SNS agonists Flashcards
How do presynaptic alpha 2 receptors influence NA synthesis and release?
High [NA] in synapse
Stimulates presynpatic a2 receptors
Negative feedback effect on NA synthesis and release
Impairs sympathetic function
Explain the relative selectivity of SNS agonists
- All adrenoceptors can be activated by NA and A
- NA is more selective for alpha receptors
- A is more selective for beta receptors
List some SNS agonists and whether they are selective. If they are, what for?
Adrenaline - non-selective Phenylephrine - a1 Clonidine - a2 Dobutamine - b1 Salbutamol - b2 Isoprenaline - b1 + b2
What does adrenoceptor selectivity depend on?
- Concentration of drug
- At low conc, drugs are selective
- Increase conc, chance of binding to other receptors increases
What are the clinical uses of adrenaline (non-selective adrenoceptor agonist)?
ADRENALINE
- Allergic reactions and anaphylactic shock - reverses potentially life-threatening hypotension and bronchoconstriction
- Cardiogenic shock
- COPD - relieves breathing difficulties
- Acute management of heart block
- Spinal anaesthesia (i.v.) - maintains BP
- LA - vasoconstricts, prolongs action
- Glaucoma
What are the principal pharmacological features of adrenaline (non-selective adrenoceptor agonists)?
a1 - vasoconstriction b1 - tachycardia b2 - bronchodilation Suppression of mediator release (histamine from mast cells) Relaxation of throat muscles
- im, iv, sc
- poorly absorbed
- doa = mins
- metabolised by MAO and COMT
How does adrenaline (non-selective adrenoceptor agonist) work?
Allergic reaction, anaphylactic shock:
- B2 - bronchodilation to allow breathing
- B1 - tachycardia to support BP
- A1 - vasoconstriction
- Suppression of mediator release (histamine)
- Acute bronchospasm, asthma: B2-mediated bronchodilation and suppression of mediator release
- Cardiogenic shock - B1 inotropic effects
A1 - maintains BP in spinal anaesthesia and vasoconstricts to prolong action in LA
Glaucoma - stimulates a1Rs in BVs in ciliary body –> vasoconstriction –> less blood to CB –> reduced AH production
What are the unwanted effects of adrenaline (non-selective adrenoceptor agonist)?
ADRENALINE
- Reduced and thick secretions
- CVS: tachycardia, palpitations, arrhythmias, cold extremities, hypertension, overdose - cerebral haemorrhage, PE
- Skeletal muscle tremor
What are the clinical uses of phenylephrine (a1-selective adrenoceptor agonist)?
Vasoconstriction - iv, topical (slightly elevated BP)
Mydriatic - eye drops
Nasal decongestant - nose drops, oral
What are the principal pharmacological features of phenylephrine (a1-selective adrenoceptor agonist)?
a1 - phenylephrine:
Chemically related to adrenaline
More resistant to COMT degradation
Not resistant to MAO degradation
What are the unwanted effects of alpha-selective adrenoceptor agonists?
a1 - phenylephrine: Headache Reflex bradycardia Excitability, restlessness Cardiac arrhythmias
a2 - clonidine: Sedation Dry mouth Hypotension Persistent colds
How do alpha-selective adrenoceptor agonists work?
a1 - phenylephrine
Binds to a1Rs to cause vasoconstriction
a2 - clonidine: 2 actions 1. Stimulates pre-synaptic a2Rs in vasomotor centre in BS Decreases presynaptic [Ca] Inhibits NA release Less stimulation at effector organ Less vasoconstriction Reduced TPR and BP
- Acts on baroreceptors to reduce symp drive out of brain
Reduces TPR and NA release at nerve terminal
Reduces TPR further and BP
What are the clinical uses of beta-selective adrenoceptor agonists?
b1 + b2 - isoprenaline:
Heart block - i.v.
b1 - dobutamine:
Cardiogenic shock
Acute HF - all i.v.
MI
b2 - salbutamol:
Asthma - inhalation, oral
Threatened uncomplicated premature labour - i.v.
What are the principal pharmacological features of beta-selective adrenoceptor agonists?
b1 + b2 - isoprenaline:
-A derivative of nor-adrenaline, but less
susceptible to breakdown by Uptake 1 and MAO
- Longer plasma half-life - 2h
- Some tissue uptake, metabolised by COMT
b1 - dobutamine:
- Plasma half-life = 2 mins
- Rapidly metabolised by COMT
- i.v.
b2 - salbutamol:
- Synthetic catecholamine derivative
- Relative resistance to MAO, COMT and Uptake 1
- oral or aerosol
- half life = 4h
What are the unwanted effects of beta-selective adrenoceptor agonists?
b1 + b2 - isoprenaline:
- Pooling of blood in muscles
- Decreased venous return
- Reflex tachycardia
- Tf b2 stimulation is bad for HF patients
- Exacerbates arrhytmias
b1 - dobutamine:
- Exacerbates arrhytmias
b2 - salbutamol:
- Reflex tachycardia
- Fine tremor in skeletal muscles
- Blood sugar dysregulation
- Caution with cardiac patients, hyperthyroidism (increased
sensitivity of adrenoceptors) and i.v. use in diabetics
How does isoprenaline (b1+2-selective adrenoceptor agonist) reduce blood pressure?
- Stimulates cardiac b1/2Rs on arteriolar SM
- Positive chronotropic and inotropic effects elevate SBP
- Stimulates b2Rs in VSM –> vasodilation in muscles –> lowers DBP
- Overall lower MAP
What are the principal pharmacological features of clonidine (a2-selective adrenoceptor agonist)?
- Stimulates pre-synaptic a2Rs - negative effect on NA synthesis and release
- Less NA released –> less stimulation at effector organ –> less vasoconstriction –> fall in TPR and BP
- In kidneys, reduced renin secretion –> reduced angiotensin II production (potent vasoconstrictor)
- Also central action on brainstem:
- Works on baroreceptors to reduce sympathetic drive coming out of brain
- Reduction in sympathetic activity –> reduces TPR and amount of NA released at nerve terminal –> reduces TPR further
What are the clinical uses of clonidine (a2-selective adrenoceptor agonist)?
Hypertension (not anymore)
Migraine
What are the actions of tyramine (indirectly-acting sympathomimetic)?
- Some weak agonistic activity at post-synaptic adrenoceptors
- Displaces NA from intracellular vesicles, tf increasing cytosolic [NA] –> leakage into synaptic cleft
How does dobutamine (b1-selective adrenoceptor agonist) help treat cardiogenic shock, acute HF and MI?
Stimulates b1Rs on heart
Positive inotropic effect
Increases FoC and CO
How does salbutamol (b2-selective adrenoceptor agonist) treat asthma and threatened premature labour?
Asthma:
- b2-mediated relaxation of bronchial smooth muscle
- Inhibits release of bronchoconstrictor substances from mast cells
- Inhaler gives localised effects on lungs
- Tablets for chronic asthma in hospital
Threatened premature labour:
- b2-mediated relaxation of uterine smooth muscle
- Prevents abortion of foetus
What are adrenoceptor agonists principally used for?
Their actions in CVS, eyes and lungs
In general, how do adrenoceptor agonists work?
Mimic the action of NA/A by binding to and stimulating adrenoceptors
How do the different types of adrenoceptor exert their action intracellularly?
a1 - PLC, IP3, DAG
a2 - decrease cAMP
b1 + b2 - increase cAMP
What adrenoceptor is the heart mainly controlled by?
b1 Increases contractility (inotropic) Increases HR (chronotropic)
What adrenoceptor is the vasculature mainly controlled by?
a1
Vasoconstriction
Why may foods which contain tyramine (indirectly acting sympathomimetic) represent no harm to the normal subject, but may precipitate a life-threatening hypertensive crises in patients taking monoamine oxidase inhibitors?
- Tyramine competes with catecholamines for Uptake 1, i.e. taken up into adrenergic nerve terminals
- It displaces NA from IC storage vesicles into cytosol
- NA and tyramine compete for sites on MAO
- Cytoplasmic NA leaks thr neuronal membrane to act at post-synaptic adrenoceptors
- Under normal conditions this is not a problem (extensive first pass metabolism, short half-life, does not enter CNS)
- When MOAs are inhibited (e.g. antidepressant drugs), tyramine may cause a hypertensive crisis (‘cheese reaction’) bc too much NA released and can’t be broken down
What is tyramine?
A dietary amino acid found in foods such as cheese, red wine and soy sauce
Indirectly-acting sympathomimetic
