2016A08 Outline the pharmacology of agents used in the acute management of hypertension in pregnancy.

Causes of hypertension in pregnancy

· Pregnancy-induced hypertension

· Pre-eclampsia

Teratogenic drugs

· ACE inhibitors

· Angiotensin receptor antagonists

· Beta blockers

Other contra-indicated drugs

· GTN -> foetal methaemoglobinaemia

Pharmacodynamics

-Mechanism of action (MoA)

-Side effects (SE)

Pharmacokinetics

-Absorption (A)

-Distribution (D)

-Metabolism (M)

-Excretion (E)

Labetalol

· MoA: α₁, β₁, β₂ antagonist

o IV α:β 1:7

o PO α:β 1:3

· Isomers: SS/SR inactive, RS α, RR α and β

· Membrane-stabilising (VdNaC blockade)

· Weak ISA

· SE: bradycardia, bronchospasm (avoid in asthma)

· IV 20-40mg q2 mins

· PO 200-400mg bd

· Inset 2-5 min, duration 2-4h

· A: oral bioav 25%

· D: V_D 10L/kg, 50% protein bound

· M: hepatic, t_1/2β 6-8 hours

· E: urine

Hydralazine

· Direct acting vasodilator

· MoA unknown

· SEs: tachycardia, myocardial ischaemia, headache, flushing, peripheral oedema, SLE-like syndrome, peripheral neuropathy

· IV 5-10mg q15 min

· Onset 5-20 min, duration 2-6 h

· A: oral bioav10-30%

· D: V_D 0.5L/kg, 90% protein bound

· M: N-acetylation (subject to polymorphism; t_1/2β 3-7 hours)

· E: urine

Magnesium

· MoA: physiological antagonist at L-Ca²⁺ channel

↓Risk of seizures in pre-eclampsia
↓SVR

· SE: sedation, resp depression

· IV 10mmol slow push in severe PET

· Onset <1 min

· D: ICF 30mM, ECF 1mM; bone ++

· E: urine, faeces

Nifedipine

· Dihydropyridine peripheral L-Ca²⁺ antagonist

· Vasodilatation -> ↓SVR

· SE: reflex ↑HR, dizziness, oedema

· PO 10-20mg q6h

· Onset: 30-45 mins

· A: oral bioav 90%

· D: V_D 0.7L/kg, 90% protein bound

· M: hepatic CYP450

· E: urine

Methyldopa

· Prodrug: DBH to α-methylnoradrenaline -> central α₂ agonist -> ↓SNS outflow

· Also inhibits DOPA decarboxylase -> ↓DA, NAd

· SE: Parkinsonism, depression

· 200-400mg bd only

· Not suitable for crisis

· A: oral bioav 25%

· D: V_D 0.6L/kg, <15% protein bound

· M: activation in CNS

Alfentanil

· ↓Pressor response to laryngoscopy

· MoA: MOP agonist -> ↓SNS output

· IV 10-20mcg/kg bolus

· Peak 1-1.5 min, offset 5 min

· Offset by distribution

· M: CYP3A4

· E: urine

Esmolol

· ↓Pressor response to laryngoscopy

· MoA: β₁ antagonist -> ↓HR, ↓contractility -> ↓CO

· SE: difficult to titrate analgesics

· Bolus 0.5mg/kg over 30 seconds

· Infusion 0.05-2mg/kg/min

· Onset 2-10 mins, offset 10-30mins

· D: V_D 3.5L/kg, 60% protein bound

· M: RBC esterase, Cl 285mL/kg/min, t1/2b 10 mins

· E: urine

Neuraxial

·  e.g. epidural ropivacaine and fentanyl: blockade at spinal nerve roots -> ↓SNS output

·  Usually both anaesthetic (local) and analgesic (opioid)

·  Highly effective

·  T5-L2: ↓SVR, ↓mAP

·  If T1-4: ↓HR, ↓SVR, ↓↓mAP

General

·  e.g. propofol (only under GA)

·  MoA ↓mAP: L-Ca²⁺ inhibition, ↑NO release, ↓SNS output from medulla

·  SEs: maternal and foetal anaesthesia, respiratory and cardiovascular depression