Pharmacology – II [PHL 322]

Opioids Analgesics

Dr. Mohd Nazam Ansari

What is Misuse?• Misuse = “Non-medical use” or any use that is outside of

a medically prescribed regimen

• Examples can include:

• Taking for psychoactive “high” effects

• Taking in extreme doses

• Mixing pills

• Using with alcohol or other illicit substances

• Obtaining from non-medical sources

Commonly Misused Rx Drugs

Classified in 3 classes• CNS Stimulants: ADHD, weight loss

- E.g. Ritalin,

• CNS Depressants (Sedatives - Hypnotics): treat anxiety and sleep disorders

- E.g. Xanax, Ativan, Valium,

• Opiates: pain-killers-E.g. Morphine, Codeine

What are opioids? • Opioids are the most powerful analgesics available

• Opiates: are the alkaloids found in opium, a white liquid extract of unripe seeds of the poppy plant (e.g. morphine and codeine).

• Opioids: are derivatives of opiates, any compound that binds to opiate receptors in the CNS or GIT.

1. Endogenous opioid peptides produced in the body (endorphins, dynorphins, enkephalins)

2. Semi-synthetic opioids (heroin, oxycodone, hydrocodone)

3. Fully synthetic opioids (Demerol, methadone, fentanyl, tramadol)

• Oral, transdermal and intravenous formulations

Effects of Opioids• Desired action is analgesia• Unwanted actions on both CNS and PNS:

• Analgesic tolerance• Physical dependence• Respiratory depression

- Main cause of death from opioid overdose- Combination of opioids and alcohol is especially dangerous

• Nausea, vomiting, sedation, euphoria, dysphoria• Acute urine retention• Constipation (inhibition of GIT motility and decreasing biliary and

pancreatic secretions to cause indigestion)• Suppression of cough by direct inhibition of cough center.• Pupil constriction (meiosis)• Slurred speech • Impaired attention/memory • Seizures• Slowed heart rate

Opioid Receptors• Receptors located throughout body, all opioid receptors belongs to a

group of G-protein coupled receptors • Receptor types

• Mu (µ), delta (δ), kappa (κ), Sigma (σ)• Mu: receptors produce the most profound analgesia, and can cause

euphoria, respiratory depression, physical dependence and bradycardia.

• Kappa: receptors trigger a lesser analgesic response, and may cause meiosis, sedation and dysphoria.

• Delta: receptors modulate mu receptor activity. • Sigma: receptors provide little to no analgesia.• Some investigators classify sigma receptors as phencyclidine, rather

than opioid, receptors.

• Side effects: constipation, sedation, itch, mental status changes

2nd messenger systems

G-proteins G-protein

Opioids have been proposed to inhibit neurotransmitter release by inhibiting calcium entry, by enhancing outward movement of potassium ions, or by inhibiting adenylate cyclase (AC), the enzyme which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).

Opioids or narcotic analgesics: classified based on their pharmacology action at various receptor subtypes:• Pure agonists (bind and stimulate receptors),

e.g. morphine, methadone, fentanyl

• Pure antagonists (bind and block or inhibit activity), e.g. naltrexone

• Partial agonists (bind and stimulate, but with less than full activity at certain receptor subtypes), e.g. Buprenex (buprenorphine) – does produce some analgesic effects, but does not depress respiration as much…a good thing

• Mixed agonist/antagonists (stimulating some receptors while blocking others).e.g. Talwin (pentazocine) which is a weak, less efficacious analgesic (agonist at kappa, blocks mu)

Classification

Endogenous Opioids• Produced naturally in body

• Naturally increased when one feels pain or experiences pleasure

• Act on opioid receptors

• Produce euphoria and pain relief

• Examples: endorphins, enkephalins, dynorphins, endomorphins

Morphine• A pure opioid agonist• The most potent & efficacious analgesic we have today still• Routes: oral, IM, IV, rectal (avoids nausea/ vomiting)• Sustained release preparations:

• MS Contin, Oramorph, Kadian, Avinza

Pharmacological effects:• Analgesia • Relaxation • Calm euphoria • Sedation • Reduced cough reflex• Respiratory depression• Meiosis

Codeine• A most commonly prescribed opioid analgesic in the world (often

combined with aspirin or acetaminophen)

• Low potency

• Pain relief via 10% conversion to morphine

• Note: some SSRIs will block the conversion of codeine to morphine via liver enzyme inhibition, and will block/lessen the analgesic effects of codeine

Semi-synthetic Opioids• Hydrocodone with Tylenol: Norco, Lortab, Vicodin, Lorcet • Hydrocodone with ibuprofen: Vicoprofen• Hydromorphone: Dilaudid • Oxycodone with Tylenol: Percocet • Oxycodone with aspirin: Percodan • OxyContin

Heroin• x3 more potent than morphine• Intense “rush” esp. if smoked or used IV• Legal for clinical use outside USA, not inside USA• When used along with free-base cocaine (“crack”) ---

increased euphoria, decreased anxiety & paranoia,

Dilaudid (hydromorphone), Numorphan (oxymorphone)

• x6-10 more potent than morphine• Slightly less sedating, about same degree of respiratory

depression

OxyContin• Used to treat pain associated with arthritis, lower back

injuries, and cancer

• Most commonly in tablet form: 10mg, 20mg, 40mg, 60mg, and 80mg

• Dose: every 12 hours, half-life 4.5 hours

• Abuse: may be chewed, crushed, snorted or injected

Synthetic Opioids

• Methadone

• Demerol (meperidine)

• Fentanyl

Partial Agonists• Buprenorphine

• Tramadol

Methadone• Synthetic opioid agonist

• Analgesic, CNS depressant

• Effects last 24 hours; once-daily dosing maintains constant blood level

• Prevents withdrawal, reduces craving and use

• Facilitates rehabilitation

• Clinic dispensing limits availability

Buprenorphine for Opioid Dependence

• FDA approved 2002, age 16+• Mechanism: partial opioid agonist• Analgesic properties• Ceiling effect • Lower abuse potential • Safer in overdose

Formulations• Sublingual administration

• Subutex (Buprenorphine)• Suboxone (4:1 Bup:naloxone)

• Dose: 2mg-32mg/day • Once-daily dosing

Opioid Withdrawal• Dysphoric mood• Nausea or vomiting• Diarrhea• Tearing or runny nose• Dilated pupils• Muscle aches• Goosebumps• Sweating• Yawning• Fever• Insomnia

Opioid Detoxification • Medications used to alleviate withdrawal symptoms:

- Opioid agonists (methadone, buprenorphine)

- Clonidine

- Other supportive medications

- Anti-diarrheals,

- Anti-nausea agents,

- Ibuprofen,

- Muscle relaxants,

- Anti-anxiety medications

Thanking you