Vasodilator pharmacology Flashcards
How do vasodilators have an indirect action on heart function
they work on smooth muscle cells
How does smooth muscle contract
when a smooth muscle cell is stimulated hormones, local factors, nervous system effects
1. calcium enters teh cell
2. calcium binds to proteins inside the muscle cells
3. leading to the activation of an enzyme called myosin light-chain kinase (MLCK)
4. MLCK then phosphorylates (adds a phosphate group to) myosin,
5. causes more stuff to happen
6. myosin and actin bind together
How do drugs interfer to cause vasodilation
-they can affect the vasoconstrictor
-or affect what happens in the smooth muscle
How do indirect vasodilators work
these are drugs which block vasoconstriction
-they use natural circulating substances released by the autonomic nervous system
How do indirect vasodilators use cirlcuating factors
like what natrual stuff does our body release, that indirect vasodilator
s like to affect
- ANS
- causes a sympathetic blockade, by blocking alpha 1 receptors,
- blocks noradrenaline, which decreases vasocontriction, which means guess what VASODILATION
RAAS
- Angiotensin 2 is a vasoconstrictor,
- if we block angiotensin 2 we can have a vasodilator action
- this mechnaims uses a angiotensin two antagonist
Endothelins - usually released by smooth muscle cells - drugs don't usually work here, but they can - since endothelins does vasoconstriction - they block natural vasoconstriction
just a note: there are significant differences between biological sexes between action of endothelial receptors, this can lead to differences in how we treat it
How do vasodilators act direlecty
- can work on calcium inside cells
How can they interfre with this
– voltage-gated calcium channels can be affected by anything changing membrane potential
- can impact channels and calcium levels
- cyclic GMP determines smooth muscle action as it affects calcium channels(hwo long they are open for), and also intermediates affect myosin actin interaction
What clinical conditiosn do we use direct vasodilators for
-Hypertension
-Angina pectoris
What are the causes of angina pectoris
- Atheromatous obstruction
- Arterial spasm (smooth spasms)
So how do these drugs work for angina pectoris or hypertension
- increase coronory flow
- decrease increase cardiac work
Drugs treating angina
How do do we classify drugs that treat angina
Class A, B
Give an example of drug class A
Beta blockers
Ivabradine
What is the mechanism of beta blockers
they block the beta 1 receptor
How does Ivabradine woek
inhibits the I-F channel
which is responsible for pacemaker curve
by inhibiting reduce HR
reduces CW
True or False
Class A drugs are vasodilators
FALSE
some of them are not vasodilators
Give an example of class B drugs
Organic nitrates
Glyceryl trinitrate (GTN)
* they do not selectivley target coronary vasculature, they act systemitcally
Isosorbide mono/dinitrate
-these are more selective
How do class B drugs vasodilate
- contain nitrogen, so when they are brokendown it makes NO
- NO via actions on a the enzyme guanylate cyclase can increase cyclic GMP
- by increasing cGMP can promote relaxation
- Increasing cGMP can be done by two ways
1. action of calcium channels
2. or actions on Actin-Myosin interactions
How does GTN treat angina
Works on systemic vessels
- has action on venous vessels compared to aterial vessels
- means we decrease venous return
- which decreases cardiac work (starling),
- so we reduce oxygen demand,
- so specific reduction in cW, -coronary blood supply has o2 for cardiac mycoutes
GTN can also effect on coronary vessels (minor effect)
- it increases cornory blood flow
- BUT… if there’s an obstruction, causing vasodilation may not help
so main action is to reduce preload for systemic vessles
What are the unwanted effects of GIT
- too much vasodilation
- can be hard to titrate drug
- can cause hypotension (low bp) → can lead to syncope (fainting)
- can also have headache due to excess vasodilation of blood vessles in brain
- can affect GIT, smooth muscle relaxtion means reducing motlity, so you may need to chnage diet
How do we adminster GTN
- Sublingual
- sprayed under tongue
- under tongue highly vasocisled, since there;s thin mucosa,
- means there’s rapid diffusion to enter circulatory system
- short duration because metabolsied fast in liver
- people with angina need it on a need basis, since it works fast
NOT TAKEN ORALLY:
because it is completely metabolsied through liver, so it doesn’t reach its target
When can you take GTN transdermally
- prophylaxis
- use patches, where drug is constantly diffusing to prevent angina attack
What tolerances can GTN cause
therapeutic issues of GTN
- repeated use can cause a change in response (tolerance)
- Physiological tolerance
- if GTN works on one pathway, the other pathways can adapt an counteract the GTM effect
- Pharmacological tolerance
- can build tolerance
- Can also cause Monday morning headache
- Physiological tolerance
What are class C drugs
They are caclicum channel blockers: guess what they do?
-they block calcium, which causes vasodilation
How do Class C drugs work
-calcium determines contractile state
-and some of the calcium entering through voltage-gated channels
-so reduce contraction if we block calcium channels
-causing vasodilation
Give an example of class C drugs
Dihydropyridines (DHPs)
for example amlodipine (have ipine part of name)
What is the diference between Verapamil and DHPs
- Verapamil has relative selectivity for calcium channels
- whereas DHPs has relative activity for vasculature
- but diltiazem has characteristics of both
What affects do Class C drugs have on vasculatoure
- they affect the aterial system more than the venous
- they decrease total pressure resistance
- which decrease cardiac work
- this can then increase coronary flow
What are the unwanted effects of class c drugs
- flushing
- and decreases smooth muscle activity of GIT,
What peripheral conditions can vasodilators affect
Raynaud’s syndrome
- Spasm induced by cold weather, so if they are warmer
- can be painful
What drug can we use yo treat raynauds
Nifedipine works for some
Vasodilators can also help erection
how?
During an erection, the orpora cavernosa needs to fill with blood
-this is controlled by NO, and how it works with cGMP
-PDEs can degrade cGMP
-so if there’s more cyclic GMP in the cell, and causes smooth muscle relaxation
When targetting PDE how do we ensure that we don’t have systemic effects
- there’s lots of types of PDE
- so targeting a certain type can keep effects localised
What drug can we use to cause erectioms
and how does it work
Sildenafil
- found primarily in genital tissue
- so this means it has a relatively localised action in these genetial tissue
Can sildenafil interact with other drugs
if you are taking GTM and sildenafil can lead to serious effects
Which vasodilator can we use to support hair growth
Minoxidil
How do we use Minoxidil
- hypertrichosis
- topical application causes localised vasodilation → causes more blood flow to that area
- can support hair growth
How does minoxidil work
- opens k+ channels
- allows k+ to leave
- causes membrane hyperpolarisation
- these means calcium channels less likley to open,
- so less intracellaur calcium
How can using vasodilators help improve cerebral function
- using drugs to change blood flow to brain
- Stroke
- Post-haemorrhagic vasospasm (blood vessels go into vasospasm)
- this lasts for a long time
- all things downstream of BV means its not supplied by blood,
- so neurones are living in hypoxic conditions
- Post-haemorrhagic vasospasm (blood vessels go into vasospasm)
- calcium channel blockers are used
