Pharmacology Flashcards
what are the regulatory influences on the action potential of the nodal tissue of the heart
autonomic input (para and symp), stretch, temp, hypoxia, blood pH, thyroid hormones
what phase is the upstroke of the action potential in nodal tissue and describe it
phase 0, increased ICal (long calcium current)
what phases are missing from the action potential of nodal tissue that are present in cardiac myocytes
phases 1 and 2
describe phase 3 of the action potential in nodal tissue
downstroke of AP, repolarisation, increased Ik (delayed rectifier potassium current) (outward)
describe phase 4 of the action potential in nodal tissue
pacemaker potential; Ib (background sodium channel (inward)), increase If (funny channel), ICaL (long calcium current (inward)) and decreased IK (delayed rectifier potassium current outward)
Ib, ^IF, ICal, -Ik
what is funny current (If)
mediated by hyperpolarisation-activated and cyclic neucleotide gated (HCN) channels that conduct Na+ and K+ (inward)
what determines the upstroke of the action potential
opening of voltage gated calcium channels (L-type channels)
why are they called calcium long channels
as produce a long calcium current by staying open for a long period of time
during phase 0 what is the inward movement is calcium being opposed by
outward movement of positive charge (hyperpolarisation) via back currents and V activated potassium channels (slow to open) why mem potential only reaches +10mV
what causes the down stroke of a membrane potential in nodal tissue
opening of V activated potassium channels (delayed rectifier)
how do potassium channels cause repolarisation
as move positive charged potassium ions out of cell making inside membrane potential negative
what state are the calcium channel in during repolarisation of AP in nodal tissue
inactivated
what give rise to the pacemaker potential
net movement of pos charge into the cell by different types of ion channel (e.g. sodium selective channels background)
what is the role of the transient calcium channel ICaT
opens very briefly during pacemaker potential to give final kick to reach threshold and initiate opening of L type channels
when do Ik channels open
during downstroke of AP
when are Ik channels closed
during pacemaker potential to speed up depolarisation
what activates funny channels
neg mem potentials (v neg= hyperpolarisation)
what current is active during phase 1 of myocyte AP
Ito- transient outward potassium current
what current is active during phase 0 of myocyte AP
sodium current (inward)
what is phase 4 of myocyte AP
diastolic potential, resting potential, steady
what is phase 4 in normal tissue similar to
pacemaker potential
what maintains the steadiness diastolic potential
potassium’s ability to move out of the cell and maintain potential
what opens V activated sodium channels in cardiac myocyte AP
AP form SA node at ventricular muscle
what is the upstroke of the AP in cardiac myocytes regulated by
sodium channels
what upstroke AP’s do calcium channels mediate
normal and PM
is the upstroke of a cardiac myocyte or PM quicker
cardiac myocyte
what stops the depolarised membrane potential from reaching +100mV
competing conductance
describe phase 1 of a cardiac myocyte AP
brief stage of repolarisation caused by transient outward current due to potassium channel that opens very briefly
what is Ik1 current
inward rectifier potassium current
what happens to calcium channels during the upstroke of a cardiac myocyte AP
opened- slightly delayed, opened for long period of time
what currents are present during the plateau phase
ICal (increased) and INal
why does the membrane potential not change greatly during the plateau phase
a calcium ions are moving out of the cell
what enters muscle cells to dribe contraction
calcium
can another action potential be fired during the plateau phase, why
no, because of v activated sodium channels being activated (only conduct or a millisecond but long plateau period permits calcium entry over a long period of time)
what provides small current to the plateau but could also disrupt rhythm of the heart
late sodium current INaL
in phase three what are the two currents that activate and reduce membrane potential to the resting pot of -90mV
Ik and Ik1
what direction is sodium channelled
inward
what direction is potassium channelled… except in?
outward, funny channel
what direction is calcium channelled
inward
what is noradrenaline
post-ganglionic transmitter
what is adrenaline
adrenomedullary hormone
what do adrenaline and noradrenaline activate
B1 adrenoceptors in nodal and myocardial cells
what does the activation of B1 adrenoceptors by the sympathetic system activate and via what mechanism
activates adenylyl cyclase in increase cAMP concentration. By coupling through Gs protein
what mechanisms cause the positive chronotropic effect of sympathetic stimulation in terms of the pacemaker potential
increase in slope of pacemaker potential caused by enhanced If and ICa
changes in what current cause a decrease in the AP threshold
increased ICa
generally which beta receptors are present where in the body
beta 1 heart, beta 2 airways
what are increases in heart rate mediated by
action on SA node
what is a positive inotropic effect
increased contractility
changes in what part of the cardiac action potential in atrial and ventricular myocytes cause increased contractility
increase in phase 2
changes in which current cause increase contractility
enhanced Ca2+ influx
sensitisation of what to what causes increased contractility
sensitisation of contractile proteins to Ca2+
what is a positive dromotropic response
increase in conduction in AV node
what changes in current increase conduction in the AV and SA node
increased If and ICa
what is automaticity
tendency for non nodal regions to acquire spontaneous activity
what is a positive Lusitropic action
decreasing the duration of systole
what cause a decrease in the duration of systole
increased uptake of Ca2+ into the sarcoplasmic reticulum
what effect does sympathetic stimulation have on the activity of the Na+/K+ ATPase
increases it
what effect does sympathetic stimulation have on mass of cardiac muscle
increases it (cardiac hypertrophy)
how is the frank staling curve affected by sympathetic stimulation
curve elevated
what happens at any end diastolic pressure during symp stimulation
stroke volume increased
why is contractility increased during sympathetic stimulation
as more calcium enters cell during plateau phase
proteins in the contractile apparatus become more sensitive to calcium
what affect does symp stim have on systole and why
reduces it so heart has more time to refill (if not would reduce stroke volume)
what is acetylcholine
post-ganglionic transmitter for the parasympathetic system
what does acetylcholine activate
M2 muscarinic cholinoceptors, largely in nodal cells
what effect does coupling of activated M2 muscarinic cholinoceptors with Gi protein do
1- decreases activity of adenylate cyclase and reduces [cAMP]I
2- opens potassium channels (GIRK) to cause hyperpolarization of SA node
what effect does the parasympathetic system have on heart rate
reduces it
what effect does the parasympathetic system have on slope of pacemaker potential and how
reduces it by reducing If and ICa
what effect does the parasympathetic system have on the threshold for AP and how
increases it via reducing ICa channels
what happens when GIRK channels are opened
potassium leaves cell, hyper polarising it and making it less excitable
what inotropic effect does para stim have and why
(negative) decreases contractility (in atria only) as decrease in phase 2 of cardiac action potential and decreased Ca2+ entry
what dromotropic effect does para symp have and how
(negative) decreases conduction in AV node- decreases activity of voltage dependent Ca+ channels and hyper polarisation via opening of K channels
what may para stim cause in the atria and why
arrhythmias as AP duration is reduced and so too the refractory period
what do vagal manoeuvres do
increase parasympathetic output
when may vagal manoeuvres be employed
in atrial tachycardia, atrial flutter, or atrial fibrillation to suppress impulse conduction through the AV node
what is the valsalva manoeuvre used to do
activates aortic baroreceptors (popping your ears)
what does massage of the bifurcation of the carotid artery do and why is it not recommended
stimulates baroreceptors in the carotid sinus- could dislodge deposit causing thrombis= stroke
what current mediates pacemaker potential
funny current (If)
what are the channels that mediated funny current activated by
(gated HCN channels)
hyperpolarisation
cyclic AMP
what does hyperpolarisation follow action potential do to HCN channels
activates HCN channels in the SA node
what does activation of CHN channels in the SA node cause
a slow phase 4 (pacemaker potential) depolarisation
what does block of HCN channels do to the slope of pacemaker potential and therefore heart rate
decreases slope and heart rate
what increases the activation of HCN channels
cAMP
what drug can be used as a selective blocker of HCN channels
ivabradine
what is ivabradine used to treat, how
angina as slow HR and reduces O2 consumption
angina is a coronary artery disease which reduces the blood supply to the cardiac muscle
what is RyR2
the major mediator for sarcoplasmic release of stored calcium ions
what activate RyR2
Ca2+ influx during muscle contraction
what plasma membrane ATPase allows calcium efflux during muscle relaxation
Na+/Ca2+ exchanger 1 (NCX1)
only when what happens can muscle relaxation occur
when calcium has been removed from the cytoplasm
what ion rato does NCX1 move in/out of cardiac muscle cells
1 calcium out 3 sodium in
how is Ca put back into the SR
via Ca2+ATPase (SERCA), (sequesters calcium back into SR)
summarise how B1 adrenoceptor activation modulates cardiac contractility
(sympathetic stimulation)
B1 adreno activated= make cAMP
cAMP activate protein kinase A= phosphorylation reactions
L type Ca channels phosphorylated= opens= calcium influx= increased force of contraction
PKA also phosphorylates proteins in contractile machinery= more sensitive to calcium= pro-contractility
phospholamban phosphorylated by PKA= increase activity of CaATPase= increased pumping of Ca2+ into SR= increased rate of relaxation
how is cardiac force affected when you prevent the breakdown of cAMP
increase cardiac force
what are three agonists that act on B adrenoceptor
dobutamine, adrenaline and noradrenaline
what class of drugs do dobutamine, adrenaline and noradrenaline belong to
catecholamines
what are the pharmacodynamic effects of of B-adrenoceptor ligands
increase force, rate, CO and O2 consumption
decrease cardiac efficiency (O2 consumption less than cardiac work)
can cause disturbances in cardiac rhythm
what is adrenaline used to treat
cardiac arrest (IV), anaphylatic shock (IM)
what is dobutamine used to treat
acute (but potentially reversible heart failure)
how is adrenaline a mixed antagonist
as acts on both alpha and beta adrenoceptors
why does adrenaline have a short half life
as rapidly metabolised and removed from plasma by uptake systems of many tissues and nerves
what effect does adrenaline have on blood supply to organs
causes constriction of vessels around organs not essential at the time which reduces blood flow and redirects it to the heart
what type of beta receptor is present in cardiac muscle
B1
what type of beta receptor is present in respiratory smooth muscle
B2
how does adrenaline affect the coronary artery
dilates it to improve blood supply to the heart
what is a beta blocker
beta adrenoceptor antagonist
what do the physiological effects of B-adrenoceptor blockade depend upon
the degree to which the sympathetic nervous system is activated
name a non-selective beta blocker
propanolol
name 3 selective beta blockers
atenolol, bisoprolol, metoprolol
name a non selective and partial agonist
alprenolol
what are the pharmacodynamic effects of non-selective blockers
little effect at rest, during exercise; HR, force and CO significant depressed, O2 requirement and coronary vessel diameter reduced too
what is meant when a beta blocker has mixed activity
mildly stimulates heart and acts as antagonist to block agonist behaviour)
what are the clincal uses of a B-adrenoceptor antagonist
arrhythmias (tachycardia,atrial fibrillation or supraventricular tachycardia), angina, heart failure (compensated), hypertension
how do beta blockers treat excessive sympathetic activity (arrhythmias)
-blockers decrease excessive sympathetic drive and help restore normal sinus rhythm
how do beta blocker treat Atrial fibrillation (AF) and supraventricular tachycardia (SVT)
delay conduction through the AV node and help restore sinus rhythm
how do beta blockers treat angina
calcium entry blockers, help reduce O2 consumption and pain
what are stress induced arrhythmias
Increased delivery of noradrenaline and adrenaline causes emergence of latent pacemakers-stress induced arrhythmias
what is heart failure
when heart is giving insufficient cardiac output to provide adequate tissue perfusion
what is compensated heart failure
patient is stable and managed by drugs
what list the adverse effects of beta blockers
bronchospasm, aggravation of cardiac failure, bradycardia, hypoglycaemia, fatigue, cold extremities
why do beta blockers cause bronchospasma
block of airway smooth muscle B2-adrenoceptors (can be severe in asthmatics)
why do beta blockers cause aggravation of cardiac failure
patients with heart disease may rely on sympathetic drive to maintain an adequate CO
why do beta blockers cause bradycardia
heart block – in patients with coronary disease; B-adrenoceptors facilitate nodal conduction
why do beta blockers cause hypoglycaemia
in patients with poorly controlled diabetes – the release of glucose from the liver is controlled by B2-adrenoceptors
why do beta blockers cause fatigue
CO (β1) and skeletal muscle perfusion (β2) in exercise are regulated by adrenoceptors
why do beta blockers cause cold extremities
loss of B2-adrenoceptor mediated vasodilatation in cutaneous vessels
what adverse effects are at less of a risk with B1-selective agents
bronchospasm and hypoglycaemia
why do beta blockers pose an extra risk in hypoglycaemia
as hypo warning mechanisms (anxious, tremor, HR and force increases) could be suppressed by beta blocker
what is atropine
a non selective competitive antagonist of Muscarinic ACh Receptor
what are the pharmacodynamic effects of atropine
increase HR (more pronounced in athletes), no effect on arterial BP (as resistance vessels lack para innervation), no effect on response to exercise
how does atropine act
blocks effect of parasympathetic stimulation on the heart
why does atropine increase HR in athletes more
as have increased vagal tone and HR is much lower
what are the clinical uses for atropine
first line for severe bradycardia, particularly following MI (IV) and in anticholinesterase poisoning
why must you give a dose of a least 300-600 micrograms of atropine to treat bradycardia after an MI
as low doses will decrease HR
what is digoxin
A aardiac glycoside that increases contractility of the heart
how does Digoxin Increases Contractility
by Blocking the Sarcolemma ATPase
what does the Na+/Ca2+ exchanger move in and out
3 na out 2 k in
what are the by Sarcolemma ATPase
sodium potassium pump, Na+/Ca2+ exchangerm L-type Ca2+ channel
what part of Na+/K+ ATPase
alpha subunit
what can dangerously enhance the effect of digoxin and how
low plasma K+ as in competition with this to bind
what are the indirect electrical effects of digoxin
increased vagal activity, slows SA node discharge, slows AV node conduction (increases refractory period)
what are the direct electrical effects of digoxin
shortens action potential and refractory period in atrial and ventricular myocytes
does digoxin increase or decrease parasympathetic drive
increases it
what is oscillatory afterpotentials and what causes it
because of Ca2+ overload, ‘delayed after depolarisation’, id reaches threshold for AP then could cause self propagating AP= ventricular arrhythmia= tachy cardia= ventricle fibrillation
what are the clinical uses of digoxin
Iv in acute heart failure, orally in chronic heart failure
how does digoxin help in heart failure with atrial fibrillation
increase in AV node refractory period is beneficial, helps to prevent spreading of the arrhythmia to the ventricles
what causes the most severe adverse affects of digoxin
suppression of both nodes
what are the severe adverse effects of digoxin (2)
excessive depression of AV node conduction (heart block)
propensity to cause arrhythmias
what are the extracardiac effects of digoxin
(all involving Na/K ATPase) nausea vomiting diarrhoea disturbances of colour vision
what is Levosimendan
inotropic drug and calcium sensitiser
what does Levosimendan do
Binds to troponin C in cardiac muscle sensitizing it to the action of Ca2+
opens KATP channels in vascular smooth muscle causing vasodilation (reduces afterload and cardiac work)
name two inodilator drugs
amrinone and milrinone
how do inodilators act
Inhibit phosphodiesterase (PDE) in cardiac and smooth muscle cells and hence increase [cAMP]i
what effect to inodilators cause
Increase myocardial contractility, decrease peripheral resistance (haemodynamic indices are improved), but worsen survival – perhaps due to increased incidence of arrhythmias
what is the use of inodilators limited to
IV administration in acute heart failure
what are three common types of anti hypertensive drugs
Thiazide Diuretics
Beta Blockers
Vasodilators
what are 4 types of vasodilator drugs commonly used to treat hypertension
Calcium Antagonists
Alpha Blockers
ACE Inhibitors (ACEI) Angiotensin Receptor Blockers (ARB)
what are 6 types of anti anginal drugs
Beta Blockers Calcium Antagonists Nitrates Nicorandil Ivabradine Ranolazine
what are the three types of anti thrombotic drugs
antiplatelet, anticoagulants, fibrinolytics
what do antiplatelet drugs do and name 4
prevent platelets from forming; Aspirin, Clopidogrel, Prasugrel, Ticagrelor
what do anticoagulant drugs do and name 3
attack clotting factors; Warfarin, Rivaroxaban, Dabigatran
what do fibrinolytic drugs do and name 2
streptokinase, tPA
what are two types of anti cholesterol drugs
statins, fibrates
what do diuretics do
block Na reabsorbtion in the kidneys (makes you pee out more sodium)
describe thiazide diuretics (strength, use and an example)
mild, used in hypertension, Bendrofluazide
describe loop diuretics (strength, use and an example)
stronger than thiazidem used in heart failure, furosemide
what are the side effects of diuretics
hypokalaemia (low potassium) = tired, arrhythmias
hyperglycaemia= diabetes
increased uric acid= gout
impotence
what beta adrenoceptor do cardioselective B blockers act on
B1 receptors
what are cardioselective beta blockers use in and give an example of one
used in angina, hypertension and heart failure; atenolol
what beta adrenoceptor do non selective B blockers act on
B1 and B2
give and example of a non selective beta blocker and what it is used in
propanolol, used less in cardiology, more in thyrotoxicosis (hyperactive thyroid as B2 involved with these symptoms)
what are the side effects of a beta blocker
never use in asthma= bronchospasm
tiredness
heart failure (can worsen is short term, good in long/medium term)
cold peripheries
what are the two types of calcium agonist
Dihydropyridines, Rate limiting calcium antagonists
describe rate limiting calcium antagonists (use, what to avoid and 2 examples)
used in hypertension, angina and supraventricular arrhythmias (AF, SVF), avoid use with beta blockers, Verapamil, Diltiazem
describe Dihydropyridines (use, side effects and an example of one)
used in hypertension and angina, can cause ankle oedema, amlodipine
why do you avoid the use of rate limiting calcium antagonists with a beta blocker
as they block AV node in heart and use with beta blocker would suppress conduction in the heart why too much- heart block
what do alpha blockers do
Block aplha adrenoceptors to cause vasodilatation
what are alpha blockers used in
hypertension and prostatic hypertrophy
give an example of an alpha blocker
doxazosin
what are the side effects of alpha blockers
postural hypotension
what do Angiotensin Converting Enzyme Inhibitors do
Block angiotensin I becoming angiotensin II
what are ACE inhibitors used in
hypertensio, heart failure
give an example of an ACE inhibitor
lisinopril
how do ACE inhibitors affect the kidneys
most neutral but…
Good for kidneys in diabetic nephropathy
Bad for kidneys in renal artery stenosis
what are the side effects of ACE inhibitors
cough (irritating and dry), renal dysfunction, Angioneurotic oedema
what is Angioneurotic oedema
life threatening response, if causes larynx to swell which could obstruct breathing. If patient had this reaction in the past never give ace inhibitor
what should you never use ACE inhibitors in and why
pregnancy induced hypertension and damages fetus
what do angiotensin receptor blockers do
block angiotensin II receptors
give an example of an angiotensin receptor blocker and their side effects
losartan, renal dysfunction
how do Angiotensin receptor blockers affect the kidneys
Good for kidneys in diabetic nephropathy
Bad for kidneys in renal a stenosis
what do all angiotensin blocker drugs name end in
artan
why would you swap an ACE inhibitor for an Angiotensin Receptor Blocker
if patient has dry irritating cough or ankle oedema
can you use an Angiotensin Receptor Blockers in pregnancy induced hypertension
no
what do nitrates do and give an example of one
Venodilators
e.g. Isosorbide monoritrate
what are nitrates used in
angina and acute heart failure
what are the side effects of nitrates
headache and hypotension/collapse
tolerance in nitrates is common how is it avoided
have 8 hours a day nitrate free
what are antiplatelet agents used in
angina acute MI, CVA(cerebralcasvualr accident (stroke))/TIA (transient ischaemic attack), patients at high risk of MI and CVA
what are the side effects of antiplatelet agents
haemorrhages, peptic ulcer= haemorrhage
aspirin sensitivity= asthma
what is a haemorrhage
escape of blood from a damaged vessel
what do anticoagulants do
prevent new thrombosis via blocking factors 2, 7, 9, 10
name two examples of anticoagulants and how they are administered
heparin IV, warfarin oral
when should anticoagulants be used
DVT, pulmonary embolism, NSTEMI, atrial fibrillation
what is NSTEMI
Non-ST-elevation myocardial infarction
what are the side effects of anticoagulants
haemorrhage anyway
what can the effects of warfarin be overcome with
Vitamin K
what is rivaroxaban
factor X a inhibitor
what is dabigatran
thrombin factor IIa inhibitor (Xa converts Prothrombin (II) to Thrombin (IIa)
what is the dose of anticoagulants controlled by
INR- international normalised ratio
what do fibrinolytic drugs do
dissolve formed clot
give two examples of fibrinolytic drugs
streptokinase, tissue plasminogen activator (tPA)
when should fibrinolytic drugs be used
STEMI (selected cases only of pulmonary embolism and CVA)
what are the side effects of fibrinolytic drugs
haemorrhage
when should fibrinolytic drugs be avoided
recent haemorrhages (some CVAs), trauma, bleeding tendencies, severe diabetic retinopathy, peptic ulcer
what are the two types of anticholesterol drugs
statins and fibrates
give an example of statins
simvastatin
what does simvastatin do
blocks HMG CoA reductase
what are statins used in
hypercholesterolaemia diabetes Angina/MI CVA/TIA High risk of MI and CVA
what are the side effects of statins
myopathy and Rhabdomyolysis renal failure
give an example of fibrates
bezafibrate
what are fibrates used in
hypertriglyceridaemia,
low HDL cholesterol
what do the names of all statins end in
statin
what anti arrhythmic drugs should be used to treat supra ventricular arrhythmias (SVT)
use adenosine in acute phase
what does adenosine do
creates transient blockage in AV node
what anti arrhythmic drugs should be used to treat Ventricular/ Supraventricular Arrhythmias
Amiodarone
Beta Blockers
Flecainide
what is Amiodarone
long acting anti arrhythmic drug
what are the side effects of anti arrhythmic drugs
Phototoxicity
Pulmonary fibrosis
Thyroid abnormalities
(Hypo or Hyper)
what are the two effects of digoxin
blocks AV conduction, increases ventricular irritability which produces ventricular arrhythmias
what should digoxin be used to treat
atrial fibrillation
why must the administration of digoxin be carefully monitored
as has narrow therapeutic window and can result in digoxin toxicity
what are the symptoms of digoxin toxicity
Nausea, vomiting
Yellow vision
Bradycardia, Heart Block
Ventricular Arrhythmias
when do you not use diuretics
gout
what does CCF stand for
conjested cardiac failure
