MORPHINE

Oleh:
Chau Febriani Kharisma
1971002014

Pembimbing:
DR. Dr. Gede Budiarta Sp. An, KMN
◦ Opos greek for juice
◦ Opium derived from Greek word opion (“poppy juice”); The opium poppy
(Papaver somniferum)  source of 20 distinct alkaloids
◦ Opiates  drugs derived from opium
◦ Opioid  all exogenous substances, natural and synthetic, that bind specifically to
any of several subpopulations of opioid receptors and produce at least some
agonist (morphine-like) effects
◦ Narcotic derived from Greek word for stupor  refer to potent morphine-like
analgesics with the potential to produce physical dependence
HISTORY
◦ 1806  german youth Frederich Serturner
isolated primary active ingredient in opium
◦ He tested the new drug in his friends at 10
times the modern recommended dose
◦ Active agent was 10x more potent than
opium  He named it morphium after
morpheus (god of dreams)
◦ 3rd century BC : 1st reference of poppy juice
◦ 1527 : Paracelsus formulated laudanum
◦ 1806 : Serturner isolated soporific principle in opium
(alkaloid)
◦ 1817 : isolated alkaloid named morphine
◦ Mid 1800’s : medical use of pure alkaloids began to spread
◦ 1869 : morphine widely used to treat wounded soldiers
during American Civil War
◦ 1939 : meperidine (1st synthetic opioid produced)
◦ 1960 : fentanyl synthetized
◦ 1974-1976 : development of sufentanil and alfentanil
◦ 1991 : remifentanil
◦ Unique in producing analgesia without loss of touch, proprioception, or consciousness
◦ Classification:
A. Interaction with Opioid Receptors
◦ Opioid agonists
◦ Opioid agonist-antagonists
◦ Opioid antagonists
B. Compound
◦ Natural
◦ Semisynthetic
◦ Synthetic
Structure
◦ The active components of opium:
◦ Phenanthrenes
◦ Benzylisoquinolines.
◦ Phenanthrene alkaloids
◦ Morphine
◦ Codeine
◦ Thebaine
◦ Benzylisoquinoline Alkaloids: (lack analgesic activity)
◦ Papaverine
◦ Noscapine
◦ Three rings of phenanthrene core  14 carbon atoms
◦ Chiral molecules, levorotary isomers  biologically active at opioid receptors
Semisynthetic and Synthetic
SEMISYNTHETIC
◦ Simple modification  many derivative compounds with differing properties
◦ Codeine (Methylmorphine)  substitution of a methyl group for the hydroxyl group on carbon
3
◦ Heroin (Diacetylmorphine)  Substitution of acetyl groups on carbons 3 and 6
◦ Hydromorphone  Carbonyl group instead of hydroxyl at position 6 and lacks a double bond
between carbons 7 and 8.
◦ Thebaine  insignificant analgesic activity, precursor for etorphine (analgesic potency > 1.000
times morphine)
SYNTHETIC
◦ Contain phenanthrene nucleus of morphine but are manufactured by synthesis rather than
chemical modification of morphine
Opioid Receptors
◦ Belongs to superfamily of seven transmembrane-segment guanine (G)
protein–coupled receptors that includes muscarinic, adrenergic, and
somatostatin receptors
◦ Three subtypes:
◦ μ (mu – morphine)
◦ δ (delta—isolated from mouse vas deferens)
◦ κ (kappa—ketocyclazocine)
◦ Names  developed from ligands originally found to bind to them or
their tissue of origin
◦ Response of μ opioid receptors to agonists  significantly affected by β-arrestins,
(proteins that regulate the activity of G protein–coupled receptors)
◦ E.g, β-arrestins  promote receptor desensitization (or resensitization) as well as
clathrin-mediated endocytosis.
◦ Pharmacologic modulation of β-arrestin activity  improve efficacy and
tolerability of opioid agonists
◦ κ receptors  less effective analgesia for high-intensity painful stimulation than μ
◦ Opioid agonist-antagonists often act principally on κ receptors
◦ δ receptors  modulate activity of μ receptors
◦ σ receptors (types 1 and 2)  Previously considered opioid
receptors  endoplasmic reticulum-resident protein 
widespread in the CNS and peripheral tissues
◦ Now known not to be true opioid receptors  diverse roles in
intracellular signaling, metabolic regulation, mitochondrial
metabolism, and other functions.
Receptor Location
CNS
◦ Brain : Periaqueductal gray, locus ceruleus, and the rostral ventral medulla
◦ Spinal Cord : Substantia gelatinosa  interneurons and primary afferent neurons in the dorsal
horn
Outside CNS
◦ Sensory Neurons
Intraarticular morphine  analgesia after knee surgery  action on peripheral nerves
◦ Immune Cells
Sites of inflammation  secrete opioid peptides  local analgesia
Endogenous Pain Modulating Mechanism
◦ Existence of opioid receptors and
endogenous opioid agonists 
endogenous pain suppression system
◦ Ideal Opioid  highly specific for
receptors, producing analgesia with
minimal side effects
COMMON SIDE
EFFECTS
CNS
◦ In the absence of hypoventilation  ↓ CBF and possibly ICP
◦ Caution in Head Injury:
1. Associated effect on wakefulness
2. Production of miosis
Excitatory action on the parasympathetic nerve.
Light  excitation Edinger-Westphal nucleus of the oculomotor nerve  constriction
3. Depression of ventilation  hypercarbia  vasodilatation  ↑ICP
4. Impairment of Blood Brain Barrier  ↑ sensitivity
◦ EEG  same with sleep  replacement of rapid α waves by slower δ waves, no seizure activity
◦ Hallucination  auditory, visual or rarely tactile
◦ Clonic skeletal muscle activity (myoclonus) can
resemble grand mal seizure (no changes in EEG)
◦ Skeletal muscle rigidity (thoracic and abdominal)
 chest wall rigidity  large dose, IV of
Fentanyl and its derivatives  Inhibition of
striatal release of γ-aminobutyric acid and
increased dopamine production -- difficult
ventilation
◦ Treatment : NMBA or Opioid antagonist
Sedation
◦ Occurs in 60% patient with titration
◦ Postoperative titration of morphine frequently induces sedation that precedes
the onset of analgesia
Cardiovascular
◦ Morphine (large doses)  supine and normovolemic  unlikely to cause
direct myocardial depression or hypotension
◦ Positional changes  orthostatic hypotension and syncope  morphine-
induced impairment of compensatory sympathetic nervous system responses
◦ Decrease sympathetic nervous system tone to peripheral veins  venous
pooling  ↓ venous return, CO, BP
◦ Drug Induced-Bradycardia  Stimulation of vagal nuclei in medulla 
increased activity over vagal nerves
◦ Direct depressant on SA Node & Slower conduction through AV Node
◦ Histamine Release  Hypotension
Minimized by:
1. Limiting rate of morphine infusion to 5 mg/min intravenously (IV)
2. Maintaining position in supine to slightly head-down position
3. Optimizing intravascular fluid volume.
◦ Pretreatment H1 - and H2 -receptor antagonists  prevent changes in systemic
blood pressure and systemic vascular resistance  NOT alter release of histamine
evoked by morphine
◦ Does not sensitize the heart to catecholamines or predispose to cardiac
dysrhythmias  except in ventilatory depression resulting in hypercarbia or
arterial hypoxemia
◦ Tachycardia or hypertension  painful surgical stimulation not suppessed by
morphine
◦ Combination with IV or inhaled anesthetic  effects does not occur when
either drug is administered alone
◦ morphine or fentanyl with nitrous oxide  cardiovascular depression (decreased cardiac
output and systemic blood pressure plus increased cardiac filling pressures)
◦ opioid and a benzodiazepine  decreases in systemic vascular resistance and systemic
blood pressure
◦ Protect myocardium from ischemia  most prominently through κ receptors
 enhance resistance to oxidative and ischemic stresses
 Ventilation
◦ Rapid and persist for several hours
◦ Decrease responsiveness of these ventilation centers to CO2
◦ ↑ resting arterial partial pressure of CO2
◦ Displacement of the carbon dioxide response curve to the right
◦ Suppress pontine and medullary ventilatory centers that regulate the rhythm of
breathing  prolonged pauses between breaths and periodic breathing
◦ Clinically manifest as ↓ frequency of breathing  compensated by ↑ VT
◦ High dose  apnea, patient conscious and able to initiate breath if asked
◦ Dose-dependent depression of ciliary activity in the airways
◦ Direct effect on bronchial smooth muscle + histamine release  ↑ airway
resistance
◦ Analgesic and ventilatory effect of opioid  similar mechanism
◦ Equianalgesic doses ~ ventilatory depression,
Reversal of ventilatory depression ~ reversal analgesia
Biliary Tract
◦ Spasm of biliary smooth muscle  Gallbladder contracts against closed or
narrowed sphincter Oddi  ↑ biliary pressure  colic or epigastric distress
Equal analgesic doses:
Fentanyl, morphine, meperidine, pentazocine = 99%, 53%, 61%, 15%
◦ May be confused with angina
Naloxone relieve biliary spasm not myocardial ischemia
NTG relieve all
◦ Glucagon, 2 mg IV  reverse spasm without antagonizing analgesic effect
GI Tract
◦ Spasm of GIT smooth mucles  constipation, biliary colic, and
delayed gastric emptying.
◦ Morphine:
◦ ↓ propulsive peristaltic contractions of the small and large intestines 
delayed passage
Increased tone at gastroduodenal junction  delayed gastric emptying 
potentially ↑ risk of aspiration or delay absorption of oral drugs
Large intestine  ↑ water absorption  constipation
◦ ↑ tone of the pyloric sphincter, ileocecal valve, and anal sphincter
Nausea and Vomiting
◦ Opioid agonist  partial dopamine agonist at dopamine receptors in
Chemoreceptor Trigger Zone (CTZ) in the floor of the fourth ventricle
◦ Consistent with antiemetic efficacy of butyrophenones and phenothiazines.
Genitourinary System
◦ Increase tone and peristaltic activity of the ureter  Urgency is
produced by opioid-induced augmentation of detrusor muscle tone,
but tone of the urinary sphincter is enhanced  voiding difficult
Cutaneous Changes
◦ Histamine release:
◦ Urticaria and erythema at injection site  DOES NOT represent allergic
reaction
◦ Dilatation of cutaneous blood vessel  warmer and flushed skin of the face,
neck and upper chest
◦ Conjunctival edema and pruritus
Placental Transfer
◦ Opioids can pass through placental barrier  depression of neonatal
ventilation
◦ Morphine > Meperidine
◦ Fentanyl DOES NOT produce significant neonatal depression unless large doses are used
◦ Chronic maternal use  physical dependence
Hormonal Changes
◦ Prolonged therapy  influence hypothalamic-pituitary-adrenal axis and the
hypothalamic-pituitary-gonadal axis  endocrine and immune effects
◦ ↑ prolactin
◦ ↓ luteinizing hormone, follicle stimulating hormone, testosterone, estrogen
◦ Morphine  progressive ↓ in plasma cortisol
Overdose
◦ Principal manifestation  ventilatory depression  ↓ RR, may
progress to apnea
◦ Symmetric and miotic pupils  mydriasis in severe arterial hypoxemia
◦ Flaccid skeletal muscle  upper airway obstruction
◦ Hypotension and seizure  persistence arterial hypoxemia

TRIAD  MIOSIS, HYPOVENTILATION, COMA

Drug Interactions
◦ Ventilatory depression  exaggerated by:
◦ Amphetamines
◦ Phenothiazines
◦ Monoamine oxidase inhibitors
◦ Tricyclic antidepressants
Provocation of Coughing
◦ Preinduction  fentanyl, sufentanil, or alfentanil  significant reflex
coughing
◦ Morphine and hydromorphone  no effect
◦ Exact cause is unclear  imbalance between sympathetic and vagal
innervation of the airways and/or stimulation of juxtacapillary irritant
receptors
Tolerance and Physical Dependence
Tolerance
Development of the requirement for increased doses of opioid to achieve the
same effect previously achieved with a lower dose.
◦ Usually after 2-3 weeks
◦ Analgesic, euphoric, sedative, depression of ventilation, and emetic effects
NOT miosis and bowel motility
Physical dependent (Addiction)
◦ Repeated opioid administration
◦ Can occur after only 48 hours of continuous medication (morfin ~ 25 days)
◦ Depend on agonis effect, less likely with agonist-antagonist
◦ Discontinuation  withdrawal abstinence syndrome
Withdrawal
◦ Peak in 72 hour, decline over 7-10 days
◦ Insomnia and restlessness prominent
◦ Yawning, diaphoresis, lacrimation, or coryza
◦ Abdominal cramps, nausea, vomiting, diarrhea
◦ Tolerance lost, can be terminated by modest dose  longer period, smaller
dose required
Treatment
◦ Clonidine
◦ Small dose of ketamine
MORPHINE
Pharmakokinetic (ADME)
◦ Oral (capsules, syrups, tablets), IV, IM, Aerosol, Intratecal, Epidural, Subcutaneous
◦ Onset:
◦ IM : 15-30 min , peak 45-90 min
◦ IV : 5-10 min , peak 15-30 min
◦ Only small amount of IV morphine entered CNS (0,1%)
◦ relatively poor lipid solubility,
◦ high degree of ionization at physiologic pH
◦ protein binding
◦ rapid conjugation with glucuronic acid
◦ Alkalinization of blood  enhance passage to CNS  ↑ nonionized fraction
◦ CO2 induced ↑ CBF  ↑ delivery
to the brain  more important than
fraction of drug that exists (either
ionized or nonionized)
◦ Accumulates rapidly in the kidneys,
liver, and skeletal muscles.
◦ Unlike fentanyl, does not undergo
significant first-pass uptake into the
lungs
Metabolism
◦ Primary  conjugation with glucuronic acid in hepatic and extrahepatic sites
(kidneys)
◦ 75-85% : 5-10% (9:1)  morphine-3-glucuronide : morphine-6- glucuronide
◦ Morphine-3-glucuronide inactive. While morphine-6- glucuronide 
analgesia and ventilatory depression (duration of action greater than
morphine, analgesic potency 650x higher)
◦ 5% demethylated to normorphine, small amount to codeine
◦ Metabolite eliminated primarily in urine, 7-10% biliary secretion
◦ Prolong depression of ventilation (< 7 days)  patient with renal failure
◦ Urine  morphine-3-glucuronide detectable up to 72 hours, some unchanged
◦ CAUTION!
◦ Plasma concentrations are higher in the elderly
◦ In the first 4 days of life, the clearance decreased and elimination half-time is prolonged
Sex
◦ May affect, but direction and magnitude depends
◦ Women  greater analgesic potency and slower speed of offset  higher
consumption of postoperative opioid in men
◦ Women  greater respiratory depression
SIDE EFFECTS
◦ Miosis
◦ Orthostatic Hypotension
◦ Respiratory Depression
◦ Pain Suppression or Pruritus
◦ Histamine Release or Hormonal Release
◦ Increased Intracranial Tension
◦ Nausea
◦ Euphoria
◦ Sedation
THANK YOU