MOP receptor agonists

-strong agonists (6)

-mild to moderate agonists (3)

Strong agonists:

- morphine

- meperidine

- methadone

- fentanyl (& derivatives)

- levorphanol

- heroin

Mild to moderate agonists:

- codeine

- oxycodone

- tramadol

- nalbuphine

- pentazocine

- buprenorphine

- butorphanol

Naloxone

Nalmefene

Naltrexone

Morphine

- properties

- metabolite

Properties:

- first pass metabolism via liver when taken orally

- can cross BBB but not as effective as other drugs

- can induce histamine release

Metabolites:

- morphine-3-glucuronide = excitotoxic metabolite, excreted in urine

- morphine-6-glucuronide = 2x potentency of morphine

Meperidine

-properties

-metabolites

Properties:

- MOP agonist; analgesic

- greater oral efficacy than morphine

- not used for antitussive or antidiarrhetic

- can induce histamine release w/ parenteral admin

- respiratory depressant

- less urinary retention, constipation than morphine

- antimuscarinic action IV (not IM) --> increased HR

- not good for chronic pain (short duration of action)

Metabolites:

- normeperidine = toxic, causes CNS excitation (seizures, tremors, hallucinations etc)

    ~eliminated by kidney, liver

    ~if on MAO inhibitor, may exhibit severe excitatory rxns (MAO-I's contraindicated)

Methadone

-properties

-used to treat/contraindications

Properties:

- long lasting MOP agonist

- good oral efficacy

- binds plasma proteins well --> gradual tissue accumulation

- tolerance develops slowly

- can block NMDA receptors and monoaminergic reuptake

Treat/Contraindications:

- treate opioid addicts (heroin), chronic pain, opioid abstinence syndromes

- should not used in labor

Fentanyl

Sufentanil

Alfentanil

Remifentanil

-properties

-uses

Properties:

- synthetic MOP agonists

- administered IV, epidurally, and intrathecally

- highly lipid soluble

- short time to peak analgesia

- rapid respiratory depression

- muscle rigidity after infusion

- sufentanil (1000X) > fentanyl = remifentanil (100X) > alfentanil (3-5X) > morphine

- Fentanyl, sufentanil, and alfentanil metabolized by liver

- Remifentanil metabolized by plasma esterases

Uses:

- fentanyl and sufentanil used for surgical pain management and combined with local anesthetic the doses needed and side effects of each (opioid and anesthetic) are reduced

- alfentanil and remifentanil are used for short painful procedures, rapid recovery

Levorphanol

-properties

Properties:

- synthetic opioid

- may produce less nausea and vomiting than morphine

- higher oral potency than parenteral

Heroin

-properties

-metabolites

Properties:

- strong MOP agonist

- given IM about 2X more potent than morphine

- not uniquely advantageous as a therapeutic agent

Metabolites:

- 6-monoacetylmorphine (6-MAM) which can then be hydrolyzed to morphine

- 6-MAM and heroin are very lipid soluble

- excreted in urine as free and conjugated morphine (basis for drug testing for heroin)

Codeine

-properties

Properties:

- partial agonist; low affinity for opioid receptors

- greater oral efficacy than morphine

- ~10% hydrolyzed to morphine

- high oral potency vs parenteral

- moderate pain and antitussive uses; rarely used alone (tylenol or aspirin too)

- metabolites excreted into urine

- oxycodone (oxycontin) and hydrocodone (vicodan)

    ~metabolized into stronger MOP agonists

Propoxyphene

-reason for FDA removal

Properties:

- pulled by FDA due to generation of a toxic metabolite (norpropoxyphene) causing cardiac electrical abnormalities

Tramadol

-properties

-metabolites

Properties:

- weak MOP agonist

- synthetic codeine analong

- inhibits serotonin and NE uptake

- effective mild-moderate tx of pain w/ less constipation than codeine

- NO clinically relevant effects on respiration or CV system

- Hepatic metabolism and renal excretion

- risk of CNS excitatory rxn

Metabolites:

- M1, trans-O-demethyletramadol = 2-4X potency with longer 1/2 life

Opioids with active opioid metabolites

-names

Morphine = morphine-6-glucuronide

Heroine = 6-MAM + morphine

Codeine and conegers

Naltrexone

Morphine = morphine-3-glucuronide

Merperidine = normeperidine

Tramadole = M1, trans-O-demethyltramadol

Meperidine = monoamine

Methadone = NMDA and monoamine

Tramadol = serotonin and NE

Dextromethorphan = NMDA antagonist, serotonin reuptake

Nalbuphine

-properties/uses

Properties:

- strong KOP agonist, competitive MOP antagonist

- poor oral efficacy

- 10 mg equianalgesic to 10 mg morphine if IM admin

- ceiling effect on respiratory depression and analgesia at 30 mg

- antagonist resistant respiratory depression possible

- precipitates withdrawal in patients on low therapeutic opioid doses

- at 10 mg no significant alterations in CV indices in stable CAD cases (i.e. good analgesic for CVD/CAD patients)

- sweating, sedation, HA @ therapeutic doses

- high doses psychotomimetic

Pentazocine

-properties

-metabolites

Properties:

- agonist at KOP receptors, weak MOP receptor agonist or partial

- poor oral efficacy

- effects generated similar to morphine like opioids

- ceiling effect on analgesia and respiratory depression

- high dose dysphoric and psychotomimetic effects

- increase BP, HR, and cardiac work 

- precipitates withdrawal in MOP agonist dependent person

- does not antagonize morphine induced respiratory depression

- does not prevent or alleviate withdrawal

- used as analgesic

- hepatic metabolism, renal excretion

Buprenorphine

-properties

Properties:

- partial MOP receptor agonist (high binding affinity, low intrinsic activity)

- KOP and DOP antagonist

- slow dissociation from MOP receptor

- highly lipophilic and 25-50X more potent than morphine

- increased respiratory depression preventable w/ prior opioid antagonist but not easily reversed once set in

- antagonizes respiratory depression produced by fentanyl

- may induce abstinence syndrome in those receiving therapeutic opioids

- as effective as methadone in detoxification and maintenance of heroin-dependent individuals

- most is excreted unchanged in feces and urine

- derived from thebain

Butorphanol

-properties

Properties:

- agonist of KOP receptors

- competitive MOP receptor antagonist, or partial agonist

- equianalgesic doses to morphine produces similar respiratory depression

- extensive 1st pass metabolism in liver

- analgesic doses increase pulmonary arterial pressure and cardiac work

- women > men analgesic effect

- acute pain relief

Codeine

Hydrocodone

Dextromethorphan

Dextromethorphan

-properties

Properties:

- no analgesic or addictive properties

- does not act through opioid receptor

- NMDA receptor antagonist

- inhibits Ca²⁺ channels, serotonin reuptake

- equal to codeine potency w/ fewer subjective and GI side effects

- antitussive effects persist for 5-6 hrs

- extremely high doses may produce CNS depression

Loperamide (Imodium)

-properties

Properties:

- meperidine derivative acting on GI muscles to slow motility

- not well absorbed orally, no BBB cross

- no pleasureable opioid effects at high doses

- anti-diarrheal

Properties:

- meperidine derivative whose only approved use is to treat diarrhea

- at high doses shows typical opioid activity

- low solubility

Naloxone

-properties

Properties:

- MOP, DOP, and KOP receptor antagonist; highest for MOP

- produce few effects with normal endogenous opioid peptide levels or in absence of prior opiod agonist admin

- no tolerance develops and no recognizeable withdrawal syndrome after prolonged antagonist administration

- respiratory depression reversed in 1-2 mins with IM/IV admin

- higher doses required to reverse buprenorphine respiratory depression and agonist/antagonist (pentazocine, nalbuphine) psychotomimetic and dysphoric effects

- almost completely metabolized by liver (2% bioavailability)

- rapid onset and short duration

Nalmefene

-properties

Properties:

- MOP, DOP, and KOP receptor antagonist; highest for MOP

- produce few effects with normal endogenous opioid peptide levels or in absence of prior opiod agonist admin

- no tolerance develops and no recognizeable withdrawal syndrome after prolonged antagonist administration

- respiratory depression reversed in 1-2 mins with IM/IV admin

- higher doses required to reverse buprenorphine respiratory depression and agonist/antagonist (pentazocine, nalbuphine) psychotomimetic and dysphoric effects

- more potent than naloxone

- metabolized by liver (40% bioavailablity); admin parenterally

Naltrexone

-properties/uses

-metabolites

Properties/Uses:

- MOP, DOP, and KOP receptor antagonist; highest for MOP

- produce few effects with normal endogenous opioid peptide levels or in absence of prior opiod agonist admin

- no tolerance develops and no recognizeable withdrawal syndrome after prolonged antagonist administration

- respiratory depression reversed in 1-2 mins with IM/IV admin

- higher doses required to reverse buprenorphine respiratory depression and agonist/antagonist (pentazocine, nalbuphine) psychotomimetic and dysphoric effects

- duration of action = ~24hrs

- efficacy retained with oral admin (100% bioavailability)

- approved to treat alcoholism

Metabolites:

- 6-naltrexol, weaker antagonist with t_1/2 = 13 hrs

Acute opioid toxicity

-signs

-treatment

-when to give antagonists

Signs:

- triad of

   ~coma

   ~miosis

   ~depressed respiration

- decreased temp

- convulsions

Treatment of choice = naloxone (t_1/2 = 1 hr)

When to give antagonists:

- morphine treated patient (agonist effect reversed)

- acutely depressed patient (normalized)

- opioid dependent person (transient explosive abstinence syndrome)

- normal opioid naive person (no immediate effects)

Impaired respiratory function

Hepatic disease

Renal disease

Asthmatics

Pregnant women

Head injuries

Patients with reduced blood volume (vasodilatory effects)

Elderly

Patients receiving other CNS depressants

Patients receiving antipsychotic tranquilizers

Patients receiving MAO inhibitors