pharmacologynotes

OPIOID ANALGESICS & ANTAGONISTS

Dr. George Firmalino

CLASSIFICATION BASED ON SOURCE A. NATURAL OPIUM ALKALOIDS morphine, codeine, papaverine B. SEMISYNTHETIC heroin, oxycodone, hydrocodone, oxymorphone C. SYNTHETIC methadone, meperidine, fentanyl, propoxyphene

I.
o o

BASIC PHARMACOLOGY
opium from plant PAPAVER SOMNIFERUM 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

SOURCE

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 o PENTAPEPTIDES o methionine-enkephalin, leucine-enkephalin 3 PRECURSORS o propio melano cortin (pomc), pro-enkephalin (pro enkephalin-a), pro-dynorphin (proenkephalin-b) POMC CONTAINS o met enkephalin, beta endorphin, non opioid peptides (acth, lipo proteins, melanocyte stimulating hormone) PRO ENKEPHALIN-A CONTAIN o met enkephalin, leu enkephalin

CLASSIFICATION
o o FULL AGONIST (morphine) - strong agonist PARTIAL AGONIST (codeine) - produce agonist effect, may displace other full agonist in binding sites & reduce their effect (antagonist effect) MIXED AGONIST / ANTAGONIST (nalbuphine) when one opioid has agonist effect on one receptor & antagonist effect on another receptor ANTAGONIST - binds to receptor site w/o producing effects associated w/ agonist (like naloxone) o

PRO DYNORPHIN CONTAIN o dynorphin-a, dynorphin-b, & neo endorphins

PHARMACOKINETICS
A. ABSORPTION
o o subcutaneous, im, iv, intra-spinal, mucus, transdermal (like fentanyl), git (subject to first pass metabolism in the liver by glucorinidation high dose is required to produce the desired therapeutic analgesic effect

CLASSIFICATION BASED ON CHEMICAL STRUCTURE & MAIN EFFECT

STRUCTURE PHENANTHRENES STRONG (FULL) AGONIST morphine hydromorphone oxymorphone methadone meperidine fentanyl levorphanol MILD / MOD (PARTIAL) AGONIST codeine oxycodone hydrocodone propoxyphene diphenoxylate butorphanol pentazocine levallorphan MIXED AGONIST ANTAGONIST nalbuphine ANTAGONIST nalorphine naloxone naltrexone

PHENYLHEPTYLAMINES PHENYLPIPERIDINES MORPHINANS BENZOMORPHAN

buprenorphine

B. DISTRIBUTION
a. b. c. d. e.

rapidly leaves the blood concentrate in lungs, liver, kidneys, spleen in muscles has lower concentration but has greater bulk & acts as the main reservoir in fat also a reservoir for lipophilic opioid like fentanyl brain low conc. due blood-brain barrier

OPIOID ANALGESICS & ANTAGONISTS

MauChua PHARMACOLOGY S.Y. 2011-2012

pharmacologynotes
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 cross the placenta & into the brain

3. CELLULAR ACTION
a. -

2 direct actions to neurons Close a voltage-gated Ca channel on presynaptic 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

C. METABOLISM
o o O

compounds w/ free hydroxyl like morphine & levorphanol are readily conjugated w/ glucoronic acid ester compounds like heroin & remifentanyl are rapidly hydrolyzed by common tissue esterases heroin (a diacetylmorphine) is hydrolyzed to monoacetylmorphine & finally to morphine w/c is 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

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

D. EXCRETION - mainly in the kidneys

PHARMACODYNAMICS
A.

MECH OF ACTION - binds to specific receptor site in

brain & spinal cord regions involved in transmission & modulation of pain 1. -

RECEPTOR TYPES - (mu), (delta), (kappa)

RECEPTOR MU Agonist SUBTYPE DELTA agonist agonist weak agonist agonist agonist agonist

RECEPTOR SUBTYPE ACTIVITY OF OPIOIDS

ENDOGENOUS OPIOID PEPTIDES AGONISTS DRUG ENKEPHALINS ENDORPHINS DYNORPHINS CODEINE ETORPHINE FENTANYL MEPERIDINE METHADONE MORPHINE AGONISTANTAGONISTS BUPRENORPHINE DEZOCINE NALBUPHINE PENTAZOCINE NALOXONE

KAPPA

Agonist Weak agonist Weak agonist Agonist Agonist Agonist Agonist Agonist partial agonist partial agonist Antagonist antagonist or partial agonist Antagonist

5. TOLERANCE & PHYSIOLOGIC DEPENDENCE

a.

weak agonist

weak agonist

agonist agonist antagonist antagonist

TOLERANCE - gradual loss of effectiveness of an opioid w/ frequently repeated administration, 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

ANTAGONISTS

B. ORGAN SYSTEM EFFECTS OF MORPHINE

A. CNS at mu receptors 1. ANALGESIA - both sensory & affective components of pain are affected 2.

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

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)

OPIOID ANALGESICS & ANTAGONISTS

MauChua PHARMACOLOGY S.Y. 2011-2012

pharmacologynotes
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) RESPIRATORY DEPRESSION - secondary to inhibition of the brain stem respy mech. (pCO2 but w/ response), dangerous for patients w/ ( intracranial pressure, asthma, COPD, cor pulmonale COUGH SUPPRESSION - esply codeine, only for pathologic dry cough, dangerous (may lead to accumulation of secretions & atelectasis), tolerance may develop MIOSIS - constriction of pupils, no tolerance develops (valuable in diagnosis of opioid overdose), blocked by antagonist, mediated thru parasympathetic (may be blocked by atropine) TRUNCAL RIGIDITY - supraspinal effect (interfere w/ respiration), noted in high doses of lipid soluble opioids (fentanyl, sulfentanyl, alfentanyl) if given rapid IV NAUSEA / VOMITING - effect on brain stem chemoreceptor & on vestibular area on ambulation

C. EFFECTS OF MIXED AGONIST ANTAGONIST

-

4.

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

5.

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 it happen, the antagonist Naloxone is given Renal & biliary colic may cause a paradoxical in pain in dose may provide adequate analgesia

6.

7.

8.

B. PERIPHERAL EFFECTS
1. 2.

CVS bradycardia, hypotension (arterial & venous dilatation) GIT - stomach ( motility, tone, HCl secretion), small & large intestine ( motility, tone, peristalsis, passage of stool, water absorption, constipation), benzomorphans like pentazocine has less constipation than others Biliary tract - constricts smooth muscle (colic), Sphincter of Oddi constricts (reflux of bile & pancreatic secretions into circulation plasma amylase & lipase ) GUT - renal fxn, ureter & bladder tone (colic & retention) Uterus - tone (prolonged labor) Neuroendocrine (hypothalamus) - release of: (ADH, prolactin, somatotropin), inhibit release of: (luteinizing hormone) Miscellaneous - histamine release (flushing & warming of skin, sweating, itching), modulate immune system (lymphocyte proliferation, antibody production, chemotaxis)

ACUTE PULMONARY EDEMA

3.

4. 5. 6.

relieves pain of dyspnea assd w/ left ventricular failure preload ( w/ in venous tone ) afterload ( w/ peripheral resistance) perception of dyspnea & anxiety (affective component)

COUGH

Use of opioids as antitussive agent has been replaced by non-opioid & nonaddicting agents like: carbetapentane, caramiphen, chlophedianol, diphenhydramine, glaucine

7.

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

OPIOID ANALGESICS & ANTAGONISTS

MauChua PHARMACOLOGY S.Y. 2011-2012

pharmacologynotes
Presently, synthetic ones replaced it w/ less CNS effects like phenylpiperidine (diphenoxylate)

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 PRECIPITATED WITHDRAWAL - 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.

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
-

d. Psychologic dependence

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

- 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. b.

Diagnosis - needle marks, miosis, S/S - already mentioned, coma 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 o Use of pure agonist w/ mixed agonistantagonist

b. Physiologic dependence
-

Accompanies tolerance due to repeated use Stopping the drug causes withdrawal or abstinence 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

Giving Pentazocine ( a mixed agonistantagonist ) to a patient already using morphine ( a pure agonist ) may analgesic effect of morphine or induce withdrawal syndrome W/ head injuries - CO2 retention cause more respy depression w/ cerebral vasodilatation & further in ICP In pregnancy -if mother is an addict, consider withdrawal syndrome in baby upon delivery W/ impaired pulmonary function - respy depression may lead to respy failure W/ impaired hepatic & renal function - opioid metabolites may accumulate in patients w/ liver & kidney failure W/ endocrine disease - patients w/ hypothyroidism & adrenal insufficiency (Addisons disease) may have prolonged & exaggeratedn response to opioids

o o o

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

OPIOID ANALGESICS & ANTAGONISTS

MauChua PHARMACOLOGY S.Y. 2011-2012

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DRUG INTERACTION W/:

1. 2.

SEDATIVE HYPNOTICS - CNS depression, particularly respy depression ANTIPSYCHOTIC TRANQUILIZERS - sedation & respy depression, accentuation of cardiovascular effects (antimuscarinic actions, alpha blocking actions) MAO INHIBITORS (ANTIDEPRESSANTS) relative contraindication to all opioids because of the high incidence of hyperpyrexic coma & hypertension

o Characteristics - less efficacious than morphine, adverse effect may develop if dose is to achieve analgesia o Present use - combined w/ aspirin or acetamenophen at a low safe dose B. PHENYLHEPTYLAMINES 1. 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

3.

SPECIFIC AGENTS
A. STRONG AGONIST
A. PHENANTHRENES

o Strong analgesics morphine, hydromorphone, oxymorphones, heroin 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 (Lacetylmethadol) - longer half-life than methadone, for detoxication (given once every 2-3 days)

B. PHENYLHEPTYLAMINES

C. MIXED AGONIST-ANTAGONIST

A. PHENANTHRENES - caution w/ patients taking a pure agonist (may analgesia, may cause explosive withdrawal syndrome) 1. Nalbuphine (Nubain) - strong kappa receptor agonist but a mu receptor antagonist, may cause respy depressionthat is resistant to Naloxone reversal Buprenorphine - long acting, partial mu receptor agonist, resistant to naloxone reversal, may be used for detoxification of heroin addicts

2.

C. PHENYLPIPERIDINES
1. Meperidine - has antimuscarinic effect, w/ negative inotropic effect, seizures develops if retained & increased due to renal failure 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

B. MORPHINANS 1. Butorphanol - produce analgesia similar to nalbuphine but has more sedation, kappa agonist

2.

C.

BENZOMORPHANS 1. Pentazocine - kappa agonist, weak mu antagonist, oldest mixed agonistantagonist, oral/parenteral, not recommended for subcutaneous injection (its an irritant) Dezocine - high sffinity for mu receptor, less affinity for kappa receptor, analgesia similar to morphine

2.

D. MORPHINANS

o Levorphanol - synthetic analgesic, may have less nausea & vomiting, less effective orally

D. MISCELLANEOUS

B. MILD TO MODERATE AGONIST

A. PHENANTHRENES o Samples codeine, oxycodone, dihydrocodeine, hydrocodone

A. Tramadol synthetic, weak mu agonist, inhibitory to norepinephrine, serotonin reuptake in CNS, weak analgesic similar to propoxyphene, partially antagonized by naloxone

OPIOID ANALGESICS & ANTAGONISTS

MauChua PHARMACOLOGY S.Y. 2011-2012

pharmacologynotes

E. ANTITUSSIVE

A. 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)

o Nalorphine - weak agonistantagonist, 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.

F. OPIOID ANTAGONIST

A. 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 will completely 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

OPIOID ANALGESICS & ANTAGONISTS

MauChua PHARMACOLOGY S.Y. 2011-2012