LECTURE 10: WHAT IS IN YOUR MEDICINE CABINET? Flashcards
WHAT IS IN YOUR MEDICINE CABINET?
q Content
q List
q Expiration dates
q Storage and disposal
Common Items
- aspirin, acetaminophen, ibuprofen, naproxen, decongestants, cough
medicines, antihistamines, eye drops, calcium carbonate tablets
(tums), anti-diarrhea (loperaminde), omeprazole, calamine lotion,
benzoyl peroxide, antifungal cream, hydrogen peroxide, toothpaste,
mouthwash, benzocaine, neosporin, polysporin etc..
- Prescription drugs
- Mercury thermometers, tweezers, bandages, pill cutter, nail polish,
perfume, IPECAC
ACETAMINOPHEN
pharmacology
Acetaminophen (paracetamol; N-acetyl-p-aminophenol
(APAP), Tylenol)
- adult ~ 325-650 mg/4-6h, total daily 3-4g
- child ~10-15 mg/kg, no more than 5 doses/24h, 0.4-2.4g
Pharmacology
§ Analgesic and antipyretic effect, weak anti-inflammatory
§ Non-selective inhibitor of COX (COX-2>COX-1)
§ Blocks production of prostaglandins by reducing
heme on peroxidase (differs from NSAIDs –
occupy COX binding site)
Evidence analgesic effects
- serotoninergic, opioid, cannabinioid, TRV1 receptors
they’re blocking their non selective inhibitors of cycloxygenase pathway. The tend to favor COX 2 over 1
Affeects peroxidase activity
reduce and prevent the production of your prostaglandins
- central, nervous, and analgesic effects are involving these pathways. So if you can add a serotonin antagonist and opioid antagonists can basically reduce some of those analgesic effects.
ACETAMINOPHEN
PK
Pharmacokinetics/ADME
§ Majority of APAP absorbed within 2h, peak 4h
§ 90% undergoes hepatic conjugation
§ 40-67% glucuronide, UGT;
§ 20-46% sulfation, SULT1A1
§ 5% unchanged
Key point
§ 5% is oxidized by CYP2E1
§ N-acetyl-p-benzoquinoneimine (NAPQI)
§ NAPQI conjugated with glutathione to
cysteine/mercaptate conjugates eliminated by
urine
Toxicity
§ Leading cause of acute liver failure/transplant
§ Mortality rate ~0.5%
CYP2Eq generates NAPQI
NAPQI is toxic metabolite
- . But what happens under conditions where you deplete your antioxidant system, you deplete your your cysteine and gluathione levels.
- or you produce too much of this reactive metabolite. This is going to result in toxicity.
ACETAMINOPHEN – MOA TOXICITY
Toxic Doses
Adult ~ 7-12 g/day; Child ~150-300 mg/kg
2 groups – (acute) suicide (50%) vs
(chronic) unintentional overdose (50%)
Key points NAPQI
- Covalently binds to proteins
- Glutathione deficiencies
- Primarily hepatic zone III
- Mitochondrial effects – cell death
You have individuals who try to commit suicide, so half the people who are coming in have these overdoses, and there’s also you get elderly individuals, or tend to be more chronic, unintentional use, not always elderly individuals.
NAPQI binds proteins leading to cell death
Glutathione def resutls in increased lvls of reactive metabolite
if you cause mitochondrial damage, you can increase your reactive oxygen species production, and you can trigger various cell death pathways.
ACETAMINOPHEN –TOXICITY
stage I-IV
Stage I (0-24h): Incubation (quiescent – might be missed)
§ Asymptomatic or nonspecific symptoms (nausea/vomiting, malaise, diaphoresis)
Stage II (24-72h): Latent Period
§ Resolution/Improvement of stage I symptoms
§ Onset of hepatic injury (~5% of patients who overdose), AST/ALT lab value
abnormalities, elevated AST then ALT (1000 IU/L)
§ Nephrotoxicity may occur
Stage III (72-96h): Peak Liver Toxicity
§ Systemic symptoms re-appear
§ Fulminant hepatic failure (encephalopathy, jaundice, coagulopathy, hypoglycemia)
§ Abnormalities transaminase peak (3-4d), PT, INR, glucose, lactic acidosis
§ Highest risk of death
Stage IV (4d-2 weeks): Resolution
§ Survivors make a complete recovery and/or death
N-ACETYLCYSTEINE (NAC) - ANTIDOTE
§ Successful antidote when administered within critical time (~4-8h)
§ Two options: 24h IV and a 72h oral
§ IV – extremely safe, fast, rare ADR
§ Oral – strong smell, makes patient vomit, logistical hard
§ Precursor for synthesis of GSH
§ NAC detoxifies NAPQI several non-specific mechanisms
§ Free radical scavenger
§ Increase oxygen delivery/microvascular tone
§ Increase mitochondrial ATP production
§ Antioxidant effects
Clinical Tests
- Serum APAP
- Aminotransferases (ALT/AST)
- INR
- Serum creatinine
ACETAMINOPHEN – NOMOGRAM (ACUTE TOXICITY)
Rumack-Matthew nomogram
§ Based on empirical data of initial plasma [APAP] - patients
developed AST above 1000IU/L separated those who did
not have elevated
§ Validated for half-lives following an acute ingestion (should
½ every 4 hrs)
§ ex. 1000uM at 4hrs should be 500uM at 8 hrs
Note: Slope based on clinical data not any discriminatory
APAP t½ or APAP kinetics or hepatic failure
§ Factors impact interpretation:
§ Incorrect history
§ Multiple/chronic ingestions
§ CYP inducers
§ Chronic alcohol use
§ Extended-release
GOAL: To determine the risk of hepatoxicity and need to
initiate NAC therapy – [APAP] above the line start NAC
therapy
N-ACETYLCYSTEINE (NAC) - ANTIDOTE
Traditional 3 bag regimen
NOTE: AHS – New one concentration , 2-step NAC regimen
(30mg/ml adult/children; 40mg/ml neonate)
Step 1 – 150 mg/kg IV over 60 minutes
Step 2 – 15 mg/kg/hr over a minimum of 20 hrs
traditionally, they called it a 3 bag regimen, and they basically start a loading dose about 150 milligrams per kilogram for about an hour followed by second dose, 50 milligrams for 4 h, and then a third dose back up to 100 milligrams per kilogram for 16 h.
N-ACETYLCYSTEINE (NAC) – ANAPHYLACTOID??
Anaphylactic Reaction (ADR Type B – Type I
hypersensitivity response)
§ Cross linking allergen to specific IgE molecules
§ Mast cells and basophils
§ Re-exposure – degranulation release of histamine
Anaphylactioid Reaction (non-immunological)
§ Non-IgE mediated response
§ Does not require previous exposure
§ Drug triggers sudden/massive mast cells and
basophils degranulation (release histamine) in
absence of immunoglobulins
§ Problematic – asthma (‘bronchospasm’ –pre-treat)
Clinical Manifestation
§ Signs and symptoms same (‘acute allergic reaction’)
§ Treatment – antihistamines, beta-2 agonist,
corticosteroids
So basically the compound is going to trigger a sudden release of mass
activation, the mass cells and in basel cell degranulation.
if they have asthma or they have other reactions you dont want to stop NAC
Obviously, if there’s too much of an adverse effect you’re going to have to stop it. Problematic to stop and restart antidote
Unlike anaphylaxis, you can readminister NAC once you attenuate that response so they don’t develop aby, non-immunological response
CAN GIVE AGAIN
NSAIDs - COXIBs
COX-1 - constitutive
*COX-2 – inducible
*NSAIDs (Diclofenac, naproxen, ibuprofen, indomethacin)
*COXIB (celecoxib (Celebrex®), rofexcoxib (Vioxx®)
NSAIDS -TOXICITY
pharmacology
Pharmacology
* Heterogenous group of drugs
* Inhibit prostaglandin synthesis – non-selective inhibitors of COX are reversible
* Extensive protein binding, wide distribution, t½ 1-2h to 60h
* Hepatic metabolism
Recommended dose (variable range)
* Adult ~0.15-2g/day; Child ~40 mg/kg/day
Toxicity
* Adult ~ 6 g/day; Child ~400 mg/kg
* 2 groups – (acute) suicide (50%) vs (chronic) unintentional overdose (50%)
* NSAIDs have similar presentations in overdose situation
* Asymptomatic or nonspecific symptoms appear within 0-4h
NSAID –TOXICITY
clinical manifestations
Clinical Manifestations
§ GI upset - nausea/vomiting, malaise, diaphoresis
§ CNS effects – develop drowsiness, headache, tinnitus, dizziness, blurred vision
§ Moderate to severe toxicity
§ Coma, seizures, CNS depression, metabolic acidosis, hypotension,
hypothermia, rhabdomyolysis
§ Lethargic, unresponsive
§ Massive overdose
§ Multisystem organ failure, death
Diagnosis
§ No specific test but recommended to check APAP (acetaminophen) levels
Management
§ Supportive care (clinical signs/symptoms)
§ Antacids (GI upset)
§ Children >400mg/kg (GI decontamination with activated charcoal)
SALICYLATES - ASPIRIN
Pharmacology
- One of the most common drugs used
- Ranks one of the top drugs reported with ADR
- Analgesic, anti-inflammatory, antipyretic –
irreversible inhibitor of COX
Note: CV benefit - platelets cannot induce COX-1 and
do not express COX-2, therefore, ASA daily dose
inhibits COX-1 for the duration ~8-12d lifespan of
platelet
SALICYLATES - ASPIRIN
Pharmacology
cont’d
- Rapid absorption
- T½ ~15min – 2-3h
- Hepatic metabolism
- Overdose impacts ADME
- Decrease protein binding
- Increase tissue disposition
Rapid absorption
Salicylic acid highly protein bound
Glucaronite plays a big role in the secondary conjugation, and glycine is important in the metabolism
what happens with an overdose situation is, you’re going to shift and impact the distribution.
You’re going to decrease that protein binding. Increasing from lvl 10mg-40mg
• This is going to change the tissue. Distribution is going to increase the tissue disposition.
• This is one of the primary ways. It gets moved into the tissue and causing adverse effects.
SALICYLATES – CLINICAL MANIFESTATIONS (ACUTE VS. CHRONIC)
Acute toxicity
* Non-specific GI symptoms
* Early tachypnea
* Development of anion gap metabolic acidosis – Impact mitochondria
* Worsening clinical effects and evolve to severe CNS toxicity – primary toxicity (brain)
