pharmacology Flashcards
describe phase 4 of the ventricular AP
- Resting potential
- the outward flux of K+ is dominant
describe phase 0 of the ventricular AP
- Upstroke
- the inward fluff Na+ is dominant
describe phase 1 of the ventricular AP
- early repolarisation
- outward flux of K+ is dominant
describe phase 2 of the ventricular AP
- plateau
- inward flux of Ca2+ is roughly balanced by outward flux of K+
describe phase 3 of the ventricular AP
- final repolarisation
- the outward flux of K+ I dominant
What is the difference between the ventricular AP and the atrial AP?
- an additional ultra rapid delayed rectifier means that is absent in ventricular cells means that the plateu phase is less evident in atrial cells
how is the pacemaker potential generated in pacemaker cells?
the outward flux of K+ is reduced and the inward flux of Ca 2+ and Na+ is increased which generates the pacemaker potential
adrenaline activates …… receptors coupled to …… to …… HR in sympathetic stimulation
- B1
- Gs
- increase
sympathetic stimulation causes decreased contractility T/F?
False
increased contractility
sympathetic stimulation …….. conduction velocity to the AV node
increases
sympathetic stimulation increases automaticity, what does this mean?
- the tendency for non nodal regions to acquire spontaneous activity
sympathetic stimulation decreases the duration of systole T/F?
True
due to increased uptake of Ca2+ into the SR
sympathetic stimulation decreases activity of the Na+/K+ ATPase T/F
false
increases
sympathetic stimulation causes an increased mass of cardiac muscle T/F
true
in parasympathetic stimulation acetylcholine actives …… receptor coupling through …… causes …… HR
- M2
- Gi
- Decreased
What does parasympathetic stimulation cause?
- decreased contractility
- decreased conduction in AV node
- may cause arrhythmias to occur in atria
what effect does blocking HCN channels have?
- decreases the slope of the pacemaker potential
- reduces HR
Name a drug that selectively blocks HCN channels and what it is used for?
- ivabradine
- used to slow HR in angina
Name some beta adrenoreceptor agonists that act on the heart?
- dobutamine, adrenaline and noradrenaline
Describe the effect of beta adrenoceptor agonists on the heart?
- increase force, rate and cardiac output
- decrease cardiac efficiency (O2 consumption increased more than cardiac work) can cause disturbances in cardiac rhythm
Name a B1 adrenoceptor agonist that is given as an IV infusion for the treatment of acute Heart failure?
Dobutamine
propanolol is a selective blocker of beta adrenoceptors T/F
False
It is non selective
name some selective blockers of beta 1 adrenoceptors?
atenolol
bisoprolol
metoprolol
Name an antagonist that is non selective and a partial agonist?
alprenolol
describe the pharmacodynamic effects of non selective blockers?
- at rest, little effect on rate, force, CO or MABP
- during exercise or stress, rate, force and CO are slightly depressed - reduction in max exercise tolerance
- coronary vessel diameter marginally reduced but myocardial O2 requirement falls, thus better for oxygenation of the myocardium
how can beta adrenoceptor antagonists be used clinically?
For the treatment of:
- arrhythmias
- atrial fibrillation
- supra ventricular tachycardia
- angina
- heart failure (low dose in compensated cardiac failure)
- hypertension
describe some adverse effects of beta blockers?
- bronchospasm (in asthmatics)
- aggravation of cardiac failure
- bradycardia (in patients with coronary disease)
- hypoglycaemia (in patients with poorly controlled diabetes)
- fatigue
- cold extremities
What is atropine?
non selective muscarinic ACh competitive antagonist
describe the pharmacodynamic effects of atropine?
- increase HR
- no effect on arterial BP
- no effect on response to exercise
describe the clinical uses of atropine in relation to the heart?
- first line management of severe or symptomatic bradycardia - following MI
- also used in anti cholinesterase poisoning
Describe the effect of digoxin?
- Na+/K+ ATPase inhibited
- increased [Na} and reduced Vm
- decreased Na+/Ca2+ exchanged and increased [Ca2+]
- increased storage of Ca2+ in SR
- increased CICR: increased contractility
What do inotropic drugs do?
enhance contractility
describe the pharmacodynamics of digoxin?
- Binds to the alpha subunit Na+/K+ ATPase in competition with K+ - effects can be dangerously enhanced by low plasma [K+]
describe the indirect action of digoxin on electrical activity?
- increased vagal activity
- slows SA node discharge
- slows AV node conduction - increases refractory period
describe the direct action of digoxin on electrical activity?
- shortens the AP and refractory period in atrial and ventricular myocytes
- toxic concentration cause membrane depolarisation and oscillatory afxterpotentials likely due to Ca2+ overload
what are the clinical uses of digoxin?
- IV in acute HF
- oral in chronic HF (in patients remaining symptomatic despite other treatment)
- HF with atrial fibrillation
describe the side effects of digoxin?
- excessive depression of AV ode conduction
- propensity to cause arrhythmias
- nausea
- vomiting
- diarrhoea
- disturbances of colour vision
name an inotropic drug that is a calcium sensitiser?
Levosimendan
describe the mechanism of levosimendan?
- makes troponin C more sensitive to calcium
- opens KATP channels in vascular smooth muscle causing vasodilation
What is levosimendan used for?
- treatment of acute decompensated HF
name some inodilators?
amrinone and milrinone
What do inodilators do?
- inhibit phosphodiesterase in cardiac and smooth muscle cell and hence increase [CAMP] I - increase myocardial contractility, decrease peripheral resistance
- use limited to IV administration in acute HF
describe the clinical use of adrenaline?
given in cardiac arrest and the immediate management of anaphylactic shock
adrenaline has a ….. plasma t1/2 due to uptake/metabolism
short
Describe the mechanism of adrenaline in cardiac arrest?
- positive inotropic and chronotropic effects via B1
- redistribution of blood flow to the heart from ‘non-essential tissues’
- dilates coronary arteries via activation of B2
Name 3 types of common anti cholesterol drugs
- statins
- fibrates
- PCSK 9 inhibitors
Name 3 common types of hypertensive drugs
- thiazide diuretics
- beta blockers
- vasodilators (calcium antagonists, alpha blockers, ACE inhibitors, ARBs)
describe the mechanism of simvastatin and when it is used?
- statin that blocks HMG coA reductase
- used in: hypercholesterolaemia
diabetes
angina/MI
CVA/TIA
Describe the side effects of simvastatin?
- myopathy
- rhabdomyolysis (renal failure)
what is bezafibrate and what is it used for?
- it is a fibrate used in hypertriglyceridaemia and low HDL cholesterol
Name 2 PCSK 9 inhibitors and describe their use?
- alirocumab, evolocumab
- used in the treatment of familial hypercholesterolaemia
How do PCSK 9 inhibitors work?
- they inhibit the binding of PCSK 9 to LDLR, PCSK9 inhibitor increase the number of LDLRs available to clear LDL thereby lowering LDLC levels
What do diuretics do?
block Na reabsorption in kidneys
Give an example of a thiazide diuretic and its use?
- bendrofluazide
- used in Hypertension
Give an example of loop diuretics and its use?
- furosemide
- used in HF
Give the side effects of diuretics?
- hypokalaemia - tired
- arrhythmias
- hyperglycaemia - diabetes
- increased uric acid - gout
- impotence
give examples of cardioselective beta blockers and their use?
- atenolol, bisoprolol
- only block beta 1 receptors
- used in angina, acute coronary syndrome, MI, hypertension, HF
give examples of non selective beta blockers and their use?
- propanolol, carvedilol
- block beta 1 and beta 2 receptors
- used in thyrotoxicosis, migraine
what are the side effects of beta blockers?
- asthma - contraindicated in brittle/severe asthma
- tired
- HF
- cold peripheries
- can worsen HF
Give examples of dihydropyridine calcium antagonists and their use and SE?
- amlodipine
- used in hypertension and angina
- SE: ankle oedema
give examples of rate limiting calcium antagonists and their use and SE?
- verapamil, diltiazem
- used in hypertension, angina and supra ventricular arrhythmias
- SE: avoid use with beta blocker
What do ACE inhibitors do?
block angiotensin I becoming angiotensin II
give an example of an ACE inhibitor and its uses and SE?
- lisinopril
- used in hypertension and HF
- SE: cough, renal disturbance, angioneurmtic oedema
- cannot be used in pregnancy: hypertension
What do ARBs do?
- block angiotensin II receptors
Give examples of ARBs and their use and SE?
- losartan
- used in hypertension and HF
- SE: renal dysfunctional and no cough
- never use in pregnancy - hypertension
what do alpha blockers do?
block alpha adrenoceptors to cause vasodilation
Give examples of alpha adrenoceptors and their use and SE?
- doxazosin
- used in hypertension and prostatic hypertrophy
- SE: postural hypotension
What do mineralocorticoid antagonists do?
block aldosterone receptors
give examples of mineralocorticoid antagonists and their use and SE?
- spironolactone, eplenerone
- used in HF and resistant hypertension
- SE: gynaecomastia, hyperkalaemia, renal impairment
Name some common anti anginal drugs?
- vasodilators: nitrates, nicorandil, calcium antagonists
- slow HR: beta blockers, calcium antagonists, ivabradine
- metabolic modulator: ranolazine
Give an example of a nitrate, its use and SE?
- isosorbide mononitrate
- ventilators used in angina and acute HF
- SE: headache, hypotension/collase
- tolerance common
What is Nicorandil?
- vasodilator
- K ATP channel inhibitor
- SE: Headache, mouth/GI ulcers
What is ivabradine?
- If channel modulator in the sinus node
- slows HR only in sinus rhythm
- does not work in atrial fibrillation
- altered visual disturbance
What is ranolazine?
- late sodium channel modulator
- decrease calcium load on the heart
- effective in refractory angina
what do anti platelet and anti coagulant agents do?
- prevent new thrombosis
Give examples of anti platelet agents, their use and SE?
- aspirin, clopidogrel, ticagrelor, prasugrel
- used in: angina, acute MI, CVA/TIA
- SE: haemorrhage anywhere, peptic ulcer = haemorrhage, aspirin sensitivity = asthma
Give examples of anticoagulants?
- heparin
- warfarin
- rivaroxaban
- dabigatran
How is Warfarin used and what are the SE?
- blocks clotting factors (2,7,9,10)
- used in DVT, PE, NSTEMI, atrial fibrillation
- SE: haemorrhage anywhere
how is streptokinase used and what are the SE?
- tissue plasminogen activator
- use in STEMI, PE, CVA
- SE: haemorrhage
What do fibrinolytic drugs do?
dissolve formed clot
Name some common types of drugs used in HF?
- ACE inhibitor
- ARBS
- beta blockers
- mineralocorticoid antagonists
- neprilysin inhibitors
- diuretics
- digoxin
What does digoxin do?
- produces delay in AV node conduction (good in AF)
- increases ventricular irritability which produces ventricular arrhythmias (bad)
Name some of the side effects of digoxin?
- narrow therapeutic window
- nausea
- yellow vision
- bradycardia, heart block
- ventricular arrhythmias
What is Salcubitril valsartan and what are its SE?
- neprilysin inhibitor
- SE: hypotension, renal impairment, hyperkalaemia, angioneurotic oedema
cardiovascular disease is strongly associated with elevated ……. and decreased ………….
LDL, HDL
What are lipoproteins?
microscopic spherical particles of 7-1000 nm diameter consisting of:
- a hydrophobic core
- a hydrophilic coat
- apoproteins
What are apoproteins?
- recognised receptors in liver and other tissues allowing lipoproteins to bind to cells
What apoproteins do HDL particles contain?
- apo-A-I and apoA-II
What apoproteins do LDL particles contain?
- apoB-100
What apoproteins do VLDL particles contain?
-apoB-100
What apoproteins do chylomicrons particles contain?
- apoB-48
What do ApoB containing lipoproteins do?
Deliver TAGs i) to muscle for ATP biogenesis
ii) to adipocytes for storage
where are chylomicrons formed?
In intestinal cells and transport dietary triglycerides - the exogenous pathway
Where are VLDL particles formed?
In liver cells and transport TAGs synthesised by that organ - the endogenous pathway
Summaries the life cycle of ApoB containing liposomes?
- assembly: with apoB-100 in the liver and ApoB-48 in the intestine
- intravascular metabolism: involves hydrolysis of the TAG core
- receptor mediated clearance
How are chylomicrons and VLDL particles activated?
by the transfer of ApoC-II from HDL particles
What is the role of MTP?
lipidates apoB-100 forming nascent VLDL that coalesces with TAG droplets
ApoC-II facilitates the binding of ……… and …… to …..
chylomicrons/VLDL/LPL
What does LPL do?
hydrolyses core TAGs to free fatty acids and glycerol which enter tissues
What are chylomicron and VLDL remnants?
particles depleted of triglycerides (but still containing cholesteryl esters)
What is the clearance of LDL particles dependent on?
- LDL receptor expressed by the liver and other tissues
How does cellular uptake of LDL particles occur?
- through receptor mediated endocytosis
What does released cholesterol do?
- inhibits HMG coA reductase (rate limiting enzyme in cholesterol synthesis)
- may be stored as cholesterol ester or used as a precursor for bile salt synthesis
Why is LDL the ‘bad’ cholesterol?
- triggers the release of inflammatory substances which causes division of smooth muscle cells and deposition of collagen in the TI resulting in an atheromatous plaque
Describe the structure of an atheromatous plaque?
- lipid core which is the produce of dead foam cells
- fibrous cap which is made up of smooth muscle cells and connective tissue
Why is HDL the ‘good’ cholesterol
- plays a key role in removing excess cholesterol by transporting it in plasma to the liver
How do statins work?
- act competitively to inhibit HMG coA reductase which is the rate limiting step in cholesterol synthesis in hepatocytes
What does decreased hepatocyte cholesterol cause?
- compensatory increase in LDL receptor expression and enhanced clearance of LDL
What do fibres do?
act as agonists of a nuclear receptor (PPARalpha) to enhance the transcription of several genes including that encoding LPL
Name some drugs that inhibit cholesterol absorption and how do they work?
- bile acid binding resins (colestyramine, colestipol, colsevlam) cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling
How does ezetimibe work?
inhibits NPC1L1 transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol causing a decrease in LDL
Describe the use of anticoagulants?
- mainly used in the prevention and treatment of venous thrombosis and embolism
- carries a risk of haemorrhage
How does warfarin work?
- competes for binding to hepatic vitamin K reductase preventing the production of active hydroquinolone
- renders factors II, VII, IX and X inactive
Warfarin has a high therapeutic index T/F?
False
It has a low therapeutic index
How does heparin work?
- binds to antithrombin III, increasing its affinity for serine protease clotting factors to increase their rate of inactivation
Give examples of LMWH and how they work?
- enoxaparin and dalteparin
- inhibit factor Xa
The elimination of heparin is first order T/F?
- false
- elimination of LMWH is first order, heparin is 0 order
Name an orally active inhibitor that acts as a direct inhibitor of thrombin?
- dabigatran
When are anti platelet drugs used?
- in the treatment of arterial thrombosis
How does aspirin work?
- irreversibly blocks cycloxygenase in platelets preventing TXA2 synthesis but also COX in endothelial cells inhibiting the production of prostaglandin I2
What is the main side effect of aspirin
GI bleeding and ulceration
How does clopidogrel work?
Links to P2Y12 receptor by a disulphide bond producing irreversible inhibition
When in Tirofiban used?
- given IV in short term treatment to prevent MI in high risk patients with unstable angina
How are fibrinolytic used?
- principally to reopen occluded arteries in acute MI or stroke
- IV administration ASAP
What does streptokinase do?
- reduces mortality in acute MI
what do alteplase and duteplase do?
- recombinant tissue plasminogen activators
- more effective in fibrin bound plasminogen
- show affinity for clots
