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
Diuretics (2)
Block Na+ reabsorption in kidneys
Side effects are hypokalaemia (fatigue and arrhythmia), hyperglycaemia (diabetes), increased uric acid (gout), impotence
Thiazide diuretics (2)
Bendrofluazide - Mild effect
Used in hypertension
Loop diuretics (2)
Furosemide - Stronger effect
Used in heart failure
When are selective beta blockers used (5)
Angina Acute coronary syndrome Hypertension Heart failure Myocardial infarction
When are non-selective beta blockers used (2)
Migraine
Thyrotoxicosis (Excess of thyroid hormone)
Calcium Antagonists types (2)
Dihydropyridines
Rate limiting calcium antagonists
Dihydropyridines (3)
Amlodipine
Used in hypertension and angina
Side effect is ankle oedema
Rate limiting calcium antagonists (3)
Verapamil and Diltiazem
Used in hypertension, angina and supraventricular arrhythmias (AF, SVT - Supraventricular tachycardia)
Normally avoid use with beta blockers
Angiostenin Converting Enzyme Inhibitors (7)
Lisinopril
Blocks angiotensin I becoming angiotensin II
Used in hypertension and heart failure
Good for kidneys in diabetic nephropathy
Bad for kidneys in renal artery stenosis
Side effects are cough, renal dysfunction, angioneurotic oedema (More common in people of African heritage)
NEVER use in pregnancy induced hypertension
Angiotensin Receptor Blockers (7)
Block angiotensin II receptors
Losartan
Used in hypertension and heart failure
Good for kidneys in diabetic nephropathy
Bad for kidneys in renal artery stenosis
Side effects is renal dysfunction but no cough
NEVER use in pregnancy induced hypertension
Alpha blockers (4)
Doxazosin
Block α adrenoreceptors to cause vasodilation
Used in hypertension and prostatic hypertrophy
Side effects are posterior hypotension
Mineralocorticoid antagonist (4)
Spironolactone and eplerenone
Blocks aldosterone receptors
Use in heart failure and resistant hypertension
Side effects are gynaecomastia (Male breast enlargement), hyperkaelamia, renal impairment
Anti Anginal drugs (3)
Vasodilators - Nitrates, Nicorandil, Calcium Antagonist
Slow heart rate - Beta blockers, Calcium Antagonist, Ivabradine
Metabolic modulator - Ranolazine
Nitrates (5)
Isosorbide mononitrate
Taken sublingual or as spray (GTN)
Used in angina and acute heart failure
Side effects are headache and hypotension
Patients must be nitrate-free for 8 hours a day as drug to have effect
Nicorandil (2)
K+ channel activator
Many side effects like headaches and mouth/ GI ulcers
Ranolazine (3)
Late Na+ channel modulator
Decreases Na+ load on heart
Effective in refractory angina
Anti Thrombotic Drug types (3)
Anti-platelet
Anticoagulants
Fibrinolytics
Anti-platelet drugs (4)
Aspirin, Clopidogrel, Ticagrelor, Prasugrel
Prevents new thrombosis
Given to patients at high risk of MI and TIA
Side effects are haemorrhages, peptic ulcers, asthma (aspirin sensitivity)
Anticoagulants (6)
Heparin (IV only) and Warfarin (Oral only)
Prevents new thrombosis
Used in DVT, pulmonary embolism, NSTEMI, AF
Side effect is haemorrhage
Dose is controlled by INR
Reversed by vitamin K
Fibrinolytic drugs (4)
Streptokinase and tissue Plasminogen activator (tPA)
Used in STEMI, pulmonary embolism, stroke
Risk of haemorrhage
Avoided in recent haemorrhage, trauma, peptic ulcer and severe diabetic retinopathy
Heart failure drug types (7)
ACE Inhibitors ARBs Beta-blockers Mineralocorticoid antagonists Neprilysin inhibitors Diuretics Digoxin
Digoxin bad effect
Increases ventricular irritability which produces ventricular arrhythmias due to narrow therapeutic window
Neprilysin inhibitors (4)
Salcubitril
Endopeptidase inhibitor causing vasodilation, decreased sympathetic tone and anti-proliferative effect
Side effects are hypotension, renal impairment, hyperkaelaemia, angioneurotic oedema
Superior to ACEI and ARB but more expensive
Property and uses of lipids (3)
Insoluble in water
Essential for membrane biogenesis and integrity
Use as energy source, precursors for hormones and signalling molecules
How are non-polar lipids transported in the blood
By lipoproteins
CVD is associated with (2)
Elevated LDL
Decreased HDL
Lipoproteins (2)
Spherical particles of 7 - 1000 nm in diameter
Contains hydrophobic core of esterified cholesterol and triacylglycerols and hydrophilic coat of amphipathic cholesterol, phospholipids and apoproteins
What are apoproteins
They are recognized by receptors in liver allowing its binding to cells
4 major classes of lipoproteins and what they contain
HDL: Contains apoA-I and apoA-II
LDL: Contains apoB-100
VLDL: Contains apoB-100
Chylomicrons: Contains apoB-48
ApoB-Containing Lipoproteins functions and pathways (3)
Delivers triacylglycerols to muscle for ATP biogenesis and adipocytes for storage
Chylomicrons are made in ilium and transport dietary TAGs - Exogenous
pathway
VLDL particles are formed in hepatocytes and transport TAGs by that organ - Endogenous pathway
Life cycle of ApoB-Containing Lipoproteins (3)
Assembly, with apoB-100 in liver and apoB-48 in intestine
Intravascular metabolism - Involves TAG core hydrolysis
Receptor mediated clearance
Assembly of apoB-containing Lipoproteins in intestine (2)
Monoglyceride and free fatty acids from dietary fat diffuse over the apical membrane of enterocytes where TAGs are synthesized
Cholesterol from dietary fat and bile attaches and passes through NPC1L1 protein where esterification makes cholesteryl ester
Assembly of apoB-containing Lipoproteins with chylomicrons (4)
ApoB48 attaches to TAGs in endoplasmic recticulum of enterocyte
Lipidation occurs and the TAG is transferred by MTP (Microsomal triglyceride transfer protein) to the chylomicron
Cholesteryl ester then enters the chylomicron as it exits the enterocyte following the addition of ApoA-I
It enters the systemic circulation via the thoracic duct
Assembly of apoB-containing Lipoproteins with VLDL particles (3)
VLDL particles containing TAGs are assembled in hepatocytes from free fatty acids
MTP lipidates apoB-100 forming nascent VLDL that coalesces with TAG droplets
To target TAG delivery to adipose and muscle tissue, chylomicrons and VLDL particles must be activated by the transfer of ApoC-II from HDL particles
Intravascular Metabolism of ApoB-containing Lipoproteins
4
Lipoprotein lipase (LPL) is a lipolytic enzyme associated with endothelium of capillaries in adipose and muscle tissue
ApoC-II facilitates binding of chylomicrons and VLDL particles to LPL
LPL hydrolyses core TAGs to free fatty acids and glycerol which enter tissues
Particles depleted of triglycerides (still containing cholesteryl esters) are termed chylomicron and VLDL remnants
Clearance of ApoB-containing Lipoproteins stages (6)
LPL causes chylomicrons and VLDL particles to be rich in cholesteryl esters due to TAG metabolism => Chylomicrons and VLDL dissociate from LPL => ApoC-II is transferred to back to HDL particles in exchange for ApoE where the particles become remnants => Remnants return to the liver and are further metabolized by hepatic lipase
=> All chylomicron remnants and 50% of VLDL remnants are cleared by receptor-mediated endocytosis into hepatocytes => Remaining VLDL remnants loose more TAG by hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (IDL) become LDL particles lacking apoE and retaining only apoB-100
Clearance of LDL particles is dependent upon
LDL receptor expression by hepatocytes
Clearance of ApoB-containing Lipoproteins mechanisms (2)
Cellular uptake of LDL particles occurs via receptor-mediated endocytosis
Within the cell at the lysosome, cholesterol is released from cholesteryl ester by hydrolysis
Effect when cholesterol is released (4)
Inhibits HMG-CoA reductase that is the rate limiting step in anew cholesterol synthesis
Regulates LDL receptor expression
Stored as cholesterol ester
Precursor for bile salt synthesis
Why is LDL the ‘Bad’ Cholesterol (6)
Upon dysfunction/injury of blood vessels LDL is uptaken from blood into intima
LDL is then oxidized to atherogenic oxidised LDL (OXLDL)
Monocytes migrate into the across endothelium into intima where they become macrophages
Uptake of OXLDL by macrophages converts them to cholesterol-laden foam cells that form a fatty streak
Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
The formation of an atheromatous plaque consisting of a lipid core and a fibrous cap
Why is HDL the ‘Good’ Cholesterol (6)
HDL has a role in removing excess cholesterol from cells by transporting it in plasma to the liver
HDL is formed mainly in the liver, initially as apoA-I with a small amount of surface phospholipid and unesterified cholesterol (pre-beta-HDL)
Disc-like pre-beta-HDL matures in plasma to spherical beta-HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the particle core
Mature HDL accepts excess cholesterol from the plasma membrane of cells and delivers cholesterol to the liver known as reverse cholesterol transport
HDL reaching the liver interacts with a receptor allowing transfer of cholesterol and cholesteryl esters into hepatocytes
In the plasma, cholesterol ester transfer protein (CETP) mediates transfer of cholesteryl esters from HDL to VLDL and LDL indirectly returning cholesterol to the liver
Why are statins ineffective in homozygous familial hypercholesterolaemia
LDL receptors are absent
Other benefits of statins (4)
Decreased inflammation
Reversal of endothelial dysfunction
Decreased thrombosis
Stabilization of atherosclerotic plaques
Drugs that Inhibit Cholesterol Absorption (5)
Colestyramine, Colestipol, Colsevelam
Causes excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling
Taken orally
Binding resins causes decreased absorption of TGAs and increased LDL receptor expression
Adverse effect is G.I. tract irritation
Ezetimibe (6)
Inhibits NPC1L1 transport protein reducing cholesterol absorption
Causes LDL decrease but same HDL
Taken orally that undergoes enterohepatic recycling contributing to long half-life of 22 hours
Side effects are diarrhoea, abdominal pain and headache
Contraindicated in breast feeding females
Used in combination with statin if response is insufficient
Haemostasis definition
Arrest of blood loss from a damaged vessel
Haemostasis sequence (3)
Vascular wall damage exposing collagen and tissue factor
Primary haemostasis (soft plug) - Local vasoconstriction, platelet adhesion, activation and aggregation by fibrinogen
Coagulation and formation of stable clot by fibrin enmeshing platelets
Primary haemostasis key events 1 (4)
Vessel damage exposes collagen where platelets bind and become activated
Activated platelets extend pseudopodia, synthesize and release thromboxane A2 (TXA2)
TXA2 binds to platelet GPCR TXA2 receptors causing serotonin and ADP release
TXA2 and vascular smooth muscle causes vasoconstriction by serotonin binding to smooth muscle GPCR 5-HT receptors
Primary haemostasis key events 2 (3)
ADP binds to purine receptors (P2Y12) that activates more platelets, aggregates platelets by increased expression of platelet glycoprotein receptors binding fibrinogen and expose acidic phospholipids that initiate blood coagulation
Late coagulation cascade events (4)
Key event of pro-enzymes being converted to active enzymes is the production of the protease thrombin that cleaves fibrinogen to fibrin to form a solid clot
Inactive factor 10 is converted by tenase to the active factor 10a
Prothrombin is converted by prothrombinase to thrombin
Fibrinogen is converted by thrombin to fibrin forming a solid clot
Thrombosis definition
Pathological haemotological plug in absence of bleeding
Predisposing factors of thrombosis (3)
Injury to vessel wall
Abnormal blood flow
Increased blood coagulability
Type of thrombosis (2)
Arterial thrombus
Venous thrombus
Arterial thrombus (3)
White thrombus - Mainly platelets in fibrin mesh
Forms embolus if it detaches from site of origin (mostly arteries)
Primarily treated with anti-platelet drugs
Venous thrombus (3)
Red thrombus - Jelly like, white head, red tail, fibrin rich due to RBCs
If detaches forms an embolus that lodges in lung
Primarily treated with anticoagulants
Role of Vitamin K (3)
Clotting factors 2, 8, 9, 10 are glycoprotein precursors of active factors 2a, 8a, 9a and 10a that act as serine proteases
Precursors produce active factors by undergoing gamma carboxylation
Carboxylase enzyme mediating gamma carboxylation requires vitamin K in reduced form as cofactor
Anticoagulants is used in (4)
DVT
Post-operative thrombosis
Patients with artificial heart valves
AF
Warfarin (5)
Competes with vitamin K to bind to hepatic vitamin K reductase preventing hydroquinone production by rendering factors 2,7,9 and 10
Blocks coagulation in vivo NOT in vitro
Taken orally
Slow onset of action (2-3 days) while inactive factors replace activated factors that are slowly cleared from plasma - Heparin may be used for rapid anti-coagulation
Has long half-life - 40 hours
Warfarin danger (2)
Due to low therapeutic window warfarin must be monitored by international normalized ratio (INR)
Overdose is treated by phytomenadione (Vitamin K1) or concentrate plasma clotting factors
Factors increasing risk of haemorrhage of warfarin (3)
Liver disease - Less clotting factors
High metabolic - Increased clearance of clotting factors
Drug interactions - Inhibits hepatic warfarin metabolism, platelet function or decreased vitamin K availability
Factors increasing risk of thrombosis of warfarin (3)
Physiological state - Pregnancy, hypothyroidism
Vitamin K consumption
Drug interactions - Increasing hepatic warfarin metabolism
Role of Antithrombin 3 (2)
Vital inhibitor of coagulation by binding to active site of serine protease factors
Heparin binds to Antithrombin 3 increasing affinity for serine protease clotting factors to increase inactivation rate
Heparin and Low Molecular Weight Heparins (LMWHs) (7)
Heparin - Naturally occurring sulphated glycosaminoglycan of variable molecular size
LMWHs examples are enoxaprin and - Preferred except in renal failure
LMWHs inhibit factor 10a but not 2a
Heparin is given IV or SC but LMWHs are only SC
Heparin needs in vitro clotting test to determine optimum dosage
Elimination of heparin is zero order but HMWHs is first order
LMWHs is eliminated via renal excretion hence heparin is preferred in renal failure
Adverse effects of heparin and LMWHs (4)
Haemorrhage
Osteoporosis
Hypoaldosteronism
Hypersensitivity reactions
Orally active inhibitors (4)
Acts as direct inhibitors of thrombin - Dabigatran
Rivaroxaban inhibits factor 10a
Pros are convenience of administration and predictable anti-coagulation but no agent is available to reduce haemorrhage in overdose
Used to prevent venous thrombosis for hip/knee replacements
Alteration in impulse formation involve (2)
Changes in automaticity
Triggered activity
Abnormalities in impulse conduction arise from (3)
Re-entry
Conduction block
Accessory tracts
Changes in Automaticity (4)
SAN is heart pacemaker but all other components demonstrate slower phase 4 depolarization
SAN pacemaking is dominant over AVN and Purkinje fibres - Overdrive suppression
In order for the SAN to exert normal rate and rhythm control it must discharge action potentials at a regular frequency greater than any other structure in the heart
Altered automaticity is either physiological or pathophysiological when SAN is taken over by ‘latent pacemaker’ losing its overdrive suppression
Loss of Overdrive Suppression (3)
Occurs when SAN firing frequency is pathologically low or conduction of impulse is impaired - Latent pacemaker initiates impulse generating an escape beat causing an escape rhythm
Occurs if latent pacemaker fires at intrinsic rate faster than SAN - Latent pacemaker initiates ectopic beat generating an ectopic rhythm
Occurs in response to tissue damage (Post MI) or non-pacemaker cells being partially depolarized assuming spontaneous activity
Triggered activity (3)
A normal AP may trigger abnormal oscillations in membrane potential termed afterdepolarizations
These occur during or after repolarization
ADs of amplitude sufficient to reach threshold cause premature action potentials and beats
Types of afterdepolarizations (2)
Early afterdepolarizations (EADs) Delayed afterdepolarizations (DADs)
Early afterdepolarizations (5)
Occurs during inciting AP between Phase 2 and 3
Most likely to occur in slow heart rate
Happens in Purkinje Fibres
Associated with prolonged AP and drugs prolonging QT interval
When sustained can lead to ‘torsades de points’
Delayed afterrepolarizations (5)
Occurs after complete repolarization by large Ca2+ increase
Excessive Ca2+ causes oscillatory Ca2+ release from sarcoplasmic recticulum and transient inward current (Na+ influx)
Occurs with fast heart rate
Increased or decreased by prolongation and shortening of AP duration by drugs
Could be triggered by drugs increasing Ca2+ influx
Defects in impulse conduction - Re-entry (2)
Normally a self sustaining circuit (2 parallel conduction pathways) which requires unidirectional block prohibiting anterograde conduction, allowing retrograde conduction and slowing
retrograde conduction This causes a re-entrant ‘circus movement’ current when the impulses don’t cancel out and one side has a stronger AP
1st degree block on ECG (3)
Long PR interval >0.2 seconds
Each following P wave is longer
No treatment
2nd degree block - Mobitz type 1 on ECG (2)
PR interval gradually increases until AVN fails completely and a ventricular beat is missed where a QRS complex is missed
Usually vagal in origin
2nd degree block - Mobitz type 2 on ECG
PR interval is constant but every nth ventricular depolarization is missing so no QRS complex
3rd degree block on ECG
No correlation between P wave and QRS complex
Accessory tract pathways (3)
Some people possess electrical pathways parallel to AVN - Bundle of Kent
Impulse in bundle of Kent is conducted more quickly than AVN
Ventricles receive impulses from both pathways that sets up re-entrant loop causing tachyarrhythmias
