SNS agonists Flashcards
14.10.2019
What intracellular actions happen at alpha1, alpha 2, beta1 and beta2?
Alpha-1: PLC, IP3, DAG
Alpha-2: decrease in cAMP
Beta-1: increase in cAMP
Beta-2: increase in cAMP
Where are adrenoreceptors found?
- at effector organs in the SNS
Relative selectivity SNS agonists
All Adrenoreceptors can be activated by A and NA.
- Selectivity for A: b1 = b2 > a1 = a2
- Selectivity for NA: a1 = a2 > b1 = b2
Heart
Beta-1 tissue
Lungs
Beta-2 tissue
Blood Vessles
Alpha-1 tissue
Noradrenaline Metabolism
1) Tyrosine -> DOPA (via tyrosine hydroxylase)
2) DOPA -> Dopamine (via DOPA decarboxylase)
3) Dopamine enters vesicle
4) Dopamine -> NA (via dopamine beta hydroxylase)
5) exocytosis
- NA binding to Alpha 2 receptor (prejunctional receptor)
- > controls its own secretion
Directly Acting SNS agonists
- Adrenaline (non-selective)
- Phenylephrine (a1)
- Clonidine (a2)
- Dobutamine (b1)
- Salbutamol (b2)
How does NA control its own secretion?
- alpha-2 receptor on presynaptic cell
- NA binding negatively feeds back on NA release
Name a non-specific SNS agonist
Adrenaline (e.g. epi-pen)
Why is adrenaline used in the treatment of anaphylaxis?
b2 – broncho dilation
b1 – tachycardia
a1 – vasoconstriction
- suppression of mediator release
What are the effects on alpha 2 receptors?
- suppresses the release of NA (neg. feedback)
What are other clinical uses of Adrenaline?
- Asthma (i.m. or s.c. in emergencies) beta-2
- Acute bronchospasm (ass. with chronic bronchitis or emphysema) beta-2 mediator release
- cariogenic shock - sudden inability of the heart to pump sufficient O2 rich blood (beta-1 inotropic effect)
- spinal anaesthesia (alpha 1 maintains BP)
- local anaesthesia (alpha 1 vasoconstrictor - prolongs action)
- anaphylactic shock
What are some unwanted effects of adrenaline?
Secretions – reduced and thickened mucous
- CNS – minimal
- CVS effects
- tachycardia, palpitations, arrhythmias
- cold extremities, hypertension
- overdose – cerebral haemorrhage,pulmonaryoedema
- GIT – minimal
- Skeletal muscle - tremor
Name an alpha-1 specific agonist?
Phenylephrine
Selectivity of phenylephrine
a1»_space; a2»_space;> b1/b2
Why might phenylephrine be used as an anticongestant?
- e.g. sudafed or lemsip
- vasoconstriction: less white cell infiltration, less fluid exudation
Properties of phenylephrine
- chemically related to adrenaline
- more resistant to COMT but not MAO
- clinical use as a decongestant
- Mydriatic (induces pupil dilation)
- vasoconstriction
Name an a2 selective SNS agonist
Clonidine
Selectivity of Clonidine
a2»_space; a1»_space;> b1/b2
What are the clinical uses of clonidine?
- Treatment of hypertension and migraine
- Reduces sympathetic tone
- a2 adrenoceptor mediated
- presynaptic inhibition of NA release
-Central action in brainstem within baroreceptor
pathway to reduce sympathetic outflow.
- Glaucoma
Properties of clonidine
- agonist, however acts like an antagonist because a2 receptor suppresses release of NA
- a2 selective
What is glaucoma?
- raised intraocular pressure in the anterior chamber of the eye
What causes glaucoma?
- poor drainage of aqueous humour
- If untreated, it permanently damages the optic nerve, blindness.
What produces the aqueous humour in the eye?
- the cilary body
Why are sympathomimetics used in Glaucoma?
Think about the receptors on the ciliary body:
- a1: vasoconstricton -> effective for glaucoma because restricted blood flow -> restricted humour production
- a2: negative feedback, interferes with beta function
What is the difference between blood vessel control in the brain and in other parts of the body?
- body: predominantly alpha-1 controlled, vasoconstriction
- brain: predominantly beta-2 controlled, vasodilation (associated with increased blood flow)
Isoprenaline
- beta selective but not for b1 or 2
- chemically related to adrenaline
- more resistant to MAO and uptake 1
Selectivity of Isoprenaline
b1 = b2»_space;» a1/a2
Clinical use of isoprenaline
- cariogenic shock
- MI
- acute HF
What do you have to be careful about earn giving beta2 receptor agonists?
Caution - b2-stimulation in vascular smooth muscle in skeletal muscle results in fall in venous blood pressure which triggers a reflex tachycardia via the stimulation of baroreceptors.
massive vasodilation + reflex tachycardia
Dobutamine selectivity
b1»_space; b2»_space;> a1/a2
Name a b1 selective agonist
Dobutamine
What are the properties of dobutamine?
- short acting
- lacks isoprenaline’s reflex tachycardia
- plasma half life is 2 minutes (rapid metabolism by COMT)
What are the clinical uses of Dobutamine?
- Cardiogenic shock
- Lacks isoprenaline’s reflex tachycardia
- Plasma half life 2 minutes (rapidly metabolised by COMT)
Name a beta-2 selective agonist
Salbutamol (ventolin)
Selectivity of Salbutamol (Ventolin)
b2»_space; b1»_space;> a1/a2
What are the properties of salbutamol?
- Synthetic catecholamine derivative with relative resistance to MAO and COMT
- more resistant to breakdown!!
What are the clinical uses of salbutamol?
- Treatment of Asthma
- b2-relaxation of bronchial smooth muscle
- inhibition of release of brochoconstrictor substances
from mast cells.
- Treatment of threatened premature labour
- b2-relaxation of uterine smooth muscle
Side effects- Reflex tachycardia, Tremor, blood sugar dysregulation
- b2-relaxation of uterine smooth muscle
Which ventilators are salbutamol?
the blue ones
How does salbutamol cause dilation of airways?
- inhalation
- binds to b2R
- increase in ic cAMP
- almost hyperpolarisation
- K+ efflux
- relaxation of the muscle
- dilation of airways -> breathing is easier
How does adrenaline help in anaphylactic shock?
- it produces the opposite effect of that of histamine
= physiological antagonism - effects like bronchodilation, tachycardia, vasoconstriction
Which enzyme converts dopamine to NA?
dopamine beta hydroxylase
Directly acting SNS agonists
APCDS
Adrenaline (non-selective) Phenylephrine (a1) Clonidine (a2) Dobutamine (b1) Salbutamol (b2)
What happens during anaphylaxis?
- IgE coated mast cells
- degranulation and release of inflammatory mediators
a) heart and vasculature: increased capillary permeability, entry of fluid into tissues, swelling of tissues incl. tongue, fall in BP, reduced O2 to tissues, irregular heart beat, anaphylactic shock, loss of conciusness
b) resp: contraction of SM and constriction of throat and airways; difficulty swallowing; difficulty breathing wheezing;
c) GIT: contraction of SM, cramps, vomiting, fluid outflow into gut, diarrhoea.
Clinical use of phenylephrine
- nasal decongestant
- mydriatic
- vasoconstriction
