MORPHINE - Pharmacological Profile

INTRODUCTION

A. PHARMACOLOGICAL ACTIONS ON CNS

1. Depressant Actions

• Morphine is a strong analgesic; relieves dull, poorly localized visceral pain better than sharply defined somatic pain
• Higher doses can mitigate even severe pain; degree of analgesia increases with dose
• Relieves nociceptive pain (e.g., trigeminal neuralgia from inflammation) better than neuritic pain
• Suppresses both the perception of pain AND its emotional component (suffering, distress, anxiety, fear) - patient tolerates pain better
• Analgesic action has both spinal and supraspinal components
• Acts in substantia gelatinosa of dorsal horn to inhibit release of excitatory transmitters (glutamate, substance P) from primary afferents
• At supraspinal sites: acts in periaqueductal gray matter, limbic and cortical areas to alter processing and interpretation of pain
• Simultaneous action at spinal + supraspinal sites greatly amplifies analgesia

• Produces drowsiness, mental dullness, and indifference to surroundings without motor incoordination or ataxia
• Higher doses progressively induce sleep then coma
• No anticonvulsant action; fits may be precipitated

• Prominent calming effect; loss of apprehension, feeling of detachment, lack of initiative
• Limbs feel heavy, body warm, mental clouding, inability to concentrate
• In pain/anxiety patients and addicts: perceived as pleasurable "high"
• Rapid i.v. injection gives addicts a "kick/rush" - intensely pleasurable, akin to orgasm
• Euphoria mediated by DA release in nucleus accumbens

• Depresses respiratory centre in a dose-dependent manner; both rate and tidal volume decreased
• Neurogenic, hypercapnoeic and then hypoxic drives suppressed in succession
• Death in morphine poisoning is due to respiratory failure

• Depresses the cough centre (more sensitive than respiratory centre)

• Depresses hypothalamic thermostatic centre → hypothermia in cold surroundings

• Depressed at higher doses → fall in BP

2. Stimulant Actions (CNS)

3. Neuro-endocrine Actions

• Hypothalamic activation dampened → pituitary influence reduced
• FSH, LH, ACTH levels lowered; Prolactin and GH levels raised
• Heavy abusers: loss of libido, impotence, menstrual irregularities, infertility
• Morphine can release ADH → reduces urine volume

B. ADVERSE EFFECTS - ACUTE MORPHINE POISONING

Acute Poisoning

• In nontolerant adult: 50 mg i.m. produces serious toxicity
• Human lethal dose: ~250 mg
• Can be accidental, suicidal, or in drug abusers

Classic Triad of Features:

Coma + Respiratory Depression + Pinpoint Pupils

Full Clinical Features:

Treatment of Acute Poisoning:

1. Respiratory support - positive pressure respiration (also opposes pulmonary edema formation)
2. Maintain BP - i.v. fluids, vasoconstrictors
3. Gastric lavage with potassium permanganate (even when morphine injected - drug partitions into acid gastric juice, ionizes, does not diffuse back)
4. Specific antidote: Naloxone 0.4-0.8 mg i.v., repeated every 2-3 min till respiration picks up; repeated every 1-4 hours as needed (short duration of action)
   • Acts rapidly, no agonistic action, does not depress respiration

C. THERAPEUTIC USES

1. Analgesia
   • Acute severe pain: myocardial infarction, post-operative pain, trauma, burns, cancer pain
   • Pain of terminal illness (palliative care)
   • Biliary/renal colic (combined with antispasmodic)
2. Pre-anaesthetic medication - reduces anxiety, provides sedation
3. Acute left ventricular failure (pulmonary edema)
   • Reduces preload by venodilatation, reduces anxiety and dyspnoea
   • Shifts blood from pulmonary to systemic circuit
4. Antidiarrhoeal (reduces GI motility)
5. Cough suppression (codeine preferred; morphine used in terminal cases)
6. Intrathecal/epidural analgesia for surgery, labour, post-operative pain

D. CONTRAINDICATIONS

QUICK MEMORY AIDS

• Pinpoint pupils = pathognomonic of morphine/opioid toxicity (no tolerance to miosis)
• Death = respiratory failure
• Antidote = Naloxone
• Avoid in = Head injury, Asthma, COPD, Hypovolaemia (mnemonic: HACH)
• Tolerance does NOT develop to: Constipation, Miosis, Convulsant action

MECHANISM OF ACTION OF MORPHINE

Receptor-Level Mechanism

Cellular/Molecular Mechanism

• The α subunit directly inhibits adenylyl cyclase → decreases intracellular cyclic AMP (cAMP)
• This reduces protein kinase A-dependent phosphorylation of various proteins

• The βγ dimer inhibits voltage-gated Ca²⁺ channels on presynaptic nerve terminals
• This reduces Ca²⁺ influx → decreases release of excitatory neurotransmitters such as glutamate and substance P from primary afferent nerve terminals in the dorsal horn (substantia gelatinosa)

• The βγ dimer also opens G protein-coupled inwardly rectifying K⁺ channels (GIRK)
• This causes hyperpolarization of the postsynaptic neuron → reduced neuronal firing/excitability

Site of Action - Spinal and Supraspinal

• Spinal level: Acts on the substantia gelatinosa of the dorsal horn, inhibiting release of glutamate and substance P from primary afferents carrying pain impulses; also acts via interneurons involved in "gating" of pain impulses
• Supraspinal level: Acts in the periaqueductal gray matter, limbic system, and cortical areas to alter processing/interpretation of pain, and augments descending inhibitory pathways to the spinal cord (via inhibition of GABA release in the ventrolateral periaqueductal gray, which disinhibits/activates descending antinociceptive pathways)
• Peripheral action: On small primary afferent terminals in skin/deeper tissues, attenuating sensitization following tissue injury (relevant in burns, trauma)
• Several aminergic (5-HT, NA) and GABAergic systems are also involved; simultaneous spinal + supraspinal action greatly amplifies analgesia

Mechanism Behind Specific Actions (linking receptor action to effects seen)

Summary Flow Diagram (for exam)

Morphine → binds μ-opioid receptor (GPCR, Gi/Go coupled)
        ↓
   G protein activation → α subunit + βγ dimer
        ↓                        ↓
 ↓ Adenylyl cyclase        ↓ Ca²⁺ channel opening (presynaptic)
 ↓ cAMP                    ↑ K⁺ channel opening (GIRK, postsynaptic)
        ↓                        ↓
 ↓ PKA-mediated            ↓ Neurotransmitter release   Hyperpolarization
 phosphorylation           (glutamate, substance P)      ↓ neuronal firing
        ↓                        ↓                       ↓
              ↓ Pain transmission / ↓ Neuronal excitability
                            ↓
                        ANALGESIA + other CNS effects