NSAIDS / Opiods / Asthma / COPD Flashcards
(45 cards)
1
Q
Aspirin (ASA)
MOA & PK
A
acetyl-salicylic acid –> met. to reactive acetyl group + salicylate
- Effects due to salicylate moiety (binds to COXs)
- 10x more potent on COX-1
-
covalently acetylate COXs –> inactivates irreversibly (due to acetyl effect on COX)
- new COX synthesis req. to terminate action
- **PK: **Oral, 325 mg, slows accumulation of free drug
- rapidly hydrolyzed to salicylic acid + acetic acid
- COVALENT acetylation may only occur near site of absorption (platelets, endothelial cells). Before acetyl group is hydrolyzed
- Low dose –> met by liver conjugation (1st order)
- 2-3 tabs –> analgesic & antipyretic
- High dose –> excreted unmetabolized by kidneys
- __4+ tabs –> anti-inflammatory dose
- 0 order (drug can build up, non-saturable)
- High dose required for anti-inflammatory for COX-2 effect (toxic doses that take more time to eliminate)
- Half-lives - 2 hr for low dose
- 15-30 hr for high dose
2
Q
Aspirin Therapy
A
- Blocks PG synthesis and PG release
-
Analgesia
- mild to moderate pain
- PGs sensitize receptors for peptide mediators of pain (bradykinin, substance P)
- Aspirin inhibition of PGs limits inflammation-related pain
- Antipyresis
- acts on hypothalamus to return thermoreg set-point to normal
- Anti-inflammatory
- double-dose
- COX-2 effect, requires higher dose
- for acute rheumatic fever, rheuatoid arthritis
- __Unique use –> Reduce risk of MI and Stroke
- reduce thrombus formation (after event or prophylactic)
- effects on platelets = about 7 days
- Shift balance to anti-thrombotic PGI (prosta**cyclin) **formation from endothelial cells (COX-2) -> sustained reduction in TXs
- decreases clotting, increases bleeding time
- Also beneficial in Colorectal Cancer, esp with FAP
- COX-2 elevation
- Closure in patent ductus arteriosus
3
Q
Aspirin Adverse Effects
A
-
GI Effects:
- PGs protect Gi mucose from acid damage, salicylates are acids
- gastric irritation, bleeding, ulceration, ulcers
- less irritation with enteric coated, use w/ PG analog or omeprazole
- CV Effects
- dilation of peripheral vessels with large doses
- avoid in pts with blood-clotting disorders
-
Premature closure of Ductus Arteriosus (avoid in 3rd trimester)
- patency mediated by PGs
4
Q
Aspirin Toxicity
A
-
Low Therapeutic Dose - in balance
- uncouple ox-phos in skeletal muscle –> Increase O2 consumption, CO2 production
- Increase CO2 –> Increase respiration
- Higher Dose - therapeutic or toxic
- directly stim CNS resp center –> respiratory alkalosis
- renal bicarb excretion compensates
- Toxic Overdose
- central vasomotor paralysis
- decreased blood flow -> renal failure
- leads to metabolic acidosis and hypokalemia
- respiratory paralysis –> resp acidosis. Plasma becomes acidic –> many organs fail
- Mild Toxicity – Salicylism. Ringing in ears, dizziness, drowsiness, hyperventilatio –> reduce dose
- Overdose Toxicity - children, large acute dose. GI duscurbances, CNS disturbances, skin eruptions, hyperpnea, then resp and metabolic acidosis
- hospitalize and maintain vitals
- prevent absorption with activated charcoal, whole bowel irrigation, volume repletion
- Sodium Bicarb –> iorn trapping of salicylate in urine
5
Q
Ibuprofen / Naproxen
A
- Propionic Acid Derivatives
- **Therapy: **analgesic, antipyretic, anti-inflammatory
- **MOA: **similar to aspirin
- but reversible and competitive only
- better than aspirin for dysmenorrhea
- useful in treatment for gout
-
**Adverse: **GI concerns, prolongs bleeding time initially
- not as long-lasting as aspirin
- Binds to albumin –> displaces warfarin, other drugs
- Cross-sensitivity w/ aspirin (dont use w/ allergy)
- Ibuprofen - chronic use increase risk of MI and stroke, block effects of low-dose aspirin
- Naproxen - greater ulcer risk
- **Toxicity - **similar to aspirin
- nausea, vomiting, Gi bleeds.
- treat with activated charcoal, monitor respiration and vitals
6
Q
Indomethacin
A
- Acetic Acid Derivative
- 10-20x more potent than aspirin
- mainly used in severe inflammation (rehumatoid arthritis, gouty arthritis), limited use for analgesia and antipyresis
- also approved for PDA
*
- also approved for PDA
7
Q
Celecoxib
A
- Selective COX-2 inhibitor
- most inflammation effects due to COX-2
- many adverse effects are COX-1
- **Therapy: **osteoarthritis, theumatoid arthritis, FAP
- equal to naproxen for osteoarthritis and rheumatoid arthritis
- pain relief, worse than naproxen after dental surgery
- fewer problems for asthmatics than aspirin
- Drug Interactions
- metabolized by CYP-2C9, inhibts 2D6 in some pts
- altered met of tricyclic and SSRI anti-depressants
- **Adverse: **Edema is most common (dec kidney function)
- GI problems
- Cant use with Sulfa allergy
- Not during pregnancy
- increased risk of MI (tip balance to COX-1 –> increase TXs, platelet aggregation, risk of thrombosis, stroke)
8
Q
Acetaminophen
A
- Non-opioid analgesic -> not inflammatory
- Inhibition of COXs and PG Synthesis
- PK: well absorbed GI, metabolism in liver (CYP2E1)
- **MOA: **analgesia and anti-pyresis (similar to aspirin)
- no anti-inflammatory action
- CNS effects - relaxation, drowsiness, euphoria
- safer alternative for pain and fever in children
-
Adverse: Differences from aspirin
- No GI effects, No hematologic effects, No Reye’s syndrome, No CV effects, no acid-base effects
- but no anti-inflammatory actions either
- hepatic damage is major concern with chronic use
- Alcohol increases liver damage risk
- chronic abuse - nephrotoxicity
- No GI effects, No hematologic effects, No Reye’s syndrome, No CV effects, no acid-base effects
9
Q
Acetaminophen Toxicity
A
- GI Distress
- nausea, vomiting, anorexia, abdominal pain
- hepatotoxicity - major concern (occurs at 8 hours)
- jaundice at 24-48 hrs, usually reversible
- formation of reactive electrophile –> modifies and inactivates liver proteins (unless adequately removed by glutathione (GSH)
- CYP2E1 forms reactive electrophile
- Treatment
- remove drug –> activated charcoal, vomiting, gastric lavage in the first 4 hours
- After 4 hrs –> N-acteyl-cysteine - reverse toxicity (reacts with AC toxic metabolite) and restores endogenous glutathione
10
Q
Opiate Receptors
A
-
Mu - morphine-like. In CNS, periphery, spinal cord.
- analgesia, anti-anxiety, resp depression
- **Kappa - **petnazocine-like. CNS, spinal cord
- Aanalgesia, miosis, sedation, dysphoria, hallucinations
- Delta - Enkephalin-like. CNS, periphery
- dependence, euphoria, analgesia
Morphine acts at mu, kappa, & delta. All full agonists act at mu receptors
11
Q
Morphine
A
Prototype for opioid drugs
- Natural constituents of opium
- **PK: **readily absorbed. Analgesia in 5-15 min. Duration 4-5 hrs
- __EtOH can break down slow-release matrix
- Metabolism: conjugation with glucoronic acid - major
- most inactive metabolites (3-B - seizures)
- Excreted in urine as conjugate
- Additional caution with impaired liver and renal function
- Tolerance – develops to some effects, not others
12
Q
Morphine Actions
A
-
Analgesia –> without LOC at therapeutic doses
- peripheral and spinal levels to block pain transmission and block response to pain
- more effective in continuous dull pain
- Raises pain threshold - useful for moderate pain
- Much more selective than anesthetics, barbituates, alcohol. Tolerance can develop
- **Respiratory Depression - ** even at low doses
- primary cause of death in overdose
- increase in chemoreceptor sensitivity to CO2 levels (hypoxic response still present) (same for given level of analgesia between opioids)
- Tolerance develops
- Nausea & Vomiting - chemoreceptor trigger zone
- Rapid Tolerance develops
- GI Effects - constipation (decrease in propulsive contractions in LI and SI). No tolerance
- **Drowsiness - **Tolerance develops
- Miosis - diagnostic sign. No tolerance
- Histamine release –> itching, hypotension
- Inhibits immune system. Increase ACTH, PRL, ADH. Decrease TSH, LH
13
Q
Morphine Therapy
A
- Moderate to severe pain
-
Primarily in acute pain
- Acute pain - injury/disease. Treat normally
- Chronic - terminal -> disease. Continuous. Treat aggressively
- Chronic - neuropathic -> treat carefully
- First start with drugs for moderate pain (codeine, hydrocodone, codeine + aspirin), then morphine for moderate to severe pain (morphine)
- Used in sickle cell crisis pain
- Dyspnea in lung cancer (relax pt -> improve breathing)
14
Q
Morphine Adverse
A
- Dependence
- Increased biliary and urinary tracts (worsen biliary colic and UTI)
- Allergy
- Neonates and elderly more sensitive
-
Limitations / Contraindications
- Decreased resp reserves (asthma, emphy, cor pulmonale)
- Head injuries (obscure important signs)
- Pregnancy
- Drug Interactions
- Any CNS Depressant (sedative-hypnotics, MAO-I)
- Sustained release are compromised by ethanol
15
Q
Codeine
A
- Structurally similar to morphine
- More reliable when given orally (better first-pass metabolism)
- Primarily to treat mild to moderate pain (30-60 mg)
- moderate (combo w/ asprin or acetaminophen)
- Effective for cough suppression
- More constipation
- Less potential for addiction compared to morphine
16
Q
Methadone
A
- Range of effects same as morphine, different PK
- **PK: **very effective orally
- Met by CYP3A4 slowsly (half life 15 hours) & 22 hours chronically
- Chronic use: 6-8 hrs analgesia
- **Therapy: **analgesia, treatment of drug dependence
- **Adverse: **serious CV effects. (QT prolongation, Torsades)
- Parenteral methadone - euphoria and dependence
17
Q
Fentanyl
A
- Compared to Morphine
- Analgesia - Short onset time. 15-30 min peak effects. Shorter duration of action
- Produces suphoria, drowsiness, sedation, dependence
- Similar respiratory and hormonal effects but does not induce histamine release
- CV: less effect than morphine. Maintains cardiac stability
- More likely to produce muscle rigidity of chest and abdomen
- used in anesthesia
18
Q
Hydrocodone / Oxycodone
A
- Hydrocodone
- Schedule II
- Most commonly prescribe drug in US
- CYP3A4
- Oxycodone
- More potent than codeine. Effective orally. Abuse of timed release formation
- CYP2D6
19
Q
Loperamide HCl (Imodium)
A
- Potent anti-diarrheal agent.
-
Full opioid agonist that crosses mucosal membranes poorly
- Limited to GI tract
- Not a scheduled drug
20
Q
Dextromethorphan
A
- Antitussive
- Full opioid agonist
- Effective cough-suppressant
- Abuse is increasing
- No analgesia effects
21
Q
Pentazocine
A
-
Partial Opioid Agonist
- Kappa receptor agonist (not as efficacious as full agonist, antagonist effect when on-board with full agonists)
- Analgesia, sedation, resp depression similar to morphine
- resp depression and analgesia plateau
- High doses –> produce dysphoria
- May increase BP and Heart Rate
-
May precipitate withdrawal in opioid depednent pts due to antagonist action
- Very reliable orally
- Use: analgesia in moderate to severe pain (not in high dose because of dysphoria and hallucinations
*
22
Q
Buprenorphine
A
- Partial agonist at Mu receptors
-
Antagonist at kappa receptors
- Ceiling for producing analgesia, resp depression, euphoria
- Similar morphine effects on eyes, GI tract, high dose may prolong QTc
- Uses: analgesia – only IV
- Treatment of opioid dependence
- Treatment of cocaine abuse
23
Q
Tramadol
A
-
Very weak partial opioid agonist
- Weak Mu Partial Agonist plus inhibits NE and 5HT transport
- Can produce dependence, difficult withdrawal
- Adverse: Seizures, serotonin syndrome
24
Q
Naloxone (Narcan)
A
-
Opioid Antagonist
- Blocks opiate receptors (more effective vs full agonists than partial agonists) at mu receptors (competitive antagonist)
- Use: Little to no effect on its own
- to counteract the effects of opioids (resp depression after surgery, overdose, drug abuse)
- Short acting (1-4 hrs)
-
Will precipitate withdrawal when physical dependence is present
- Cannot treat resp depression due to non-opioid effects
25
Acute Opioid Overdose
* **Diagnosis**
* Resp depression
* Miosis
* Coma
* **Treatment**
* Support respiration, intubate
* Prevent further absorbance
* Naloxone --\> to reverse resp depression (partial agonists are not very responsive)
26
Albuterol
* **Short Acting Beta-2 Selective Agonist (SABA)**
* Treating **acute bronchoconstriction and exercise-induced asthma**
* **PK**: Inhalation - onset within _1-5 minutes, duration 2-6 hrs_
* Longer duration orally
* **Adverse:** Tachycardia, palpitations.
* CNS stimulatory
* Receptor desensitation with chronic drug use
* Inhalation reduces systemic effects
27
Salmeterol
* **Long-acting beta-2 selective agonist (LABA)**
* most widely used
* High B-2 selectivity, long-lasting action
* Exosite on B-2 receptor --\> _persistent & repeated activation of receptor_
* **Therapy: **Useful for _maintenance_ and patients with _nocturnal symptoms_
* **__****Inappropriate for acute bronchoconstriction**
* **Always** used together with anti-inflammatory steroid
* Fixed-combo dose in inhalers
28
Formoterol
* **Maintenance** and **Prevention** of exercise-induced bronchospasm
* Long-action due to _lipophilicity_
* More _rapid onset_ than salmeterol
* **Always together with ** anti-inflammatory steroid
* LABAs also used in **COPD**
* safe _alone for COPD_
* Oral therapy less effective --\> for children who cannot use inhaler or with severe asthma
29
Fluticasone / Budesonide
* **Inhaled Corticosteroids (ICS)**
* **MOA: **Do not relax airway smooth muscle --\> little effect on acute bronchoconstriction
* **Inhibit inflammation**
* Bind to agonist transcription factors - stimulate anti-inflammatory products
* Modulate cytokine / chemokine production - inhibit basophils, eosinophils, other leukocytes
* **Therapy: **moderate persistent asthma & severe asthma
* Used prophylactically
* Control symptoms, prevent irreversible airway changes
* **PK: **Inhaled - enhanced therapeutic index. Longer durations action, higher affinities and selectivities for GC receptors
* **Adverse: **Mostly free of toxicity - localized
* Hoarseness and pharyngeal candidiasis due to inhalation - rinse mouth after delivery
* Other GC effects (HPA, decreased bone density, cataracs)
* Combo with LABA (salmeterol + fluticasone)
30
Prednisone
* **Systemic Glucocorticoid**
* used for _acute exacerbations_ of asthma unresponsive to inhaled dilators
* Sometimes for chronic, severe asthma
* Much greater concern for GC toxicity
* increased BP, Glucose intolerance, osteoporosis, cataracts, and glaucoma, HPA suppression
31
Long-term asthma control
* Mild intermittent --\> None
* Mild persistent --\> low-dose inhaled steroid
* Moderate persistent --\> low-dose inhaled steroid + LABA. Or medium steroid
* Severe persistent --\> high dose inhaled steroid plus LABA or oral steroid
Quick relief --\> always SABA
32
Theophylline
* **Methylxanthine** - Bronchodilators for asthma
* structural analog of caffeine
* Orally, short duration of action
* Not inhaled
* **Therapy: **weak bronchodilator (not useful for acute)
* mainly _used as adjunct for long-term preventative therapy_
* Decrease freq and severity of symptoms (especially nocturnal)
* **MOA: ****Phosphodiesterase inhbition** - cAMP elevation
* PDE3 - bronchodilation
* Antagonist at bronchoconstrictor adenosine receptors
* Calcium release in muscle contraction
* **Adverse: **Higher dose: nausea, nervousness, anxiety, headache
* Toxic: vomiting, hypokalemia, hyperglycemia, tachy, seizures
* Many drugs and foods can increase concentrations
33
Montelukast / Zileuton
* **Leukotriene Modifiers**
* LT increase eosinophil migration, mucus production, airway wall edema, bronchoconstriction
* **Use: **_Decrease LT levels_
* Alternatives to inhaled steroids in _mild-persistent asthma_
* Add-on therapy in moderate-persistent asthma
* Use in _aspirin-sensitive asthma_ (NSAIDS shift PG-LT balance to favor LTs)
* Limited for acute attacks - no major dilation effect
* **Adverse: **Mild ehadache, GI disturbance
* Reversible liver toxicity with zileuton
* risk of psychosis or depression with montelukast
* Comparisons
* oral is convenient for children
* **Montelukast** - only one LT receptor (_antagonist of CysLT1) - LTD4 receptor_ (LT bronchoconstriction, CYP450)
* **Zileuton** blocks All LT actions. (_inhibitor of 5-lipoxygenase enzyme_). **More anti-inflammatory** than montelukast
34
Omalizumab
* **Recomb human monoclonal antibody against IgE**
* Administered SC injection every 2-4 weeks
* Use for _moderate to severe asthma_ whose asthma is due to reactivity to allergens and not controlled with steroids
* **Adverse: **skin irritation / recation at injection site
* Occaisonal anaphylactic reactions upon injection
35
Cromolyn Sodium
* **Mast Cell Stabilizer**
* **MOA: **prevent release of mast cell mediator
* **Use: **decrease airway hyperresponsiveness --\> prevent asthmatic attacks in _mild to moderate asthma_
* Not useful in acute attacks (limited use overall)
* **PK: **Inhaled powder or aerosol, short duration of action
* **Adverse: **bronchospasm, reflex wheezing, throat irritation, cough, dry mouth
* joint swelling and pain, headache, rash
36
Indacaterol
* **Inhaled LABA **for **COPD use only**
* NOT indended for asthma or acute COPD exacerbations
* Once-daily maintenance for airflow obstruction in chronic bronchitis and emphysema
37
Ipratropium / Tiotropium
* **Muscarinic Antagonist (Tiotropium - LAMA)**
* **MOA: **derivatives of atropine
* non-selective blockade of _M1-M5 receptors_ (**M3** **blockade** - main target for bronchodilation
* Block only part of bronchoconstriction that is _mediated by acetylchoine release_
* Prevent constriction, not actively dilate
* dilation occurs more slowly and less intense. Also reduce mucus hypersecretion
* **Clinical Use: **_Only for COPD_ and emphysema
* **PK: **Inhalation. Ipratropium - short acting
* Tiotropium - long (24 hr)
* **Adverse: **Some dry mouth and pharyngeal irritation
* increase ocular pressure in glaucoma patients
* Anti-chol effects: constipation, tachycardia, blurred vision, urinary retention
38
Roflumilast
* **PDE4-selective inhbitor**
* _Orally_ effective
* Specifically for _reducing exacerbations in adults with severe COPD assoc. with chronic bronchitis & history of exacerbations_
* Reduces inflammation but NOT bronchoconstriction
* NOT a bronchodilator and should NOT be used for bronchospasm
* **Adverse: **Diarrhea & nausea
* Insomnia, anxiety, depression
* weight loss
* should not be used in liver impairment
39
Dephenhydramine (Benadryl)
* **First Generation H1-Receptor Antagonist**
* Oral & topical preparation for allergic symptoms
* **Use: **Allergic rhinitis, derm pain and itching, Sleep Aid, motion sickness (anti-muscarinic effect)
* **Adverse: **due to _anti-muscarinic effects_
* ****_Sedation_ is prominent
* topical allergic responses (dermatitis)
* may reduced lactation / enters breast milk
* Avoid in _narrow angle glaucoma_
40
Chlorpheniramine (Chlor-Treimetron)
* **First Generation H1-antagonist**
* Oral preparation
* **Use: **Allergic rhinitis, derm pain and itching, OTC cold remedy
* **Adverse: **Sedation (less than diphenhydramine)
* less effects at muscarinic receptors than diphenhydramine, but similar side effects (glaucoma, reduced lactation)
41
Promethazine
* **First Generation H1-antagonist**
* Oral preparation
* **Use: **in similar fashion to diphenhydramine / chlorpheniramine
* ****_Antiemetic agent (for nausea and vomiting)_
* **Adverse: **similar to antihistamines
* also _photosensitivity_
42
Meclizine
* **First generation H1-antagonist**
* Used for **vertigo**, preventing motion sickness
* _Less sedating _ than other 1st generation antihistamines
43
Doxylamine
| ( + pyridoxine = **Diclegis**)
* First generation anti-histamine
* Approved for **Morning Sickness in Pregnancy**
44
Fexofenadine (Allegra)
* **Second Generation H1-Antagonist**
* Oral prep. _Do not take with fruit juice_ (reduced absorption via OATPs)
* **Use: **Allergic rhinitis
* Derm pain and itching (better if before onset of symptoms)
* **Adverse: **generally **not** sedating
* nausea, vomiting, dysmenorhea, drowsiness, enters breast milk
45
Cetirizine (Zyrtec)
* **Second Generation H1-antagonist**
* Oral prep. Long duration of action
* **Use: **allergic rhinitis, derm pain and itching
* **Adverse: **relatively _sedating_ for a 2nd-gen
* Weak anti-musc. effects (dry mouth)
* Metabolized by CYP3A4
