Pharm 11/12 - Drugs and the Cardiovascular system Flashcards
Through what channels does calcium enter the myocyte upon depolarisation?
Dihydropyridine receptors (DHPR)
Explain the movement of calcium in a myocyte contraction
- Ca enters via DHPR
- Ca then binds to calcium release channels (Ryanodine receptors Ryr) - stimulates Ca release from sarcoplasmic reticulum
- Ca then removed via Plasma Membrane Calcium ATPase (PMCA) or Na+ - Ca2+ exchangers (both found on plasma membrane) OR taken back into SR by SERCA2A
70% of myoplasmic Ca is removed via?
SERCA2A
How is SERCA2A regulated?
Via its interaction with Phospholamban (PLN)
Dephosphorylated PLN = inhibitor of PLN
PLN is phosphorylated by?
PKA
In the heart, what ion drives depolarisation?
Ca
What are the 4 channel types involved in regulating SAN AP?
- If channel = “hyperpolarization-activated cyclic nucleotide-gated (HCN) channels”
2/3. ICa (transient / long-lasting L type) Calcium channel - Ik - Potassium K channels
What type of channel is the If channel?
Sodium
Explain how the channels are involved in SAN AP
- If channel begins depolarisation
- T type and then L type Ca channels become involved
- Once voltage is over threshold voltage, Ik channels become involved and cause repolarisation
Which ion is responsible for repolarisation in the heart?
K
How does a SNS nerve increase HR?
Releases NA, which increases cAMP conc in If & ICa channels, which increases the pacemaker potential gradient (phase 4)
What is phase 4
The pacemaker potential - spontaneous depolarisation that triggers AP
How does parasympathetic decrease HR?
Negatively coupled to cAMP via M2 receptor. Acts on Ik channels . Prolongs repolarisation step - bigger gaps between depolarisation steps
Out of HR, Preload, Afterload and contractility, which one has the least impact on the heart work
Preload
Currents in which channels do B-blockers stop
If and ICa
They block the amount of cAMP being produced
Which channel do calcium channel blockers block
ICa
Which channel does Ivabradine block
If
How do B blockers and Ca antagonists decrease heart contractility
B blockers - Decrease contractility as less cAMP produced so less downstream signalling of Ca influx
Ca antagonists block L type Ca channels - also means less Ca released from SR
Therefore B blockers and Ca antagonists reduce heart work
What are the 2 classes of Ca antagonists
- Rate slowing - cardiac and smooth muscle
2. Non-rate slowing - exclusive to SM
What are 2 types of rate-slowing Ca antagonists
- Phenylalkylamines (e.g. Verapamil)
2. Benzothiazepines (e.g. Diltiazem)
What is a type of non-rate slowing Ca antagonist
- Dihydropyridines (e.g. amlodipine)
Why can non-rate slowing Ca antagonists cause reflex tachycardia
No effects on heart but can cause profound vasodilation
Which 2 drugs influence myocardial oxygen supply/demand by influencing coronary blood flow
Organic nitrates
Potassium channel openers
How do organic nitrates cause smooth muscle relaxation?
Activates guanylate cyclase
When are organic nitrates given?
In angina - profound atherosclerosis which reduces blood supple to the heart - causes coronary vessels to dilate
How do potassium channel openers work?
- Promote potassium efflux - leads to hyperpolarisation
2. Thus reduces its ability to contract
Organic nitrates and K channel openers increase the amount of blood reaching the heart but also decrease the amount of work the heart needs to do. How?
- Decreases preload (venodilation)
2. Decreases afterload (vasodilation)
Which group of drugs are used for immediate vasodilation and is short acting?
Nitrates
5 side effects of taking beta blockers
- Worsening Heart failure - reducing CO and increased vascular resistance (blockade of B2 receptors which cause vasoconstriction)
- Bradycardia
- Bronchoconstriction
- Hypoglycaemia
- Cold extremeties
What do b2 receptors do when stimulated?
They cause SM relaxation - i.e. bronchodilation, vasodilation, etc
in vascular SM, increased cAMP leads to?
SM relaxation
cAMP inhibits MLCK which phosphorylates SM myosin
Which 2 groups of patients should not be given B blockers?
Asthmatics and diabetics
What are side effects of Ca channel blockers
Rate limiting - (Verapamil)
- AV block
- Constipation
Non-rate limiting (DHPs - Amlodipine)
- Ankle oedema
- Headache/flushing
- Palpitations (reflex adrenergic activation)
K channel openers and nitrates, what side effects may they give rise to?
- Ankle oedema
2. Headache/flushing
How can arrhythmias be classified by site of origin?
- Supraventricular arrhythmias
- Ventricular arrhythmias
- Complex arrhythmias (supraventricular + ventricular)
What are the mechanisms of action of each class of Vaughan-Williams drugs
Vaughan-Williams classification is of limited clinical significance
- Class 1 - Na channel blockade
- Class 2 - Beta adrenergic blockade
- Class 3 - Prolongation of repolarisation (membrane stabilisation - due to K channel blockade)
- Class 4 - Ca channel blockade
Adenosine is a good acute antiarrhythmic. It doesn’t sit within the Vaughan-Williams classification. How does it work
- Binds to A2 receptor in VSMC - up regulates cAMP which causes VSMC relaxation
- Binds to A1 receptors in SAN/AVN and down regulates cAMP, causing decreased chronotropy and dromotropy
Why is adenosine safer than Verapamil?
Its actions are short lived (20s - 30s)
Which drug is used intravenously to terminate supraventricular tachyarrhythmias?
Adenosine
Verapamil mainly acts on the L-type Ca channels. How does it work
Slows down the ability of nodal tissue to depolarise - useful in tachyarrhythmias
Amiodarone is a class 3 antiarrythmic (VWC) - but it is quite messy. How does it work
- Complex action - probably involves multiple ion blockade.
- Prolongs repolarisation by blocking K channels
- Heart CAN’T depolarise when it is hyperpolarised / during prolonged repolarisation
- Prolonging repolarisation aims to reduce likelihood of re-entry
What are adverse effects of amiodarone
- Photosensitive skin rashes
- Hypo/hyperthyroidism
- Pulmonary fibrosis
How does digoxin/cardiac glycosides work?
- Inhibit Na/K ATPase.
- Causing Na buildup inside the cell.
- Na/Ca exchanger is also present and more heavily used - causing buildup of Ca in the cell
- This causes increased inotropy (contractility)
- Digoxin also causes vagal stimulation - increases refractory period and reduces rate of conduction through AVN
Why must you be careful if you are hypokalaemic when taking Digoxin
- Digoxin competes w/ K for K binding site
2. If hypokalaemic = less competition for digoxin, so digoxin has a much more powerful effect - could be toxic
What conditions may digoxin be used for
Atrial fibrillation and flutter
BP = ?
BP = CO x TPR
What is the clinical definition of hypertension
Consistently above 140/90 mmHg
What is the most common RF for strokes?
Hypertension
Where does renin come forom and what does it do?
Comes from juxtaglomerular cells in kidney and converts angiotensinogen into Ang 1
3 things that stimulate renin release from the kidney
- Decreased Na reabsorption
- Decreased renal perfusion pressure
- Increased SNS drive
What are 4 actions of Ang 2
- SNS activation / thirst
- Powerful vasoconstriction
- Salt and water retention
- Aldosterone secretion
Drugs ending in -pril are usually?
ACEi
How do ACEi decrease BP
- Reduces vasoconstriction (decreases TPR)
2. Reduces salt and water retention - less venous return - less CO
How can ACEi treat heart failure
- Decreased TPR = less afterload = less work heart has to do
- Less venous return = less preload, heart doesn’t have to work as hard
How do ARBs work and give an example of one
ARBs are AT1 receptor antagonists - block renal and vascular actions of Ang 2
e.g. Iosartan
What is a problem with ACEi
ACE also converts bradykinin into metabolites.
ACEi causes bradykinin buildup, which can cause cough
What is a risk when taking ARBs or ACEi
Hypotension, hyperkalaemia, renal failure in patients with renal artery stenosis
Why can ARBs or ACEi cause hyperkalaemia
Less aldosterone secreted = less Na reuptake and less K excretion, caused K buildup in the blood
How can ARBs or ACEi cause renal failure
Prevents ability of efferent arteriole to constrict - less GF pressure, less GF, causing renal failure
Which CCB would you give to treat hypertension
Amlodipine (Non-rate limiting)
Non-rate limiting CCBs can cause reflex tachycardia and increase myocardial oxygen demand
Why are ARBs or ACEi not given to over 55s or afro-carribeans?
They tend to have low plasma renin - Hypertension not linked to RAS
Give an example of a mixed beta-alpha blocker
Carvedilol
A1 blockade = additional vasodilator properties
Name 2 types of a blockers
Prazosin
Phentolamine
