opioids

Analgesic Agents/Opioids Anesthesiology

ANALGESIC AGENTS OPIOIDS (mainstay for post-op pain and cancer pain) ANTIPYRETIC ANALGESICS

I. Carboxylic Acid and Enolic Acid groupsII. Benzenesulfonic Acid derivatives

III. Phenol groups

TERMINOLOGIES: OPIATES= drugs derived from opium, which is obtained from the juice of the poppy Papaver somniferum. OPIOID= applies to substances with morphine-like activity, including agonist and antagonist as well as

naturally occurring & synthethic opioid peptides ENDORPHIN= generic term applying to the endogenous opioid peptides. 4 Families of endogenous opioids

1. Endorphins2. Enkephalins3. Dynorphins4. Nociceptin

NARCOTIC =derived from the Greek word for stupor; originally referred to drug that induced sleep, nut later associated with strong opiate analgesic.

CLASSIFICATION OF OPIOIDS:I. ACCDG TO THEIR EFFECT ON THE FOUR MAJOR OPIOID RECEPTOR TYPES

RECEPTOR CLINICAL EFFECTS AGONISTSMOR mu opioid receptor Supraspinal analgesia µ1

Respiratory Depression µ2

PhysicalDependence Muscle Rigidity

Morphine Met enkephalin β Endorphin Fentanyl Nalbuphine (partial)

KOR kappa opiod receptor Sedation Spinal analgesia

Morphine Nalbuphine

DOR delta opioid receptor Analgesia BehavioralEpileptogenic

Leu enkephalinβ EndorphinNalbuphine(antagonist)

Orphanin FQ/Nociception (NOP) receptor

II. ON BASIS OF SYNTHESIS1. NATURALLY OCCURING

Morphine,codeine,thebainePapverine,noscapine

2. SEMI SYNTHETICHeroin, hydromorphone, hydrocodeine, buprenorphine, oxycodone, etorphine, oxymorphone

3. SYNTHETIC (morphine-like activity)Morphinan series (levophanol, butorphanol)Diphenylpropylamine series (methadone)


Benzomorphinan series (pentazocine)Phenylpiperidine (meperidine, fentanyl, sufentanil, alfentanil, remifentanil)

III. According to POTENCY1. WEAK opioids: codeine, dextropropoxyphine, tramadol, hydrocodone2. MEDIUM Potency (INTERMEDIATE): morphine, methadone, oxycodone, hydromorphone, buprenorphine3. STRONG opioids: fentanyl (75-125x more analgesic potency than morphine), sufentanil, alfentanil,

remifentanil*usually, intra operatively, strong opioids are used, while post op phase, weak to medium strength.

Non-Opioid Receptor: NMDA receptorMethadone is most potent; 6-18x more potent than morphineAntagonism of the NMDA receptor is useful in reducing opioid tolerance, OIH, & chronic pain states.

The properties of specific opioids depend on w/c receptor is bound and the binding affinity of the drug.The physicochemical properties influence both pharmacokinetics & pharmacodynamics.To reach its site of action, an opioid must cross the BBB which depends on molecular size, ionization, lipid solubility, & protein binding.

PHARMACOKINETICSABSORPTION

Transmucosal fentanyl lollipopTransdermal: fentanyl patch, buprenorphine patchSpinal & epidural: fentanyl, morphine, hydromorphone

DISTRIBUTION:Bound to 2 major plasma proteins: Albumin & Alpha Acid Glycoprotein (AAG)Low fat solubility= slow onset, prolonges duration of actionDistribution ½ lives of all opioids= 5-20 minutesFirst-pass uptake in the lungs in lipid soluble opioids

(Fentanyl)= retained by the lungs; the amount of uptakes is reduced by prior administration of other drugs, concurrent inhalation anesthetic, but increased by history of tobacco use

NOTE: Unbinding of receptors & redistribution terminate opioid effects

PHYSICAL PROPERTIES that DETERMINE DISTRIBUTIONAGENT NON-IONIZED

FRACTIONPROTEIN BINDING LIPID SOLUBILITY

MORPHINE ++ ++ +MEPERIDINE + +++ ++FENTANYL + +++ ++++SUFENTANIL ++ ++++ ++++ALFENTANIL ++++ ++++ +++REMIFENTANIL +++ +++ ++very low +++ high

Fentanyl- Lipid soluble- Faster onset

Morphine- More water soluble


++ low ++++ very high

BIOTRANSFORMATION:All except remifentanil depend on liver metabolism (CYP system & conjugation or both)

Clearance depends on HBF because of high extraction ratioConjugation: morphine→M3G & M6GDemethylation: meperidine→normeperidine: active metabolite including seizureCodeine is a prodrug of morphine (responsible for its analgesic property)

Remifentanil- ester structure-hydrolysis in RBC & tissues by non-specific esterases in liver illness, no dose adjustments- safe opioid for patients with liver problems

EXCRETION:Kidneys= morphine & meepridine end products (not given to renal patients – prolongs respiratory depression)10% bile excretion

EEFECTS ON ORGAN SYSTEMS : CARDIOVASCULAR:

General Effect: Cardiac Rate except MeperidineFew direct effects on the heartMeperedine = HR (used in preventing intraoperative chilling, 10-25 mg IV)Vagus-mediated bradycardua hypotension, venodilation, decreased sympathetic reflexesHistamine release by morphine, hydromorphone & meperidine = SVR, BP

RESPIRATORY:RR, Ventilator depression (most serious side effect)

PaCO2, may increase apneic threshold decreasing hypoxic driveChest wall rigidity in rapid administration (especially Fentanyl)Bronchoconstrictive response to AW stimulation is bluntedCough center in the medulla is depressed

CEREBRALCerebral oxygen consumption reduced CBF, CBV, ICPNausea & vomiting is triggered thru the CTZ

-most common side effect (Risk Factor: Hx of Postoperative opioid use)Miosis (papillary constriction)IOP is reduced by morphine


Shivering in the PACU = Meperidine (Demerol) 10-25 mg

GASTROINTESTINAL: Gastrointestinal motility delayed gastric emptying, delayed digestion, ileus to constipation

*tx: stimulant laxatives, not bulk-forming laxatives (for opioid-induced constipation)Biliary colic

ENDOCRINE:Release of stress hormones (glucocorticoids & catecholamines) is blocked

OTHERS:Ureter & bladder = inhibit urinary voiding reflex, detrussor muscle relaxation, bladder capacity increases

urinary retention (common side effect in young males)Skin= morphine can produce dilation of cutaneous blood vessels 2° to histamine releaseLocal urticaria, pruritusIV Opioids: Pruritus at the Nose due to the distribution of Trigeminal Nerve where opioid receptors are

abundant.

4 CLASSIC SIDE EFFECTS OF NEURAXIAL OPIOIDS:Spiral or epidural route(combined with local anesthetics)

1. Pruritus2. Nausea & vomiting3. Urinary retention4. Depression of ventilation

PRURITUS = most common S/E, 60-90%May be generalized but more likely localized on the face, neck, upper thoraxMay or may not be dose-relatedMore seen in OB pxs—interaction of opioids w/ estrogen

UNRINARY RETENTION = most common un young malesNot dose related

DEPRESSION OF VENTILATION = most serious S/E may occur w/ in minutes or maybe delayed for hours (especially for epidural morphine)

Early depression: fentatnyl or sufentanilDelayed: morphine

Depressed level of consciousness is a reliable sign of respiratory depression_______________________________________________________________________________________________

1. MORPHINEPrototype opioid agonist (in Mu and Kappa receptors)Widely available, low costProvides analgesia, euphoria, sedation, diminished ability to concentrateContinuous dull pain > sharp intermittent pain


<0.1% IV morphine enters CNS because:1. Poorly lipid soluble2. Highl degree of ionization ot physiologic pH3. Low protein-binding4. Rapid conjugation w/ glucuronic acid

Metabolism: liver & kidnesys

2 metabolites:1. Morphine 3 glucoronide (M3G) = 75-85%, inacgive2. Morphine 6 glucoronide (M6G) = 5-10 %, active, producine analgesia & ventialatory depression at MOR;

potency & duration of action > morphine

TRAMADOL (Tramal)

Mode of Action:1. Centrally acting analgesic with a low affinity at the MOR2. Inhibit norepinephrine & serotonin uptake

5-10x less potent than morphineRacemic mixture of 2 enantiomersHigh incidence of nausea & vomitingFor Chronic pain: (-tolerance) & addictionSeizures may occur in concomitant tx w/ anti depressantO-desmethyltramadol: metaboliteAlso cause constipation

Dose: 50-100 mg q 4-6 hrs, 400 mg max dose/ day_______________________________________________________________________________________________

NALBUPHINENubain

Agonist-antagonist opioid related chemically to naloxone (which reverses its agonist effect)Equal analgesic potency as morphine¼ anatagonistic potency as nalorphineCeiling effect on analgesia & resp depression >30 mg has no further effect (give another pain reliever)**chief agonist: KOR**antagonist: MOR --- analgesia & resp depression are reversed

Dose: 10 mg q 3-6 h; onset 5-10 min, duration 3-6 h_______________________________________________________________________________________________

NALOXONE (Narcan)Antidote for Opioid OverdoseN-alkyl derivative of oxymorphone

Do not give agonist and antagonist at the same time. – It produces negative effect.


Pure MOR antagonistFor the treatment of:

1. Opioid-induced depression of ventilation as maybe present post op2. In neonatal depression to maternal administration of opioid3. Facilitate tx of deliberate opioid overdose4. Defect unsuspected physical dependence

Liver conjugation –N3G as metabolite (Naloxone 3 Glucoronide)

Dose: 1-4 ug/kg IV bolus; 5ug/kg/hr infusion Side Effects: reversal of analgesiaDuration of action: 30-45 min N/V in rapid injectionElimination ½ time: 60-90 min Cardiovascular stimulation

HR, BP; pulm edemaArryhtmias

OXYCODONESemi-synthetic thebaine derivative, with similar profile & potency as morphineLong acting preparations & immediate release for breakthrough pain (in between pain medications)In elderly patients: avoid sedation, mental status change, M6G accumulationPreparation with Naloxone: constipation is avoided (in Cancer Patients)For Chronic Cancer Pain

TRITATION PRINCIPLEBest principle to avoid detrimental S/ETo start low and titrate up (or down) increments until optimal (maximal) analgesia is achieved

opioids

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