pharmacology and physiology of opioids · •opium is the semidried sap of the plant and is ......

Pharmacology and physiology of Opioids

Danai Indrakamhaeng, M.D.Consultant Psychiatrist at Bangkok Hospital Chiang Mai

International Certified Addiction Professional (ICAPIII)

Trainer; The Colombo Plan Drug Advisory Program & SEAHATTC

Origin

• Opos: Greek for juice

• Opium: A mixture of alkaloids from the poppy plant

• opium poppy: Papaver somniferum.

Pharmacology of Opioids: Mahesh Tridedi et al. Update in Anesthesia 2007

• Opioid: Any naturally occurring, semi-synthetic or synthetic compound that binds specifically to opioid receptors

• Shares the properties of one or more of the naturally occurring endogenous opioids.


• Opiate: Any naturally occurring opioid derived from opium (e.g. morphine).


• Narcotic: From the Greek meaning ‘to numb or deaden’.

• It is often used to denote an opioid

• but also widely used to describe drugs of addiction and hence includes non-opioid compounds.


Opioids

• Natural Opioids

• Semisynthetic Opioids

• Synthetic Opioids

Natural Opioids

• Opium is the semidried sap of the plant and is 100 percent natural.

• Two of the most prevalent alkaloids (plant compounds with psychoactive properties) in opium are morphine and codeine.

Universal Treatment Curriculum for Substance Use Disorders – Basic level, Course 1: Physiology abd Pharmacology for addiction professionals

Natural Opioids

• Friedrich Wilhelm Serturner: A German Pharmacist isolated morphine in 1803 and named it after the Greek god of Dreams “Morpheus”

• Morphine and codeine can be isolated and processed as separate drugs.


Semisynthetic opioid

• Heroin: synthesized from opium.

• Other semisynthetic opioids are hydrocodone, oxycodone, and hydromorphone.


Synthetic opioids

• Synthetic Opioids are not derived from natural opium but are manufactured to work in similar ways.

• E.g. Methadone, fentanyl, and meperidine


• Heroin is the most widely abused opioid.

• Originally developed in an attempt to find an effective painkiller with less addictive potential than morphine

• It turned out to be five to eight times more powerful than morphine and to act more quickly, making it even more addicting.


Appearance of Opioids

• Opium and heroin are generally sold in tar-like black or brown chunks or blocks.

• Heroin often is sold as a white or brown powder.

• Morphine is available as a liquid (for injecting) or tablet.

• Most synthetic opioids are available as tablets or capsules.

• Methadone is available in tablets or an oral liquid.


Modes of Administration of Opioids

• Opium is most commonly smoked.

• Heroin can be smoked, inhaled (either as a powder or liquefied in a nasal spray bottle), or injected (intramuscularly or intravenously).

• Other opioids are more commonly taken orally, in tablet form.


Modes of Administration of Opioids

• Some opioids are administered via slow-release capsules or patches.

• OxyContin, a slow-release capsule: People break open the capsule, dilute the contents, and inject the solution.

• Oxycontin patches are sometimes abused by cutting them open and eating or injecting the contents.


Pharmocokinetic

Absorption

• Routes of opioid administration

• Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes

• Other routes of opioid administration include oral mucosa via lozenges, and transdermal via transdermal patches.

Opioid Analgesics: Sameen Rashid

Absorption: Methadone

• Following oral dosing methadone is detected in the plasma within about 30 minutes

• Peak plasma levels 2-4 hours after ingestion

Pharmacology of Methadone and Physician-Pharmacist collaborative care: Nicole Nakatsu

Absorption: Buprenorphine

• Used sublingually

• Peak plasma concentrations are achieved 90 minutes after sublingual administration.

https://slideplayer.com/slide/6303854/

Distribution

• All opioids bind to plasma proteins with varying affinity.

• The drugs rapidly leave the blood compartment and localize in highest concentrations in tissues.

• Morphine distribution is wide: concentration in liver, spleen and kidney*

• Morphine freely crosses placenta*

Opioid Analgesics: Sameen Rashid(*Morphine&Fentanyl by Dr.Nida Fatima Jawaharlal)

Distribution: Methadone

• Highly protein bound to both plasma proteins and tissue proteins

• 5-7 days to reach steady state with repeated dosing

• Withdrawal typically suppressed for 24-36 hours with therapeutic doses


Distribution of Buprenorphine

• The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours).


Metabolism

• The opioids are converted in large part to polar metabolites.

• Morphine is metabolized to M3G (Morphine-3 Glucoronide) and M6G.

• M3G, a compound with neuroexcitatoryproperties and M6G, an active metabolite with analgesic property.

• Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid.


Metabolism: Methadone

• Primarily metabolized by cytochrome P450 3A4 to the inactive metabolite EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine)


Metabolism: Buprenorphine

• CYP3A4 is responsible for the N-dealkylationof buprenorphine.


Excretion

• Polar metabolites are excreted mainly in the urine.

• Small amounts of unchanged drug may also be found in the urine.

• Some are found in the bile.


Excretion: Methadone

• Methadone is excreted both as unchanged drug and as metabolites in urine and feces.

• Amount of methadone excreted in urine increases as pH decreases.


Excretion: Buprenorphine

• Buprenorphine excreted in the faeces by biliary excretion (70%)

• The rest excreted in the urine.


Pharmacodynamic

MECHANISM OF ACTION

• Opioids produce their actions at a cellular level by activating opioid receptors.

• These receptors are distributed throughout the central nervous system (CNS)

• High concentrations in:– the nuclei of tractus solitarius

– peri-aqueductal grey area (PAG)

– cerebral cortex

– Thalamus

– the substantia gelatinosa (SG) of the spinal cord.


http://appetiteregulation.blogspot.com/2010/05/nucleus-tractus-solitarii-nts.html

http://quantum-mind.co.uk/opioid-receptors/

http://vanat.cvm.umn.edu/neurLab2/pages/T10GrayFeatures.html

• Opioid receptors have also been found on peripheral afferent nerve terminals and many other organs.

• Opioid receptors are coupled with inhibitory G-proteins and their activation has a number of actions

• Overall, the effect is a reduction in neuronal cell excitability that in turn results in reduced transmission of nociceptive impulses.


• Mechanism of euphoria: unclear but thought to involve dopaminergic pathways in nucleus accumbens.

Opioids

Compounds such as oxycodone, hydrocodone, morphine, fentanyl, heroin and others

Opioids interact with opioid receptors on nerve cells in the brain and nervous system to produce pleasurable effects and relieve pain

OPIOID RECEPTOR

opioid

Opioid receptor

Opioid Use, Dependence and Clinical Interventions. Reka Danko M.D.

https://www.pharmacytimes.com/publications/issue/2011/june2011/an-overview-of-opioids

Pain, Opiate analgesics and antagonists: Dr.Israa

Methadone and Euphoria

Right dose should not cause euphoric or

tranquilizing effects.

Reduces/blocks effects of other opioids.

Tolerance is slow to develop.

Relieves cravings.

Allows the individual to feel “normal”.

The Disease of Opioid Addiction and Medication Assisted Treatment by Michele F.McCarthy

Buprenorphine and Euphoria

Virtually no euphoric or tranquilizing effects.

Blocks effects of other opiates.

Relieves cravings to use other opiates.

Allows “normal” function.

The Disease of Opioid Addiction and Medication Assisted Treatment by Michele F.McCarthy

https://www.drugabuse.gov/publications/medications-to-treat-opioid-addiction/what-are-misconceptions-about-maintenance-treatment

At the receptor level

methadone

Opioid receptor

naloxoneOpioid receptor

Opioid receptor

AGONIST: long acting activation of receptor

PARTIAL AGONIST: partial activation, partial blockade

ANTAGONIST: no activation, blocks opioids

naltrexonebuprenorphine

Reference: Opioid Use, Dependence and Clinical Interventions. Reka Danko M.D.

Endogenous Opioid peptides

• Opioid alkaloid

• Produce Anlagesia through action at CNS receptors

• Families of endogenous opioids: Endorphins, Enkephalins, Dynorphin


• How long an opioid high lasts depends on the specific drug.

• Some opioids are short acting, and some are long acting.

• The effects of heroin usually last 3 to 4 hours.


https://www.medscape.org/viewarticle/507483_5

Medical Uses of Opioids

• The primary medical use for opioids is for pain relief.

• Opioids also can be used to treat severe diarrhea and coughing.


“Desirable” Effects of Opioids

• Physical pain relief

• Emotional numbness

• Euphoria, followed by a sense of well-being

• Calm drowsiness or sedation

• Alternating wakefulness and drowsiness

• Dreaminess


Side Effects of Opioids

• Nausea and vomiting

• Confusion

• Slowed breathing

• Constipation

• Blurred or double vision

• “Pinpoint” pupils

• Dizziness, faintness, floating feeling, light-headedness

• Uncoordinated muscle movements, rigid muscles


Side Effects of Opioids

• Rash, hives, itching

• Facial flushing

• Dry mouth

• Weakness

• Agitation

• Headache

• Appetite loss

• Memory loss


Possible Medical Consequences With Chronic Opioid Use

• Infection of the heart lining and valves

• Liver or kidney disease

• Pulmonary complications, including various types of pneumonia, resulting from the poor health of the user as well as from the depressing effects on respiration

• Intestinal complications resulting from chronic constipation

• Consequences directly associated with injecting, including abscesses and collapsed veins

• Spontaneous abortion


Babies born to women who are opioid addicted:

• Low birth weight

• Go through withdrawal, with symptoms lasting 5 to 8 weeks. Unlike adults, babies can die from opioid withdrawal.


Opioid Overdose

• Overdose is a major risk of opioid abuse.

• Signs and symptoms of opioid overdose include:

– Cold, clammy skin

– Weak, floppy muscles

– Fluid in the lungs

– Greatly lowered blood pressure and heart rate

– “Pinpoint” or dilated pupils


Opioid Overdose

• Signs and symptoms of opioid overdose (Cont.):

– Stupor

– Coma

– Slow and difficult breathing

– Bluish-colored fingernails and lips from reduced oxygen intake

– Muscle cramping


https://www.bhchp.org/blog/guidelines-opioid-overdose-preparedness-and-response-congregate-housing-shelters

• Overdose is a particular risk when opioids are combined or are used with other depressant drugs (including alcohol).


Withdrawal Syndrome of Opioids

• Restlessness

• Severe muscle, joint, and bone pain

• Muscle cramping

• Sweating and running nose

• Rapid pulse

• Coughing and yawning



• Dilated pupils

• Insomnia

• Diarrhea and vomiting

• Fever and chills with severe shivering and goose bumps

• Kicking movements



• Symptoms can begin as early as a few hours after the last drug administration.

• Major withdrawal symptoms peak between 48 and 72 hours after the last dose

• typically subside after about a week.


https://americanaddictioncenters.org/withdrawal-timelines-treatments/opiate


• Some individuals may show persistent withdrawal symptoms for months.

• Withdrawal from opioids is usually not medically dangerous for adults (unless the person is in very poor health) but is extremely painful.

• For this reason, medically managed withdrawal using medications to control symptoms is more likely to be successful than “just quitting.”


Protracted withdrawal Symptoms

• The presence of substance-specific signs and symptoms common to acute withdrawal but persisting beyond the generally expected acute withdrawal timeframes

Substance Abuse Treatment Advisory, News for the Treatment field: Protracted Withdrawal. SAMHSA 2010

How do protracted withdrawal symptoms develop?

• Chronic substance use causes molecular, cellular, and neurocircuitry changes to the brain that affect emotions and behavior and that persist after acute withdrawal has ended.

• Adaptive changes in the central nervous system may lead to affective changes that persist for many weeks or longer beyond acute withdrawal.


How do protracted withdrawal symptoms develop?

• For example, repeated use of a substance causes the brain to respond more readily to its effects but less readily to naturally rewarding activities such as listening to music.

• This state, in which a person’s ability to experience pleasure is decreased, is called anhedonia.


Protracted withdrawal symptoms of Opioids

• Anxiety

• Depression

• Sleep disturbances

• Fatigue

• Dysphoria and irritability

• Decreased ability to focus on a task


https://www.evergreendrugrehab.com/blog/opioid-withdrawal-kicking-habit-without-losing-mind/

Interaction between opioids and other substances.

• All opioids:

– Benzodiazepines: increased CNS depression, respiratory depression, death

– Alcohol: increased CNS depression

Addiction Pharmacotherapy: Steve Batki, M.D.

pharmacology and physiology of opioids · •opium is the semidried sap of the plant and is ......

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