

Hematopoietic suppression is most serious toxicity

68
Q

Dacarbazine

A

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

69
Q

Etoposide

A

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

70
Q

Methotrexate

A

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

71
Q

Filgrastim

A

G-CSF

Increases neutrophil count during chemotherapy

72
Q

Bleomycin

A

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

73
Q

Vincristine

A

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

74
Q

Chemoprophylaxis

A

antimicrobial give before and during surgery

use beyond 24hrs bad b/c of inducing resistance

cephalosporins or vancomycin are drugs of choice

75
Q

Superinfection

A

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

76
Q

Delayed treatment of osteomyelitis

A

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

77
Q

Methicillin-resistance treatment

A

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)

78
Q

Linezolid

A

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

79
Q

Quinupristin/dalfopristin

A

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

80
Q

Daptomycin

A

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

81
Q

Lyme disease treatment

A

First choice:

Oral- *doxycycline or amoxicillin for kids

IV- ceftriaxone for late phase

82
Q

Metronidazole

A

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

83
Q

Treat C. bolulinum in GI

A

Metronidazole and Penicillin G to eliminate C. botulinum from GI tract

84
Q

Diethylcarbamazine citrate

A

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

85
Q

Filariasis treatment

A

benzimidazole, albendazole, in combination with ivermectin

Benzimidazole and albendazole inhibit microtubule polymerization by binding to parasite beta-tubulin

86
Q

Onchocerciasis treatment

A

Ivermectin, causes tonic paralysis of musculuture by activation glutamate Cl channels, well tolerated

87
Q

Trichinosis treatment

A

Mebendazole or albendazole

Both inhibit microtubue polymerization by binding parasite beta-tubulin

88
Q

Osteomyelitis Treatment

A

S. aureus

Give penicillin G

Nafcillin, oxacillin, dicloxacillin to penicillin-resistant

Vancomycin to methicillin-resistant

89
Q

Nafcillin

A

Synthetic penicillin, resistant to beta-lactamase

Used for osteomyelitis (IM or IV)

90
Q

Oxacillin

A

Synthetic penicillin, resistant to beta-lactamase

Used for osteomyelitis (IM or IV)

91
Q

Dicloxacillin

A

Synthetic penicillin, resistant to beta-lactamase

Used for osteomyelitis (IM or IV)

92
Q

Piperacillin-tazobactam

A

Piperacillin is very broad spectrum

Not beta-lactamase resistant so must be given with tazobactam which is beta-lactamase inhibitor

93
Q

Imipenem

A

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

94
Q

Cefazolin

A

Cephalosporin

Cephalosporins used to treat infections of bones and joints, usually look to beta-lactamase resistant penicillins before cephalosporins

Others include cephalothin, cefuroxime, ceftriaxone

95
Q

Septic arthritis cause/treatment

A

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)

96
Q

Infectious arthritis cause/treatment

A

Gonococcal urethritis (N. gonorrhoeae)

Ceftriaxone, ciprofloxacin, ofloxacin, cefixime

97
Q

Atropine

A

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

98
Q

Scopolamine

A

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

99
Q

Acetylcholine

A

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

100
Q

Bethanechol

A

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

101
Q

Carbachol

A

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

102
Q

Muscarine

A

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.

103
Q

Muscarinic Receptor Types (M1-M5)

A

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)

104
Q

Nicotine

A

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

105
Q

Lobeline

A

Tertiary Natural Cholinomimetic Alkaloid
Plant derivative similar to nicotine

Meth, Cocaine, Smoking cessation aid.

106
Q

Pilocarpine

A

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.

107
Q

Acetylcholinesterase

A

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

108
Q

Butyrylcholinesterase

A

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

109
Q

Malathion

A

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.

110
Q

Parathion

A

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

111
Q

Sarin (“Nerve gas”)

A

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.

112
Q

Echothiophate

A

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
113
Q

Edrophonium

A

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

114
Q

Neostigmine

A

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

115
Q

Physostigmine

A

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

116
Q

Pyridostigmine

A

Intermediate-Acting AChE Inhibitor (Carbamate)

Like neostigmine, but longer-acting (4-6 h)

Tx: Myasthenia Gravis

117
Q

Ambenonium

A

Like neostigmine, but longer-acting (4-6 h).

Intermediate-Acting AChE Inhibitor (Carbamate)

Tx: Alternative to pyridostigmine for MG.

118
Q

Carbaryl

A

AChE Inhibitor

Carbamate insecticide - very high lipid solubility –> CNS entry rapid

119
Q

Pralidoxime

A

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

120
Q

Triorthocresyl phosphate (TOCP)

A

Organophosphate AChE Inhibitor found in lubricating oils

Neurotoxic: Causes delayed neuropathy associated with demyelination of axons and intermediate syndrome (not related to cholinergic effects)

121
Q

Pyrethrum

A

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.

122
Q

Rotenone

A

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

123
Q

Baclofen

A

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

124
Q

Diazepam

A

spasmolytic

acts at GABA/A synapses

Adv: sedation when given at high enough doses to reduce muscle tone

125
Q

Benzodiazepines (midazolam, lorazepam, and diazepam)

A

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.

126
Q

Botulinum Toxin

A

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

127
Q

salsalate

A

salicylate NSAID
azo link of mesalamine with sulfapyridine
Tx: IBS, rheumatoid arthritis

128
Q

NSAIDs

A

Cyclooxygenase inhibitor

GI proglems (Unless COX2 selective)

129
Q

Plicamycin

A

An antibiotic that can be used to inhibit osteoclast driven bone resorption

Pharmacology (12 decks)

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