Pharmacology Opioidanalgesics
Transcript of Pharmacology Opioidanalgesics
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pharmacologynotes
MauChuaPHARMACOLOGY S.Y. 2011-2012
PIOID ANALGESICS & ANTAGONISTS
OPIOID ANALGESICS &ANTAGONISTS
Dr. George Firmalino
I. BASIC PHARMACOLOGY
SOURCEo opium from plant PAPAVER SOMNIFERUM
o opium has 20 ALKALOIDS
o ANALGESIC morphine, codeine
o NON-ANALGESIC thebaine, papaverine
MORPHINE - principal alkaloid of opium ( 10 % )
from w/c codeine (0.5 %) is synthesized
HEROIN - derived from morphine during acetylation
of hydroxyl group, penetrates blood brain barrier
more than morphine
THEBAINE
o precursor of several semisynthetic agents
ETHORPHINE a veterinary agent 500
1000 x as potent as morphine
NALOXONE an opiate antagonist
PAPAVERINE - a vasodilator w/ no clinical
application but led to the development of
VERAPAMIL a calcium channel blocker
antihypertensive
CLASSIFICATION
o FULL AGONIST (morphine) - strong agonist
o PARTIAL AGONIST (codeine) - produce agonist
effect, may displace other full agonist in binding
sites & reduce their effect (antagonist effect)
o MIXED AGONIST / ANTAGONIST (nalbuphine) -
when one opioid has agonist effect on one
receptor & antagonist effect on another receptor
o ANTAGONIST - binds to receptor site w/o producing
effects associated w/ agonist (like naloxone)
CLASSIFICATION BASED ON CHEMICAL STRUCTURE & MAIN
EFFECT
STRUCTURESTRONG(FULL)
AGONIST
MILD / MOD(PARTIAL)AGONIST
MIXEDAGONIST -
ANTAGONISTANTAGONIST
PHENANTHRENES morphinehydromorphoneoxymorphone
codeineoxycodonehydrocodone
nalbuphine nalorphinenaloxonenaltrexone
PHENYLHEPTYLAMINES methadone propoxyphene buprenorphine
PHENYLPIPERIDINES meperidinefentanyl
diphenoxylate
MORPHINANS levorphanol butorphanol levallorphan
BENZOMORPHAN pentazocine
CLASSIFICATION BASED ON SOURCE
A. NATURAL OPIUM ALKALOIDS
morphine, codeine, papaverine
B. SEMISYNTHETIC
heroin, oxycodone, hydrocodone,
oxymorphone
C. SYNTHETIC methadone, meperidine, fentanyl,
propoxyphene
OPIOIDS USED AS ANTITUSSIVE
Codeine
Dextromethorpan
Hydrocodone
Hydromorphone
Levopropoxyphene
Noscapine
ENDOGENOUS OPIOID PEPTIDES --- present in CNS w/
opioid-like analgesic pharmacologic properties &
function like a neurotransmitter
o PENTAPEPTIDES
o methionine-enkephalin, leucine-enkephalin
o 3 PRECURSORS
o propio melano cortin (pomc), pro-enkephalin
(pro enkephalin-a), pro-dynorphin (pro-
enkephalin-b)
o POMC CONTAINSo met enkephalin, beta endorphin, non opioid
peptides (acth, lipo proteins, melanocytestimulating hormone)
o PRO ENKEPHALIN-A CONTAIN
o met enkephalin, leu enkephalin
o PRO DYNORPHIN CONTAIN
o dynorphin-a, dynorphin-b, & neo
endorphins
PHARMACOKINETICS
A. ABSORPTION
o subcutaneous, im, iv, intra-spinal, mucus,
transdermal (like fentanyl), git (subject to first
pass metabolism in the liver by glucorinidation
o high dose is required to produce the desired
therapeutic analgesic effect
B. DISTRIBUTION
a. rapidly leaves the blood
b. concentrate in lungs, liver, kidneys, spleen
c. in muscles has lower concentration but
has greater bulk & acts as the main
reservoir
d. in fat also a reservoir for lipophilic opioid
like fentanyl
e. brain low conc. due blood-brain barrier
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MauChuaPHARMACOLOGY S.Y. 2011-2012
PIOID ANALGESICS & ANTAGONISTS
MORPHINE - cross the blood-brain barrier less
readily
HEROIN & CODEINE - cross the blood-brain
barrier more readily
neonates has no blood-brain barrier thus makes
them prone to respiratory depression when an
opioid is given during labor where drugs crossthe placenta & into the brain
C. METABOLISM
o compounds w/ free hydroxyl like morphine &
levorphanol are readily conjugated w/
glucoronic acid
o ester compounds like heroin & remifentanyl
are rapidly hydrolyzed by common tissue
esterases
O heroin (a diacetylmorphine) is hydrolyzed to
monoacetylmorphine & finally to morphine w/cis then conjugated w/ glucoronic acid in the
liver
this morphine 6 glucoronide was
thought to be inactive but actually
produces more profound analgesia if
accumulated in cases of renal failure
D. EXCRETION - mainly in the kidneys
PHARMACODYNAMICS
A. MECH OF ACTION - binds to specific receptor site inbrain & spinal cord regions involved in transmission &
modulation of pain
1. RECEPTOR TYPES - (mu), (delta), (kappa)
RECEPTOR SUBTYPE ACTIVITY OF OPIOIDS
RECEPTOR SUBTYPE
DRUG MU DELTA KAPPA
ENDOGENOUS
OPIOID
PEPTIDES
ENKEPHALINS Agonist agonist
ENDORPHINS Agonist agonistDYNORPHINS Weak agonist agonist
AGONISTS CODEINE Weak agonist weakagonist
ETORPHINE Agonist agonist agonist
FENTANYL Agonist
MEPERIDINE Agonist
METHADONE Agonist
MORPHINE Agonist weak
agonist
weak
agonist
AGONIST-
ANTAGONISTS
BUPRENORPHINE partial agonist
DEZOCINE partial agonist
NALBUPHINE Antagonist agonist
PENTAZOCINE antagonist or
partial agonist
agonist
ANTAGONISTS NALOXONE Antagonist antagonist antagonist
2. RELATION OF PHYSIOLOGIC EFFECTS TO
RECEPTOR TYPES
a. MU RECEPTOR - target of morphine in
brain, produces typical agonist effect
(analgesia, euphoria, respiratory
depression, physiologic dependence
b. DELTA & KAPPA RECEPTORS - also
contribute to analgesia at spinal cord level
3. CELLULAR ACTION
a. 2 direct actions to neurons
- Close a voltage-gated Ca channel on pre-
synaptic nerve terminals & thereby transmitter release (like acetylcholine,
norepinephrine, glutamate, serotonin,
substance-P)
- They hyperpolarize & thus inhibit post
synaptic pain transmission neurons by
opening K+
channels at mu receptors
4. RECEPTOR DISTRIBUTION & NEURAL
MECHANISMS OF ANALGESIA
- Receptors are present in dorsal horn of spinal
cord pain transmission neurons & on the
primary afferents that relay message to the
dorsal horn
- Opioid agonist inhibit the release of excitatory
transmitter from these primary afferents &directly inhibit the dorsal horn pain
transmission neuron
- Thus, opioids exert a powerful analgesic effect
directly upon the spinal cord by direct
application (as in spinal anesthesia + morphine)
w/c provides regional analgesic effect w/o
respiratory depression, nausea, vomiting &
sedation noted w/ supra-spinal actions w/
systemic drugs
- systemic drugs generally act on both spinal &
supraspinal sites, thus increasing overall
analgesic effect
- Exogenous opioids (like morphine) act
primarily & directly at mu receptors but this
action may evoke the release of endogenous
opioids that additionally act at delta & kappa
receptors
5. TOLERANCE & PHYSIOLOGIC DEPENDENCE
a. TOLERANCE - gradual loss of effectiveness
of an opioid w/ frequently repeatedadministration, to reproduce the original
effect, the dose must be b. PHYSIOLOGIC DEPENDENCE - occurrence of
a characteristic WITHDRAWAL or
ABSTINENCE SYNDROME when the drug is
stopped or an antagonist is given,
mechanism is unknown
B. ORGAN SYSTEM EFFECTS OF MORPHINE
A. CNS at mu receptors
1. ANALGESIA - both sensory & affectivecomponents of pain are affected
2. EUPHORIA -a pleasant floating sensation &
freedom from anxiety & distress noted by
patients in pain or by addicts, other patients or
normal subjects may experience Dysphoria
(restlessness & a feeling of malaise, nausea &
vomiting)
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MauChuaPHARMACOLOGY S.Y. 2011-2012
PIOID ANALGESICS & ANTAGONISTS
3. SEDATION - drowsiness & clouding of
mentation, little or no nausea, deep sleep if
taken w/ sedative hypnotic drugs, marked
sedation w/ phenanthrene (like morphine &
hydromorphone), less sedation w/ synthetics
(like meperidine, fentanyl)
4. RESPIRATORY DEPRESSION - secondary to
inhibition of the brain stem respy mech. (pCO2
but w/ response), dangerous for patientsw/ ( intracranial pressure, asthma, COPD, corpulmonale
5. COUGH SUPPRESSION - esply codeine, only for
pathologic dry cough, dangerous (may lead to
accumulation of secretions & atelectasis),
tolerance may develop
6. MIOSIS - constriction of pupils, no tolerance
develops (valuable in diagnosis of opioid
overdose), blocked by antagonist, mediatedthru parasympathetic (may be blocked by
atropine)
7. TRUNCAL RIGIDITY - supraspinal effect
(interfere w/ respiration), noted in high doses
of lipid soluble opioids (fentanyl, sulfentanyl,
alfentanyl) if given rapid IV
8. NAUSEA / VOMITING - effect on brain stem
chemoreceptor & on vestibular area on
ambulation
B. PERIPHERAL EFFECTS1. CVS bradycardia, hypotension (arterial &
venous dilatation)
2. GIT - stomach ( motility, tone, HClsecretion), small & large intestine ( motility, tone, peristalsis, passage of stool, waterabsorption, constipation), benzomorphans like
pentazocine has less constipation than others
3. Biliary tract - constricts smooth muscle (colic),
Sphincter of Oddi constricts (reflux of bile &pancreatic secretions into circulation plasmaamylase & lipase )
4. GUT - renal fxn, ureter & bladder tone(colic & retention)
5. Uterus - tone (prolonged labor)
6. Neuroendocrine (hypothalamus) - release of:
(ADH, prolactin, somatotropin), inhibit release
of: (luteinizing hormone)
7. Miscellaneous - histamine release (flushing &
warming of skin, sweating, itching), modulate
immune system (lymphocyte proliferation,
antibody production, chemotaxis)
C. EFFECTS OF MIXED AGONIST ANTAGONIST- ex pentazocine
- produce sedation & analgesia
- high dose sweating, dizziness nausea, vomiting,
respy depression (less severe as w/ pure agonist)
- respy depression is reversed by naloxone but not by
another agonist-antagonist like nalorphine
- may cause psychoto-mimetic effect: hallucination,
nightmares, anxiety
II. CLINICAL PHARMACOLOGY
CLINICAL USE OF OPIOID ANALGESIC
ANALGESIA
Severe constant pain is relieved BUT
sharp, intermittent & colicky pain is
not
Pain of terminal cancer should be
relieved & fear of tolerance &
dependence should be set aside
Regular dose at regular time is more
effective than whwen given on
demand
Stimulant drugs like amphetamine may
enhance analgesia & is thus useful as
adjunct for chronic pain
For obstetric labor pain,
phenylpiperidines (like Meperidine) is
the choice since it causes less respy
depression for the infant. Should ithappen, the antagonist Naloxone is
given
Renal & biliary colic may cause a
paradoxical in pain in dose may provide
adequate analgesia
ACUTE PULMONARY EDEMA
relieves pain of dyspnea assd w/ left
ventricular failure
preload ( w/ in venoustone )
afterload ( w/ peripheralresistance)
perception of dyspnea & anxiety (affective
component)
COUGH
Use of opioids as antitussive agent has
been replaced by non-opioid & non-
addicting agents like: carbetapentane,
caramiphen, chlophedianol,
diphenhydramine, glaucine
DIARRHEA
Opioids such as crude opium or
paregoric stops peristasis but they
must not be used infectious diarrhea
since retention of the bacteria will
worsen the infection
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MauChuaPHARMACOLOGY S.Y. 2011-2012
PIOID ANALGESICS & ANTAGONISTS
Presently, synthetic ones replaced it
w/ less CNS effects like
phenylpiperidine (diphenoxylate)
ANESTHESIA
As pre-op meds sedative, anxiolytic,
analgesic For post-op analgesia epidural or
subarachnoid morphine 3-5 mg
gives long lasting effect
TOXICITY & UNDESIRED EFFECTS
A. TOLERANCE & DEPENDENCE
a. Tolerance
- Develops usually 2-3 wks after usual
frequent therapeutic dose- Readily develops w/ large dose at short
interval
- Usually in analgesia, euphoria, respy
depression, antidiuresis, emetic &
hypotensive effects
- Not noted in: miosis, convulsion,
constipation
- Tolerance to methadone develops slowly
than w/ morphine
- Cross tolerance is possible due to similar
mu receptor site effect between:
morphine, meperidine, methadone
- Tolerance to euphoria & respy depression
dissipates w/in a few days after stopping
the drug
- But tolerance to emetic effect persist for
months
- Tolerance does not develop to the
antagonistic action of agonist-antagonists
group nor to those of pure antagonists
b. Physiologic dependence
- Accompanies tolerance due to repeated
use
- Stopping the drug causes withdrawal orabstinence syndrome (rebound from the
effects of the drug)
- S/S rhinorrhea, lacrimation, yawning,
chills, gooseflesh (piloerection),
hyperventilation, hyperthermia, mydriasis,
muscle aches, vomiting, diarrhea, anxiety,
hostility
c. Toxic effects
- Common S/S dysphoria (behavioral
restlessness, tremulousness, hyperactivity),
respy depression, nausea & vomiting,increased intracranial pressure, postural
hypotension, constipation, urinary
retention, itchiness, urticaria
- TIME
MORPHINE & HEROIN - toxic effects start
6-10 hrs after the last dose, peaks in 36
48 hrs, disappears in 5 days, some s/s may
persist for months
MEPERIDINE - withdrawal syndrome
subside w/in 24 hrs.
METHADONE - peaks in several days, last
for 2 wks, its slow subsidence makes it a
choice in detoxification of heroin addicts
ANTAGONIST PRECIPITATEDWITHDRAWAL - transient, explosive
abstinence syndrome is noted when an
antagonist like naloxone is given to an
opioid dependent w/in 3 min. of injection,
peaks in 10 n- 20 min, subsides in 1 hr.
d. Psychologic dependence
- Euphoria, indifference to stimuli &
sedation tends to promote compulsive
use
- Especially the abdominal effects
likened to an intense sexual orgasm- This makes the abuse liability of
opioids very high & the individual
rationalize that if he stops using the
drug, withdrawal symptoms will follow
B. DIAGNOSIS & TREATMENT OF OVERDOSE
TOXICITY
a. Diagnosis - needle marks, miosis, S/S - already
mentioned, coma
b. Treatment - naloxone 0.2 0.4 mg IV will
reverse the coma secondary to opioid overdose
but not if caused by other CNS depressants
C. CONTRAINDICATIONS & CAUTIONS IN THERAPY
o Use of pure agonist w/ mixed agonist-
antagonist
o Giving Pentazocine ( a mixed agonist-
antagonist ) to a patient already using morphine
( a pure agonist ) may analgesic effect ofmorphine or induce withdrawal syndrome
o W/ head injuries - CO2 retention cause morerespy depression w/ cerebral vasodilatation &
further in ICP
o In pregnancy -if mother is an addict, consider
withdrawal syndrome in baby upon delivery
o W/ impaired pulmonary function - respy
depression may lead to respy failure
o W/ impaired hepatic & renal function - opioid
metabolites may accumulate in patients w/ liver
& kidney failure
o W/ endocrine disease - patients w/
hypothyroidism & adrenal insufficiency
(Addisons disease) may have prolonged &
exaggeratedn response to opioids
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MauChuaPHARMACOLOGY S.Y. 2011-2012
PIOID ANALGESICS & ANTAGONISTS
DRUG INTERACTION W/:1. SEDATIVE HYPNOTICS - CNS depression,
particularly respy depression
2. ANTIPSYCHOTIC TRANQUILIZERS - sedation & respy depression, accentuation
of cardiovascular effects (antimuscarinic
actions, alpha blocking actions)
3. MAO INHIBITORS (ANTIDEPRESSANTS) -
relative contraindication to all opioids
because of the high incidence of
hyperpyrexic coma & hypertension
SPECIFIC AGENTS
A. STRONG AGONIST
A. PHENANTHRENES
o
Strong analgesics morphine,hydromorphone, oxymorphones,
heroin
B. PHENYLHEPTYLAMINES
o Methadone - similar to morphine,
longer acting, reliable even orally,
tolerance & dependence develops
slowly, withdrawal symptoms are
mild but more prolonged, useful
for detoxification of heroin addicts
(dose 5-10 mg oral, 2-3x / day
for 2-3 days)
o Levomethadyl acetate (L-
acetylmethadol) - longer half-life
than methadone, for detoxication
(given once every 2-3 days)
C. PHENYLPIPERIDINES
1. Meperidine - has antimuscarinic effect,
w/ negative inotropic effect, seizures
develops if retained & increased due to
renal failure
2. Fentanyl
a. Sufentanil 5 to7x more
potent than fentanyl
b. Alfentanil - less potent than
fentanil, rapid onset, short
duration
c. Remifentanil - rapidly
metabolized by tissue
cholinesterase, extremely
short half life
D. MORPHINANS
o Levorphanol - synthetic analgesic,
may have less nausea & vomiting,
less effective orally
B. MILD TO MODERATE AGONISTA. PHENANTHRENES
o Samples codeine, oxycodone,
dihydrocodeine, hydrocodone
o Characteristics - less efficacious
than morphine, adverse effect
may develop if dose is toachieve analgesia
o Present use - combined w/ aspirin
or acetamenophen at a low safe
dose
B. PHENYLHEPTYLAMINES1. Propoxyphene - related to methadone
but has low analgesic properties, w/
low abuse potential, not suitable as
analgesic even if combined w/ aspirin
C. PHENYLPIPERIDINES
1. Diphenoxylate (Schedule V), Difenoxin
(Schedule IV)
a. Not used for analgesia
b. Used to treat diarrhea in
combination w/ atropine
2. Loperamide - low abuse potential,antidiarrheal w/ limited access to brain
C. MIXED AGONIST-ANTAGONISTA. PHENANTHRENES - caution w/ patients
taking a pure agonist (may analgesia, maycause explosive withdrawal syndrome)
1. Nalbuphine (Nubain) - strong kappa
receptor agonist but a mu receptor
antagonist, may cause respy
depressionthat is resistant to Naloxone
reversal
2. Buprenorphine - long acting, partial
mu receptor agonist, resistant to
naloxone reversal, may be used for
detoxification of heroin addicts
B. MORPHINANS
1. Butorphanol - produce analgesia
similar to nalbuphine but has more
sedation, kappa agonist
C. BENZOMORPHANS
1. Pentazocine - kappa agonist, weak mu
antagonist, oldest mixed agonist-
antagonist, oral/parenteral, not
recommended for subcutaneous
injection (its an irritant)
2. Dezocine - high sffinity for mu
receptor, less affinity for kappa
receptor, analgesia similar to morphine
D. MISCELLANEOUSA. Tramadol synthetic, weak mu agonist,
inhibitory to norepinephrine, serotonin
reuptake in CNS, weak analgesic similar to
propoxyphene, partially antagonized by
naloxone
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MauChuaPHARMACOLOGY S.Y. 2011-2012
PIOID ANALGESICS & ANTAGONISTS
E. ANTITUSSIVEA. Opioids have good antitussive effect even
at low doses below analgesia
B. OPIOID DERIVATIVE
o Dextromethorphan - free of analgesic
properties & of addictive effect, less
constipation
o Codeine - useful antitussive at low dose
below analgesia
o Levopropoxyphene - devoid of opioid
analgesic effects, still has sedative
effects
o Noscapine - naturally occurring, no CNS
analgesic effect, potent releaser of
histamine (causes bronchoconstriction
& transient hypotension)
C. Use w/ caution on patients taking MAO
inhibitors (antidepressants)
F. OPIOID ANTAGONISTA. Site of action - Binds w/ mu receptors &
also reverses agonist effects at kappa &
delta receptor sites
B. Morphine derivatives Naloxone,
Naltrexone, Nalmefene
C. Pharmacokinetics
o Naloxone - poor effect if given oral
due to first pass metabolism in liver,
short duration after injection, half life
10 hrs, single oral dose of 100 mg
will block effects of heroin injection
for 48 hrs
D. Pharmacodynamics
o When given in the absence of an
agonist drug, it has no effect
o When given IV to a morphine treated
patient, the antagonist effect willcompletely reverse the opioid effect
of morphine w/in 1-3 minutes
o In patients w/ opioid overdose, it will
normalize (respiration, level of
cosciousness, pupil size, bowel
activity)
o In patients taking an opioid but
appear normal, will trigger an
explosive withdrawal symptoms
o There is no tolerance to antagonist
effect nor withdrawal symptoms
develop if treatment is stopped
E. Clinical use
o Naloxone - pure antagonist,
treatment of acute opioid overdose,
short acting, 0.1-0.4 mg IV may
reverse the toxicity, but 1-2 hrs after,
relapse may occur, repeat dose may
be necessary
o Nalorphine - weak agonist-
antagonist, used as an antagonist
o Naltrexone - long acting, used as
maintenance for treatment programs
for addicts, given every other day,
may be used also to treat alcohol
withdrawal syndrome.