exam 2 Flashcards
T/F
Sedative/hypnotic agents possess good analgesic properties
false
chronic pain
difficult to identify source
assoc. with a complicated set of behavioral issues
pharm approach is only one comp. of management of chronic pain
acute pain
- tissue injury and inflammation
- mediated by biochemical mediators: histamine, prostaglandins, bradykinin
- PGE2 causes hyperalgesia by sensitizing afferent nociceptive receptors to histamine and bradykinin
- CNS A delta and C fibers of cranial nuclei V, VII, IX, X to nucleus caudalis of medulla and then to higher brain centers
pharmacological management as adjunct to treatment of _______ is appropriate
acute pain
Non-narcotic analgesics
- salicylates (aspirin)
- acetaminophen
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- COX 2 inhibitors
examples of NSAIDs
- ibuprofen
- naproxen
- naproxen sodium
- diflunsial
- flurbiprofen
- ketorolac
- etodolac
ibuprofen
best in dentistry Non-selective NSAID adverse GI effects COX inhibitor ( 1--regulates homeostasis; 2--inducable
COX 2 inhibitors
celebcoxib
Rofecoxib (withdrawn)
better for GI tract
selective
what do corticosteroids inhibit?
Phospholipase A 2
antiinflammatory
what does aspirin & NSAID inhibit?
cyclooxygenase (non-selective)
PGI2
prostacyclin (endothelium)
- vasodilation; decreased platelet aggregation
PGE2/PGF2e
prostaglandin smooth muscles vasodilation, edema - sensitizes free nerve endings - mediates pain and inflammation
TXA2
thrombozanes
platelets
vasoconstriction; increased platelet aggregation
aspirin made of
salicylic acid, sodium salicylate, acetylsalicylic acid
antipyretic action of apsirin
occurs centrally (ibhibition of PGE2)
effective in febrile pts
little effect on normal body temp
IL1 (endogenous pyrogen) triggers synthesis of CNS Prostaglandins
analgesic action of aspirin
mediated thru central and peripheral mechanisms:
- salicylates inhibit synthesis of prostaglandins in inflamed tissues–> prevent sensitization of pain receptors
- analgesic site close to antipyretic region in hypothalamus (doesn’t cause sedation)
- max effect–> 650-1000 mg
antiinflammatory effects of aspirin
inhibition of PG synthesis
also inhibition of leukocyte phagocytosis, suppression of immulogical process and stabilization of lysosomal membranes
hematologic effects of aspirin
- products of PG path (thromboxane A2, prostacycline, ,PGI2) have major influence on initiation and inhibition of platelet aggregration
- platelet agg. related to clot formation and bleeding time
- aspirin decreases platelet aggregation (more bleeding)
- **effect of aspirin on platelets due to irreversible inhibition (acetylation) of enzyme cyclooxygenase
- inhibition of platelet TXA2 synthesis –> over activity of vascular PGI2
at high doses, aspirin decreases ______and impairs _____
decreases plasma prothrombin and impairs coagulation
sodium salicylate has much less effect on prolonging bleeding time
maximum dose of aspirin’s effect on respiratory system
- partial uncoupling of oxidative phosphorylation
- increased CO2 production
- compensatory increase in ventilation prevents changes in plasma pH
toxic dose of aspirin effect on resp system
stimuates ventilation by effects on receptors in medulla
- –> respiratory alkalosis (due to increased CO2)
- compensated by renal elimination of bicarbonate, sodium, and potassium
- reduction in bicarbonate impairs bicarbonate buffering capacity
therapeutic dose of aspirin on resp system
minimal effect
what happens as aspirin doing increases?
metabolic acidosis due to uncoupling of oxidative phosphorlyation
- other factors that contribute: acidity depression of resp center, loss of bicarbonate buffering capacity, changes in carb met
- *fatal metabolic/respiratory acidosis and respiratory paralysis
effects of aspirin on cardio system
little effect at therapeutic doses
GI effect of aspirin
GI distress
occult bleeding
sudden acute hemorrhage
effect on kidney from aspirin
analgesic nephropathy (loss of prostaglandins that regulate bloodflow)
effect on liver from aspirin
subclinical hepatoxicity
no overt changes
diflunsial
salicylate that can be taken twice daily
pharmokinetics of aspirin
- absorption from stomach and small intestine
- rate limiting step: disintegration/dissolution
- hepatic metabolism (glycine and glucuronide conjugates)
- weak acid
- renal elimination
therapeutic uses of aspirin
- analgesic, antiinflammatory, antipyretic
- dose: 650-1000 mg
- all painful conditions
- not rec for gout
- low dose for reducing cardio incidents
therapeutic uses of aspirin in dentistry
equal or greater pain relief than codeine (narcotic)
- ceiling effect in pain relief (will end up with more adverse effect)
adverse effects of aspirin
nausea, GI irritation, occult GI bleeding, increase in bleeding time
chronic toxicity of aspirin
“salicylism”
tinnitis, nausea, headache, hyperventilation, menal confusion
acute toxicity of aspirin
- cardinal signs: tinnitis, hyperthermia, hyperventilation
- followed by combined resp and metabolic acidosis accompanied with dehydration
- acidosis is more common as level of overdose increases
- impaired vision, hallucination, delirium
treatment of aspirin overdose
- palliative and supportive
- resp support
- gastric lavage
- maintenance of electrolyte balance
- maintenance of plasma pH
- alkalization of urine by bicarbonate
why can some people not tolerate aspirin?
- range from rhinitis to severe aspirin
-bc of: - loss of production of bronchodilator PGE 2
- lipooxygenase pathway predominates (SRSA pathway)
- intolerance also shown by: urticaria (hives) and angioedema
- cannot switch to NSAIDS
(alternative–> acetometophin)
contraindications to use of aspirin
ulcer, asthma, diabetes, gout, flu, varicella, hypocoagulation
adverse effects of aspirin with flu, varicella
reye’s syndrome in children
recent viral infection–> use acetometophin instead
warfarin + aspirin
internal bleeding, poss hemorrhaging
heparin + aspirin
internal bleeding, poss hemorrhaging
probenecid, sulfinpyrazone + aspirin
decreased urocosuric effect, reappearance of gout (drugs should be treatment of gout)
chemical name of acetaminophen
n-acetyl-p-aminophenol; APAP
(phenacetin & acetanilid –> APAP
acetaminophen has effective analgesic and antipyretic agent but has little _____
antiinflammatory activity
(inhibitor of PG synthesis centrally but less effective at inhibition peripherally)
- interaction of APAP with peroxide (present in inflamed tissues) that may reduce APAP effectiveness
at therapeutic dose, acetaminophen has little effect on _____
cv/respir systems
no effect on platelet aggregation
no GI bleeding
no gastric irritation or effect on uric acid excretion
pharmacokinetics of acetaminophen
- well absorbed from small intestine
- well distributed to tissues and crosses placenta
- hepatic metabolism (glucuronide conjugation)
- renal elimination via both GFR and tubular secretion
general therapeutic uses of acetaminophen
- pts for whom aspirin/NSAIDs are contraindicated
- 650-1000 mg dose
adverse effects of acetaminophen
-major metabolite of this drug cause **hepatotoxicity (toxic doses range >4 /day )–> depletion of glutathione and subsequent alkylation of liver proteins causing cellular injury
tx of acetaminophen overdose
gastric lavage
n-acetylcysteine (reducing agent) (must be given during initial 36 hours)
rec dose of acetaminophen
325-600 mg and max daily dose less than 3 g
analgesic, antipyretic, and anti-inflamm effects of NSAIDs due to?
- inhibition of PG pathway at level of cyclooxygenase
- inhibition of PG results in reduction of inflammation and pain
- ceiling effects exist
major side effects of NSAIDs
erosive and ulcerative lesions in the stomach
possible nephrotoxicity
-cross-hypersensitivity reactions have been reported between NSAID’s and aspirin
_______ is an effective treatment of post op pain and inflammation. It is a weak organic acid, highly protein bound (99%) and undergoes extensive hepatic metabolism. Conjugates are excreted in urine.
ibuprofen
dosage of ibuprofen
400-600 mg q4-6 hrs
max daily dose of 3200mg
naproxen
- free acid or sodium salt (aleve)
- similar to ibuprofen
- highly protein bound
- doesn’t interact with oral anticoagulants and hypoglycemic agents
- eliminated from kidney
dosage of naproxen
220-440 mg naproxen sodium q4-6 h
max daily dose 660 mg
______ is formulated for oral and parentral routes of admin. Has potential of renal toxicity if taken for more than 5 days. It has antiplatelet activity and is contraindicated before surgery
ketorolac
also comes in nasl spray
diflunisal
- derivative of salicylic acid
- not met. into salicylate
- extended duration of action
dosing of diflunisal
loading dose of 1000 mg followed by 500 mg q8-12 hr
adverse effects of NSAIDs
- gastric irritation (with long term use; ulcers in 6% of pts; 100,000 hospital admissions and 16,000 death/year)
- fluid retention
- nephrotoxicity
- transient and reversible inhibition of platelet aggregreation
- dizziness
- clinical signs of OD similar to salicylates
- contraindications: similar to aspirin
- risk of kidney injury in fetus if taken while preg
examples of selective COX2 inhibitors
- rofecoxib and valdecoxib (removed from market)
- celecoxib
- etoricoxib
- etodolac
- melxicam
selective COX2 inhibitors
- 8-35X more selective for COX2 isozyme
- 50-60% reduction in adverse GI effects; adverse renal effects can still occur
- increased CV events
- potentially life threatening asthmatic or allergic reactions in aspirin intolerant individuals
- allergy to sulfonamides should avoid use of celecoxib
- interact with warfarin to increase risk of bleeding
opium poppy made of:
- 5-20% morphine
- 0.5-2.5% codeine
- papaverin (smooth muscle relaxant)
- other alkaloids
opiates
alkaloids that are derived or isolated from opium
ex: morphine (greek god of sleep)
opioids
substances that are not derived from opium and do not have morphine-like structures, but do have morphine-like pharmacological properties
- whole group known as opioids analgesics
narcotic analgesics
compounds that produce analgesia, drowsiness, and dreamy detached feeling (euphoria)
endogenous opioids
enkephalins, endorphins, dynorphins
narcotic agonists
- naturally occurring substances (opiates): opium, morphine, codeine
- semisynthetic derivatives (opioids): heronin (acetylmorphine), hydromorphone (dilaudid), hydrocodone, and oxycodone
- synthetic derivatives (opioids): meperidine (demerol), fentanyl, sufentanyl (fent and suf used in IV general anesthesia)
narcotic agonist/antagonists
pentazocine (talwin)
nalbuphane (nubain
narcotic antagonists
- naloxone (narcan)
- naltrexone (trexan)
effects of opioids
analgesia respiratory depression constipation GI spasm dependence
endogenous opioid peptides ranked in order of size
endorphins»_space;dynorphins>enkephalins
opioid receptors are linked to—
g proteins
how many membrane spanning alpha helical segments are there for opioid receptors?
7
mu receptors
principle mediator of opioid analgesia (morphine)
mu1: supraspinal analgesia (above spinal cord)
mu2: spinal analgesia; respiratory depressant & GI actions
delta receptors (2 subtypes)
- endogenous ligand: -enkephalins
- produce both spinal and supraspinal analgesia: opioid reinforcement
kappa receptors (3 subtypes)
- endogenous ligand: dynorphins
- spinal analgesia: kappa 1 and 2
- supraspinal analgesia: kappa 3
- also dysphoric effects
sigma receptors
- mediating/may be involved in antianalgesic effect observed with dextroisomers of certain opioids
- dysphoric effects of opioids and phencyclidines (PCP–receptor may be inhibit. comp. of NMDA receptor complex which regulates opioid tolerance and dependence
where do enkephalins primarily act?
in local circuits or CNS interneurons
inhibitory effects
what is an important site to morphine analgesia?
periaqueductal gray
______ opioids modulate the secretion of pituitary gonadotropin from the pituitary
endogenous
naloxon causes increases in LH and FSH secretion
where does analgesia of opioids take place?
central and peripheral mechanisms
PAG
pathway of opioids
descending pathway – indirect (synaptic relay in medulla)
_____ and _____ are the neurotransmitters that ultimately inhibit pain transmission
5HT (serotonin) and NE
opioids do not affect the response threshold to painful stimuli but the ______
interpretation and emotional reaction to stimulus
mechanism of action of opioids relate to:
- increase in potassium conductance (relative hyperpolarization and decrease neuronal activity); post-synaptic
- decrease in calcium influx thru vol. dep. channels (decrease NT release); presynaptic
net effects of opioids
general inhibitory acute effects mediated by effects of opioids on ion channels of neurons
Pharm effect of opioids on CNS
analgesia drowsiness euphoria/dysphoria resp depression decrease cough reflex pupillary constriction decrease secretion of LH and FSH increase prolactin secretion stimulation of medullary CTZ (enhanced emesis followed by depression of vomiting rxn)
pharm effect of analgesia of opioids
- dose dependent pain relief which is selective (vision and hearing unaffected by therapeutic doses
10 mg parenteral or 30 mg oral/ 70 mg morphine - no ceiling effect
- sites: peripheral, central (spinal/supraspinal)
- usually parenterally given
emergency measure for chest pain
10 mg morphine
what kind of pain are opioids best at controlling?
dull, aching pain
-neuropathic pain less responsive to opioids
aging does what to pain?
- decreases sensitivity to pain
- reduces ability to clear morphine (increases elimination 1/2 life)
- morphine-induced pain relief increases with age in elderly
effects of opioids on resp. system
- dose-dependent
- decreases in tidal volume and rate
- decreases response of brainstem resp center to CO2 tension in blood
- suppresses pontine/medullary centers that regulate respiratory frequency
- all opioids suppress respiration
chest wall rigidity
- seen with IV opioids (e.g. fentanyl)
- increase in muscle tone
- —> truncal stiffness
- more prevalent with bolus administration, in elderly patients and those receiving N2O:O2
- can be treated with naloxone or a neuromuscular blocker
cough suppression with opioids
- antitussive effect by depression neuronal activities in brainstem
- codeine, dextrometorphan
- suppression occurs at dosages lower than analgesic or respiratory doses
pupillary constriction
- morphine causes miosis in humans
- mediated by oculomotor nerve
- tolerance does not develop
why nausea/vomiting with opioids
- stimulate CTZ in medulla –> vomit (emesis)
- initial stimualtion followed by depression of brainstem medullary center
- vestibular component freq seen in ambulatory rather than recumbent patients
effect of opioids on GI tract
constipation
increase smooth muscle tone and decrease propulsive motility throughout GI tract (stomach/duodenum transit delay)
treatment of diarrhea
diphenoxylate + atropine
- biliary smooth muscle spasm (painful)
- inhibition of intestinal hypersecretion (treats diarrhea), gastric acid, pancreatic, biliary, intestinal secretion
opioid effect on smooth muscle cells
- increase tone of smooth muscles of ureter, urinary bladder, uterus, and bronchioles (minimal effect at therapeutic dose)
- decrease urine flow
- antidiuretic effect of opioids
- increases tone of uterus but labor duration not affected
- may aggravate asthmatic attack–> histamine release
- may lead to : stop urine flow, increased uterine tone during labor, increase neonatal morbidity, bronchoconstriction at HIGH doses
effects of opioids on cardiovascular system
- toxication decreases BP bc of resp depression and hypoxia
- release of histamine–> vasodilation (more for morphine than fentanyl)
- decrease peripheral vascular response –> orthostatic hypotension
- cerebral vasodilation : may relate to morphine-induced decreased respiration causing increases in blood CO2
why is morphine helpful in pulmonary edema?
peripheral pooling of blood
acute opioid toxicity
- death bc of resp depression
- cardinal signs: stupor, constricted pupils, decreased respiration
- as severity of intoxication increases –> coma, decrease in BP if hypoxia is not altered
management of acute opioid toxicity
- support of respiration; patient airway
- dilation of pupils and shock: both caused by persistent hypoxia
- administer naloxone: short duration of action: continuous monitoring
- naloxone admin to opioid-dep pt —> withdrawal symptoms
opioid tolerance signs
- tolerance develops to depressant (anal, drowsiness, and resp depression) but NOT to stimulant effects (pup constriction and constipation)
- tolerance develops to euphoria
- the greater the opioid dose and shorter the interval between doses, the more rapid the development of tolerance
signs of dependence on opioids
- only apparent in absence of drugs
- physical vs psych dep
- dose related
- greater dose and longer duration, greater dep
- blockade of NMDA receptors and NO synthase prevent tolerance and dependence without reducing analgesic effects of morphine
physical dependence can occur in absence of _____ dependence
psychological dependence (chronic tx of cancer pain) -tolerance, physical dependence, psych dependence are reversible
S & S of opioid withdrawal
anxiety and drug craving
anxiety, insomnia, GI disturb, runny nose, mydriasis, diaphoresis
tachycardia, nausea vomiting, hypertension, diarrhea, fever, chills, tremors, seizure, muscle spasms
feel normal after ____ days of opioid cessation
7-10 days
opioids withdrawal symptoms managed with slow taper of either ____ or partial agonist _____ with or without an alpha 2 adrenergic agonist
-methadone or buprenophine
treatment of choice for most opioid patients
buprenorphine with or without naloxone
when should methadone be used?
when buprenorphine is unavailable or ineffective or in patients who would benefit from daily supervised dosing
clonidine and lofexidine
alpha2 adrenergic agonists
less effective than methadone or buprenorphine
useful as adjunct to opioid agonist and in settings where use of an opioid agonist is prohibited
what works better for morphine–oral or parenteral?
oral does NOT work as well
pharmocokinetics of morphine
- good parenterally
- hepatic first pass effect: morphine»_space;codeine
- morphine –morphine-6-glucoronide (acts on mu receptors and exerts potent analgesic effect)
- conjugated morphine excreted via kidney; small amount in urine
- morphine does not accumulate in tissues
- oral dose 10-2500 mg/24 hrs (cancer–200mg/day): dose titrated, tolerance present, controlled release tabs or caps produce longer lasting analgesia
breakthrough pain treated with
fentanyl lollipop
general therapeutic uses of morphine
analgesia
tx of pulmonary edema
inducing sleep for pain or cough
general uses for codeine
OCH3 sub for OH at C3 increase oral effect analgesic, antitussive 10% met into morphine resp depressant, sedation 10 mg morphine=120 mg codeine increased nausea or vomiting slower dev of tolerance little physical dep at therapeutic dose
antitussive dose of codeine
15-20 mg
analgesic dose of codeine
30-60 mg po
codeine
opioid agonist post operative analgesic low first pass effect (useful po : 60% bioavail) onset of action -- 30-45 min about 10-20% converted to morphine remaining drug is antitussive
hydrocodone and oxycodone
opioid agonists
- derivatives of codeine
- converted to hydromorphone (dilaudid) and oxymorphone (numorphan) (10-20% conversion)
- good oral bioavailability
- alternatives to codeine
- pharm effects similar to codeine
- hydrocodone is schedule II substance
opioids listed by relative strength (strongest first)
morphine and oxycodone
hydrocodone
codeine
meperidine
- atropine-like activity –> less pupillary constrict or biliary spasm
- similar to morphine: analgesic, sedation, resp depress
- oral effect 1/5 of parenteral effect
- shorter duration than morphine
- acute intoxication –> cns excite
- can & will cause dependence
- poor CV stability with IV sedation ; fentanyl replaced it
- contraindicated in pts taking MAOI or amphetamine or with asthma (histamine release)
serotonin syndrome
- meperidine inhibits 5Ht reuptake
- when combined with SSRIs and other antidepressants
- mild version : shivering and diarrhea
- severe: CNS manifest—tremors and seizure
methadone
- equipotent to morphine
- better oral efficacy than morphine; otherwise differs little
- analgesia, sedation, resp depress, miosis, antitussive, subjective effects similar to morph
- replacement for heroin addicts
- oral efficacy
- persistent effect when repeated- single daily dose –less withdrawal
- less intense withdrawal S & S
- treatment of opioid depend related to cross tolerance and cross-dependence
cross dependence
if pt is dependent on one opioid, they can be switched to another opioid to suppress S & S of withdrawal
alternatives to methadone
levomethadyl (ORLAM)
dose: q3d bc long duration of action
propxyphene
type of methadone
analgesic
subject to abuse, physical dependence during high dose, long-term use
-less dependence than codeine
fentanyl and congeners (fentanyl like things)
- potent analgesics with relatively short duration of action
- IV supplements during general anesthesia with inhalation
- more lipid soluble than morphine
- meperidine: poor CV stability
- more rapid onset of action and short duration of action (80-100X more potent than morph)
advantages of fentanyl
provide cardiovascular stability and reduce endocrine and metabolic responses during surgery
what drug replaced meperadine and why?
fentanyl
because meperidine has a poor CV stability
neurolepanlgesia
sedated analgesia
fentanyl + droperidol (INNOVAR)
examples of mixed-acting agonist-antagonist
- pentazocine
- butorphenol
- buprenorphine
- nalbuphine
what is an agonist at the kappa and partial agonist or weak antagonist at mu receptors?
pentazocine
what was developed as effect to produce agonist without abuse potential or dependability?
pentazocine (still abused)
what preparation was made to prevent abuse of pentazocine?
mixture of pentazocine and naloxone (Talwin NX)
- Naloxone has little effect po
- therefore preparation is still good po but without effect parenterally
why can’t pentazocine be used as a substitute for morphine?
does not antagonize resp depressant property of morphine or suppress withdrawal symptoms in individuals dependent on other opioids
pentazocine can cause an abstinence syndrome bc of ______
residual antagonist effect at mu receptors
what is the metabolism of pentazocine?
well absorbed po–> liver metabolism–> glucuronide conjugate–> urine
how potent is pentazocine compared to morphine?
1/3 as potent parenterally (I.m.)
adverse effects of pentazocine
-n/v and sedation (similar to other opioids)
whats different about pentazocine compared to other opioids ?
can increase both heart rate and blood pressure
toxic doses of pentazocine cause—
dysphoria (kappa receptor effect)
respiratory depression but does not increase with increasing dose as it does for opioid agonists
buprenorphine
- multi-mechanistic–partial agonist of mu receptor, partial antagonist of kappa receptor and some nonopiod receptor activity
- agonist effects qualitatively similar to morphine
- produces less respiratory depression than morphine at same dose; may be more difficult to reverse using naloxone
- causes less euphoria than many other opioids
- *useful in chronic addiction control
naloxone
- short acting
- iv admin
- antidote for resp depression secondary to opioid overdose
- rapidly improves ventilation; additional doses may be required
- additional doses may be required to antagonize long-acting opioid agonists
naltrexone
- long acting
- oral admin
- maintenance of detoxified opioid abusers
- single dose can suppress the effect of opioid agonist 48-72 hrs
- tx of morphine overdose – monitor pt in case of resp depression relapse
tramadol (ultram)
- weak mu receptor agonists (metabolite is more potent)
- inhibits reuptake of NE and 5HT
- analgesic effect partially reversed by naloxone
- perioperative agent–relieves mod-severe pain
most common adverse effects of tramadol
n/v
drowsiness
minimal resp and CV issues
_____ have been reported for tramadol
seizures
admin of tramadol
oral and terminal half life is 7 hrs
dosage of tramadol
50-100 mg q4-6 po
don’t exceed 400 mg/day
severe pain — 100 mg initial dose
tramadol is what level substance?
schedule IV
ultrased
combo of tramadol with APAP
tapentadol (nucynta)
- opioid agonist
- inhibits norepinephrine reuptake; schedule II
- lower incidence of adverse effect than opioids
- inferior analgesic effect in acute postsurg dental pain
- **may cause serious, life-threatening, breathing problems initially or after dose increase
- add on agent for breakthrough pain with NSAID or APAP
when do you prescribe Rx NSAID and opioid?
severe pain (codeine, hyrdocodone, oxycodone)
Rx NSAID used with
moderate pain
mild pain–you use–
OTC aspirin, aceto, ibu, naproxen
pre-emptive measures before surgery
NSAID
3 and #4
aspirin and codeine
325/30 mg
325/60 mg
percodan
apsirin and oxycodone
325/5
tylenol #3
acetaminophen and codeine
300/30
vicodin
lortab
norco
acetaminophen and hydrocodone
325/5
325/7.5
325/10
percocet
acetaminophen and oxycodone
325/5
325/10
ultram
tramadol
50
ER: 100, 200, 300
ultracet
acetaminophen and tramadol
325/37.5
vicoprofen
ibuprofen and hydrocodone
200/7.5
combunox
ibuprofen and oxycodone
400/5
1 grain of tylenol =
60 mg
tylenol 4 is how many grains
full grain
tylenol 3 is how many grains
1/2 grain
national drug overdose deaths for opioids
17,029
______ are leading contributer to epidemic drug abuse. Safe and informed prescribing practices and sensible guidelines can stop it.
safe prescribing practices
