pharm

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