Canonical Question
Obs Pharm – Tocolytics
Master answer
Excitation Contraction Coupling in SM
- Motor neuron depolarisation
- ACh vesicular release
- Multiple MEPs → End plate potential
- Muscle AP propagates via T-tubles
- Opens L-type Ca channels
- Influx of EC Ca → ↑ IC [Ca]
- Variable amount of Sarcoplamic reticula in SM
- Can have some ↑ IC [Ca] via Ca induced Ca release.
- Ca binds Calmodulin → Ca-Calmodulin complex
- Ca-Calmod → ↑ MLCK activity
- → Phosphorylation of Myosin Light Chain (MLC)
- → Activation of Myosin ATPase
- Cross-bridge cycling.
Cross Bridge Cycling
- “Flexed” Myosin without ATP binds to Actin.
- Binding of ATP to Myosin causes release of Actin/Myosin complex and extension of the head
- In the presence of Ca-Calmod complex
- Actin binding sites are open and binding of myosin/Actin/ATP complex is formed
- Hydrolysis of ATP to ADP + P in myosin head by Myosin ATPase
- → conformational change “initial flexing” the myosin head and releasing phosphate
- Release of ADP further flexes Myosin head
- In presence of Ca return to step 2.
Relaxation
- Ca removed from cell
- Ca ATPase
- Ca2+/Na+ antiport
- Myosin Light Chain Phosphatase
- dephosphorylates MLC → inhibition of myosin ATPase
Differences in Gravid Uterus
These physiological adaptations in the gravid uterus maintain quiescence throughout most of pregnancy, ensuring fetal development, while preparing it to transition into a highly excitable and contractile state essential for effective labor.
| Feature | Gravid Uterus | Other Smooth Muscle |
|---|---|---|
| Resting Membrane Potential | Less negative near term, increasing excitability | Stable, less variation in response to hormones |
| Hormonal Regulation | Progesterone dominance (quiescence early), estrogen dominance (contractility late) | Task-specific, less pronounced |
| Gap Junctions | Increased (connexin-43) near term for synchronized contractions | Sparse, localized contraction |
| Calcium Handling | Increased L-type calcium channel activity and intracellular calcium recruitment near term | Stable calcium influx and release mechanisms |
| Oxytocin Sensitivity | High near term, upregulated oxytocin receptor density | Minimal, plays minor or no role |
| Relaxation Mechanisms | Progesterone/NO-mediated quiescence during pregnancy, reduced near term | Nitric oxide, prostaglandins, or sympathetic input |
| Action Potentials | Long, frequent, propagating bursts near term | Short, localized |
| Structural Adaptations | Hypertrophy and hyperplasia of myocytes | Minimal structural changes |
| Functional Synchrony | Whole-organ synchronization with gap junctions, pacemaker cells, and oxytocin | Localized function, no whole-organ synchronization |
Gladwin / JC 2024
Exam appearances
| Exam | Exact wording | Relationship | Success |
|---|---|---|---|
| 2024A Q10 | (a) Explain the excitation contraction mechanism as it relates to the smooth muscle of the myometrium including a gravid uterus (50% of marks). (b) For each tocolytic agent: salbutamol, nifedipine, magnesium sulphate, provide the following information: (i) List the class (10% of marks) (ii) Provide a dose (10% of marks) (iii) Describe the mechanism of action (20% of marks) (iv) Outline the adverse effects (10% of marks) | historical_member | — |