Pharmacology 8 - SNS agonists Flashcards
What are SNS agonists principally used for?
Actions in the CVS, eyes and lungs
Compare the selectivity of noradrenaline and adrenaline
- Noradrenaline is more alpha than beta selective
- Adrenaline is more beta than alpha selective
Describe the process noradrenaline metabolism
- Tyrosine converted to noradrenaline, via DOPA then dopamine - last step in the vesicle
- Action potential causes noradrenaline release from vesicles
- Noradrenaline is then taken up into the cells and broken down
- Noradrenaline controls its own secretion, by binding to alpha 2 receptors on the presynaptic neurone (this slows NA secretion)
List the directly acting SNS agonists
- Adrenaline (non-selective agent)
- Phenylephrine (alpha 1)
- Clonidine (alpha 2)
- Dobutamine (beta 1)
- Salbutamol (beta 2)
What is the main use of adrenaline?
Allergic reactions and anaphylactic shock
- B2 causes bronchodilation
- B1 causes tachycardia
- alpha 1 causes vasoconstriction
- Suppression of mediator release from mast cells
- Relaxing effect on the gut (less stomach cramps)
List the other clinical uses of adrenaline
- Asthma (emergencies - asthma attack) => beta 2
- Acute bronchospasm (associated with chronic bronchitis or emphysema) => beta 2
- Cardiogenic shock (sudden inability of the heart to pump sufficient oxygen rich blood) => beta 1
- Spinal anaesthesia (maintains BP) => alpha 1
- Local anaesthesia (vasoconstricts to prolong action, slow the anaesthesia getting into systemic circulation) => alpha 1
List the unwanted effects of adrenaline
- Reduced and thickened mucous
- Tachycardia, palpations, arrhythmias
- Cold extremities
- Hypertension
- Overdose results in cerebral haemorrhage and pulmonary oedema
- Skeletal muscle tremor
What is phenyleprine?
- Chemically related to adrenaline
- More resistant to COMT (peripheral enzyme - therefore longer lasting peripherally) but not MAO (central enzyme)
What is phenylephrine used for?
- Nasal decongestant (reduces white cell infiltration to the nasal sinus due to vasoconstriction)
- Mydriatic (pupil dilation)
- Vasoconstriction
Describe the mechanism of action of clonidine?
Selective to alpha 2 (anti-sympathetic effects), then 1 then beta 1/2
What is glaucoma, describe its cause and the risks if untreated.
- Increase in intraocular pressure
- Caused by poor drainage of aqueous humour
- If untreated, it permanently damages the optic nerve causing blindness
How are sympathomimetics used in glaucoma treatment?
- A1 receptors causes vasoconstriction of ciliary body arterioles
- A2 receptors causes decreased aqueous humour formation
List the clinical uses of clonidine
- Treatment of hypertension (decreased vasoconstriction) and migrane (link between sympathetic vasodilation + migrane)
- Reduces sympathetic tone (a2 adrenoreceptor mediated inhibition of NA release, central action in the brainstem to reduce sympathetic outflow)
List the uses of isoprenaline
- Selective for beta 1/2
- Chemically related to adrenaline (more resistant to MAO and uptake 1, less easily broken down in the brain)
- Used in cardiogenic shock, acute heart failure and myocardial infarction
List the clinical uses of dobutamine
- Cardiogenic shock, an emergency medication
- Plasma half life of 2 minutes
List the clinical uses of salbutamol
- Used in asthma inhalers (beta 2 relaxation of smooth muscle, and inhibits release of bronchoconstrictor substances from mast cells)
- Used to treat threatened premature labour (relaxation of uterine smooth muscle)
- Long lasting as it is resistant to breakdown
List the side effects of salbutamol
- Reflex tachycardia
- Tremor
- Blood sugar dysregulation
List the mechanisms following binding to alpha 1, 2, beta 1, 2 adrenoreceptors
- alpha 1 - PLC, IP3, DAG
- alpha 2 - Decrease cAMP
- beta 1 - increase cAMP
- beta 2 - increase cAMP
Why is it a problem that isoprenaline stimulates beta 1 as well as beta 2?
- Blood vessel dilation at the gut, lowers blood pressure
- Also causes reflex tachycardia (an issue if using this to treat asthma)
How does salbutamol cause muscle relaxation?
- cAMP makes protein kinase A, causes potassium efflux
- Causes muscle relaxation
What are alpha 1 adrenoreceptors responsible for?
- Pupil dilation
- Liver glycogenolysis and gluconeogenesis
- Adipose lipolysis
- Constriction of the trigone and sphincter
- Piloerection
- Constriction of blood vessels
What are alpha 2 adrenoreceptors responsible for?
- Inhibits noradrenaline release (decreases vasoconstriction and aqueous humour production from ciliary body)
- Lipolysis
- Glycogenolysis and gluconeogenesis
What are beta 1 adrenoreceptors responsible for?
- Increased renin secretion
- Increased heart rate and contractility
What are beta 2 receptors responsible for?
- Blood vessel dilation (skeletal muscle)
- Relaxes detrusor muscle
- Dilates trachea and broncheoles
- Glycogenolysis and gluconeogenesis
Describe the process of contraction of the cardiac myocytes
- Depolarisation of cardiac myocytes leads to Calcium entry via the DiHydropyridine Receptor.
- Ca2+ then binds to the Ryanodine receptor on the sarcoplasmic reticulum causing calcium release.
- Ca2+ then binds to troponin to allow contraction.
- To end the contraction, intracellular Ca2+ is pumped out by Plasma Membrane Calcium ATPase and the rest is re-uptaken into the sarcoplasmic reticulum by SERCA2a (main method)
- SERCA interacts with Phospholamban (PLN) which is an inhibitor of SERCA when dephosphorylated.
- When PLN gets phosphorylated by Protein Kinase A, it dissociates from SERCA allowing faster Calcium reuptake. To dephosphorylate PLN you require protein phosphatase 1 (PP1).
