Upload
dhriti-brahma
View
12.394
Download
3
Tags:
Embed Size (px)
DESCRIPTION
Undergraduate MBBS level theory class power point presentation
Citation preview
Opioid AnalgesicsDepartment of
Pharmacology, NEIGRIHMS
Opioid Analgesics (against algesia) – some important
terms• Analgesics: Are the Drugs which selectively relieves pain by
acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness – Opioids and NSAIDS
• Opioids: Any drug which binds to the opioid receptors (Pharmacologically related) in the CNS and antagonized by Naloxone . They may be – Natural, Synthetic and semi-synthetic
• Opiates: Drugs derived from opium – Natural or semi-synthetic
• Narcotics: Drugs derived from opium or opium like compounds, with potent analgesic effects associated with significant alteration of mood and behavior, and with the potential for dependence and tolerance following repeated administration.
Types of Pain
Types of Pain – contd.
Types of Pain – contd.
Opioids - Opium• A dark brown, resinous material
obtained from poppy (Papaver somniferum) Capsules.
OPIUM
PHENANTHRENE•Morphine 9-14%•Codeine 0.5-2%•Thebaine 0.2-1%
BENZYLISOQUINOLINE•Papaverine 0.8-1%•Noscapine 3-10%•Narcine 0.2-0.4%
Poppy Plant - image
Poppy to Opioids
Opium - History• Friedrich Wilhelm Serturner
– A German Pharmacist– Isolated Morphine in 1803 and named
it after the Greek god of Dreams “MORPHEUS”
MORPHINE (Pharmacological actions) - CNS
• Analgesia:• Strong analgesic• Visceral pain is relieved better than somatic
pain• Degree of analgesia increases with dose• Nociceptive pain is better relieved than
Neuretic pain• Associated reactions to pain are also relieved
– apprehension, fear and autonomic effects• Tolerance to pain is better
MORPHINE – Analgesia action
• Two components – spinal and supraspinal
• Inhibits release of excitatory transmitters from primary afferents – at Substantia gelatinosa of dorsal horn
• Exerted through Interneurones – gating of pain• At supraspinal level in cortex, meidbrain and
medulla - alter processing and interpretation and send inhibitory impulses through descending pthway
D
E
Morphine - The Gate Theory
Pharmacological actions of Morphine (CNS) –
contd.• Sedation:
– Drowsiness and indifference to surroundings– Inability to concentrate and extravagant imagination –
colorful day dream– Apparent excitement– Larger doses produce sleep – EEG resembles normal sleep
• Mood effects:– In Normal persons calming effect, mental clouding, feeling
of detachment, lack of initiative etc. - unpleasant in absence of pain
– Sometimes DYSHORIA– But in persons with pain & addicts sense of wellbeing,
pleasurable floating feelings – kick– EUPHORIA
Pharmacological actions of Morphine (CNS) –
contd.• Depression:
1. Respiratory centre depression – Both rate and depth of respiration are diminished• Dangerous in Head
injury and asthmatics2. Cough Centre –
Depressed3. Temperature regulating
centre – depressed4. Vasomotor centre – high
doses cause fall in BP
• Stimulation:1. CTZ – sensitize CTZ to
vestibular and other impulses
2. Edinger Westphal Nucleus – miosis
3. Vagal centre – Bradycardia
4. Hippocampal cells – convulsions (inhibition of GABA release)
Morphine - Effects
Pharmacological actions of Morphine –
contd.• Neuro-endocrine:
• GnRH and CRH are inhibited – FSH, LH and ACTH levels are lowered – only short term – tolerance develops
• Decrease in levels of Sex hormone and corticosteroids, but no infertility
• Increases ADH release – oliguria• CVS: NO DIRECT EFFECT ON HEART
• Vasodilatation – histamine release, depression of vasomotor centre and directly on blood vessels decreasing the tone
• Cardiac work reduction due to consistent vasodilatation
Pharmacological actions of Morphine –
contd.• GIT: CONSTIPATION
• Due to direct action on intestine reducing propulsive movement, spasm of sphincters, decrease in all GIT secretions
• Smooth Muscles:• Billiary Tract: Billiary colic – closure of sph. Of
Oddi• Bladder: Urinary urgency but difficulty• Bronchi - Bronchospasm
Morphine - Pharmacokinetics
• Absorption and Distribution:• Variable orally (usually not given orally – 1st pass metabolism,
given IM or IV)• Widely distributed – liver, spleen, kidney etc.• Enters Brain slowly• Readily crosses placental barrier – dependence in fetus
• Metaboloism:• In Liver by glucoronidation – water soluble metabolites • Morphine-6- Glucoronide – analgesic – in renal failure prolong
analgesia• Morphine-3-glucoronide – No analgesia – neuroexcitatory
• Excretion: • Via Urine, Plasma t1/2 = 2-3 Hrs• Action lasts for 4-6 Hrs• Completely eliminated in 24 Hrs
• Preparation: 10, 15, and 20 mg. (IV: 2 – 10 mg)
Morphine - Pharmacokinetics
Morphine – Adverse Effects
1. Respiratory Depression: Infant and Old2. Vomiting3. Sedation, Mental Clouding – sometimes dysphoria4. Hypotensive effect5. Rise in Intracranial Pressure6. Apnoea: Newborn7. Urinary retention8. Idiosyncrasy and allergy9. Acute Morphine Poisoning: occurs if >50 mg (Lethal dose –
250 mg), Gastric lavage with KMNO4, Specific antidote: Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up
10. Tolerance and dependence
Morphine – Therapeutic uses
• Analgesic:1. Long Bone Fracture2. Myocardial Infarction3. Terminal stages of cancer4. Burn patients5. Postoperative patients6. Visceral pains – pulmonary embolism, pleurisy,
acute pericarditis7. Biliary colic and renal colic8. Obstetric analgesia9. Segmental analgesia
Morphine – Other Therapeutic uses
• Preanaesthetic Medication• Balanced anaesthesia and surgical
analgesia• Acute Left ventricular failure – Cardiac
asthma• Cough – not used but Codeine is used• Diarrhoea – colostomy - Loperamide,
Diphenoxylate
Morphine - Contraindications
1. Two Extremes of Age2. Bronchial asthma 3. Respiratory insufficiency - empysema4. Head Injury5. Shock – Hypotension6. Undiagnosed acute abdomen7. BHP8. Renal Failure, Liver diseases and hypothyrodism9. Unstable personalities
Opioids - Classification1. Natural Opium Alkaloids: Morphine and Codeine2. Semi-synthetic: Diacetylmorphine (Heroin) and
Pholcodeine3. Synthetic Opioids:
• Phenylpiperidines: • Pethidine (Mepiridine) and its congeners –
Diphenoxylate and Loperamide• Fentanyl and its congeners – sufentanil, remifentanil
and alfentanil• Phenyl-heptylmines: Methadone and congeners like
Propoxyphene and Dextropropoxyphene• Benzomorphans: Pentazocine• Morphinan compounds and congeners: Levorphanol and
Butorphanol
Pethidine • Morphine Vs Pethidine:
– 1/10th as potent as Morphine, but Efficacy is similar– Produces as much sedation, euphoria and
respiratory depression in equianalgesic dose and similar abuse potential
– Less spasmodic action in smooth muscles – less miosis, constipation and urinary retention
– Rapid but short duration of action (2-3 Hrs)– Vagolytic effect - Tachycardia– Devoid of antitussive action– Less histamine release – safer in asthmatics– Better oral absorption
Pethidine – contd.• Pharmacokinetics
– Well absorbed orally, bioavailability 50%– Effects appear in 10-15 min. after oral
absorption– On parenteral administration action lasts
for 2-3 Hrs– Metabolized in liver – mepiridinic acid and
norpethidine– Norpethidine accumulates on chronic use– Excreted in urine
Pethidine – contd.• Adverse Effects:
• Similar to Morphine• Atropine like effects – dry mouth, blurred vision,
tachycardia• Overdose – tremors, mydriasis, delirium and
convulsion due to norpethidine accumulation• Uses:
• Analgesic as substitute of Morphine• Preanaesthetic medication• As analgesic during labor – less fetal respiratory
depression• Dose 50-100 mg IM/SC, oral – 50-100 mg tabs.
Methadone• Chemically dissimilar but similar in most of pharmacological
actions – analgesic, respiratory depression etc.• High action orally as well as parenterally• Single dose effect is – same with Morphine including duration
of action• Cumulation – on repeated administration (t1/2 24-36 Hrs)• Highly bound to plasma protein 80 to 90%• Metabolized in liver by – demethylation and cyclization• Excreted in urine• Slow action and less subjective effect – abuse potential is low• Used as substitution therapy as opioid dependence: 1:4mg
and 1:20 mg of Morphine and Pethidine respectively• Codeine is used as substitution in Methadone addiction
Tramadol• Centrally acting analgesic• Very low action on opioid receptors • Other mechanisms involved in analgesic action – 5-HT
and NA reuptake inhibition – spinal inhibition of pain• Effective both orally and IV (100mg = 10 mg Morphine)• Side effects are similar to Morphine but less prominent• Well tolerated and low abuse potential• Only Partially reversed by Naloxone• Used in chronic neuropathic pain and short diagnostic
procedures• Dose: 50-100 mg IM/IV/Oral (Contramol)
Opioid Receptors• Mainly 3 (three) types of receptors – μ (mu), κ (kappa)
and δ (delta)• Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2 • Location: Peripheral Nerve endings, SG in spinal chord,
Periaqueductal gray (PAG) in midbrain and Brain stem (medulla, hypothalumus and also amygdala
• Opioids are – agonists, partial agonist or competitive antagonists of these receptors
• Overall effect depends on nature of interaction and affinity to these
• Morphine is agonist of all but affinity is higher for mu
μ receptor κ receptor δ receptorLocation μ1 – supraspinal
μ2 - spinalκ1 – spinalκ3 -supraspinal
Spinalsupraspinal
Effects AnalgesiaRespiratory depressionSedationEuphoriaMiosisPhysical dependenceLoss of GI motility
Spinal analgesiaDysphoriaSedationPsychomimeticPhysical dependence (nalorphine type)
Spinal analgesiaAffective behaviour (Supraspinal) Respiratory depressionReduced GI motility
Agonists Morphine, Codeine, Fentanyl and pentazocine weakly
Pentazocine
Effects of Different Opioid Receptor Stimulation:
Effects of Opioid Receptor Stimulation
Effects of Opioid Receptor Stimulation – contd.
Opioid Receptors – Intracellular mechanism
• All are G-protein coupled receptors• Located on prejunctional neurones• Inhibits release of transmitters – NA, DA, 5-HT,
GABA and Glutamate• Activation reduces intracellular cAMP
formation - Opening of K+ channel via μ and δ. and supression of N type of Ca++ channels
• Ultimately Hyperpolarization and reduced intracellular Ca++ Reduced Neurotransmitter release
Endogenous Opioid Peptides
• Endorphins: • Derived from POMC• ß-endorphins: 2 Types - ß-endorphin1 and ß-endorphin-2• Primarilty μ agonist and also has δ action
• Enkephalins: • Derive from Proenkephalin• Met-ENK and leu-ENK• Met-ENK - Primarily μ and δ agonist and leu-ENK – δ
agonist• Dynorphins:
• Derive from Prodynorphin: DYN-A and DYN-B• Potent κ agonist and also have μ and δ action
Opioid Antagonists1. Pure antagonists: Naloxone, Naltrexone and
Nalmefene• Affinity for all receptors (μ, δ and κ)• Can displace opioids bound to α-receptors• No action on Normal person but reverses poisoning and
withdrawal symptoms in addicts2. Mixed Agonist-antagonists: Nalorphine,
Pentazocine, Butorphanol and Nalbuphine3. Partial/weak μ agonist and κ antagonist:
Buprenorphine
Nalorphine• Not used anymore• Previously used as Opioid antagonist• But, antagonism is restricted to μ-
receptor only and agonist of κ-receptor
• Drawbacks - dysphoria and psychomimetic effects
Pentazocine• Weak μ-receptor antagonist, but agonist of κ-receptor• One of the commonly used agents, given orally and IM• Low abuse liability• Pharmacokinetics:
– High 1st pass metabolism but effective orally– Half life = 3-4 Hrs– Metabolized in liver by glucoronide conjugation– Dose: orally 50-100 mg and parenterally 30-60 mg IM
• Uses:Moderately severe pain in Injury, Burns, Fracture Trauma, Cancer and Orthopaedic manuevers
(Fortwin, Fortagesic)
Pentazocine Vs Morphine
• Spinal analgesia via kappa receptor• Dose is 30 mg Vs 10 mg and low ceiling effect• Sedation and Respiratory depression at lower doses• Tachycardia and rise in BP – dangerous in MI• Lesser smooth muscle spasms• Vomiting and other side effects are less• Subjective effects – lower ceiling (psycomimetic effects)• Tolerance develops on repeated use, but lesser than
Morphine• Withdrawal symptoms – both Morphine and Nalorphine like• Good analgesic in subjects not exposed to Morphine• Precipitate withdrawal – in Morphine addicts
Buprenorphine• Synthetic thebaine congener and highly lipid soluble• Given Sublingually or parenterally but not oral – high 1st pass
metabolism• Selective μ-agonist analgesic• 20-30 times more potent than Morphine• Slow but longer duration of action upto 24 Hrs• Pharmacological effects are similar to Morphine• Has ceiling effect in analgesic and respiratory depression • Good analgesic for naive patients but addicts – precipitates
withdrawal syndrome• Lower tolerance and physical dependence than Morphine and
abuse liability• Withdrawal syndromes are similar to Morphine
Buprenorphine – contd.• Adverse Effects:
– Hypotension (Postural)– Respiratory depression (fatal in neonates) and
cannot be reversed by Naloxone• Uses:
– Long lasting painful conditions – cancer– Postoperative pain– Myocardial infarction
• Preparations: Norphine, Tidigesic• 0.3 mg/ml injections and 0.2 mg sublingual tablets
Naloxone• Competitive antagonist of all types of opioid
receptors• But, blocks μ-receptors at much lower dose• Always injected IV (0.4 t0 0.8 mg) - All
symptoms of Morphine action are antagonized – respiratory stimulation
• At higher doses 4-10 mg: antagonizes actions of Nalorphine and Pentazocine – dysmorphic and psychomimetic effects are not suppressed (δ)
• Withdrawal symptoms: 0.4 mg doses – Morphine and 4-5 mg doses – Nalorphine and Pentazocine
Naloxone – contd.• Buprenorphine actions are prevented but not
reversed fully – tight bond with receptors• Also acts on endogenous opioids• Antagonizes respiratory depression of
Diazepam and N2O• Uses:
• Acute Morphine Poisoning (0.4 – 0.8 mg IV 2-3 min, maximum 10 mg.
• New Born – opioid poisoning• Reverse respiratory depression intr-aoperatively• Diagnosis of Morphine addiction• Alcohol intoxication
Opioids – other uses• Antidiarrhoeal agents:
Diphenoxylate and Loperamide• Antitussives: Codeine,
Dextromethorphan, Noscapine, Pholcodeine, Levopropoxyphene
Important• Classification of opioids• Remember - Pharmacological actions,
adverse effects, indications and contraindications of Morphine, Pethidine, Pentazocine
• Remember in short – Methadone, Tramadol, Buprenorphine and Naloxone
• Opioid receptors
THANK YOU