Prokinetic Drugs

PROKINETIC DRUGS


PROKINETIC DRUGS

Introduction:

  • Are drugs used for increasing GI motility.
  • Mainly used for treatment of gastroparesis, postoperative paralytic ileus & constipation.

MOA:

    • ACh – Main excitatory neurotransmitter in GIT.
  • Presynaptic receptors in cholinergic neurons:
    • Excitatory (5-HT4) & Inhibitory (5HT 3, D).
    • Hence, D2 & 5HT3 antagonists and 5 HT4 agonists – Increases ACh release & stimulates GI motility.

Drugs included:

  • Metoclopramide, domperidone, cisapride, mosapride, renzapride, prucalopride & tegaserod.

Important drugs:

1. Metoclopramide:

  • MOA:
    • Blocks both central & peripheral D2.
    • Central D2 blocking action – Mainly antiemetic effects
  • Prokinetic properties:
    • Due to 5HT4 receptor agonism (main mechanism) & 5HT4 receptor antagonism –> ACh release.
  • Other uses:
    • Antiemetic agent.
    • In GERD.
    • Gastroparesis treatment (in diabetic patients).
    • During emergency general anesthesia – Enhances gastric emptying, if patient has taken food within 4 hrs.
  • Side effects:
    • Extrapyramidal side effects (muscle dystonia, parkinsonism) – Due to D2 blocking action.
    • Hyperprolactinemia –> leading to galactorrhoea.
  • Treating overdose effects:
    • Antagonized by atropine.
    • It increases gastric peristalsis –> Enhances gastric emptying & LES tone.
    • No effect on colonic motility.

2. Domperidone:

  • D2 receptor antagonist.
  • Doesn’t cross blood-brain barrier.
  • Mainly as an antiemetic (less efficacious than metoclopramide).
  • Decreases l-dopa induced vomiting without interfering with its efficacy.
  • Devoid of extrapyramidal & hyperprolactinemic adverse effects.

3. 5HT4 agonists:

  • Drugs: Cisapride, mosapride, renzapride, prucalopride & tegaserod.
  • MOA: 
    • 5-HT4 agonistic activity.
    • No action on D2 receptors – Hence, no antiemetic property.
    • Increases whole GI motility including colon.

Individual drug description:

  • Cisapride:
    • Previously used for GERD treatment.
    • Withdrawn in some countries – Due to QT-prolonging action.
    • Metabolized by CYP 3A4 – Hence, should not be administered with microsomal enzyme inhibitors like ketoconazole & erythromycin.
    • Increased chances of torsades de pointes (arrhythmia with QT prolongation).
  • Mosapride & renzapride:
    • Does not prolong QT interval.
  • Tegaserod: 
    • Used for constipation dominant irritable bowel syndrome.
    • Recently withdrawn from India – Due to increased incidence of myocardial infarction & stroke.

4. Other prokinetic drugs:

  • Levosulpiride:
    • l-isomer of sulpiride.
    • Newer D2 blocker with prokinetic activity.
    • Also an antipsychotic drug.
  • Loxiglumide:
    • CCK1 receptor antagonist.
    • Indicated for constipation dominant IBS.
  • Macrolides (mainly erythromycin):
    • Acts as motilin agonists.
    • Indicated in diabetic gastroparesis.
    • Rapid tolerance development limits this use.

Exam Important

  • Prokinetic drugs are drugs used for increasing GI motility.
  • 5-HT4 receptors are excitatory & 5HT3, Dare inhibitory are in nature among presynaptic receptors in cholinergic neurons.
  • Prokinetic drugs include Metoclopramide, domperidone, cisapride, mosapride, renzapride, prucalopride & tegaserod.
  • Prokinetic properties of metoclopramide are mainly due to 5HT4 receptor agonism (main mechanism) & 5HT4 receptor antagonism resulting in ACh release.
  • Metoclopramide is also an antiemetic drug, useful in gastroparesis treatment (in diabetic patients) & also during emergency general anesthesia by enhancing gastric emptying, if patient has taken food within 4 hrs.
  • Prokinetic drug with extrapyramidal side effect is Metoclopramide.
  • Extrapyramidal side effects (muscle dystonia, parkinsonism) – Due to D2 blocking action.
  • Metoclopramide can cause hyperprolactinemia, leading to galactorrhoea.
  • Domperidone is a D2 receptor antagonist which doesn’t cross blood-brain barrier.
  • Domperidone is less efficacious than metoclopramide & mainly as an antiemetic.
  • Domperidone decreases l-dopa induced vomiting without interfering with its efficacy.
  • Domperidone is devoid of extrapyramidal & hyperprolactinemic adverse effects.
  • 5HT4 agonists like Cisapride, mosapride, renzapride, prucalopride & tegaserod have no action on D2 receptors, hence, no antiemetic property.
  • Cisapride is withdrawn in some countries, due to QT-prolonging action.
  • Cisapride is metabolized by CYP 3A4 not administered with microsomal enzyme inhibitors like ketoconazole & erythromycin.
  • Cisapride has increased chances of torsades de pointes (arrhythmia with QT prolongation).
  • Mosapride & renzapride does not prolong QT interval.
  • Tegaserod used for constipation dominant irritable bowel syndrome.
  • Tegaserod has recently withdrawn from India, due to increased incidence of myocardial infarction & stroke.
  • Levosulpiride is a newer D2 blocker with prokinetic activity.
  • Loxiglumide is a CCK1 receptor antagonist, indicated for constipation dominant IBS.
  • Macrolides (mainly erythromycin)acts as motilin agonists, indicated in diabetic gastroparesis.
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