excitatory neurotransmitters
prostaglandins, nitric oxide, bradykinin, histamine
neurotransmitters that inhibit pain
norepinephrine, dopamine, serotoninendogenous morphines- can affect actual nerve excitation or the release of excitatory neurotransmitters
3 opioid receptors
main one is muother two are kappa and delta
4 classes of opioids
opioid receptor agonistsmixed agonist-antagonistantagonistscentral analgesics
major ADR for opioids
sedationrespiratory depressionn/vpostural hypertensionconstipationurinary retentionpruritusallergic reactions
pharmacokinetics of opioids
phase 1 and phase 2 metabolismsome are active metabolitesmetabolized in liverfentanyl: CYP 450 metabolismphenylpiperidine: phase 1 metabolism
morphine
opioid agonist- everything is compared to morphinet1/2: 2 hours converted to active metabolite: 6 glucuronide, twice as potentoral doses are higher than IV due to first pass
meperidine
Demerol,opioid agonistshorter duration of action than morphinemetabolite: normeperidine, excreted in urine, caution w/ renal failurecan cause CNS issues, leads to seizures, muscle tremors and twitchesrarely used continuously
Fentanyl
most lipophilic, multiple formulations availabletransdermal patch- replace every 72 hours, takes 24 hours to exert effectslollipops used when you want to avoid IV routemetabolizd by CYP 3A4opioid agonist
methadone
main uses are pain, controlled withdrawal from heroin, morphinehas a long half lifevery sedating, even with only 1 or 2 dosesopioid agonist
Hydromorphone
opioid agonistdilaudidmore potent, better oral absorption
oxymorphone
opioid agonistactive metabolite of oxycodoneno pharmacologic advantages
codeine
opioid agonistprodrug of morphine, converted by CYP 2D6often combined with other compounds use for depression of cough reflex
hydrocodone
opioid agonistoften used in combination productsvery similar to morphine
oxycodone
opioid agonistgood as analgesic when combined with peripherally acting non-opioid agent
Mixed agonist/antagonist
stimulate one receptor and block anotherhas ceiling effect: at a certain dose, everything above that dose will have no effectless abuse potential, less constipationrarely used for pain, more for anesthesia b.c of CNS effects- anxiety, hallucinations
opioid naive
if you havent used opioids before, mixed agonist/antagonists will relieve pain, will have agonist activity
opioid dependent
if you have used opioids before mixed agonist/antagonists will block effects and will cause withdrawal symptoms, pain- you will see antagonist effects
buprenorphine
for treatment of opioid addiction, similar to methadonepentazocine and Nalbuphine have significant cardiovascular effects
Antagonists
compete with endogenous and exogenous opioids at mu receptor sitesused to reverse side effects of opioids, usually in overdose situation
Naloxene
most commonly used antagonistIV, will bind to receptor but not produce any responseshorter t1/2, may need repeated dosing to maintain consciousness
Central Analgesic
Tramadol: weak opioid receptor agonist, also inhibits NE and SE reuptake to decrease pain transmissiondecreases seizure threshold, option for people who dont want to take opioids
acetaminophen
NSAID, tylenolless side effects than aspirinanti-pyretic, weak anti-inflammatory, no platelet effects MOA: weak inhibitor of prostaglandins in CNS
liver effects of acetaminophen
in overdose, minor metabolism pathway that produces toxic metabolite, NAPQI, is overwhelmed by too much acetaminophen and too much NAPQI is produced for the body to excrete, not enough glutathione to metabolize NAPQI
doses of acetaminophen
normal adult: 4000 mg/dayunderlying liver disease: 2000 mg/day
NSAIDs MOA
inhibition of 2 enzymes: COX-1 and COX-2anti-inflammatory, analgesic, anti-pyretic and anti-platelet effectsresponse varies from patient to patient
COX-1 effects
produce cytoprotective prostaglandins, maintain kidney function, protect gastric mucosa and aid in platelet aggregation
COX-2 effects
recruit inflammatory cells, sensitize skin pain receptors, regulate hypothalamic temperature control
NSAID Adverse drug reactions
GI irritation, promote gastric ulcers, worsen pre-existing ulcersrenal insufficiencyrashbronchospasm in asthma patientslong term use: fluid retention and edema, hypertensive effects
NSAID contraindications
history of peptic ulcer disease, pre-existing kidney disease, dehydrated patients, allergies, surgery associated with high blood loss
Ketorolac
acute pain reliever that can be used after surgery, can avoid taking opioidsmore potent than NSAID, can cause liver dysfunction, limited to 5 days use
COX-2 inhibitor
Celebrex: only inhibition of bad prostaglandins, allows COX-1 pathway to be unaffectedcontraindicated in patients with sulfa allergyincreased risk for cardiovascular effects
Aspirin
own class of NSAIDcauses irreversible inhibition of both COX-1 and COX-2 pathways need to generate new enzymes once drug is out of body
aspirin side effects
GI,more pronounced renal diseasehigh doses can cause "salicylism"- dizziness, deafness, tinnitus, reye's syndrome: not for kids with viral infections, can cause liver disorder or encephalopathy
abortive headache therapy
can use NSAIDs, opioidsfor mild to moderate pain, wont work for severe migraines
Ergots
specific for migraines, antagonist effects at serotonin, dopamine and NE receptors- end effect is venous and arterial vasoconstriction
ergots ADR
CNS effects: hallucinations, alter pituitary gland prolactin releaseconstrict blood vessels in rest of body as well, can raise BPaffect uterine smooth muscle- category XN/v, diarrheahard drugs to tolerate
contraindications
cant combine with triptansnot for cardiac or peripheral vascular disease
Triptans
first line therapy for migraines, use at any time during migrainerelieve pain by constricting intracranial blood vesselsalso suppress release of inflammatory neuropeptidesspecific to serotonin receptors- type 1B and 1D agonistsall have different T1/2 and dosing regimens can cause rebound headaches
triptans ADR
well tolerated generallychest pressure or tightness due to constriction of cardiac blood vesselsN/V, dizzinessneed different formulation for patients who already have nausea
triptan contraindications
uncontrolled BP, peripheral or cardiac pre-existing issuesprevious MI, angina
Gout
build up of uric acid- deposition of crystals at joint causes terrible painuric acid is from over-production or under-excretion- end product of purine metabolism
NSAIDs for gout
will work at any max prescription doseindomethacin is most commonly usedADR are same as all NSAIDs
corticosteroids for gout
for patients who can take colchicine or NSAIDssystemically or injected directly at site of painshort term effects, taper when finishedcomplications: altered mood, increase BP, glucose control problems
Colchicine
for patients with NSAID allergyanti-inflammatory effects, decrease leukotrienesgive until pain is gone or until diarrhea is intolerablemax dose is 8 mg- will usually get about half way through 8 hours before diarrhea becomes intolerable
colchicine ADR
N/V, intolerable diarrheabone marrow suppression
probenicid
for preventative gout therapy- to get uric acid out of the bodyincreases renal clearance of uric acid
probenicid ADR
GI, rash, hypersensitivityuric acid crystals in kidney, ureters- need to stay hydratedblocks reabsorption of drugs in renal tubule, interacts with PCN, cephalosporins, prolongs the half life in the system
allopurinol
inhibits xanthine oxidase which inhibits uric acid synthesiswell tolerated, builds up over time, has active metabolite
allopurinol ADR
rash, GI, leukopeniacan worsen attacks with start of therapy, but will decrease over time