L9: Sympathetic system

Adrenergic receptors

Synapse

• Na+ & tyrosine transported into axon via aromatic L-amino acid transporter

• tyrosin is converted into dihydroxyphenylalanin (L-DOPA) the dopamine

• dopamine is transported into vesicle by VMAT and converted into noradrenaline by dopamine beta-hydroxylase

• action potential arrives at the axon end → activate Ca2+ ion channel causes Ca2+ influx

• intracellular Ca2+ ↑ leads to release of NE from vesicle

• NE is released by the neutron and diffuse across the synapse to bind on the adrenergic receptor on the postsynaptic neuron

• excess NE

  • bind to α2 receptor on the presynaptic neuron→ suppress NE release

  • recycled via NE transporter and broken down by MAO and COMT

α1 receptor

• vasoconstriction

• smooth muscle constriction

• GI tract relaxation

• glycogenolysis

• K+ release in salivary gland

α2 receptor

• reduce presynaptic NE release

• reduce insulin secretion

• GI tract relaxation

β1 receptor

• increase contractility and rate of heart

• amylase secretion in salivary gland

β2 receptor

• vasodilation

• relaxation of smooth muscle

• slight increase of heart rate and contractility

β3 receptor

• relaxation of bladder detrusor

• thermogenesis of skeletal muscle

• lipoysis and thermogenesis in fat cells

Sympathomimetics

Characteristics

• mimic the action of sympathetic nervous

• mode of acton

  • direct: activation of the receptor

  • indirect: increase release of NE

Non-selective adrenoceptor agonist (direct)

Adrenaline

• action

  • ß1

    • increase stroke volume and heart rate→ higher blood pressure

  • ß2

    • reduce peripheral resistance (vasodilation)

    • increase smooth muscle relaxation

  • low affinity to α receptor

• clinical use

  • anaphylactic shock

    • airway relaxation and resolve blood pressure

  • cardiac arrest

  • asthma

    • bronchodialation and airway relaxation

Noradrenaline

• action

  • ß1

    • increase stroke volume and heart rate → increase blood pressure

  • stimulate α1 > ß2

    • increase peripheral resistance (vasoconstriction) → further increase blood pressure

    • reflex bradycardia occur

      • baroreceptor send signal to brain due to too high blood pressure

      • brain activates parasympathetic system to stimulate muscarinic receptor to heart

      • → reduce heart rate: bradycardia

Isoproterenol (non-selective ß1 receptor)

• action

  • ß1

    • increase stroke volume and heart rate

  • ß2

    • reduce peripheral resistance

    • smooth muscle relaxation

  • overall: reduce blood pressure

• clinical use

  • asthma

    • airway dilation

Selective receptor agonist (direct)

Phenylephrine & oxymetazoline (selective α1 receptor agonist)

• action

  • vasoconstriction → increase blood pressure

  • smooth muscle contraction except GI (smaller effect)

• clinical use

  • decongestant

    • reduce nasal mucosal swelling by vasoconstriction

Clonidine (selective α2 receptor agonist)

• action

  • inhibit presynaptic NE release

  • reduce cardiac output + reduce vaso constriction → lower blood pressure

• clinical use

  • hypertension

Dobutamine (selective ß1 receptor agonist)

• action

  • increase heart contractility and heart rate

  • → increase cardiac output and blood pressure

• clinical use

  • hypotension

  • heart failure

Terbutaline & salbutamol

• action

  • vasodilation (not affecting the heart rate)

  • smooth muscle relaxation

• clinical use

  • bronchodilator

Mirabegron (still in phase 2 clinical trial)

• action

  • urinary bladder and skeletal muscle relaxation

• clinical use

  • overative bladder

  • obesity

    • lipolysis

Indirectly acting sympathomimetic amines

Tyramine

• rich in fermented cheese

• action

  • increase NE release via NET by reversing its action

  • readily metabolised by MAO in synaptic cytoplasm and liver

    • dangerous rise in blood pressure when taking MAO inhibitor with tyramine or tyramine-rich food

• no clinical use

Ephedrine

• naturally occurring in some plants

  • such as ephedra

• stereoisomer of ephedrine: pseudoephedrine

• action

  • increase NE release via NET by reversing its action

• clinical use

  • nasal decongestion

Sympatholytics

Characteristic

• reduce the action of sympathetic nervous system

• mode of action

  • direct: block receptor activation

  • indirect: inhibit synthesis of NE

Receptor antagonist

Prazosin & Tamsulosin (selective α1 receptor antagonist)

• action

  • reduce vasoconstriction → vasodilation → reduce blood pressure

  • reduce smooth muscle contraction→ relaxation

• clinical use

  • hypertension

    • vasodilation

  • benign prostatic hypertrophy (prostate gland enlargement → block urethra)

    • relaxe prostate smooth muscle

Yohimbine (selective α2 receptor antagonist)

• action

  • block α2 receptor → increase NE release

  • increase heart contractility and heart rate→ increase cardiac output and blood pressure

  • smooth muscle relaxation

  • can block seretonin & dopamine receptor as well

• no clinical use

Propranolol (non-selective ß receptor antagonist)

• action

  • ß1

    • reduce heart contractility and heart rate

  • ß2

    • vasoconstriction

  • overall: reduce cardiac output and reduce blood pressure

  • smooth muscle contraction

• clinical use

  • angina (heart pain)

    • vasodilation of coronary artery to increase O2 supply to heart

    • reduce workload of heart by reducing heart contractility and heart rate

  • cardiac dysrhythmias

  • hypertension

  • may have side effect on bronchoconstriction

Atenolol & metoprolol (selective ß1 receptor antagonist)

• action

  • reduce heart contractility and heart rate

  • → reduce cardiac output and blood pressure

  • has no effect on smooth muscle

• clinical use (suitable for patients with asthma)

  • angina

  • cardiac dysrhythmia

  • hypertension

Butaxamine

• action

  • reduce vasodilation → vasoconstriction

  • contraction of other smooth muscle

• no clinical use

Drugs affecting NE synthesis

Methyldopa

• false transmitter of α-methylnoradrenaline

• not deaminated by MAO

  • accumulation of it can displace NE from synaptic vesicle

• action

  • less active on α1 receptors

    • less effective causing vasoconstriction

  • more active on presynaptic α2 receptor

    • reduce NE release

  • overall: reduce blood pressure

• clinical use

  • hypertension