G7iii: β-Adrenoreceptor Antagonists

  • Β blockers are antagonists of the effects of catecholamines at β adrenoreceptors

Classification

  • Competitive antagonists – all are competitive antagonists & occupy β receptor to cause no activation
  • Selectivity:
    • Non-selective: β1 & β2 → PROPANOLOL
    • Selective: β1 = cardioselective → METOPROLOL, ATENOLOL, ESMOLOL
  • Intrinsic sympathomimetic activity – ∴ classified as partial agonist, better tolerated with poor LV function → LABETALOL
  • Membrane stabilising activity → PROPANOLOL, LABETAOLOL, PINDOLOL have MSA effects similar to Class IA antiarrythmics
  • Other → SOTALOL which exhibits K channel blocking activity

Chemical

  • All are derivatives of β agonist ISOPRENALINE
  • Benzene ring substitutions determine whether drug will be an agonist/antagonist
  • Levorotary more potent

Use

  1. Hypertension
  2. Arrhythmias
  3. IHD
  4. Anxiety
  5. Migraine prophylaxis

Onset / Duration

  • PROPANOLOL: onset 2 mins (IV) → lasts 4hrs
  • METOPROLOL: onset 2 mins (IV) → lasts 6hrs
  • ATENOLOL: Prolonged OD dosing
  • ESMOLOL: onset 2 mins (IV) → ceases in 15 mins

MoA

  • Blocking β receptors inhibits catecholamine activity
    • PROPANOLOL → β1 & β2
    • METOPROLOL → β1
    • ATENOLOL → most selective β1
G1
P4

PD

CVS

  • ↓ INOTROPY = blocking β1 receptors
  • ↓ CHRONOTROPY = ↓rate spontaneous slow decay
  • ↓ DROMOTROPY = ↓conduction through AV Node; Prolonged PR interval
  • ↑SVR (v. weak because minimal β2 receptor on smooth m.)
    • Β blocking activates MLCK → smooth m. contraction

Resp

↑airway resistance

CNS

(propranolol because so lipid soluble)

    • Insomnia
    • Depression
    • Fatigue
    • Lethargy

Renal

↓RENIN release from blocking β1 receptor on juxtaglomerular apparatus

Metabolic

Disrupts gluconeogenesis/glycogenolysis that occurs in response to Adrenaline

Drug Interactions (mainly with propranolol)

  • LAs ↑Bupivacaine toxicity due to ↓clearance by lungs & liver
  • Opioids ↓1st pass pulm uptake of fentanyl
  • NDMR potentiated by propranolol
  • Ketamine does not allow its ↑symp NS effects

Toxicity/Adverse Effects

Bronchospasm

Exaggerated ↓BSL

TAGs elevated

Alopecia

Brady & HB

LVF worsened

Ouch – aching muscles

CNS – depression, fatigue, lethargy

K elevation

Enteric → N/V

Raynaud’s

Soft cock (impotence)

PK – PK differences of β-blockers reflect their lipid solubility. Mostly PROPANOLOL vs. the rest

Absorption – LIPID SOLUBILITY: Propranolol > Metoprolol > Atenolol/esmolol

  • Propranolol rapid & complete absorption
  • Metoprolol “        “        “     
  • Atenolol → poor lipid solubility → 50% absorption

Distribution

  • Propanolol → crosses BBB & placenta
  • Metoprolol → crosses placenta
  • Atenolol → unlikely to cross placenta
  • Esmolol → crosses placenta

PPB

  • Propanolol 45%
  • Metoprolol 10%
  • Atenolol 5%
  • Esmolol 55%

Clearance

Most are metabolised by liver & metabolites excreted in urine

Propanolol

  • 75% 1st pass pulmonary uptake
  • Significant 1st pass metabolism when given PO
  • ∴PO dose much higher than IV
  • Active metabolite → 4-hydroxypropanolol
  • High hepatic ER = ↓clearance if ↓hepatic BF
  • ∴↓its own clearance by↓CO!

Metoprolol

  • 60% 1st pass
  • Inactive metabolites
  • 10% unchanged in urine

Atenolol

  • Little/no hepatic metabolism
  • Excreted renally unchanged

Β Receptor

Propanolol

β1 & β2

Metoprolol

β1

Atenolol

β1

Esmolol

β1

Onset

Propanolol

2 mins (IV)

Metoprolol

Atenolol

Esmolol

Duration

Propanolol

4hrs

Metoprolol

6hrs

Atenolol

OD dosing

Esmolol

9 mins

Lipid Solubility

Propanolol

++++

Metoprolol

++

Atenolol

+

Esmolol

+

PPB

Propanolol

95%

Metoprolol

10%

Atenolol

5%

Esmolol

55%

Metabolism

Propanolol

Hepatic, active metabolites

Metoprolol

Hepatic, inactive metabolites

Atenolol

Minimal

Esmolol

RBC / plasma esterases

% In Urine

Propanolol

<5%

Metoprolol

<10%

Atenolol

>90%

Esmolol

<1%

t ½ B

Propanolol

3hrs

Metoprolol

4hrs

Atenolol

6hrs

Esmolol

9 mins