Week 7 Flashcards
three main useful effects of opioids:
– Analgesia
– Antitussive (cough suppressant)
– Treatment of diarrhea (decreased GI motility)
Opioid Side-effects
Respiratory depression– source of overdose death • Sedation • Confusion • dysphoria • euphoria– psychological addiction • miosis (pinpoint pupils)– diagnostic indicator • constipation • urinary retention
morphine (morphine sulfate salt)
Effective for serious pain
– Post-surgical, terminal cancer, post-MI
• Schedule II, high potential for addiction
• Available orally, IV, IM, rectal suppository
– MS-Contin (sustained-release pill) has 12h half-life
• Initial exposure may cause nausea,
hallucinations, dysphoria
heroin
More lipophilic than morphine
– Enters brain more quickly than morphine when
smoked or given IV
– More intense “rush”
• Schedule I in U.S.
– Legal narcotic in UK, other countries
• Withdrawal symptoms include:
– diarrhea, intestinal cramping, nausea, vomiting
– profuse cold sweating with hair standing on end
(hence the term “going cold turkey”)
– Withdrawal symptoms treated with methadone,
clonidine
hydromorphone
Dilaudid
Higher potency than morphine • Possibly less side effects than morphine – Nausea, vomiting, sedation • Available orally, SC, IM, or IV • Heroin, hydromorphone, others are chemically related to morphine – Codeine, hydrocodone, oxycodone too
codeine
Metabolized into morphine by CYP 2D6
– 7% of Americans lack the CYP 2D6 enzyme
– Also inhibited by some SSRI’s: Prozac, Paxil
• Good antitussive effect
– without conversion to morphine
– Present in low dosages in some cough syrups
• Moderate opioid
– Often effective for dental pain
– Plateau in efficacy ~60mg / dose
• Usually combined with acetaminophen (Tylenol II, III, IV)
– synergistic effect
• Schedule II on its own,
III-V (depending on dosage) in combination products
hydrocodone
Usually combined with acetaminophen – Vicodin, Norco – 142M prescriptions in 2012 in U.S. • CYP 2D6 converts it to hydromorphone – Same drawbacks as with codeine • Antitussive properties also useful • Oct 2014: hydrocodone combo products (including Vicodin) reclassified as Schedule II – No refills on prescriptions, no phone prescriptions
oxycodone
Lower frequency of nausea & vomiting than
morphine
– Constipation may still be a problem
• Oxycodone + acetaminophen = percocet
• Extended release form: Oxycontin (bid)
– Reformulated into an abuse-resistant polymer in 2010
– previously, grinding Oxycontin pills up would allow rapid release
fentanyl
Short-acting (1-2hrs) when given IV – Used for serious childbirth pain – Other breakthrough pain too • 3-day transdermal patch (Duragesic) – Helpful at home for patients who can’t swallow or who experience chronic vomiting • [buccal lozenges Abstral, Actiq for breakthrough cancer pain] • Schedule II • Synthetic opioid – Chemical structure unlike morphine, but same receptors – 80-100x higher potency than morphine
methadone
Used to suppress withdrawal symptoms of opioid
addiction, eg from heroin
– Still produces euphoria and psychological dependence
– Oral admin avoids dirty needle problems
• Also used as an analgesic [to replace oxycodone?]
• Action is relatively slow, can lead to repeated
dosing for greater effect, which in turn can lead
to respiratory depression and death
naloxone (Narcan)
Opioid pure antagonist used to lessen adverse
effects of narcotic overdose
– Especially respiratory depression
• Available IV, SC, IM
dextromethorphan
Robitussin
Cough suppressant, no analgesic effect – Chemically related to morphine – I think of it as “an orphan” in terms of how its action relates to other opioids • Available OTC – Syrup, tablet, gel capsules • “robo-tripping” can produce hallucinations at large doses
loperamide (Imodium)
OTC anti-diarrheal medication
• Opioid, but not absorbed,
only affects GI tract
• Lessens GI motility
Local anesthetics
Block sodium channels, block all nerve
conduction in nerves where they are dissolved
– Must dissolve through membrane, block channel
from the inside
• Amine chemistry: water-soluble when charged
(with H+
, lower pH), lipid-soluble when neutral
– pKa matters
Benzocaine:
strictly topical (OTC creams etc) – pKa = 3.5 –neutral at blood pH (7.4)
Lidocaine, articaine:
injected
– Dentistry, stitches, minor surgeries
– pKa = 7.7 –mix of neutral + charged forms
– Often mixed with epinephrine to cause local
vasoconstriction, keep anesthetic from spreading
• Epinephrine may cause tachycardia when injected
Local anesthetic drugs
All have “-caine” endings to their generic names
cocaine
• Schedule II, has vasoconstrictor properties as well as
local anesthesia
– Works well for oral/nasal surgeries but almost never used
due to abuse potential
– Insufficient blood supply can cause tissue necrosis with
chronic use
• Also has CNS stimulant effect, via dopamine receptors
• Free base form (“crack” cocaine) rapidly absorbed
(especially via smoking), but has shorter effect
• Side-effects include tachycardia, hypertension, visual
hallucinations, paranoid psychosis
A known side-effect of acetylsalisylic acid in susceptible individuals is
GI bleeding at low dosages through long-term use
lidocaine is often mixed with epinephrine in order to cause
vasoconstriction
lidocaine has a pKa of 7.7, so it is
an injectable local anesthetic that is an equal mix of polar and non-polar forms
Oxycodone is an opioid drug that
has lower frequency of nausea than morphine, and is available in an extended-release pill
Tylenol 3 is a combination drug that contains acetaminophen and
codeine
Hydrocodone is an opioid drug that
has a significant antitussive effect
Codeine is an opioid drug that
has a significant antitussive effect
Vicodin (or Norco) is a combination drug that contains acetaminophen and
hydrocodone
Which of the following is NOT a potential side-effect of most opioid drugs
Heart arrhythmia
Acetylsalicylic acid is
An OTC drug that is often prescribed at low doses to reduce risk of MI
Ketorolac is
A powerful NSAID that is available by prescription only.
Prostaglandins
• Local (paracrine) mediators of inflammation
– Short half-life
• Synthesized by cyclooxygenase enzyme
– From arachidonic acid (a fatty acid)
– Makes thromboxane also (platelet aggregation)
• Prostaglandins cause:
– increased sensitivity of pain receptors
– increased body temp (fever)
– secretion of cytoprotective mucus in stomach
– uterine wall contractions
– renal vasodilation
cyclooxygenases
Enzyme that controls prostaglandin
production
• COX has two isozymes
– COX1: mainly affects stomach mucus production
– COX2: pain sensitivity, fever, inflammation
• Most NSAIDs work by inhibiting
cyclooxygenases
Uses of NSAIDs
Baby aspirin to reduce risk of MIs, strokes
• osteoarthritis – degeneration of the joints
• rheumatoid arthritis
– progressive chronic inflammatory disease of the joints
– affects > 40 million Americans
– due to an autoimmune attack on the joints.
• aches and pains
• menstrual cramps (primary dysmenorrhea)
– aspirin is not particularly effective for dysmenorrhea
NSAID side-effects
stomach ulceration
• increased risk of hemorrhage
• renal failure at high dosages in predisposed patients:
– those with decreased circulation volume due to CHF, liver
cirrhosis, renal disease, use of diuretics, elderly
• May induce asthma attack in ~ 20% of asthma pts
• May reduce efficacy of ACE inhibitor drugs.
Common OTC NSAIDs
acetylsalicylic acid (ASA, Aspirin)
– Analgesic, antipyretic, anti-inflammatory
– Also inhibits thromboxane production
• Lowers MI, ischemic stroke risk
– Gastric bleeding with prolonged use is an issue
• ibuprofen (Advil, Motrin) q 4 hours
– Better than aspirin for primary dysmenorrhea
– Less risk of gastric bleeding
• naproxen (Aleve) q 8 hours
– Similar to ibuprofen, but longer half-life
Ketorolac
Most efficacious NSAID • Prescription only • Used post-surgery • IM, IV, opthalmic & oral forms – 6h half-life • Short-term use only (<5 days) – due to risk of stomach ulcers
COX2 inhibitors
• In principle, specific inhibition of COX2 should cause pain-relief without risk of COX1-related stomach ulcers, bleeding – for long-term arthritis use • celecoxib (Celebrex) is a COX2 inh – does not inhibit platelet aggregation; studies show some increase in mortality due to strokes, MIs
Acetaminophen (APAP, Tylenol)
Not actually anti-inflammatory
– Analgesic & antipyretic
– Works via CNS effects
• May be COX2 inhibitor, but only active in CNS,
not at sites of inflammation
• Does not cause stomach ulcers
– Unlike OTC NSAIDs
• OTC, but very high doses can cause liver failure
– Safe at normal doses
Combination with butalbital (barbiturate) for migraines
Migraine drugs
Migraines difficult to treat – cause of migraines is not well-understood • Triptan family of drugs – Serotonin agonists? – Work best if taken immediately at migraine onset • SC injection may be best • nasal spray, oral pill also available – sumatriptan (Imitrex) and others • Generic names all end in “–triptan”
