OPIOIDS GROUP 10

(Cranfield University)

RUELLA D’COSTASWAROOP JOHNSON

TEJASHREE BANETANISHA GHORPADE

VARSHA GHASE

CONTENTS

1. Introduction2. Opioid Receptors3. Agonists4. Antagonists5. Addiction and its treatment6. Recent Advances7. Conclusion

INTRODUCTIONNatural and semi synthetic derivatives of opium poppy, as well as similar synthetic compounds that have an analgesic or pain relieving properties because of their effect on the CNS

SOURCE : Opium poppy plant

CONSTITUENTS:

MorphineCodeineThebainePapaverineNoscapine

HISTORY OF OPIOIDS

Used as early as 1500 BC

Poppy extensively grown in Egyptian, Roman , Chinese civilizations

Biggest opium market was the British market

Used for years to produce - sedation - Analgesia - Euphoria - Relief from diarrhea - Cough suppression

CHEMISTRY

Morphine• Pentacyclic Alkaloid • Oxygen bridge at 4 and 5 position• Three major rings ( a, b , c)• Phenolic gropus ( s/a hydroxyl, Alcoholic, OH) at position 3

and 6 • Nitrogen at position 16 • Changes at the 3 and 6 position change the potency of drug

OPIOID RECEPTORSOpioid receptors are a group of G protein coupled receptors with opiods as ligands

The opioid receptors are ~40% identical to somatostatin receptors (SSTRs)

Endogenous peptides which bind opiod receptors:-Endorphins-Enkephalins-Dynorphins

Discovery: The receptors were first identified as specific molecules through

the use of binding studies in which opiates that had been labelled with radioisotopes were found to bind to brain membrane homogenates

RECEPTOR SUBTYPESReceptor Subtypes Location Functions

Delta (δ) δ1, δ2• Brain • Analgesia

• Physical dependence

Kappa (κ) κ1, κ2, κ3• Brain• Spinal cord

• Spinal analgesia• Sedation• Miosis

Mu (μ) μ1, μ2, μ3• Brain• Spinal cord• Intestinal tract

• Supraspinal Analgesia• Respiratory depression

Nociceptin receptor

ORL1• Brain• Spinal Cord

• Anxiety• Depression• Appetite

• Morphine was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is m, thus turning the m to μ.

• Ketocyclazocine was first shown to attach itself to kappa receptors

• Delta receptor was named after the mouse vas deferens tissue in which the receptor was first characterised

• Nociceptin receptor was later identified and cloned based on homology with the cDNA. is known as the or ORL 1 receptor.

ADDITIONAL RECEPTORS

• Sigma receptors (σ) were once considered to be opioid receptors due to the

antitussive actions

• Zeta (ζ) opioid receptor has shown to be a cellular growth factor modulator

• Epsilon (ε) opioid receptor produces strong analgesia and release of met-enkephalin

PHARMACOKINETICSABSORTION DISTRIBUTION BIOTRANSFOR-

MATIONEXCRETION

Orally effective within 10mins

Transdermally possible due to low mol wt n highly lipid soluble

I.M injection effective within 20-60mins

I.V route administered by trained practioner

Half live is generally rapid (5 - 20 mins)

Lower lipid solubility and crosses the BBB more slowly hence onset and duration of action are prolonged

Mainly involves the liver

High hepatic extraction fraction ratio hence the clearance of is dependant on hepatic blood flow

Morphine is conjugated with glucuronic acid forming active metabolites

Primarily excreted by the kidneys in the urine

Metabolites of morphine are eliminated by the kidneys with less than 10% excreted within the bile

PHARMACODYNAMICSCENTRAL NERVOUS SYSTEM Stimulation of the medullary

chemotrigger zone (CTZ) with nausea and vomiting

Potential for physical dependance with repeated doses of opiods

CARDIOVASCULAR SYSTEM High doses result in Bradycardia Increased heart rate Myocardial Depression Vasodilation

RESIPIRATORY SYSTEM Depress ventilatory function Decreased respiratory ventilatory

response Increased apneic threshold Decreased hypoxic drive

GASTOINTESTINAL Delay gastric emptying Induced contraction of the sphincter

ENDOCRINE Blocks the release of stress

hormones elevated during surgery (catecholamines, ADH, and cortisol)

DRUG INTERACTIONS

• Opiods with MAO inhibitors may result in:-respiratory arrest-hypertension-hypotension-coma-hyperpyrexia

• Opiods with benzodiazepines, barbiturates, and other CNS depressants can cause synergistic cvs, resp, and sedative effects

CLASSIFICATION OF OPIOIDS

BASED ON SOURCES

• NATURAL Phenanthrene - Morphine ( 10%) - Codeine ( 0.5 %) - Thebaine ( 0.2%)

• SEMI SYNTHETIC - Heroin - Oxymorphone - Hydromorphone

• SYNTHETIC - Meperidine - Methadone - Morphinians - Benzamorphans

BASED ON RECEPTORS

PURE AGONISTS - Morphine - Codeine - Meperidine - Fentanyl

AGONIST – ANTAGONISTS - Nalbuphine - Butorphanol

PURE ANTAGONISTS - Nalaxone - Naltrexone

PARTIAL AGONISTS - Pentazocine

MECHANISM OF ACTION

• Pure opioid agonists bind to opioid receptors avidly and demonstrate high intrinsic activity at the cellular level.

• Partial opioid agonists bind to opioid receptors but produce a sub-maximal effect compared to pure agonists.

PHARMACOLOGICAL EFFECTS OF OPIOID AGONISTS

CNS EFFECTS

• Analgesia – alters perception of pain and patients reaction to pain• Dysphoria/euphoria – floating sensation, free from anxiety• Inhibition of cough reflex – useful as antitussive• Miosis (except meperidine causes mydriasis)• Physical dependence• Respiratory Depression – often dose-limiting factor• Sedation – causes drowsiness and impairs thinking

CVS EFFECTS

• myocardial oxygen demand• vasodilation & hypotension

GI/BILIARY EFFECTS

• Constipation – due to decreased motility and decreased HCl secretion

• Increased biliary sphincter tone & pressure – caution in patients with gall stones

• Nausea and vomiting (via stimulation of CTZ)

GENITOURINARY EFFECTS

• Increased bladder sphincter tone

• Prolongation of labor

• Urinary retention

NEUROENDOCRINE SYSTEM EFFECTS

• Inhibition of release of LH & FSH – decreases ovarian and testicular function

• Stimulation of release of ADH and prolactin

IMMUNE SYSTEM EFFECTS

Suppression of function of natural killer cells

DERMAL EFFECTS

• Flushing

• Pruritis

• Urticaria (hives) or other rash

OPIOID ANTAGONIST• An opioid antagonist is an receptor antagonist that acts on opioid

receptors

• Naloxone and naltrexone are competitive antagonists that bind to the opioid receptors with higher affinity than agonists but do not activate the receptors.

• Weak opioid partial agonist:Nalorphine and Levallorphan

• Naloxone is used for treating opioid overdose

• Naltrexone is the only treatment which can reverse the long-term after effects of opioid addiction, which otherwise tends to produce depression and anxiety that may lead to eventual relapse

SELECTIVE ANTAGONISTS

• Cyprodime is a selective µ opioid receptor antagonist

• Naltrindole is a selective δ opioid receptor antagonist

• Norbinaltorphimine is a selective Κ opioid receptor antagonist

PURE OPIOID ANTAGONISTS

• Naloxone (Narcan)– used parenterally only, T ½ about 1

hour

• Naltrexone (Revia)– Orally effective, longer acting

• Nalmefene (Revex)– Long acting injectable form

NALOXONE

• no analgesic activity at all

• competitive antagonist at mu, kappa, and sigma receptor

• displaces morphine and other OPIOID from receptor site

• reverses all actions of the OPIOID and does it rather quickly

• it will precipitate withdrawal

• person on heroin, then naloxone will precipitate withdrawal,

• naloxone effects are seen in the first five minutes and it only lasts for 30 minutes

• increased blood pressure

• metabolized same as morphine through glucuronic acid and excreted through kidney

NALTREXONE• Same effect of naloxone except it is used orally so can't use it if for person with acute toxicity

• Long duration of activity

• Single dose block action of heroin effects for 24 hours

• Used for emergency treatment

• Once stabilized, give patient naltrexone

• Patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement)

• Approved for use by the FDA USES:- (a) Treatment of alcoholism (b) Treat opioid overdose toxicity (c) Reverse opioid-induced anesthesia (d)Adjuncts in drugs abuse programs

PARTIAL AGONISTS AND MIXED AGONIST-ANTAGONISTS

• Compounds structurally related to morphine

• Developed to reduce addiction potential while retaining analgesic properties

• Used for moderate pain, anesthetic premed, supplement to surgical anesthesia

• Characterized by binding activity at multiple opioid receptors and differential effects at each site

• Analgesia generally related to agonistic activity at κ receptors and to a lesser extent µ receptors

PARTIAL AGONISTS AND MIXED AGONIST-ANTAGONISTS

• Differ from morphine – Can produce excitability and hallucinogenic effects (κ

receptor effects)– Lower degree of physical dependence potential– Can ppt withdrawal in morphine dependence (partial

agonists at µ receptors)– Increase some SNS activity to produce positive inotropic

effects

DRUG µ receptor Κ receptor

pentazocine partial agonist agonist

butorphanol partial agonist agonist

buprenorphine partial agonist antagonist

nalbuphine partial agonist agonist

ACTIONS OF PARTIAL AGONIST, AGONIST – ANTAGONISTS AT OPIOID

RECEPTORS

ADDICTION -Weak personality or a chronic brain disease?

1. SUBSTANCE DEPENDENCE (psychological) - behavioral syndrome; compulsivedrug-seeking behavior

2. PHYSICAL DEPENDENCE - defined by abstinence syndrome (withdrawal)

3. SUBSTANCE ABUSE: Use of any drug in a manner that deviates from approvedmedical or social patterns within a given culture

4. DRUG ADDICTION:

“…is a primary, chronic,neurobiologic disease, with genetic psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviours that include one or more of the following; impaired control over drug use, compulsive use, continued use despite harm, and craving.” (American Academy of Pain Medicine)

WHAT DOES IT FEEL LIKE? "I was stared at, hooted at, grinned at, chattered at, by monkeys, by

paroquets, by cockatoos. I ran into pagodas, and was fixed, for centuries, at the summit, or in secret rooms: I was the idol; I was the priest; I was worshipped; I was sacrificed. I fled from the wrath of Brama through all the forests of Asia: Vishnu hated me; Seva laid wait for me. I came suddenly upon Isis and Osiris: I had done a deed, they said, which the ibis and the crocodile trembled at. I was buried for a thousand years, in stone coffins, with mummies and sphinxes, in narrow chambers at the heart of eternal pyramids. I was kissed, with cancerous kisses, by crocodiles; and laid, confounded with all unuttemble slimy things, amongst reeds and Nilotic mud.“

Thomas de Quincey(1785 - 1859)

Confessions of an English Opium-Eater

TREATMENT ALGORITHM

TREATMENT APPROACHES There are two medical approaches to treatment, i.e.

maintenance treatment and medically supervised withdrawal (detoxification)

Other psychosocial approaches, mutual help programme’s and the 12-step programs are used in combination with pharmacotherapy to treat addiction to heroin and other opioids

The maintenance treatment with buprenorphine, methadone or LAAM for opioid addiction has three phases induction, stabilization, and maintenance

According to federal regulations, during induction methadone should initially be given under daily observation for either 6 or 7 days per week

TREATMENT OF OPIATE ADDICTION Long acting opiate agonists (e.g. Methadone) and long acting

benzodiazepines (e.g. diazepam or chlordiazepoxide) used in opiate dependence, were found to be better than short acting drugs or preparations

Psychosocial interventions may be provided in combination with pharmacological intervention for polydrug (more than one drug) and alcohol abusers. There is evidence that the

methadone maintenance is more effective if psychosocial interventions and family support are provided

Methadone or buprenorphine have been found effective as maintenance treatment, at optimal doses. Injectable opioid treatment is used in patients who fail oral treatment.

DETOXIFICATION

Detoxification treatment normally lasts for 28 days as inpatient and upto 12 weeks as outpatient, and has been thought of as a safe and effective treatment minimizing withdrawal symptoms, in dependent opiate users

During detoxification psychosocial support is provided and a whole programme for it is in place

Methadone and Buprenorphine are used normally as part of detoxification. Following stabilization, doses can be reduced at the rate of 5mg every one or two weeks for methadone, resulting in zero in about 12 weeks, whereas for buprenorphine, doses are reduced initially at 2mg every 2 weeks or so, with final reductions amounting to 400mcg

TREATMENT OF OPIATE ADDICTION

Patients (including young people) who have decided against detoxifying using methadone or buprenorphine can opt for Lofexidine (NICE,2007b). The treatment lasts for 7-10 days starting at 800mcg daily and going to a maximum of 2.4mg in divided dose

Naltrexone is an opioid antagonist which, when taken regularly, can prevent relapse. With a usual maintenance dose of 50mg , it has been found to be effective in enabling patients maintain abstinence following detoxification

REFERENCES

1. Comparision In The treatment used to tackle drug abuse in US, Uk and Singapore, Swaroop Johnson, 2008

2. Essentials of Medical Pharmacology, K.D. Tripathi, 5th edition, Jaypee Publishers, 2003

3. Treatment Approaches for Drug Addiction, National Institute Of Drug Abuse, June 2008