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MSK > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Neuromuscular blockers

A 
1. Induce paralysis
  A. Adjuncts to general anesthesia
  B. Tracheal intubation - relax airway
  C. Control muscle contraction in status epileptics (uncommon)
2. Peripherally acting
  A. Don’t cross BBB
  B. Act on motor end plate
    1. Off-set effects
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2
Q

Neuromuscular Blocker target

A

Nicotine cholinergic receptors

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3
Q

Classes of neuromuscular blocking agents

A
  1. Depolarizing

2. Non-depolarizing

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4
Q

What allows for neuromuscular blocking agent specificity?

A

Nicotinic cholinergic receptors have several subunits that can vary in composition. Specific subunits can be targeted

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5
Q

Depolarizing agents

A
  1. Agonists of ACh receptors
  2. Mimics ACh -> action potential
  3. Opens channel gate- blocked open
  4. Can’t enter refractory period
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6
Q

Non-depolarizing agents

A
  1. Antagonist of nicotinic ACh receptors
  2. Prevent action potential
  3. Prevents gate from opening
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7
Q

Succinylcholine

A
  1. Depolarizing agent
    A. Only one used in US
  2. Extracellular Na+ -> cell -> depolarization
    A. Muscle contraction
    B. Widespread fasciculation = twitch w/ prolonged exposure
    C. Flaccid paralysis
  3. Phases
    A. Phase I block (4-8 min)
    1. Open channels maintain depolarized condition
    2. Voltage-gated Na+ channels inactivated
    3. New action potential can’t be achieved
      B. Phase II block (20 min)
    4. Nicotinic receptors -> desensitized (gates close and repolarized)
    5. Less responsive to additional agonist
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8
Q

Succinylcholine pharmacokinetics

A
  1. Rapid onset paralysis (1-2 min) and short duration (5-10 min)
    A. Administered IV or IM
  2. Metabolized in plasma by plasma cholinesterase
    A. Aka: pseudocholinesterase, butyrylcholinesterase
  3. Pharmacogenomics
    A. 1/25 people European decent deficient plasma cholinesterase
    B. Prolonged drug action
  4. No reversal agent
    A. Depends on diffusion away from synapse
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9
Q

Succinylcholine ADRs and contraindications

A
  1. Muscle weakness and pain
  2. Jaw rigidity
  3. Rhabdomyolysis -> renal failure
    A. Rare
    B. Contraindicated in Duchenne MD (and Becker) -> shred muscles
  4. Bradycardia, arrhythmia, and cardiac arrest due to off-target agonist of Nn and M receptors
  5. Inc intraocular pressure
  6. Inc serum [K+]
    A. Hyperkalemia
    B. Contraindications
    1. Burn, crush, closed-head, denervation, other injuries inc risk hyperkalemia
    2. End-stage renal disease, severe acidosis
  7. Off-target histamine release -> hypersensitivity, hypotension, and bronchospasm
    A. Pretreat w/ antihistamines
  8. Rare malignant hyperthermia
    A. Life-threatening complication if not treated (80% fatal)
    B. Inc skeletal muscle metabolism
    C. AD genetics
    1. Defective RyR1 -> massive Ca2+ release from SR
      D. Muscle rigidity, inc temp, inc arterial CO2 levels
      E. Pts on SSRIs and neuroleptics inc risk
      F. Tx: dantrolene inhibits Ca2+ release by blocking RyR1
  9. Drug-drug interactions
    A. AChesterase inhibitors may prolong effects
    B. Several antibiotics enhance effects
    1. Aminoglycosides, bacitracin, cyclosporine, polymixin B, tetracyclines, vancomycin
      C. Inhalation anesthetics (halothane) - inc sensitivity
      D. Antidepressants (SSRIs)
      E. Neuroleptics (antipsychotics)
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10
Q

Dantrolene

A 
Treatment for succinylcholine OD
1. Inhibits Ca2+ release by blocking RyR1
  A. Blocks power stroke of myosin/actin
2. ADRs
  A. Diarrhea, sedation, and Athenians
  B. Black box warning: hepatotoxicity
3. Dec affinity RyR2 in cardiac or smooth muscle
4. Dec mortality from 80% to <10%
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11
Q

Non-depolarizing neuromuscular blocker

A 
1. Tubocurarine derivative
  A. Atracurium (tracrium)
  B. Cisatracurium (nimbex)
2. Steroid derivatives
  A. Rocuronium (zemuron)
  B. Vecuronium (Norcuron)
  C. Pancuronium (Pavulon)
3. Competitive inhibitors ACh receptors 
  A. Prevent action potentials
  B. Flaccid paralysis
4. Duration of action depends on metabolism
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12
Q

Rocuronium

A
  1. Non-depolarizing blocker
  2. Short-acting metabolism by liver
  3. Non-selective M blockage -> tachycardia
    A. Don’t use on pts w/ arrhythmias
  4. Active 20-35 min
  5. Relative potency: 0.8
  6. Onset time: 0.5-2 min
  7. Reversal: sugammadex
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13
Q

Vecuronium

A
  1. Non-depolarizing blocker
  2. Short-acting metabolized by liver
  3. Duration of action: 20-35 min
  4. Relative potency: 6
  5. Onset time: 2-3 min
  6. Reversal: sugammadex
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14
Q

Pancuronium

A
  1. Non-polarizing blocker
  2. Longer-acting metabolized by kidney
  3. Non-selective M blockade -> tachycardia
    A. Don’t use on pts w/ arrhythmias
  4. Active >35 min
  5. Relative potency: 6
  6. Onset time: 3-4 min
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15
Q

Pipecuronium

A
  1. Non-depolarizing blocker

2. Longer-acting metabolized by kidney

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16
Q

Tubocruarine

A
  1. Non-depolarizing blocker
  2. Longer-acting metabolized by kidney
  3. Not used in clinic
  4. ADRs
    A. Non-selective blockage Nn receptors
    B. Histamine release
    1. Hypotension and bronchospasm
    2. Pre-medicate w/ antihistamines
  5. Active >50 min
  6. Relative potency: 1
  7. Onset time: 6 min
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17
Q

Atracurium

A
  1. Non-depolarizing blocker
  2. Spontaneously degrade in blood
    A. Hoffman elimination
    B. Laudanosine = metabolite
    1. Crosses BBB - may cause seizures => use less
  3. Active: 20-35 min
  4. ADRs
    A. Slight histamine release
  5. Relative potency: 1.5
  6. Onset time: 3 min
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18
Q

Cisatracurium

A
  1. Non-depolarizing blocker
  2. Spontaneously degrades in blood
    A. Hoffman elimination
    B. Laudanosine = metabolite
    1. Crosses BBB- may cause seizures
  3. Forms less laudanosine than atracurium => used more
  4. Active: 25-44 min
  5. Relative potency: 1.5
  6. Onset time: 2-8 min
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19
Q

Non-depolarizing blocker reversal

A
  1. Inc ACh at NMJ
  2. AChesterase inhibitors inc recovery rate
    A. Dec resp depression, pharyngeal dysfxn, post-surgical hypoxemia
    B. Dec time in recovery room
  3. Atropine given to avoid cardiac M receptor stimulation
  4. Sugammadex for rocuronium and vecuronium
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20
Q

Sugammadex

A
  1. Reverses rocuronium and vecuronium
  2. Chelates
  3. IV admin -> reversal in 3 min
  4. No cholinergic activity
  5. Renal excretion
  6. Anaphylaxis = major ADR
  7. Cost prohibitive
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21
Q

Spasm

A

Painful, involuntary muscle contraction

  1. Dehydration/electrolyte imbalance
  2. Over-exertion
  3. Infection
  4. Injury/neurodegeneration
  5. Acute local spasms from injury or muscle strain
  6. Tx: antispasmodic agents
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22
Q

Spasticity

A

Involuntary contraction of skeletal muscle -> stiffness that interferes w/ mobility and speech
1. Neurodegenerative disorders
A. MS
B. ALS
C. Cerebral palsy
D. Spinal injury
2. Tx: spasmolytic agents
A. Alleviate pain, but not effective at restoring mobility
3. Deficit in upper motor neuron signaling -> lower motor neurons hyperexcitable
A. Express more receptors
B. Disregulation stretch reflex -> contraction w/o stimulus

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23
Q

Spasmolytic agents

A
  1. Change frequency of contraction
  2. Target
    A. Lower motor neurons
    B. Interneurons in reflex arc
    C. Skeletal muscle directly
  3. CNS-active spasmolytics dec alpha-motor neuron activity
    A. Target receptors in spinal cord
    B. Inc activity inhibitory neurons
    C. Dec activity excitatory neurons
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24
Q

Inhibitory neurons

A
  1. Release gamma-aminobenzoic acid (GABA)
  2. Activates inhibitory GABAa/b
  3. Agonists of GABA inhibits neuron activity
  4. Dec firing rate of other interneurons and lower motor neuron
  5. GABA analogs dec activity alpha-motor neuron
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25
Q

Excitatory neurons

A
  1. Create glutamate
    A. Agonizes AMPA receptors (Na+ channels) -> action potential
  2. Agonism inhibitory receptors
    A. G alpha1-coupled GPCRs agonism dec intracellular activity (dec cAMP, closed Ca2+ channels, etc.)
    1. Alpha2-adrenergic receptors
    2. GABAb receptors
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26
Q

Centrally acting spasmolytics

A 
1. GABA receptor ligands 
  A. Baclofen 
  B. Diazepam
2. Alpha 2-adrenergic receptor agonists
  A. Tizanidine
3. Side effects
  A. Crosses BBB
  B. Spinal cord and brain share CSF
    1. Brain exposed to drugs
    2. Agonism inhibitory receptors in brain -> sedation (depends on drug and dose)
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27
Q

Benzodiazepines

A

GABA modulators
1. Inhibitory lower and upper neurons
2. CNS-active sedatives and anxiolytics
A. Sleep enhancers, antiepileptics, EtOH w/drawl symptoms
3. (+) allosteric modulator GABAa receptors
A. Inc CL- permeability -> hyperpolarization
4. Dec firing rate hyperactive lower motor neuron
5. BZD + EtOH -> potentially fatal

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28
Q

Benzodiazepine pharmacokinetics

A
  1. Oral almost completely absorbed
  2. Plasma protein bound
  3. Classified by t1/2
    A. Short acting (anxiety disorders)
    B. Intermediate
    C. Long acting (spasticity)
    1. Dec risk w/drawl
  4. Diazepam (Valium) most common tx for spasticity
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29
Q

Benzodiazepine abuse liability

A
  1. Abuse liability
    A. “Loss of control” or “rush” w/ onset
    B. Abuse rare, inc risk multi-drug abusers
  2. Long-term use -> physical dependence’s
    A. Sudden cessation -> w/drawl
    B. Taper drug when discontinued
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30
Q

Diazepam

A
  1. Benzodiazepine
  2. Long-acting (1-3 days)
    A. Dec risk w/drawl
  3. Hepatically metabolized -> oxazepam (short acting BZD)
    A. Interactions w/ CYP3A4 substrates inc apparent dose
    1. Grapefruit juice, ketoconazole, ritonavir
      B. Interactions w/ CYP3A4 inducers dec apparent dose
    2. St. John’s wart, carbamazepine
  4. Oxazepam excreted renally
  5. ADRs
    A. Sedation
    B. Daytime drowsiness
    C. Rebound insomnia/anxiety
    D. Coma and resp depression when used w/ other depressants (EtOH inc rate absorption and acts at GABAa receptor)
  6. Tx for OD: flumazenil
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31
Q

Flumazenil

A

Tx for diazepam OD
1. BZD-binding site antagonist
2. Only GABAa drugs
3. IV, rapid onset and shor-acting
A. Could be matabolized while long-acting still at OD level
4. Agitation, confusion, dizziness, nausea

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32
Q

Baclofen (Lioresal)

A

GABAb receptor agonist
1. 1st choice tx spascitity MS and spinal cord injuries
A. Less sedation than diazepam
2. Short-acting GABAb analog
A. “GABA-mimetic agent”
3. Causes hyperpolarization
4. Dec excitatory transmitter release in CNS
A. Dec activity Ia afferents, spinal interneurons, and motor neurons
5. DMPK
A. Rapidly and completely absorbed orally
B. T1/2 = 3-4 hrs
1. 80% eliminated renally and thru biliary excretion
C. Intro the cal catheter
1. Min ADRs
2. Risk life-threatening CNS depression

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33
Q

Baclofen ADRs

A

Not always tolerated well

  1. High dose -> xs sleepiness, resp depression, coma
  2. Inc seizure risk in epileptics
  3. Peripheral: nausea, constipation, muscle weakness, urinary frequency
  4. Abrupt discount. -> seizures
  5. Intrathecal - risk acute w/drawl symptoms
  6. Caution pregnant women - animal studies suggest birth defects
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34
Q

Gabapentin (Neuorontim)

A
  1. Anti-convulsants can be effective in tx spasticity w/ MS
  2. Doesn’t act on GABA
  3. Dec glatuameric activity
    A. Targets Ca2+ channels in presynaptic terminal that trigger synaptic vesicle release
    B. Tx: shingles and MS
  4. Eliminated unchanged: t1/2= 6hr
  5. Well-tolerated
  6. ADRs
    A. Sedation
    B. Somnolence
    C. Ataxia
    D. Fatigue
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35
Q

Tizanidine (Zanaflex)

A
  1. Alpha 2 -adrenergic agonist
  2. Dec firing rate of presynaptic neurons
    A. Inhibit GPCR
  3. Mech not well understood
  4. Tx spasms: MS, ALS, spastic diplegia, back pain, other CNS injuries
  5. Clinical trials: as effective as diazepam, baclofen, and dantrolene
    A. Less muscle weakness, but diff ADR profile
  6. ADRs
    A. CNS-related: drowsiness, dizziness, Asthenia
    B. ANS: hypotension, dry mouth
    1. Contraindicated w/ orthostatic hypotension
      C. Hepatotoexicity: dosage adjusted for pt. W/ renal and liver disease
      D. DDI’s: CYP1A2 inhibition raises apparent dose
    2. Ciprofloxacin, cimetidine, amiodarone, fluvoxamine, oral contraceptives
      E. DDI’s: CYP1A2 induction dec apparent dose (smoking)
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36
Q

Drugs that act on skeletal muscle

A
  1. 1st choice because no CNS activity and side effects
  2. Dantrolene (dantrium)
  3. Botulinum toxin type A (Botox)
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37
Q

Botulinum toxin type A (Botox)

A
  1. Clostridium botulinum
  2. Inhibit presynaptic neuron
  3. LD50: 1.3-2.1 Ng/kg, IV or IM (very low)
  4. Types A-H, A and B used medically and commercially
  5. BTX enzymatically cleaves SNARE protein in vesicular release
    A. Chemodenervation and local paralysis
    1. Muscle spasms, cosmetic purposes (1-3 mo)
    2. Local injection for tx of generalized spastic disorders (cerebral palsy)
    3. After injection, benefits persist for weeks to several months after single tx
  6. Other FDA approved indications
    A. Incontinence due to overactive bladder and chronic migraine
  7. ADRs
    A. Resp infections
    B. Muscle weakness
    C. Urinary incontinence
    D. Falls
    E. Fever
    F. Pain
  8. Injections at least 3 mo apart
  9. Relatively high cost
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38
Q

Cyclobenzaprine (Flexeril)

A

Antispasmodic
1. Centrally active agents that treat peripheral muscle spasms by targeting brain stem
2. Unknown MOA
3. Major interactions w/ CNS-depressant drugs
4. Cyclobenzapine (class prototype)
A. Strong antimuscarinic side effects
1. Significant sedation, confusion, and transient visual hallucinations, seizures, tachycardia, hypotension
2. Rare, but life threatening neuroleptic malignant syndrome
5. Carisoprodal (soma)

39
Q

Neuroleptic malignant syndrome

A

Similar to malignant hyperthermia

  1. Fever
  2. Muscle rigidity
  3. Altered mental status
  4. Autonomic dysfunction
  5. Tx: dantrolene
40
Q

Carisoprodal (soma)

A

Cyclobenzapine

  1. Metabolized to meprobamate by CYP2C19
  2. Meprobamate = schedule IV drug w/ sedative action and abuse liability
41
Q

Prostaglandins

A
  1. Mediators of inflammation
  2. Eicosanoids
  3. Cyclooxygenases -> prostaglandins and thromboxanes from arachadonic acid
  4. Many subtypes
  5. Synthesized and released endothelial cells, mast cells
  6. Mediate nociception sensitivity
    A. PGE2 and PGI2 ligands dec pain threshold peripherally
    B. PGE2, PGI2, and PGF2g dec central sensitization (dec excitability in dorsal horn neurons)
    C. NSAIDs cross BBB
  7. Fever
    A. Pyrogens -> fever
    1. Phase I, local injury cytokines
      B. Phase II: PGE2 (COX-2) cross BBB and act on EP3 (and EP1) on thermosensitive neurons -> hypothalamus inc temp
      C. Antipyretic properties mediated thru inhibition PGE2 synthesis
42
Q

Eicosanoid receptors

A
  1. Found throughout body => off-target effects
  2. Mediate inflammatory processes
  3. Prostaglandin receptors = G-couples protein receptors
43
Q

Nociceptor activation

A
  1. Thermal, mechanical, chemical damage
  2. Nociceptor activation (free nerve endings)
  3. CGRP and substance P released by activated nociceptors
  4. Blood vessel dilation and mast cell degranulation
44
Q

Chemical mediators and inflammatory response

A 
1. Vasodilation:
  A. Histamine
  B. Prostaglandins (PGI2, PGE1, PGE2, PGD2)
  C. Bradykinin 
2. Inc. vascular permeability:
  A. Histamine
  B. Bradykinin
  C. Substance P
  D. Calcitonin gene-related peptide (CGRP)
3. Fever:
  A. Prostaglandins (PGE2, PGI2)
4. Pain:
  A. Prostaglandins (PGE2, PGI2)
  B. Bradykinin
  C. Substance P
  D. Calcitonin gene-related peptide (CGRP)
45
Q

NSAID indications

A
  1. Inflammation
  2. Pain
  3. Fever
46
Q

Non-selective NSAIDs

A
  1. Salicylates (aspirin)
  2. Propionic acid derivatives (ibuprofen)
  3. Acetic acid derivatives (indomethacin, diclofenac)
  4. Oxidant derivatives (piroxicam)
47
Q

Selective NSAIDs

A

COX-2 inhibitors
1. Celecoxib
2. Rofecoxib
A. Withdrawn from market due to adverse cardiac effects

48
Q

Cyclooxygenase (COX)

A 
1. 2 genes
  A. COX-1
  B. COX-2
2. Catalyze arachadonic acid -> prostaglandin H (PGH2)
3. COX-1 = housekeeping enzyme
  A. Maintains gut integrity
  B. Vascular tone
  C. Platelet aggregation
  D. Nerve/brain fxn
  E. Kidney fxn
4. COX-2 induced by cytokines
  A. More closely interacts w/ enzymes -> pro-inflam prostaglandins
  B. Inflammation, pain, fever, cancer, allergies, etc.
49
Q

Prostaglandin synthesis

A
  1. PGE2 and PGI2 = predominant pro-inflam prostaglandins
  2. PGD2 produced by mast cells
  3. Thromboxane (TxA2) mediates clotting
  4. Prostaglandin (PGI2) balances thrombic effect of TxA2
50
Q

Salicylate

A 
Aspirin
1. Non-selective NSAID
2. MOA: irreversible
  A. Inhibits COX-1 and COX-2 enzymes
    1. Prostaglandin synthesis
    2. Platelet aggregation
3. Pharmacokinetics
  A. T1/2 = 30 min
  B. Aspirin hydrolyzed -> salicylic acid
  C. Salicylate irreversibly acetylates active site of COX enzymes
4. Pregnancy category: D in 3rd trimester
5. Breastfeeding: salicylic acid -> breast milk
6. Indications:
  A. OA
  B. RA
  C. Fever
  D. Pain
  E. Prophylaxis of stroke and MI
7. Thrombolytic 
  A. COX inhibition -> dec thromboxane A2 (TxA2) levels -> clotting
51
Q

Salicylate ADRs and considerations

A 
1. Common
  A. GI disturbances
  B. Tinnitus
2. Serious
  A. GI ulcer
  B. Hemorrhage
  C. Reye’s syndrome: encephalopathy in kids recovering from viral infection
3. Considerations: 
  A. Allergic rxn
  B. Kids and teenagers w/ chicken pox or flu symptoms (Reye’s syndrome)
52
Q

Propionic acid derivatives

A 
Non-selective NSAIDs
1. Ibuprofen (t1/2=1.8 hr)
2. Naproxen (t1/2= 2 hr)
3. Ketoprofen (t1/2 = 2.5 hr)
4. Flurbiprofen (t1/2 = 3.8 hr)
5. Fenoprofen (t1/2 = 18 hr)**
6. MOA: reversible COX-1 and COX-2 inhibitors
  A. PG synthesis
7. Pregnancy category
  A. B in 1st and 2nd trimesters
  B. D in 3rd trimester
8. Breastfeeding:
  A. Ibuprofen okay
  B. Naproxen avoided bc long half-life
9. Indications
  A. OA
  B. RA
  C. Fever
  D. Pain
10. Bind same site as aspirin
53
Q

Propionic acid derivative ADRs and considerations

A 
1. Common: 
  A. GI disturbance
  B. Tinnitus
2. Serious
  A. CHF
  B. MI
  C. GI ulcer
  d. Hemorrhage
3. Black box warning: inc risk CV thrombotic events, MI, and stroke
  A. Serious GI adverse events
    1. Bleeding
    2. Ulceration 
    3. Perforation
4. Considerations
  A. Don’t take w/ aspirin
  B. Naproxen - loungers t1/2 and lowest risk CV ADRs
54
Q

Acetic acid derivatives

A 
Non-selective NSAIDs
1. Indomethacin (t1/2 = 4-5 hrs)
2. Sulindac (t1/2 = 8 hrs)
3. Etodolac (t1/2 = 6.5 hrs)
4. Diclofenac (t1/2 = 1.1 hrs)
5. Ketorolac (t1/2 = 5 hrs)
6. MOA: reversible COX-1 and COX-2 inhibitors
  A. PG synthesis
7. Pregnancy category
  A. C in 1st and 2nd trimesters
  B. D in 3rd trimester
8. Breastfeeding: indomethacin okay
9. Indications: 
  A. OA
  B. RA
  C. Pain
55
Q

Acetic acid derivative ADRs and considerations

A 
1. Common
  A. GI disturbances
  B. Tinnitus
2. Serious
  A. CHF
  B. MI
  C. GI ulcer
  D. Hemorrhage
3. Black box warning: inc risk CV thrombotic events, MI, and stroke
  A. Serious GI ADRs
    1. Bleeding
    2. Ulceration
    3. Perforation
4. Considerations
  A. Ketorolac good alternative when can’t us opioids
  B. Not indicated for fever
  C. Treat moderate-severe pain
56
Q

Oxicams ADRs and considerations

A 
1. Common
  A. GI disturbances
  B. Tinnitus
2. Serious
  A. CHF
  B. MI
  C. GI ulcer
  D. Hemorrhage
3. Black box warning: inc risk CV thrombotic events, MI, and stroke
  A. Serious GI ADRs
    1. Bleeding
    2. Ulceration
    3. Perforation
4. Considerations
  A. Ketorolac good alternative when can’t us opioids
  B. Oxicams analgesic effects > aspirin
  C. Adjust dose for dec hepatic fxn
57
Q

Oxicams

A
  1. Prioxicam (t1/2 = 57 hrs)
  2. Meloxicam (t1/2 = 20 hrs)
  3. MOA: reversible COX-1 and COX-2 inhibitors
    A. PG synthesis
  4. Pregnancy category: D
  5. Breastfeeding: not recommended
  6. Indications:
    A. OA
    B. RA
    C. Pain
58
Q

Acetomeniphen

A 
Not NSAID
1. MOA: centrally acting analgesic and antipyretic
  A. Reversible inhibition of peroxidase site of COX-1/2 -> dec release PG in CNS and inhibit endogenous pyrogens at hypothalamic thermoregulation center
2. Half-life: 2-3 hrs
3. Pregnancy category: B
4. Breastfeeding: safe
5. Indications
  A. OA
  B. Pain
  C. Fever
59
Q

Acetaminophen ADRs and considerations

A 
1. Common
  A. Nausea
  B. Vomiting
  C. Pruritis 
2. Severe: liver failure
3. Black box warning: acute hepatic failure -> liver transplant or death
4. Considerations 
  A. Avoid use in active and severe hepatic disease
  B. Can overlap w/ ibuprofen
  C. Not anti-inflammatory
5. OD -> liver failure
  A. Required liver transplant 
  B. Reactive intermediate (toxin) depletes glutathione in liver -> damage
60
Q

COX-1 inhibition and GI bleeding

A
  1. COX-1 predominant isoform in gastric epithelial cells
  2. Cytoprotective in gastric cells
    A. PGI2 and PGE2 stimulate surface -> mucus
  3. Inhibits COX-1 -> dec protective PGs and TxA2 -> ulcers
  4. TxA2 -> platelets -> clotting and constrict blood vessels
    A. If ulcer perforated, clotting slowed
61
Q

NSAID contraindications

A
  1. Hx GI bleed and allergies
  2. Combo therapy w/ H+ - pump inhibitors - protect uppe GI
    A. omeprazole 20 mg/day
  3. Enteric coating slows drug release => better for long tern
    A. Non-coated better for acute pain/fever/inflammation
  4. GI bleeding -> dev COX-2 inhibitors
62
Q

COX-2 inhibition and CV events

A
  1. COX-2 products regulate BP
    A. Inhibition -> exacerbate HTN and inhibit blood clotting
  2. Selective COX-2 inhibition dec PGI2 inhibit platelet aggregation
  3. Rofecoxib taken off market bc inc incidence thrombotic events
63
Q

Celocoxib

A 
COX-2 selective NSAID
1. MOA: inhibit COX-2 inhibit PG synthesis 
2. Half-life: 11 hrs
3. Pregnancy category: 
  A. C in 1st and 2nd trimesters
  B. D in 3rd trimester
4. Breastfeeding: low levels in mild, wouldn’t expect ADRs in baby
5. Indications
  A. OA
  B. RA 
  C. Pain
64
Q

Celecoxib ADRs and considerations

A 
1. Common
  A. HTN
  B. GI disturbances
  C. Headache
2. Serious 
  A. MI
  B. Heart failure
  C. Stroke
3. Black box warning: inc risk
  A. CV thrombolytic event
  B. MI
  C. Stroke
4. Considerations
  A. Not for pts w/ heart failure 
  B. Dec efficacy ACE inhibitors (diuretic)
65
Q

NSAIDs and elderly pts

A
  1. Arthritis and gout common
  2. NSAIDs rarely used to treat chronic pain
    A. Renal failure
  3. Use H+-pump inhibitors in conjunction
66
Q

Disease-modifying antirheumatic drugs (DMARDs)

A 
1. RA most common indication
  A. Systemic , inflammatory
  B. Autoimmune
  C. Goal of tx: control inflammation, dec disease activity -> achieve remission
2. Modify disease process
67
Q

Managing RA w/ DMARDs

A
  1. Slow tissue destruction
  2. Don’t repair already done
  3. Start ASAP
  4. Mediate immune response- complex MOA
  5. Classes
    A. Biologics
    B. Non-biologics
68
Q

Non-biologic (traditional) DMARDs

A 
1. Antimetabolites
  A. Methotrexate
  B. Axothioprine
2. Corticosteroids
  A. Prednisone
  B. Methylprednisolone
  C. Triamcinolone
3. Aminoquiloline
  A. Hydroxychloroquine
4. 5-aminosalicylate
  A. Sulfasalazine
5. Dihydroorotate dehydrogenase inhibitor
  A. Leflunomide
69
Q

Biologic DMARDs

A 
1. Tyrosine kinase inhibitor
  A. Tofacitinib
2. Tumors necrosis factor-alpha (TNF-alpha) inhibitor
  A. infliximab
  B. Etanercept
  C. Adalimumab
  D. Golimumab
  E. Certolizumab
3. IL-1 inhibitor
  A. Anakinra
4. IL-6 inhibitor
  A. Tocilizumab
5. CD80/86 inhibitor
  A. Abatacept
70
Q

Immunosuppressant targets

A
  1. Inhibit gene expression
  2. Dec clinal expansion of lymphocytes
  3. Inhibit intracellular signaling
  4. Dec T cell stimulation by neutralizing cytokines and cytokines receptors
  5. Deplete T cells
  6. Inhibit costimulation of antigen-presenting cells
  7. Inhibit lymphocyte - target cell interaction
71
Q

Corticosteroids

A 
Traditional DMARDs
1. Prednisone (t1/2 = 2-3 hrs)
2. Methylprednisolone (t1/2 = 18-36 hrs)
3. Triamcinolone (t1/2 = 18-36)
4. MOA: inhibit numerous steps in inflammatory response
  A. Antigen presentation
  B. PG and leukotriene synthesis
  C. Neutrophil and monocyte superoxide radical generation
5. Pregnancy category: D
5. Indications
  A. RA
  B. Others
72
Q

Corticosteroid ADRs and considerations

A 
1. Common
  A. Hypothalamic-pituitary-adrenal suppression (why need tapering for discontinuation)
  B. Cushing syndrome
  C. HTN
  D. Hirsutism 
  E. Electrolytic imbalance
  F. Osteoporosis
  G. Glucose intolerance (diabetics)
  H. Inc susceptibility infection
2. Serious
  A. Cardiac arrest
  B. Impaired healing
3. Considerations
  A. RA for immunosuppressive and anti-inflammatory properties
  B. Injected joints and soft tissues
  C. Oral for systemic effect
  D. Most t1/2 long enough for 1/day dosing
  E. Don’t give as monotherapy
73
Q

Antimetabolites

A

Traditional DMARDs

  1. Methotrexate
  2. Azothioprine
74
Q

Methotrexate

A 
Antimetabolite- traditional DMARD
1. MOA: folate analogue inhibits dihydrofolate reductase (DHFR)
  A. Inhibits cytokine production
  B. Purine biosynthesis -> adenosine release
  C. Inhibit DNA/RNA synthesis
2. Half-life: 2-3 hrs
3. Pregnancy category: X -teratogen
4. Indications
  A. RA
  B. Cancer
  C. Others
75
Q

Methotrexate ADRs and considerations

A 
1. Common
  A. Nausea
  B. Vomiting
  C. Diarrhea
  D. Stomatitis
2. Serious
  A. Aplastic anemia
  B. Leukopenia
  C. Bone marrow suppression
  D. Hepatocytoxicity w/ prolonged use
3. Black box warning: embryo-fetal toxicity and fetal death
  A. Monitor for toxicities 
    1. Bone marrow suppression
    2. Infection
    3. Renal
    4. GI
    5. Hepatic
    6. Pulmonary
    7. Hypersensitive
    8. Dermatogolic 
4. Considerations
  A. 1st choice initial therapy RA
    1. Results as early as 2-3 weeks, 45-67% use for 5-7 yrs
    2. Low dose
  B. Effective against rapidly dividing cells
76
Q

Azothioprine

A 
Antimetabolite - traditional DMARD
1. MOA: imidizole derivative of 6-mercaptopurine
  A. Immunosuppression
  B. Suppresses cell-mediated hypersensitivities and alters antibody production
2. Half-life: 5 hrs
3. Pregnancy category: D
4. Indications
  A. RA
  B. Lupus
  C. Transplant rejection
77
Q

Azothioprine ADRs and considerations

A 
1. Common
  A. Nausea
  B. Vomiting
2. Serious
  A. Leukopenia
  B. Hepatotoxicity
  C. Infectious disease
3. Black box warning: chronic immunosuppression
  A. Inc risk malignancy
4. Considerations
  A. Pt. Use sunscreen, protective clothing, avoid tanning beds
78
Q

Hydroxychloroquine

A 
Aminoquinoline -  traditional DMARD
1. MOA: immunosuppressant, interferes w/ antigen presentation
  A. Inhibits enzymes: collagenase and proteases
2. Half-life: 172 hr to 50 days
3. Pregnancy category: safe
4. Indications
  A. RA
  B. Lupus
79
Q

Hydroxychloroquine ADRs and considerations

A 
1. Common
  A. Nausea
  B. Vomiting
  C. Dizziness
  D. Tinnitus
2. Serious
  A. Retinal disorder
  B. Hypoglycemia
  C. Torsades de pointes (arrhythmia)
3. Considerations
  A. May cause vision changes
80
Q

Sulfasolazine

A

5-aminosalicylate - traditional DMARD
1. MOA: prodrug bound sulfapyridine -> cleaved by azoreductase inhibits inflammation due to black age COX and PG synthesis in colon
A. Inhibits IL-1 and TNF-alpha production
B. Inhibits natural killer cells, mucosal lymphocytes and macrophages
2. Half-life: 7-14 hrs
3. Pregnancy category: B
4. Indications
A. RA
B. Ulcerative colitis
C. Crohn’s disease

81
Q

Sulfasolazine ADRs and considerations

A 
1. Common
  A. Headache
  B. Nausea
  C. Diarrhea
  D. Interstitial nephritis
2. Serious - sulfapyridine -> incidence:
  A. 40% pts can’t tolerate
  B. Allergic rxn
  C. Hemolytic anemia
  D. Leukopenia
  E. Hepatitis
  F. Slow acetylators more ADRs
3. Considerations
  A. Antibiotics -> dec azoreductase -> dec active moiety
  B. Yellow-orange urine/skin
82
Q

Leflunomide

A

Dihydrooratate dehydrogenase inhibitor - traditional DMARD
1. MOA: pyrimidine synthase inhibitor
A. Lymphocytes depend on de novo pyrimidine synthesis after immune activation
2. Half-life: 14-16 days
A. Needs loading dose
3. Pregnancy category: X - teratogenic
A. Enterohepatic recirculation-> takes months to clear enough to conceive
4. Indications
A. RA
B. Cancer

83
Q

Leflunomide ADRs and considerations

A 
1. Common: 
  A. Rash
  B. Diarrhea
  C. Stomatitis
2. Serious
  A. Stevens-Johnson syndrome
  B. Inc live enzymes
  C. Respiratory tract infections 
  D. Thrombocytopenia
3. Considerations
  A. Efficient as methotrexate
  B. Don’t use for pts w/ liver disease
  C. Avoid live vaccines
84
Q

TNF-alpha inhibitors

A

Biologic

  1. Infliximab (t1/2 = 14 days)
  2. Adalimumab (t1/2 = 14 days)
  3. Golimumab (t1/2 = 14 days)
  4. Certolizumab (t1/2 = 14 days)
  5. Etanercept (t1/2 = 102 hrs)
  6. MOA: monoclonal antibody w/ specific activity for TNF-alpha
  7. Pregnancy category: B
  8. Indications: RA
85
Q

Biologics

A

Genetically engineered proteins that block inflammatory cytokines

  1. Injected
  2. TNF-alpha inhibitors
  3. IL-1 inhibitors
  4. IL-6 receptor inhibitors
  5. CD80/86 inhibitor
86
Q

TNF-alpha inhibitors ADRs and considerations

A 
1. Common
  A. Injection site rxns
  B. Upper respiratory infection
2. Serious
  A. Autoimmune hepatitis
  B. TB reactivation 
  C. Hep B reactivation
  D. Inc risk cancer
3. Black box warning: serious infection
  A. Test for latent TB
4. Considerations
  A. No live vaccines 
  B. Etanercept also binds TNF-beta
87
Q

Tofacitinib

A

Tyrosine Kinase inhibitor - biologic DMARD
1. MOA: JAK inhibitor, JAK = tyrosine kinase facilitates STAT protein phosphorylation
A. STATs regulate inflammatory gene transcription
2. Half-life: 3-6 hrs
3. Pregnancy category: C
4. Indications: RA

88
Q

Tofacitinib ADRs and considerations

A 
1. Common
  A. Inc HDL and LDL
  B. Headache
2. Serious
  A. Skin cancer
  B. Anemia
  C. Infectious disease
3. Black box warning: serious infections
  A. TB
  B. Invasive fungal
  C. Viral
  D. Inc risk CV thrombosis w/ hx of one
  E. Lymphoma
4. Considerations
  A. Monitor cholesterol
  B. No live vaccines
89
Q

Anakinra

A

IL-1 inhibitor - Biologic

  1. MOA: competitive inhibitor IL-1 in synovial joints
  2. Half-life: 4-6 hrs
  3. Pregnancy category: B
  4. Indications: RA
90
Q

Anakinra ADRs and considerations

A 
1. Common
  A. Injection site rxn
  B. Diarrhea
  C. Nausea
  D. Vomiting
  E. Flu-like symptoms 
2. Serious
  A. Neutropenia
  B. Infectious disease
3. Considerations
  A. No live vaccines
91
Q

Tocilizumab

A

IL-6 receptor inhibitor - biologic

  1. MOA: binds IL-6 receptors and inhibits IL-6 mediated signaling
  2. Half-life: 11-13 days
  3. Pregnancy category: C
  4. Indications: RA
92
Q

Tocilizumab ADRs and considerations

A 
1. Common
  A. Injection site rxn
  B. Inc ALT/AST levels
  C. Headache
  D. HTN
  E. Hyperlipidemia
2. Serious
  A. Neutropenia
  B. Hepatic toxicity
  C. Upper respiratory infection
3. Black box warning: serious infection
  A. Test for latent TB
4. Considerations:
  A. No live vaccines
  B. Monitor inc cholesterol
  C. Tocilizumab > adalimumab monotherapy if can’t tolerate methotrexate
93
Q

Abatacept

A

CD80/86 inhibitor - biologic
1. MOA: response modifier -> Dec T cell activation
A. Binds CD80/86 receptors inhibits binding CD28 on T cells
2. Half-life: 13-14 days
3. Pregnancy category: C
4. Indications: RA

94
Q

Abatacept ADRs and considerations

A 
1. Common
  A. Nausea 
  B. Headache
  C. Infectious disease
  D. Nasopharngitis
  E. Upper respiratory infection
2. Serious: inc risk infection
3. Considerations: 
  A. False inc glucose reading because maltose in solution
  B. Can worsen COPD symptoms

MSK (13 decks)

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