OPIOID PHARMACOLOGYPG Seminar

Dr. Rohan Kolla,PG in MD PHARMACOLOGY,

JNMC, BELGAUM

Outline

• Definitions• History• Endogenous Opioids• Opioid Receptors• Pharmacokinetics• Pharmacological Effect Profile• Classification of Opioids– Pure AGONISTS– Agonist-antagonists– Antagonists

Outline (contd.)

• Clinical Pharmacology– Therapeutic use of Opiates in Pain control– Guidelines for Opiate Dosing– Non analgesic therapeutic uses– Acute Opioid toxicity

• Screening Methods

Etymology

• OPIOIDS ( from Greek opos, ‘juice’): is any substance regardless of its origin or structure that produces morphine-like effects that are blocked by antagonists such as nalaxone.

• OPIATES: includes the natural alkaloids derived from the resin of the opium poppy; – some authors also include the semisynthetic

substances derived directly from these alkaloids.

• Narcotic (from Greek narkos, ‘I benumb’): – any substance which induces sleep– any substance which acts on opioid receptors– any illicit substance– legally - opium, opium derivatives & their

semisynthetic derivatives

Papaver somniferum

History

• Oldest drug known to mankind• Sumer – 4000 BC• Greeks; Theophrastus – 3rd century BC• Arab Physicians• Used for – asthma, bad eyesight, diarrhoea

and as a euphoriant.

History (contd.)

• Opium Addiction – a lifestyle statement in 17th – 18th century

• It was the source of an important "social problem", one of the first "public health" concerns, known as "baby-doping" (giving a child opium to keep them quiet).

• East India company• Opium Wars: 1/3rd of adult chinese population

was addicted• India is a major produces of legal opium• Taliban & the Afghan War

History (contd.)

• Frederick Sertuner 1806: isolated the crystalline pure substance from opium that he named morphine ( after morpheus, the Greek god of dreams.

• Arnold Beckett in 1950: Proposed that morphine like compounds act by binding to specific receptors in the brain

Mapping of the morphinoids

•Huda Akil•John Leibeskind, UCLA

•Stimulus Produced Analgesia•Periaqueductal Grey matter

•Reversed by antagonists

Mapping of the morphinoids

•Avram Goldstein, Stanford

•Grind and Bind technique

•Radiolabelled opioids

Receptors

•Solomon Snyder &•Candace Pert, John Hopkins

•Grind and Bind technique•Improved radiolabelling techniques

•Discovery of Mu receptors in 1973

Substance X

•Hans Kosterlitz &•John Hughes, Aberdeen University, Scotland

•Pig brain soup•Guinea Pig Ileum

•Discovery of ENKEPHALINS in 1973

Endogenous Opioid Systems

• An agent found within the brain that acts through an opioid receptor is called as an endogenous opioid.

• Principally three classes – enkephalins, endorphins, dynorphins

• All are peptides derived from distinct large precursor proteins - POMC, preproenkephalin, preprodynorphin

• Common amino terminal sequence: TYR-GLY-GLY-PHE-(MET OR LEU)

Endogenous Opioid Systems

• The distribution of cells producing these three different types of endogenous opioids varies: – limited to arcuate nucleus and hippocampus in case of

POMC– in the areas of brain related to pain producing

pathways in case of preproenkephalins– Wider distribution in case of preprodynorphins

• ENDOMORPHINS – newly discovered endogenous opioids with atypical structures and selectivity towards μ receptors

Functions of Endogenous Opioids

• Modulation of pain perception

• Modulation of Motor activity for sustained periods – “runners high”

• Autonomic regulation

“When I’m tired, I go for a run and feel I have more energy when I’m done.”

OPIOID RECEPTORS

• μ, κ and δ; the three opioid receptors • Rhodopsin family of GPCRs• Disributed through the brain & spinal cord; and

also outside the CNS – vascular tissues, cardia, airway/lung, gut and cells of the immune system.

• IUPHAR – MOP, KOP & DOP• Opiate receptor-like protein (ORL1 or NOP) with an

endogenous ligand ‘nociceptin/orphanin(F/Q)’

OPIOID RECEPTORS (contd.)

• Upon activation of the receptors , Gi/Gs coupling occurs leading to a large no. of intracellular events:– Inhibition of adenylyl cyclase activity– Reduced opening of voltage-gated Ca2+ channels– Stimulation of K+ current through GIRKs (G protein-activated inwardly rectifying K+ channels)– Activation of PKC & PLCβ

Pharmacokinetics

Absorption

• Modestly absorbed through GI tract -oral, rectal,

• Depends on lipophilicity• High first pass metabolism• Morphine - ~25% bioavailability by oral route• Codeine & oxycodone – low FPM• Well absorbed through SC & IM routes• Nasal Insufflation – rapid rise in blood levels

Distribution

• 1/3rd of morphine is plasma protein bound• They achieve high concentrations in highly

perfused tissues – brain, liver, kidneys & spleen

• In chronic administration – this buildup can take place & opioids are found in the plasma long after their dosage has been stopped

Metabolism

• In liverMorphine morphine-6-glucuronide, morphine-3-

glucuronideThese have significant activity themselves.

• CYP3A4 & CYP2D6 are involved in biotransformation of morphine congeners like heroin, codeine, fentanyl etcEx: Increased & Decreased activity of CYP2D6

Excretion

• In kidneys,M6G & M3G are excreted by glomerular filtration.CRF can cause elevated levels of these metabolites

& lead to adverse effects – seizures, CNS depression

Pharmacodynamic effect profile of Clinically Used

Opioids

Central Nervous System effects

Analgesia• When given to patients in pain:

less intense, tolerable and they feel more comfortable with relief of distress

• When given to normal patients:frankly unpleasant with drowsiness, difficulty in mentation, lessened physical activity and apathy

Analgesia – Different pain states

• Acute nociception: activation of small high threshhold sensory afferents, Aδ & C fibres Spinothalamic tracts anterior cingulate cortex ( limbic system).

• Examples: hot plates, needle prick, incisions

Analgesia – Different pain states

• Tissue Injury:Ex: Burns,

abrasion, joint inflammation, musculoskeletal injury

Analgesia – Different pain states

• Nerve Injury:Activation of Aβ Ex: Nerve

compression, chemotherapy,

diabetes, etc

Analgesia – Mechanism

• Supraspinal Action

Analgesia – Mechanism

• Spinal Opiate Action

Analgesia - Mechanism

Peripheral Mechanism:• Basic tenet of Opiate pharmacology has been

that these drugs act centrally• Recently, in conditions of inflammation it has

been found that opioids act directly even on the peripheral terminals of small primary afferents.

Mood alterations & Rewarding properties

• Pathways – Mesocorticolimbic Dopamine system

Opiates increase DA release in the Nucleus Accumbens.

Mood alterations &

Rewarding properties

CNS depression – Respiration

• Respiratory depression: primary cause of morbidity secondary to opioid therapy.

• All phases of respiratory activity – rate, minute volume, tidal exchange; aperiodic & irregular breathing

1. Direct depression of rhythm generation in ventrolateral medulla

2. Desensitization of brainstem chemoreceptors which normally respond to rising PCO 2

3. Also desensitize the carotid & aortic chemosensors which usually respond to hypoxia.

Effect on Cough

• Direct inhibitory effect on the cough centre of medulla

• Without loss protective glottic function• There is no relation between the suppression

of cough & respiratory depression.• Centrally acting antitussives –

dextromethorphan, codeine, pholcodeine

Effect on Nausea & Emesis

• Direct stimulation of CTZ• A vestibular component is also involved• Apomorphine – a congener of morphine is

highly emetic but has no action on opioid receptors

• 5HT3 receptor antagonists are used for opioid induced nausea & vomiting

Seizure & Convulsions

Some opioids at a slightly higher doses can produce epileptogenic activity

• Meperidine• Frank seizures & myoclonus • Several mechanisms– Inhibition of inhibitory interneurons– Direct stimulatory effects– Actions mediated by non-opioid receptors by their

metabolites

Other effects

• Temperature regulation: Slight fall in body temperature– In withdrawal, there will be rise

• Miosis: Parasympathetic pathways by inhibition of GABAergic transmission– very last action to develop tolerance

• Motor tone: high doses increase the muscle tone chest wall rigidity, increased propensity to myoclonus

Peripheral effects

Neuroendocrine Effects

• Broadly Opioids block the release of many hormones of the HPA axis.

A. Adrenal & sex steroid hormones: general decrease in the release of testosterone, DHEA, cortisol and also the gonadotrophins from the pituitary– Direct effect on pituicytes & also a indirect effect

on hypothalamic neurons decreased releasing hormones

Neuroendocrine Effects

• endocrinopathies, Hypogonadotrophic hypogonadism, decreased libido, menstrual irregularities, effect on secondary sexual characteristics!

B. Prolactin: increased secretion due to loss of inhibitory control of dopamine

C. Oxytocin & Vasopressin: KOR agonists inhibit the release of both the hormones

Cardiovascular Effects

• Peripheral vasodilatation, reduced peripheral resistance and inhibition of baroreceptor reflexes – orthostatic hypotension– histamine release– Blunting of reflex vasoconstriction in response to PCO2

• Coronary Artery Disease:– Decreasing preload, inotropy and chronotropy– Decrease in O2 consumption, left ventricular end-

diastolic volume & cardiac work

Cardiovascular Effects – (contd.)

• This protective effect is partly mediated by increase in the centrally mediated vagal outflow.

• Can aggravate hypovolemic shock• Respiratory depression CO2 retention

cerebral vasodilatation increase in ICT• Can be arrhythmogenic

Effect on GI Tract

• Opioid receptors – dense distribution in the enteric plexuses

• Stomach: – delays gastric emptying– also decreases the secretion of HCl

• Intestine:– diminishes propulsive activity in both SI & LI– Intestinal secretions are reduced by inhibitpry

effects on secretomotor neurons

Effect on other smooth muscle

Ureter & Urinary Bladder• Inhibition of urinary voiding reflex• Increase in the tone of external sphincter increase in

the volume of the bladder Uterus• Restores the tone of hyperactive bladder secondary to

oxytocicsBiliary Tract• Sphincter of Oddi contracts – hence some pts with biliary

colic will experience more pain when morphine is given

Effect on Immune system

• Opioid receptors are present on different cells of the immune system like neutrophils, natural killer cells – direct modulation of their function

• Suppression of HPA axis• In toto, the appear to suppress the immune

function, but in the presence of pain syndromes they appear to improve immunity!!

Clinical Pharmacology

Classification

• Receptor AffinityA. Opioid Agonists: Morphine, Codeine,

Meperidine, Fentanyl, Methadone, TramadolB. Opioid Agonist/Antagonist & Partial Agonist:

Pentazocine, Nalbuphine, Butorphanol, Buprenorphine

C. Opioid Antagoinists: Nalorphine, Naloxone, Naltrexone, Naltrindole, Nalmefene,

Pethidine (Meperidine)

• Potent MOR agonist• Used in post op pain, chronic pain of severe

degree & post anesthetic shivering• Its metabolite normeperidine is epileptogenic• It can block neuronal uptake of 5HT3 – can

cause serotonin syndrome if used with MAO inhibitors & SSRIs

• Concurrent use of Antihistaminics & TCAs can cause additive CNS depression

Levorphanol

• Morphinian series• Agonist at MOR, DOR & KOR• T1/2 – 12 hours• Action & uses similar to morphine.

Loperamide & Diphenoxylate

• Piperidine derivatives• Approved for treatment of diarrhoeas• It slows GI motility • Also may act by decreasing secretions• Loperamide has very less central effects

because of the activity of P-glycoprotein• Diphenoxylate is available in FDC with

atropine

Fentanyl & Its Congeners

• Fentanyl, Alfentanil, Sufentanil & remifentanil• They are used as anesthetic adjuvants and

inducing agents• Short ‘time to peak’ analgesic effect• Rapid termination of effect if used in bolus • MAC-sparing effect on gaseous anesthetics• Can cause muscle rigidity• But very minimal effect on myocardial

parameters

Fentanyl & Its Congeners

• Uses:– Inducing agents especially in cardiovascular

operations – high dose fentanyl & sufentanil– Short procedures – remifentanil– Chronic analgesia – epidural– Cancer pain – transdermal patches

Methadone

• Long acting MOR agonist• Racemic mixture – L isomer is more potent• Similar to morphine but enhanced duration• Can cause prolongation of QT interval –series

cardiac arrhythmias

Propoxyphene: Similar to methadone

Tramadol

• Synthetic codeine analogue• Weak MOR agonist• Used in the treatment of mild to moderate

pain• Epileptogenic

Tapentadol

Pentazocine

• KOR agonist and a weak antagonist/partial agonist at MOR receptors

• Effects similar to morphine – analgesia, sedation, respiratory depression.

• At high doses – dysphoric & psychotomimetic effects

• Tachycardia & increase in BP• Can precipitate withdrawal in morphine

dependant patients

Nalbuphine

• KOR agonist with competitive antagonistic activity at MOR

• Analgesia is similar• Respiratory depression

exhibits ceiling effect – so relatively safe drug

Butorphanol

• Morphinian compound• Similar to Nalbuphine

Buprenorphine

• Highly lipophilic partial agonist at MOR• 20-50 times more affinity to MOR than

morphine• Used in analgesia & management of Opioid

dependence

Opioid Antagonists

• Nalorphine, • Naloxone, • Naltrexone, • Naltrindole, • Nalmefene

They have very little effect if given alone. They produce their effects only when given with agonists or in some cases the endogenous opioid system is activated

Opioid Antagonists

Effect in the absence of Agonists• Mild hyperalgesia• Reverse the hypotension associated with

different forms of shock to some extent• Mild dysphoria• Neuroendocrine effects

Opioid Antagonists

Effect in the presence of Agonists• Effect on Acute opioid actions:– Increase in respiratory rate & depth– Reversal of dysphoric & psychotomimetic effects– Overshoot phenomenon– Rebound release of catecholamines tachycardia,

hypertension, ventricular arrhythmias

Opioid Antagonists

Effect in the presence of Agonists• Effect on Opioid dependant patients:– Moderate to severe withdrawal – Depends on the dose of the antagonist and also

on the degree and duration of dependence– Methylnaltrexone & Alvimopan can reverse the GI

effects of opioid dependence without pptting central withdrawal syndrome.

Opioid Antagonists - Uses

• Acute toxicity /overdosage• Management of constipation• Management of abuse syndromes• Trauma – shock, stroke, brain trauma

Centrally acting antitussives

• Codeine, hydrocodone & oxycodone• Dextromethorphan:– Analog of codeine– Elevates the threshold of – Fewer subjective & GI side effects

• Pentoxyverine & Caramiphen

Therapeutic Uses of OPIOIDS

Analgesia• Most potent pain-relieving drugs available• Adequate pain relief• Many guidelines are available – WHO,

American pain Society, Federation of State medical board

Therapeutic Uses – Routes of administration

1. Patient controlled analgesia2. Spinal Delivery3. Local drug action4. Rectal administration5. Inhalation6. Oral transmucosal administration7. Transnasal Administration8. Transdermal & Iontophoretic Administration

Therapeutic Uses – Other uses

• Dyspnoea- Acute LVF & Acute Pulmonary edema– Pink puffers

• Cough• Diarrhoea• Shivering• Anaesthetic adjuvants

Contraindications & Cautions

• Use of pure agonists with weak partial agonists

• Use in patients with head injuries• Use in pregnancy• Use in impaired pulmonary reserve• Use in patients with impaired hepatic &/or

renal function• Use in patients with endocrine disease

Toxicity, Tolerence & Dependence

Tolerance

• When large doses are given at short intervals• Analgesia, sedation & respiratory depression

are the commonest effects to develop tolerance• Respiratory depression 60mg & 200mg• Tolerance does not develop to miotic,

convulsant & constipatory effects• Cross tolerance – partial & incomplete opioid

rotation

PhysicalDependence

• Dependence refers to a state of adaptation manifested by receptor/drug class-specific withdrawal syndrome produced by cessation of drug exposure.

• Signs & symptoms – rhinorrhoea, yawning, chills, piloerection, hyperventilation, hyperthermia, diarrhoea, hostility & anxiety

• Antagonist precipitated withdrawal

Psyschological Dependence

• Reason for opioid abuse:– Euphoria, indifference to stimuli, sedation, abdominal

experiences similar to intense orgasm– Reinforced by physical dependance

• Therapy:– Methadone– Clonidine– Transcutaneous electrical stimulation– Buprenorphine– Naltrexone

Toxicity & Overdosage

• Clinical overdosage, accidental overdosage or suicidal

• Signs & symptoms: – Triad of coma, pinpont pupils & depressed

respiration– Anuria, frank convulsions in children– Noncardiogenic pulmonary edema

Treatment of Opioid toxicity & Overdosage

• Ventilatory support• DOC – IV Naloxone 0.01mg/kg• Treatment should be such that reversal should

occur without precipitation of withdrawal• If the poisoning is due to methadone the pts

may slip back into coma as antagonist have short half lives

Screening Methods

Acute pain• MODELS USING THERMAL STIMULUS1. Hot plate method2. Tail –Flick method• MODELS USING ELECTRICAL STIMULUS1. Tooth pulp test2. Monkey shock titration test• MODELS USING CHEMICAL STIMULUS1. Formalin test2. Writhing test3. Rat sigmoid colon model4. Inflammatory uterine pain model

• MODELS USING MECHANICAL STIMULUS1. Haffner’s tail clip method2. Randall Selitto test_______________________________________ Chronic pain3. Neuropathic pain models4. Vincristine-induced Neuropathy model5. Diabetic neuropathy model6. Persistent postthoracotomy pain model7. Rat model of incisional pain

Cancer pain• Rat model of bone cancer pain

_____________________________________

In Vitro Methods1. 3H-Naloxone binding assay2. µ Opiate receptor binding assay3. Assay to study cannabinoids activity

References

1. Essentials of Medical Pharmacological, K D. Tripathi, 6th ed2. Pharmacology and Pharmacotherapeutics, R S. Satoskar, S

D. Bhandarkar, Nirmala N. Rege, 21st ed.3. Goodman & Gilman’s The Pharmacological Basis of

Therapeutics, 12th ed4. Rang & Dale’s Pharmacology 6th ed,5. Basic & Clinical Pharmacology, Katzung’s, 11th ed.6. Principles of Pharmacology: The Pathophysiologic Basis of

Drug Therapy, Golan, LippinCott’s7. Harrison’s Principles of Internal Medicine, 17th ed.

References

8. Anatomy of a scientific Discovery, Jeff Goldberg, Bantam Books.

Thank you!

“Religion is the opium of the masses.” – Karl Marx

Mechanisms of tolerance

• Receptor disposition• Adaptation of intracellular signalling

mechanisms in the opioid receptor bearing neurons

• System level counteradaptation• Fractional occupancy requirements

Structure Activity Relationship

• Message – Address concept• Message: a protonated nitrogen, a phenolic

ring, a hydrophobic domain.