SNS Antagonsits Flashcards
Alpha 1 effects
- Vasoconstriction!!!
- Relaxation of GIT
Alpha 2 effects
- Inhibition of transmitter release
- contraction of vascular smooth muscle
- CNS actions.
- diminish sympathetic activity
Beta 1 effects (3)
- Increased cardiac rate and force of contraction
- relaxation of GIT
- renin release from kidney
- HEART!
Beta 2 effects
- Brochodilation
vasodilation
relaxation of visceral smooth muscle - hepatic glycogenolysis
Beta 3 effects
- Lipolysis
BP Formula
BP = CO x TPR
Why is it important to treat Hypertension?
To reduce mortality from cardiovascular or renal events Hypertension is a RF for: - stroke - MI - CKD (chronic kidney disease) - heart failure
How does BP differ in people with different size?
- BP changes slighlty with size, if you are smaller BP should be lower.
- e.g. if you are small a BP below 140/90 mmHg would most likely be hypertensive
What are the main contributors to BP?
- Blood volume
- Cardiac output
- Vascular tone
What is Hypertension?
When the BP is consistently above 140/90 mmHg
How do beta blockers work on the heart?
- decrease HR and FOC -> decreased CO (which affects BP)
- beta 1
How do beta blockers work on the kidneys?
- Renin production is a sympathetically driven process
- less renin —> less AT2
- A2 is a potent vasoconstrictor and causes increased aldosterone production (-> beta blocker reduces aldosterone production)
- beta 1
Nebivolol
- some ability to potentiate NO
- b1
Sotalol
- non selective beta blocker
- inhibits K+ channels????
Carvedilol
- mixed beta + alpha blocker
- a1, b1, b2
- a1 blcokade gives additional vasodilator properties
What are some unwanted effects of beta blockers?
- bronchoconstriction (in asthma or COPD)
- Cardiac failure - you need some sympathetic drive to the heart
- Hypoglycaemia (mask the symptoms of hypoglycaemia/ inhibit glycogen breakdown)
- Fatigue (decreased CO and decreased muscle perfusion)
- Cold extremities (loss of b-receptor mediated vasodilation in skin)
- Bad dreams
Sotalol
- non selective beta blocker
- inhibits K+ channels, interferes with cell hyper polarisation
What is the advantage of atenolol over propranolol?
- Propanolol: b1-B2; Atenolol: b1 selective
- effects on lungs/liver are beta 2 mediated
- asthmatics and diabetics are less likely to respond negatively to those drugs
- b1 selective drugs are historically known as cardio selective
less effects on the airways than non selective drugs but still not safe with asthmatic patients! selectivity is concentration dependent.
What advantage does carvedilol have over atenolol and propranolol?
- more powerful hypotensive effect due to additional blocking of arteriole vasoconstriction
- if they have very high hypertension
- however more targets -> more side effects
- effect on change in HR and CO wanes off in chronic use of beta blockers.
Alpha 1 receptor
- Gq-linked
- Postsynaptic on vascular smooth muscle
Alpha 2 receptor
- Gi-linked
- Presynaptic autoreceptors inhibiting NA release
- decrease intracellular cAMP
When would you used phentolamine?
- non selective alpha-blocker
- used to treat phaechromocytoma-induced hypertension
Side effects of alpha blockers?
- diarrhoea
- overactive GI function
- increased GI motility
Why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?
- A2R: Reduce negative feedback -> more NA released -> competitive action between phentolamine and NA
- Baroreceptors: If you interfere with vasculature -> dilation -> decrease to pressure in system -> decrese BR firing -> increases SNS activity -> tries to compensate by increasing HR and SV
When is methyldopa used as an anti-hypertensive?
Improved Blood flow;
Used when hypertension is contributing to:
- renal problems: kidney disease
- CNS - cerebrovascular disease
Side effects of methyldopa
- dry mouth
- sedation
- Orthostatic hypotension
- Male sexual dysfunction
Mainly HYPOTENSION!
Arrythmia
- abnormal or irregular heart beats
- Increased sympathetic drive to heart. Precipitates arrhythmias
What drug type is generally used in arrhythmia?
- Propanolol (non selective b-blocker)
- propanolol is a class 2 drug
- If you speed the heart up it might eject blood less effecctvely -> in arrythmias it is good to decrease HR to allow better BF through heart, between the differnet chambers (atria and ventricles
- reduces mortality of patients with MI
- Particularly successful in arrhythmias that occur during exercise or mental stress.
MORE INFO
- An increase in sympathetic drive to the heart via b1 can precipitate or aggravate arrhythmias. Particularly after MI there is an increase in sympathetic tone.
- AV conductance also depends critically on sympathetic activity, and the refractory period of the AV node is increased by b-adrenoceptor antagonists, interfering with AV conduction in atrial tachycardia’s, and to slow ventricular rate.
Stable Angina
- pain on exertion
- Increased demand on the heart and is due to fixed narrowing of the coronary vessels e.g. atheroma.
Unstable angina
- pain with less and less exertion, culminating with pain at rest.
- Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel.
- Risk of infarction.
variable angina
- occurs at rest, caused by coronary artery spasm, associated with atheromatous disease.
Glaucoma
- Increase in intraocular pressure.
- if untreated: damage to optic nerve, blindness
- caused by problems with drainage (predominantly) or problems with too much production
b1 blockage in glaucoma
- if you block the b1 receptor you stop or decrease the ciliary body from producing the aqueous humour via carbonic anhydrase
- you stop epithelia cells in the ciliary body from making bicarbonate ions.
Glaucoma
- Increase in intraocular pressure.
- caused by poor drainage of the aqueous humour
- if untreated: damage to optic nerve, blindness
b1 blockage in glaucoma
- stops production of aqueous humour
What drugs can be used for treatment of glaucoma?
- beta blocker -> to decrease production
- there are also some drugs that help with drainage
What is special about the alpha 2 receptor?
- found on the presynaptic cell
- as soon as NA is released, to act on a a1/b1/b2 receptor, there is negative feedback via a2, stops the release of further NA
- allows for swift response, brief, short lasting
b1 and b2 blocker
Propanolol
b1 blocker
Atenolol
Phentolamine selectivity
a1 + a2
Prazosin selectivity
a1
Hypertension and Stroke
Single most important risk factor for stroke, causing about 50% of ischaemic strokes
Hypertension and HF
Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly
What are the tissue targets for anti-hypertensives?
- heart (CO)
- Sympathetic nerves that release the vasoconstrictor NA
- Kidney (blood volume, vasoconstriction)
- Arterioles - determines TPR
- CNS - determines BP set point and regulates some systems involved in BP control & autonomic NS
What are the tissue targets for anti-hypertensives?
- heart (CO)
- Sympathetic nerves that release the vasoconstrictor NA
- Kidney (blood volume, vasoconstriction)
- Arterioles - determines TPR
- CNS - determines BP set point and regulates some systems involved in BP control & autonomic NS
What are the main targets of beta blockers?
- heart
- sympathetic nerves
- kidney
- CNS (facilitation of neurotransmission, control of BP and ANS)
NOT: arterioles and adrenals
Which people would you not give beta blockers to?
- asthmatics / COPD patients (because the SNS is responsible for bronchodilator and blockers will inhibit this)
- diabetics (acts on liver, danger of hypoglycaemia; masks the symptoms of hypoglycaemia and inhibit glycogen breakdown)
- pregnant women (crossing of the placental barrier)
- fatigue (reduced CO and reduced muscle perfusion will make it worse)
- cold extremities (loss of beta mediated vasodilation in cutaneous vessles)
- bad dreams
Are there beta receptors on nerves terminals, like the a2 receptors?
- yes, there are presynaptic beta-adrenoreceptors that act to increase NA release
- they are there for the sympathetic F&F response
- using beta blockers also affects these and has an inhibitory effect on the SNS that way, however this effect is much smaller than the effects on the heart and kidney.
Beta blockers and hypoglycaemia
- beta antagonists mask the symptoms of hypoglycemia (sweating, palpitations, tremor). - Use of non-selective b-antagonists are more dangerous in such patients since they will also block the b2- receptors driven breakdown of glycogen
- b1- selective agents may have advantages since glucose release from the liver is controlled by b2- receptors.
Which drugs were historically called cardio-selective drugs?
- b1 selective blockers
- b1-Selective, antagonises the effects of noradrenaline on the heart but will affect any tissue with b1 receptors e.g. Kidney.
- Less effect on airways than non-selective drugs, but still not safe with asthmatic patients.
- Selectivity is concentration dependent.
Which drug has a stronger anti-hypertensive effect - phentolamine or prazosin?
- Phentolamine (non-selective)
- we don’t really know why (since prazosin also blocks a2)
What drug would you give in phaeochromocytoma?
- non selective a-blocker to block the a1 receptor to dilate the vessels to combat hypertension.
- Phaeo: tumour releasing massive amounts of adrenaline
How does methyldopa work?
- Methyldopa is converted to a false NT: alpha-methylnoradrenaline
- it is packaged into vesicles and released into the synapse upon stimulation
- it binds mainly to a2 receptors on the presynaptic cell and does not bind well to a1,b1 or b2
- Uptake 1 but it is not metabolised by MAO -> more of the compound in the presynaptic cell and therefore the c-gradient decreases -> uptake also slower.
Also displaces NA from synaptic vesicles - There is less uptake so it stays in the synapse longer and acts on the a2 receptors inhibition NA secretion (usually negative feedback mechanism)
-> heavy a2 stimulation
First line treatment for hypertension in pregnancy
What conditions can SNS antagonists be used for?
- Hypertension
- Glaucoma
- Arrhythmia
- Angina
Metoprolol
At low doses, b1-selective agents, metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle.
Reduce the oxygen demand whilst maintaining the same degree of effort
(in context of angina)
Production of aqueous humour
- Produced by blood vessels in ciliary body via the actions of carbonic anhydrase (b1 receptor is coupled to CA)
- Flows into posterior chamber, through the pupil to anterior chamber.
- Drains into trabecular network and into the veins and canal of Schlemm.
- Production indirectly related to blood pressure and blood flow in ciliary body
Blockade of the facilitatory effects of presynaptic β-adrenoceptors
- there are beta receptors on presenynaptic nerve terminals
0 theses act to increase NA secretion - less effective than a2
- for the fight and flight response (you want a bigger and more powerful sympathetic response)
- more selective for Adrenaline
- increases NA release
This is only a minor effect, the effects of beta blockers on the heart and kidney are much more profound.
Summarise the main types of beta blockers
Non-selective
b) beta-1 selevtive
c) mixed
d) Other
- e.g. Nebivolol (b1 and potentates NO)
- e.g. Sotalol (b1, b2 and inhibits potassium channels)
Sotalol
- b1 and b2 blocker
- also inhibits K+ channels
- By blocking these potassium channels, sotalol inhibits efflux of K+ ions, which results in an increase in the time before another electrical signal can be generated in ventricular myocytes.
- This increase in the period before a new signal for contraction is generated, helps to correct arrhythmias by reducing the potential for premature or abnormal contraction of the ventricles but also prolongs the frequency of ventricular contraction to help treat tachycardia.
Why is phentolamine used in phaeochtomocytoma?
- in phaeo there is a massive release of A causing all sorts of SNS symptoms incl. Hypertension
Why do you use a non-selective alpha-blocker such as phenotalmine in pheochromocytoma and not an alpha-1 selective one like prazosin?
- For some reason phentolamine is a more powerful anti-hypertensive
- this is counter intuitive because by blocking alpha-2 you block inhibition of NA but clinically it seems that the non-selective one works better in terms of lowering BP in phaeo
Prazosin
- alpha one selective blockers
- can be used for hypertension but is more of a 4th/5th line drug; used e.g. if the patient isn’t responding well to the other drug combinations or are particularly tolerant to other combinations
Non-selective alpha blockers
- Fall in arterial pressure (a-adrenoceptors main mediators of peripheral resistance).
- Postural hypotension.
- Cardiac output/heart rate increases - reflex response to fall in arterial pressure (b-receptors).
- BF through cutaneous & splanchnic vascular beds increased, but effects on vascular smooth muscle are slight
alpha blockers
- prazosin; highly selective for a1
- Less tachycardia than non-selective antagonists since they do not increase noradrenaline release from nerve terminals (no a2 actions)
- Cardiac output decreases, due to fall in venous pressure as a result of dilation of capacitance vessels.
- Hypotensive effect is dramatic.
- does not affect cardiac function much but postural hypertension is a problem.
Unlike other anti-hypertensive agents a1-antagonists cause a modest decrease in LDL, and an increase in HDL cholesterol. Starting to become more popular again as anti-hypertensive agents.
When is methyldopa used?
- as a hypertensive
- especially in kidney disease or cerebrovascular disease
- aslo used as a hypertensive in pregnancy
SE of methyldopa
MANY! - hypotension! (decreases its use) - dry mouth (decreases sympathetically driven saliva production) - N&V -
What drug would you give for angina?
- b1 selective antagonists
- e.g. metoprolol
- reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle.
- reduce oxygen demand whilst maintaining the same degree of effort.
