Pharmacology Flashcards
Types of action potential in the heart (2)
Fast response - Present in atrial muscle, ventricular muscle and Purkinje fibres
Slow response - Present in SAN and AVN
Is ion movement through a channel physiologically always passive/active
Passive
Na+ and Ca2+ physiological features (2)
Always moves in an inward direction from extracellular to intracellular fluid
Always involved in depolarization
K+ physiological features
Always moves in an outward direction from intracellular to extracellular fluid
Always involved in repolarization/hyperpolarization
Significant changes occur to the duration and phases of the action potential due to (6)
Autonomic transmitters Hormones Cardiac disease - Ischaemia pH of blood Electrolyte abnormalities Drugs either intentionally or unintentionally as adverse effects
Main difference in conductance between action potential in atrial and ventricular muscle cells
An additional ultrarapid delayed rectifier outward K+ current that is absent from ventricular cells which has the effect of initiating final repolarization more rapidly hence phase 2 is less evident
How does the slow response differ from the fast response (3)
The Vm between action potentials (phase 4) is unsteady gradually shifting with a depolarizing slope
Upstroke (phase 0) is less steep due to opening of L-type Ca2+ channels and not voltage-activated Na+ channels
There is no plateau (phase 2) but a more gradual repolarization (phase 3) caused by delayed rectifier K+ channels opening
Pacemaker potential (phase 4) in the action potential in SAN and AVN (4)
The repolarizing outward K+ current that mediates phase 3 gradually decreases facilitating depolarization
The inward Ca2+ currents that mediates a depolarizing effect increases
At the end of phase 3 a cation conductance mediated by HCN channels develops in response to hyperpolarization triggering the ‘funny current’ via Na+ conduction inwardly causing depolarization
Overall efflux of K+ is decreased and influx of Ca2+ and Na+ is increased generating the pacemaker potential
Inhibiting Ca2+ and Na+ channels increases/decreases heart rate
Decreases
Inhibiting K+ channels increases/decreases heart rate
Increases
How does noradrenaline and adrenaline activate β1 adrenoceptors in nodal and myocardial cells
Coupling through Gs protein alpha subunit stimulates adenylyl cyclase to increase the intracellular concentration of cyclic AMP
Effects of the sympathetic system in autonomic regulation (7)
Increased SAN action potential frequency and heart rate (positive chronotropic effect)
Increased contractility (positive inotropic response)
Increased conduction velocity in AVN (positive dromotropic response)
Increased automaticity
Decreased duration of systole (positive lusitropic action)
Increased Na+/K+ - ATPase activity
Increased cardiac muscle mass
How does ACh activate M2 muscarinic cholinoceptors in nodal cells
Coupling though Gi protein via alpha subunit inhibits adenylyl cyclase and reduces cAMP or via beta/gamma subunit dimer opens specific potassium channels in the SAN
Effects of the parasympathetic system in autonomic regulation (4)
Decreased SAN action potential frequency and heart rate (negative chronotropic effect)
Decreased contractility (negative inotropic effect; atria only)
Decreased conduction in AVN (negative dromotropic effect)
May cause arrhythmias to occur in the atria
Vagal manoeuvres types (2)
Valsalva manoeuvre - activates aortic baroreceptors
Massage of bifurcation of carotid artery stimulates baroreceptors in the carotid sinus - Not recommended as it can cause an embolus to break of and move to the brain where a stroke may develop
What does blocking of hyperpolarization-activated cyclic nucleotide gated (HCN) channels cause
Decreases the slope of the pacemaker potential and reduces heart rate
What is Ivabradine (3)
A selective blocker of HCN channels that slows heart rate in sinus rhythm in angina which reduces O2 consumption
Cant be used in AF
Side effect is altered visual disturbance
How Does β1-Adrenoceptor Activation Modulate Cardiac Contractility (6)
β1 adrenoceptors are activated
Alpha subunit of Gs protein dissociates and attaches to adenylyl cyclase
Adenylyl cyclase increased cytoplasmic concentration of cAMP from ATP
cAMP binds to protein kinase A gaining phosphorylation activity which phosphorylates phospholamban
This increases the Ca2+ pumping rate and rate of relaxation (decreased systole rate) as phospholamban attaches to Ca2+ ATPase on the sarcoplasmic recticulum
cAMP also makes Protein Kinase A more sensitive to Ca2+ whereby more voltage gated Ca2+ channels are activated causing more CICR in the sarcoplasmic recticulum enchancing contractility
What happens if cAMP accumulates in the cytoplasm and how is this dealt with
Accumulation prolongs the systole for too long
So cAMP is converted to inactive 5‘AMP by a phosphodiesterase enzyme
What effect does the inhibition of PDE result in
Positive ionotropic effect
Examples of agonist β-Adrenoceptor ligands on the heart (3)
Dobutamine
Adrenaline Noradrenaline
Effects of agonist β-Adrenoceptor ligands on the heart (3)
Increases force, rate and cardiac output
Decreases cardiac efficiency as O2 consumption increases disproportionally more than cardiac work
May cause arrhythmias
Clinical uses of Adrenaline (4)
Given IM, IV, Subcutaneous or IV infusion
Has short plasma half-life due to uptake
Given after cardiac arrest (IV)
In an anaphylactic shock - Given only of IM but IV if cardiac arrest occurs
Actions of adrenaline when given after a cardiac arrest (3)
Positive inotropic and chronotropic actions (β1)
Redistributes blood flow to heart via vasoconstriction in skin, mucosa and abdomen (α1)
Dilation of smooth muscle of coronary arteries (β2)
Clinical uses of dobutamine (5)
Selective for β1-adrenoceptors
Given via IV infusion
Has short plasma half-life
Given during acute heart failure that is reversible following cardiac surgery or septic shock
It causes less tachycardia than other β1 agonists
The physiological effects of β-adrenoceptor antagonists depends on
The degree the sympathetic nervous system is activated
Example of a non-selective β-adrenoceptor blocker
Propranolol
Examples of a selective β1-adrenoceptor blocker (3)
Atenolol
Bisoprolol
Metoprolol
Example of a non-selective β-adrenoceptor blocker and partial agonist
Alprenolol
Pharmacodynamic effects of non-selective blockers on β-adrenoceptors (4)
At rest - No effect on rate, force, CO or MAP
In exercise/stress - Rate, force and CO decresaes
Coronary vessel diameter decreases
But myocardial O2 requirement decreases thus better oxygenation
Clinical Uses of β -Adrenoceptor Antagonists (5)
Treatment of arrhythmias - β-blockers decrease excessive sympathetic drive and restore sinus rhythm
Treats atrial fibrillation (AF) and supraventricular tachycardia (SVT) - β-blockers delay conduction through AVN and restore sinus rhythm
Treats angina - First line as alternative to calcium entry blockers
Treats compensated heart failure - At low doses β-blockers improve improve morbidity and mortality by reducing excessive sympathetic drive
Treats hypertension - Only if co-morbidity present
Carvedilol properties and use (2)
An α1 antagonist activity causing vasodilation
Often used staring low, increase slow in heart failure treatment
Adverse Effects of β-Blockers (6)
Bronchospasm - Issue in severe asthmatics
Cardiac failure aggravation - Patients may rely on sympathetic drive to maintain CO
Bradycardia - β-adrenoreceptors facilitate nodal conduction
Hypoglycaemia - Release of glucose from the liver is controlled by β2-adrenoceptors
Fatigue - CO and skeletal muscle perfusion in exercise are facilitated by β1 and β2 adrenoceptors respectively
Cold extremities - Loss of β2-adrenoceptor mediated vasodilatation in cutaneous vessels
Example of a non-selective muscarinic ACh receptor competitive antagonist
Atropine
Pharmacodynamic effects of atropine (2)
HR increases - Especially in those with increased vagal tone
No change in arterial BP as resistance vessels lack parasympathetic innervation
Clinical uses of Atropine (2)
First line management of severe/symptomatic bradycardia especially following MI - Given as IV with caution in incremental doses
In anticholinesterase poisoning to reduce excessive parasympathetic activity - Dose must be no less than 600 micrograms
Increased ACh in the synaptic cleft increases parasympathetic/sympathetic tone
PARASYMPATHETIC
Example of a cardiac glycoside
Digoxin
Use of digoxin and appearance on a ventricular function curve
It is a inotropic drug - Enhances contractility
Causes an upward and left shift where SV increases at any EDP
How does digoxin increase contractility (4)
It inhibits the sarcolemma ATPase
In the presence of digoxin the Na+/K+ ATPase is inhibited where the Na+ current increases and the membrane potential decreases
This decreases the Na+/Ca2+ exchange and increases the Ca2+ current
Then the Ca2+ storage in in the sarcoplasmic recticulum increases, increasing CICR and finally contractility
Mechanism of digoxin and K+ (2)
Binds to the α-subunit of Na+/K+ ATPase in competition with K+
Effects can be dangerously enhanced with hypokalaemia - Vital as digoxin has low therapeutic window
Pharmacodynamics of Digoxin (2)
Indirect effect is increased vagal tone - Slows SAN discharge and AVN conduction increasing refractory period
Direct effect is shortens AP and refractory period in myocytes - toxic concentration cause membrane depolarization and oscillatory after potentials due to Ca2+ overload
Clinical use of digoxin (2)
IV in acute heart failure and orally in chronic heart failure in those remaining symptomatic
Indicated in heart failure with atrial fibrillation
Adverse effects of digoxin (5)
Excessive AVN conduction depression (heart block)
causing arrhythmias
Nausea
Vomiting
Diarrhoea
Disturbances of colour vision - Yellow vision
Calcium-sensitizers example,mechanism and use (4)
Levosimendan
Binds to troponin C in cardiac muscle sensitizing it to the action of Ca2+
Opens KATP channels in vascular smooth muscle causing vasodilation reducing afterload and cardiac work
Treats acute decompensated heart failure via IV
Inodilators examples, mechanisms and uses (4)
Amrinone and Milrinone
Inhibit phosphodiesterase in cardiac and smooth muscle cells and hence increase cAMP concentration
Increase myocardial contractility, decrease peripheral resistance but worsens survival due to increased incidence of arrhythmias
Use limited in IV acute heart failure
Anti cholesterol Drug types (4)
Statins
Fibrates
PCSK 9 inhibitors
Cholesterol absorber inhibitor - Ezetimibe
Anti Hypertensive Drug types (4)
Thiazide Diuretics
Beta Blockers
Vasodilators - Calcium Antagonist, Alpha Blockers, ACE inhibitors, Angiotensin Receptor Blockers (ARB)
Mineralocorticoid antagonist
Statins (4)
Simvastatin and atorvastatin
Acts as competitive inhibitor of HMG CoA reductase where decrease in hepatocyte cholesterol synthesis causes a compensatory increase in LDL receptor expression and enhanced clearance of LDL
Used in hypercholesterolaemia, diabetes, angina, transient ischaemic attack (TIA), Cerebrovascular accident (stroke), MI
Side effects are myopathy and rhabdomyolysis (Death of muscle fibers and release into blood stream leading to renal failure due to inability to filter fibers)
Fibrates (5)
Bezafibrate
First line drugs in patients with very high TGA levels
Used in hypertriglyceridaemia
and low HDL cholesterol
Side effects incidence is greater than statins but rarely causes myositis
Avoided in alcoholics with hypertriglyceridaemias and rhabdomyolosis
PCSK 9 inhibitors (3)
Alirocumab and Evolocumab
Inhibits PCSK 9 binding to Low Density Lipoprotein Receptor (LDLR) increasing number to clear LDL lowering LDL-C levels
Used for Familial Hypercholesterolaemia
Familial Hypercholesterolaemia signs (3)
Arcus Senilis
Xanthelasma - Deposits around eye
Xanthoma - Fatty growth under skin especially under joints like knee, elbow and ankle
