Flashcards in Pharmacology Deck (445)
In the sympathetic system, what does coupling through Gs protein activate?
Adenylyl cyclase to increase [cAMP]
During sympathetic activity, once the Gs protein has activated adenylyl cyclase to increase [cAMP], what occurs?
Increased heart rate (positive chronotropic effect) - mediated by SA node and due to an increased slope of the pacemaker potential.
During the parasympathetic system, what two things does coupling through Gi protein do?
1. Decreases activity of adenylate cyclase and reduces [cAMP]
2. Opens potassium channels to cause hyperpolarisation of SA node
In the parasympathetic system, what does acetylcholine activating M2 muscarinic cholinoceptors ultimatley lead to?
Decreased heart rate (negative chronotropic effect) - mediated by the SA node and due to decreased slope of the pacemaker potential
In relation to the generic SA node cell action potential, what causes the upstroke?
Either Na channels or L-type Ca channels responsible
In relation to the generic SA node cell action potential, what causes the downstroke?
Na and Ca channels shut and K channels open
What is an inward current, activated by hyperpolarisation?
Funny current (If)
What carries the funny current?
What does the balance of increasing inward and decreasing outward currents cause? (funny current)
What occurs as a result of blockage of HCN channels?
Decreases the slope of the pacemaker potential and reduces heart rate
Name a selective blocker of HCN channels?
What is ivabradine used for?
To slow heart rate in angina (a condition in which coronary artery disease reduces the blood supply to cardiac muscle). Slower rate reduces O2 consumption.
Name 3 things the funny current is blocked by?
2. Specific bradycardiac agents (SBAs)
3. Alinidine, UL-FS49, Ivabradine
What are channels responsible for the funny current activated by?
2. Cyclic AMP [called hyperpolarisation-activated cyclic nucleotide gated (HCN) channels]
Name two substances which can modulate the funny current?
Name the beta-adrenergic agonist which signals via cAMP to increase heart rate?
Name the muscarinic agonist that decreases cAMP and decreases heart rate?
What do an increase in thyroid hormones, increased in VIP & NPY, decrease in adenosine and increase in nitric oxide all cause?
Modulation of funny current
What do hormones that increase cAMP do?
Increase heart rate
What do drugs that block funny current reduce?
Heart rate and oxygen demand
Sympathetic stimulation: what results from an increase in phase 2 of the cardiac action potential, enhanced Ca2+ entry and sensitisation of contractile proteins to Ca2+?
Sympathetic stimulation: What causes an increase in conduction velocity in AV node?
Enhanced activity of voltage-dependent Ca2+ channels
What does increased automaticity mean (caused by sympathetic stimulation)?
Tendency for non-nodal regions to acquire spontaneous activity
Sympathetic stimulated decreases duration of systole - why does that occur?
Increased uptake of Ca2+ into the sarcoplasmic reticulum
What happens to the cardiac efficiency after sympathetic stimulation?
Decreases (with respsect to O2 consumption)
In parasympathetic stimulation, what does derease in phase 2 of cardiac action potential and decreased Ca2+ entry cause?
In parasympathetic stimulation, what does decreased conduction in AV node result from?
Decreased activity of volatge-dependent Ca2+ channels and hyperpolarisation via opening of K+ channels.
What might cause dysrhythmias to occur in the atria?
What is the Frank-Starling relationship?
An intrinisc property of cardiac muscle (i.e. not under hormonal control)
What are the 3 reasons that stretch increases venous return? (Frank-Starling relationship)?
1. Increases skeletal muscle activity
2. Adrenergic effects on blood vessels - increased venous tone
3. Respiratory pump - increased depth and frequency respiration
The rise in intracellular calcium activates contraction after a delay. What is this rise in intracellular calcium called?
The calcium transient
How is cardiac transient measured?
Using the fluoresecence indicator Fluo-3
What occurs after the action potential has sweeped across the cell and dived down into the t-tubules?
Voltage-gatyed L-type calcum channels located in the t-tubule membrane are opened by the depolarisation and they let in a small amount of calcium
What occurs after voltage-gated L-type Ca channels located in the t-tubule membrane are opened by the depolarisation and let in small amounts of calcium?
Sarcoplasmic reticulum calcium release channels release a larger amount of calcum through the process of calcium-induced calcium release
What does sarcoplasmic reticulum calcium release channels releasing large amounts of calcium through the process of calcium-induced calcium relelease cause?
Calcium in the cytoplasm to be elvated from 100nM to 1uM in about 30 msec
Once calcium in the cytoplasm has elevated from 100nM to 1uM in 30msec, what is activated?
The calcium activates the myofilaments and contraction occurs
Once calcium has activated the myofilaments and contraction has occured, what happens next to cause relaxation?
Calcium is removed from the cytoplasm by the SR Ca ATPase (SERCA) and the sarcolemmal Na/Ca exchanger, which brings about relaxation.
What causes bigger calcium transients and bigger twitches?
What are the 4 sites of action of PKA in hormonal control of cardiac output?
Give three things about regulation of voltage-gated calcium channels?
1. Phosphorylated by protein kinase A
2. Increases trigger calcium
3. Increases calcium induced calcium release
What are the two functions of Ryanodine receptors?
1. Calcium channel
2. Calcium induced calcium release from SR
Give two things about regulation of ryanodine receptors?
1. Protein kinase A activates
2. Increases size of calcium transient
What is the function of SERCA 2a?
Removal of calcium at the end of the beat
Say 4 things about the regulation of SERCA 2a?
1. Phospholamban (PLB, indirect)
2. PKA phosphorylation of PLB
3. Increases calcium uptake by SERCA
4. Accelerates relaxation
Give the function of troponin?
Troponin regulates the actin/myosin interaction using Ca
Give three things about the regulation of troponin?
1. Troponin is phosphorylated by protein kinase A
2. Phosphorylation reduces the affinity for calcium
3. Minor reduction in contraction; accelerates relaxation
What does troponin I ohosphorylation have an effect on?
Calcium binding member of the troponin complex, troponin C
What effect does troponin I phosphorylation have on tropnin c?
Reduce calcium affinity - reduce calcium sensitivity
What are the two most important contributors to positive inotrpy?
Phospholamban and the ryanodine receptor
What does phospholamban phosphorylation activate and what does it promote?
Activates SERCA and promotes relaxation by turning the beat off quicker, as well as increasing the amount of calcium in teh SR.
What causes an increase in the amount of calcium released from the SR each beat?
What does L-type calcium channel phosphorylation increase the amount of?
Trigger calcium needed to initiate a contraction
What leads to a recued affinity of troponin C for calcium?
Troponin I phosphorylation
This accelerates relaxation
What does phospholemman phosphorylation (both PKA and PKC) lead to?
Sodium pump activation which is important in maintaining the sodium gradient
What phosphorylation leads to a higher rate of sodium calcium exchange?
NCX phosphorylatyion (PKC)
What does a high rate of sodium calcium exchange mean?
Increases the trigger calcium at the start of an action potential, and accelerates calcium removal at the end of a beat
What is the ejection fraction?
The fraction of the blood in the left ventricle that is pumped out in each beat.
Give three factors that increase end diastolic volume, which increases force of contraction through the Frank-Starling mechanism?
1. Decreased venous compliance through adrenergic stimulation
2. Increased skeletal muscle activity
3. Respiratory pump
How do hormones increasing cAMP and activating PKA increase the force of contraction?
By increasing Ca influx and release
How do hormones increasing cAMP and activating PKA shorten the contractile cycle?
By increasing Ca reuptake
Name three beta-adrenoceptor agonists?
Give three pharmacodynamic effects of beta-adrenoceptor agonists on the heart
1. Increased force, rate and cardiac output (HR x SV) and oxygen consumption
2. Decreased cardiac efficiency (oxygen consumption increased more than cardiac work)
3. Can cause disturbances in cardiac rhythm (arrhythmias)
What drug can be used for cardiac arrest (sudden loss of pumping function), emergency treatment of asthma and anaphylactic shock (life threatening respiratory distress and often vascular collapse)?
Name a selective B1-adrenoceptor, used for acute, but potentially reversible, heart failure (e.g. following cardiac surgery, or cardiogenic shock)
What do the physiological effects of beta-adrenoceptor blockade depend upon?
The degree to which the sympathetic nervous sytem is activated.
What is the name of a non-selective beta-blocker, antagonist of B1 and B2?
What are the pharmacodynamic effects of beta-adrenoceptor antagonists at rest?
Little effect on rate, force, CO or MABP
What are the pharmacodynamic effects of beta-adrenoceptor antagonists during exercise or stress?
Rate, force and CO are significantly depressed - reduction in maximal exercise tolerance
What pharmacodynamic effects happen to the coronary vessel diameter by beta-adrenoceptor antagonists?
Marginally reduced (B-adrenoceptors mediate vasodilatation in small coronary vessels, but myocardial oxygen requirement falls even further, thus better oxygenation of the myocardium.
Name two selective b1-blockers?
What are the 4 treatment uses of beta-adrenoceptor antagonists?
1. Treatment of disturbances of cardiac rhythm (dysrythmias)
2. Treatment of hypertension (HT)
3. Treatment of angina
4. Treatment of heart failure
What can lead to tachycardia, or spontaneous activation of 'latent cardiac pacemakers' outside nodal tissue?
Excessive sympathetic activity associated with stress or disease (heart failure or MI)
What decreases excessive sympathetic drive and help restore normal sinus rhythm (i.e. rhythm driven by the SA node)?
What is cardiac output defined as?
Heart rate x stroke volume
What drugs can cause bronchospasm (block airway smooth muscle b2-adrenoceptors) and are dangerous in asthmatics?
What side effect do b-blockers have on cardiac failure?
What can b-blockers do to heart rate as a side effect?
Bradycardia (heart block - in patients with coronary disease; b-adrenoceptors facilitate nodal conduction)
What side effect can b-blockers have on glucose levels?
Hypoglycaemia (in patients with poorly controlled diabetes - the release of glucose from the liver is controlled by b2-adrenoceptors). Also tachycardia in response to hypoglycaemia is a warning mechanism.
What is another side effect of b-blockers in relation to energy?
Fatigue - CO and skeletal muscle perfusion in excersise are regulated by b-adrenoceptors
What can happen to peripheral temperature as a side effect of beta-blockers?
Cold extremities - loss of beta-2-adrenoceptor mediated vasodilatation in cutaneous vessels
Name a non-selective muscarnic receptor antagonist?
Give three pharmacodynamic effects of atropine on the heart?
1. Modest increase in heart rate (tachycardia) in normal subjects - more pronounced effect in highly trained athletes (who have increased vagal tone)
2. No effect upon arterial BP (resistance vessels lack a parasympathetic innervation)
3. No effect upon the response to exercise
Give three clinical uses of atropine?
1. To reverse bradycardia following MI (in which vagal tone is elevated)
2. As an adjunct to anaesthesia
3. In anticholinesterase poisoning (to reduce excessive parasympathetic activity)
Name a cardiac glycoside that increases contractility of the heart
What does digoxin block to increase the contractility?
The sarcolemma Na/K ATPase
What actively maintains ion gradients; contributes to Vm?
What does the Na/Ca exchanger do?
Couples the chemical and electrical gradient driving Na influx to Ca efflux
What does digoxin do to the Na/K ATPase?
Which drug increases Na intracellular concentration and decreases Vm?
What drug decreases Na/Ca exchange and increases Ca intracellular concentration?
What does digoxin do to the storage of Ca in SR?
What does digoxin do to CICR and contractility?
How does digoxin bind?
Binds to the alpha-subunit of Na/K ATPase in competition with K
What can effects of digoxin be dangerously enhanced by?
Low plasma (K+), hypokalaemia
What indirect effect does digoxin have on vagal activity?
What does digoxin do to the SA node discharge, AV node conduction and refractory period?
Slows SA node discharge
Slows AV node conduction; increases refractory period
What does digoxin have a direct effect on?
Shortens teh action potentials and refractory period in atrial and ventricular myocytes; toxic concentration cause membrane depolarisation and oscillatory afterpotentials
What is an increase in AV node refractory period beneficial to?
Heart failure coupled with AF (effects upon the AV node helps to prevent spreading of the dysrhythmia to the ventricles)
Give two side effects of digoxin?
1. Excessive depression of AV node conduction (heart block)
2. Propensity to cause dysrhythmias
Name a calcium-sensitiser? (inotropic drugs)
How does levosimendan work?
Binds to troponin C in cardiac muscle sensitising it to the action of calcium
What does cross bridge formation between actin and myosin result in?
What drug additionally opens Katp channels in vascular smooth muscle causing vasodilation and is a relatively new agent, used in treatment of acute decompensated heart failure?
Name 4 types of drugs that are vasodilators?
1. Calcium antagonists
2. Alpha blockers
3. ACE inhibitors (ACE)
4. Angiotensin receptor blockers (ARB)
Name three broad classes of anti hypertensive drugs?
Name 4 types of antianginal drugs
1. Beta blockers
2. Calcium antagonisits
Give three broad classes of anti-thrombotic drugs
1. Antiplatelet drugs
Name two antiplatelet drugs?
Name an anticoaglant?
Name two fibrinolytics
Give two examples of anti cholesterol drugs?
What drugs block Na reabsorption in kidneys?
What diuretics are mild and used in hypertension?
Name a thiazide diuretic?
What diuretics are stronger and used in heart failure?
Name a loop diuretic?
Give 4 side effects of diuretics
1. Hypokalaemia (tired, arrythmias)
2. Hyperglycaemia (diabetes)
3. Increased uric acid (gout)
What drugs block beta-1 and beta-2 adrenoceptors?
What beta-blockers only block beta-1 receptors and are used in angina, hypertension and heart failure?
Name a cardioselective beta-blocker?
What beta-blockers block beta-1 and beta-2 receptors and are used in thyrotoxicosis?
Non selective beta-blockers
Name a non selective beta-blocker?
Give 3 side effects of beta-blockers?
2. Heart failure
3. Cold peripheries
What should you never use beta-blockers in?
Patients with asthma
Decribe the beta-blocker effect on heart failure*?
Beta-blockers are good in medium/long term heart failure but can worsen heart failure in short term.
What are the two types of calcium antagonists?
2. Rate limiting calcium antagonists
Which calcium antagonists are used in hypertension and angina, but also have ankle oedema as a side effect?
Give an example of a dihydropyridine?
What calcium antagonists are used in hypertension and angina, plus supraventricular arrhythmias (AF, SVT), but should be alerted when given with beta-blockers?
Rate limiting calcium antagonists
Give two examples of rate limiting calcium antagonists?
What drugs block alpha adrenoceptors to cause vasodilation?
What drugs are used in hypertension and prostatic hypertrophy?
Name an alpha blocker?
Give one side effect of alpha blockers?
What drugs block angiotensin I from becoming angiotensin II?
Give an example of an ACE inhibitor?
What drugs are used in hypertension and heart failure, good for kidneys in diabetic nephropathy and are bad for kidneys in renal artery stenosis?
What are 3 side effects of ACE inhibitors?
1. Dry cough
2. Renal dysfunction
3. Angioneurotic oedema
What drugs should you never use in pregnancy induced hypertension?
Which drugs block angiotensin II receptors?
Angiotensin receptor blockers (ARBs)
Give an example of an angiotensin II receptor blocker (ARB)?
What are ARBs used in?
Hypertension and heart failure
What are ARBs good for and bad for in relation to kidneys?
1. Good for kidneys in diabetic nephropathy
2. Bad for kidneys in renal a stenosis
Give two side effects of ARBs?
1. Renal dysfunction
2. No cough
Can ARBS be used in pregnancy induced hypertension?
What drugs are venodilators?
Give an example of a venodilator (nitrate)?
What are nitrates used in?
Angina and acute heart failure
Give two side effects of nitrates
What drugs prevent new thrombosis?
What drugs are used in angina, acute MI, CVA/TIA and patients with high risk of MI & CVA?
Give three side effects of antiplatelet agents?
1. Haemorrhage anywhere
2. Peptic ulcer = haemorrhage
3. Aspirin sensitivity = asthma
What do anticoagulants prevent?
Give two anticoagulants?
1. Heparin IV
2. Warfarin oral
What does warfarin oral block?
Clotting factors (2, 7, 9, 10)
What drugs are used in DVT, PE, NSTEMI and AF?
Anticoagulants - WARFARIN
Give a side effect of anticoagulants?
How do you control the dose of anticoagulants?
What reverses warfarin?
Name two other anticoagulants, other than heparin and warfarin?
What is Rivaroxaban?
A factor X a inhibitor
What is Dabigatran?
Thrombin (factor IIa) inhibitor
What does Xa convert?
Prothrombin II to thrombin IIa
What drugs dissolve formed clots?
Name one fibrinolytic drug?
Name a tissue plasminogen activator (tPA)?
What are fibrinolytic drugs used in?
STEMI, PE, CVA
Give a side effect of fibrinolytic drugs?
Haemorrhage serious risk
What drug type should you avoid in: recent haemorrhage (some CVA), trauma, bleeding tendencies, severe diabetic retinopathy and peptic ulcers?
Fibrinolytic drugs (streptokinase)
Name two broad classes of anticholsterol drugs?
Give an example of a statin?
How does simvastatin work?
Blocks HMG CoA reductase.
Name a drug used in hypercholesterolaemia, diabetes, angina/MI, CVA/TIA, high risk patients for MI and CVA?
Give two side effects of statins?
Rhabdomyolysis renal failure
Give an example of a fibrate?
What is benzafibrate used in?
2. Low HDL cholesterol
What anti arrythmic drug would be used in acute phase of supraventricualr arrythmias (e.g. SVT)?
What 3 anti arrythmic drugs are used in ventricular/supraventricular arrhythmias?
Name an anti-arrythmic long-acting drug?
Give three side effects of anti arrhythmic drugs?
2. Pulmonary fibrosis
3. Thyroid abnormalities (hypo or hyper)
What drug blocks atrial-ventricular conduction and produces a degree of A-V conduction delay?
Name a good drug for AF?
What occurs when digoxin is given excessivly?
Heart rate falls too much giving bradycardia and heart block
What drug increases ventricular irritability which produces ventricular arrythmias and has a narrow therapeutic index?
Give 4 outcomes of digoxin toxicity?
1. Nausea, vomiting
2. Yellow vision
3. Bradycardia, heart block
4. Ventricular arrhythmias
Contraction of smooth muscle cell: Once the intracellular calcium is increasing, what converts it to Ca2+-CaM?
In smooth muscle contraction: what does Ca2+-CaM convert?
MLCK to MLCK (active)
In smooth muscle contraction: what does MLCK (active) convert?
Myosin-LC to Myosin-LC P
During smooth muscle relaxation: what converts myosin-LC-phosphatase to Myosin-LC-phosphatase (active)?
In smooth muscle relaxation: what does myosin-LC-phosphatase (active) convert?
Myosin-LC P to Myosin-LC
What do vasodilating substances like bradykinin, ADP and 5-HT cause in endothelial cells?
Increased intracellular calcium
In endothelial cells, once intracellular calcium has increased and joined to CaM, what does Ca2+-CaM release?
What does eNOS in endothelial cells convert?
(L-arginine + oxygen) to (NO + citrulline)
Once NO is in a smooth muscle cell, what does it do?
Goes to Guanylate cyclase and converts GTP to cGMP
In smooth muscle cells, once GTP has converted to cGMP, what does cGMP release?
Protein kinase G causing relaxation
As well as protein kinase G, what else causes relaxation in a smooth muscle cell?
When organic nitrates such as GTN move into smooth muscle cells, what do they react with and what do they produce?
React with enzymes/tissue thiol (SH) groups to release NO
What substances relax all types of smooth muscle via their metabolism to NO?
What effect do organic nitrates cause that as a result causes: [decreased CVP (preload) reduces SV, but CO maintained by increased HR, no change in arterial pressure]?
What dose amount is required for organic nitrates to venorelax?
What dose amounts are required for organic nitrates to cause arteriolar dilatation?
What effect of organic nitrates causes [decreased arterial pressure reducing afterload]. Large muscular arteries are more sensitive, reduces pulse wave reflection from arterial branches?
What do organic nitrates do to coronary blood flow?
Increase (in angina there is no overall increase, but blood is redirected towards the ischaemic zone)
In angina, benifits are derived from decreased myocardial oxygen requirement, via what 3 features?
1. Decreased preload
2. Decreased afterload
3. Improved perfusion of the iscaemic zone
Give two organic nitrate examples that are used in angina?
1. Glyceryltrinitrate (GTN)
2. Isosorbide mononitrate
How long does GTN take to work and why?
30 minutes (short acting)
Undergoes extensive first pass metabolism
How is GTN administered?
Sublingually for rapid effect before exertion (stable angina) or IV (in conjunction with aspirin) in unstable angina
How long does isosorbide moninitrate take to work and why?
longer acting (half-life = 4 hours)
Resistant to first pass metabolism
How is isosorbide mononitrate administered?
Orally for prohylaxis and a more sutained effect
Name two antagonists of the ETa receptor?
What are bosentan and ambrisentan (antagonists of the ETa receptor) used in?
The treatment of pulmonary hypertension
What do adrenaline, angiotensin II and ADH cause to happen in the endothelial cell, in relation to vascular smooth muscle tone?
1. Alter gene expression
2. Endothelin precursor to make endothelin-1
What does endothelin-1 act on, on the membrane of smooth muscle cells?
What two drugs act on the RAAS?
ACE inhibitors and ARBs
What plays a major role in sodium excretion and vascular tone?
What receptor does angiotenin II react on?
AT1 receptor (GPCR)
In relation to RAAS, what causes tubular Na+ reabsorption and salt retention?
Aldosterone secretion from adrenal cortex
Angiotensin II reacting on AT1 receptor causes contraction of vascular smooth muscle due to what two things?
1. Activation of smooth muscle AT1 receptors
2. Increased release of noradrenaline from sympathetic nerves
What is aliskiren?
A renin inhibitor
Where do ARBs work on?
What two functions does ACE (membrane bound enzyme on surface of endothelial cells) have?
1. Converts angiotensin I to angiotensin II (vasoconstrictor)
2. Inactivates bradykinin (vasodilator)
What drugs block the agonist action of angiotensin II at AT1 receptors in a competetive manner?
AT1 receptor antagonists (sartans)
What drugs cause venous dilatation (decreased preload) and arteriolar dilatation (decreased afterload and TPR) decreasing arterial blood pressure and cardiac load?
Do ACE inhibitors effect cardiac contractility?
What do ACE inhibitors do to the release of aldosterone?
Reduce the release of aldosterone (decrease in circulating levels of aldosterone promotes loss of Na and H2O)
What drugs reduce direct growth action of angiotensin II upon the heart and vasculature?
What do ACE inhibitors do that ARbs dont?
Inhibit the metabolism of bradykinin
What should ARBs and ACE inhibitors not be used in?
Pregnancy (foetal toxicity)
Bilateral renal artery stenosis
In cardiac failure, what do ARBs and ACE inhibitors do, 3 things?
1. Decrease vascular resistance improving perfusion
2. Increase excretion of Na+ and H20
3. Cause regression of left ventricular hypertrophy
What are adrenoceptors?
G-protein coupled receptors (GPCR) that are activatged by the sympathetic transmitter NA and the hormone adrenaline.
What adrenoceptor causes vasoconstriction?
What adrenoceptor causes increased heart rate, force, and AV node conduction velocity?
What adrenoceptors cause bronchodilatation and relaxation?
What are beta-adrenoceptor antagonists used in?
Treatment of angina pectoris (not variant angina)
What three effects do B-blockers (particularly beta-1- selective agents) have of value to angina?
1. Decrease myocardial oxygen requirements (decreased HR and SV = decreased workload and decreased oxygen)
2. Counter elevated sympathetic activity associated with ischaemic pain
3. Increase the amount of time spent in diastole (decreased HR), improving perfusion of the left ventricle
When does the window for coronary blood flow occur in the cardiac cycle?
What three ways do beta-blockers help restore normal blood pressure?
1. Reducing cardiac output
2. Reducing renin release from kidney
3. A CNS action that reduces sympathetic activity
What do calcium antagonists prevent?
The opening of L-type channels in excitable tissues in response to depolarisation and hence limit (the increase of intracellular calcium)
Where do all clinically useful calcium antagonists interact?
With L-type calcium channels found in the heart and smooth muscle
What two things do L-type channels mediate?
1. Upstroke of the action potential in the SA and AV nodes
2. Phase 2 of the ventricular action potential
During phase 2 of the ventricular AP, what can calcioum antagonists reduce?
Force of contraction
During upstroke of AP in the SA and AV node, what can calcium antagonists reduce?
Rate and conduction through the AV node
In vascular smooth muscle, what provides a pathway for calcium entry into cells?
In smooth muscle cells, what happens after NA is released from poastganglionic sympathetic neurone and reacts with alpha-1-adrenoceptor?
Alpha-1-adrenoceptor releases calcium from intracellular stores (SR)
What three clinical things can calcium antagonists be used for?
What do calcium antagonists cause, that is particularly useful in patients with angina and hypertension?
Give three side effects of calcium antagonists?
2. Dizziness and flushing
3. Swollen ankles
What are calcium channel blockers often used in combination with for prophylactic treatment of angina?
What two calcium antagonists produce negative inotropic effects but latter offset by activation of the baroreceptor reflex in response to vasodilatation and increased sympathetic activity?
Diltiazem and verapamil
How do calcium channel blockers help in dysrhythmias?
Ventricular rate in rapid atrial fibrillation reduced by suppression of conduction through the AV node.
What calcium antagonist is usually used for dysrhythmias, but should be avoided in heart failure, especially in combination with a beta-blocker?
Name two potassium channel openers?
Minoxidil and Nicorandil
What drugs open ATP-modulated K+ channels (Katp) in vascular smooth muscle?
Potassium channel openers
What drugs act by antagonising intracellular ATP (which closes the Katp channel)?
Potassium channel openers
What do potassium channel openers cause, which switches off L=type Ca2+ channels?
What drug is used as a last resort in severe hypertension but causes reflex tachycardia (prevented by a b-blocker) and salt and water retention (alleviated by a diuretic)?
Which drug (which also has NO donor activity) is used in angina refractory to other treatments?
How do alpha-1-adrenoceptors receptor antagonists cause vasodilatation?
By blocking vascular alpha-1-adrenoceptors. Reducd sympathetic transmission results in decreased MABP.
Name two alphablockers? (both are competetive antagonists)
What is benign prostatic hyperplasia?
An abnormally enlarged prostate that compresses the urethra
What do alpha-adrenoceptor antagonists also provide symptomatic relief in?
Benign prostatic hyperplasia and are particularly indicated for hypertensive patients with this condition
What drugs act on the kidney to increase the excretion of Na, Cl and H20 and exert additional, indirect, relaxant effects upon the vasculature?
What are the two classes of diuretics?
Thiazides and loop agents
Give two features of thiazide diuretics?
1. Inhibit NaCl reabsorption in the distal tubule by blocking the Na+/Cl- co-transporter
2. Cause up to 5% of filtered Na+ to be excreted along with H2O producing a moderate diuresis
Give two features of loop diuretics?
1. Inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle by blocking the Na+/K+/2Cl- co-transporter
2. Cause up to 15-25% of filtered Na+ to be excreted with accompanying H2O producing a strong diuresis
What do thiazide diuretics and loop agents both produce an undesirable loss of and how is it corrected?
Corrected by co-administration of a 'potassium sparring diuretic' or K+ supplements
Name a thiazide widely used in mild heart failure and hypertension, as well as additionally in severe resistant oedema (with a loop agent)
Name a loop diuretic used to reduce salt and water overload associated with acute pulmonary oedema (IV) and chronic heart failure?
Are lipids soluble in water?n
Give examples of two non-polar lipids?
Cholesterol esters and triglycerides
How are non-lipids transported in the blood?
Within lipoproteins [e.g. HDL and LDL]
What two factors is CVS disease (atherosclerosis) strongly associated with?
1. Elevated LDL
2. Decreased HDL
What are microscopic spherical particles of 7 to 1000 nM diameter?
What two things does a lipoprotein consist of?
1. Hydrophobic core containing esterified cholesterol triglycerides
2. Hydrophilic coat comprising a monolayer of amphipathic cholesterol, phospholipids and one or more apoprotein
What are the 4 major lipoproteins?
1. HDL particles
2. LDL particles
3. Very-low desnsity lipoprotein (VLDL) particles
What particles cosntain apoB-100 and have diameter of 3-80 nM?
Very-low density lipoprotein
What lipoproteins contain apoB-48 and have a diameter of 100-1000 nM?
What is the role of ApoB-containing lipoproteins?
Deliver triglycerides to muscle for ATP biogenesis and adipocytes for storage
Where are chylomicrons formed and what do they transport?
Formed in intestinal cells and transport dietary triglycerides - the exogenous pathway
Where are VLDL particles formed and what do they transport?
VLDL particles are formed in liver cells and transport triglycerides synthesised in that organ - the endogenous pathway
What are the 3 steps that summarise the life-cycle of ApoB-containing liposomes?
1. Assembly [with apoB100 in the liver and apoB48 in the intestine]
2. Intravascular metabolism (involving hydrolysis of the triglyceride core)
3. Receptor mediated clearance
During the assembly of apoB-containing lipoprotein chylomicron: what does cholesterol react with to enter the enterocyte?
Niemann-Pick C1-like 1 protein (NPC1L1)
During the assembly of apoB-containing lipoprotein chylomicron: what enters the enterocyte, that came from digestion of dietary fat (25%) and bile (75%)?
During the assembly of apoB-containing lipoprotein chylomicron: What two substanes from digestion of dietary fat, enter the enterocyte to make triglycerides?
2. Free fatty acid (long chain)
During the assembly of apoB-containing lipoprotein chylomicron: Once cholesterol has entered the enterocyte, what happens?
It is esterified to become a cholesterol ester
During the assembly of apoB-containing lipoprotein chylomicron: What does the ribosome produce?
During the assembly of apoB-containing lipoprotein chylomicron: What does apoB48 bind to?
During the assembly of apoB-containing lipoprotein chylomicron: what mediates lipidation of apoB48 triglyceride?
MTP - Microsomal Triglyceride Transfer Protein
During the assembly of apoB-containing lipoprotein chylomicron: what substance mediates the conversion of lipidated, apoB48 triglyceride to a chylomicron with cholesterylester?
During the assembly of apoB-containing lipoprotein chylomicron: what is added to the chylomicron before it exits the enterocyte by exocytosis?
Second apoprotein apoA1
During the assembly of apoB-containing lipoprotein chylomicron: what happens when the chylomicron exits the enterocyte?
It enters lymphatics and is carried in lymph to systemic circulation (subclavian vein) via the thoracic duct.
Where are VLDL particles containing triglycerides assembled?
In liver hepatocytes
What substances make VLDL particles containing triglycerides?
Free fatty acids from adipose tissue and de novo synthesis
During the assembly of apoB-containing lipoproteins VLDL particles, what does MTP lipidate?
apoB100 forming nascent VLDL that coalesces with triglyceride droplets
To target triglyceride delivery to adipose and muscle tissue, what must happen to chylomicrons and VLDL?
Must be activated
What activates chylomicrons and VLDL particles?
Transfer of apoCII from HDL particles
Name a lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue?
What does apoCII facilitate?
Binding of chylomicrons and VLDL particles to LPL
What does LPL hydrolyse, of which the end substances enter tissues?
Core triglycerides to free fatty acids and glycerol
What are chylomicron and VLDL remnants?
Particles depleted of triglycerides (but still containing cholesteryl esters) are termed chylomicron and VLDL remnants.
Clearance of apoB-containing lipoproteins: what causes chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism?
Clearance of apoB-containing lipoproteins: what happens once LPL has caused chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism?
Chylomicrons and VLDL dissociate from LPL
Clearance of apoB-containing lipoproteins: what happens after chylomicrons and VLDL have dissociated from LPL?
ApoCII is transferred to HDL particles in exchange for apoE which is a high affinity ligant for receptor mediated clearance. Particles are now remnants.
Clearance of apoB-containing lipoproteins: what happens after the particles have become remnants?
Remnants return to the liver and are further metabolised by hepatic lipase
Clearance of apoB-containing lipoproteins: what happens once the remnants have returned to the liver and are further metabolised by hepatic lipase?
All apoB48-containing remnants and 50% of apo100 containing remnants are cleared by receptor mediated endocytosis into hepatocytes
Clearance of apoB-containing lipoproteins: what occurs as the last stage, after all apoB48 containing remnants and 50% of apo100 containing remnants are cleared by receptor-mediated endocytosis into hepatoctes?
Remaining apoB100-containing remnants loose further triglycerides through hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (IDL) become LDL particles lacking apoE and retaining solely apoB100.
Clearance of apoB-containing lipoproteins: what is clearance of LDL particles crucially dependent on?
LDL receptor expressed by the liver and other tissues
How does cellular uptake of LDL particles occur?
Via receptor-mediated endocytosis
Clearance of apoB-containing lipoproteins: within the cell at the lysosome, what is released by hydrolysis?
Cholesterol from cholesteryl ester
What is the rate limiting enzyme in de novo cholesterol synthesis?
What 3 things does released cholesterol cause?
1. Inhibition of HMG-CoA reductase
2. Down regulation of LDL receptor expression
3. Storage of cholesterol as cholesterol ester
What is a focal disease of large and medium sized arteries?
Give three risk factors for atherosclerosis?
3. High BP
What is atherosclerosis initiated by?
Dysfunction and injury of the lining (endothelium) of blood vessels
During the disease progression of atherosclerosis: what is uptaken into the intima of the artery from the blood, and what then occurs to it?
Subsequently oxidised to atherogenic oxidised LDL (OXLDL)
During the disease progression of atherosclerosis: once OXLDL has formed, what migrates across the endothelium?
Monocytes (white blood cells) across the endothelium into the intima where they become macrophages
During the disease progression of atherosclerosis: once macropahges are involved, what then occurs?
Uptake of OXLDL by macrophages converts them to cholesterol-laden foam cells that form a fatty streak.
During the disease progression of atherosclerosis: how do macrophages uptake OXLDL?
Using scavenger receptors
During the disease progression of atherosclerosis: What cells form fatty streaks?
Cholesterol-laden foam cells
During the disease progression of atherosclerosis: Once cholesterol-laden foam cells have caused a fatty streak, what does release of inflamamtory substances from various cell tpyes cause?
Division and proliferation of smooth muscle cells into the intima and the deposition of collagen.
During the disease progression of atherosclerosis: once collagen has been deposited into the intima, what occurs?
The formation of an atheromatous plaque consitsting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muslce cells and connective tissue).
What does HDL have a key role in?
Removing excess cholesterol from cells by transporting it in plasma to the liver.
What is the only organ that has the capacity to eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesise bile salts)?
What substance is mainly formed in the liver, initially as apoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre-beta-HDL)?
What does disc-like pre-beta-HDL mature in the plasma to become?
What occurs alongside disc-like pre-beta-HDL maturing in the plasma to spherical alpha-HDL?
Surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of teh particle.
What is reverse cholesterol transport?
Mature HDL accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver.
What receptor does HDL reaching the liver interact with, and what does it allow?
Scavenger receptor-B1, SR-B1, that allows transfer of cholesterol and cholesteryl esters into hepatocytes
In the plasma, what mediates transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returing cholesterol to the liver?
Cholesterol Ester Transfer Protein (CETP)
What does primary dyslipidaemia occur through?
A combination of diet and genetic factors
What is secondary dyslipidaemia a consequence of?
Other diseases such as type II diabetes, hypothyroidism, alcoholism and liver disease
What are a subset of type IIa hyperlipoproteinaemia associated gene defects in the LDL receptor (familial hypercholesterolaemia) associated with?
A great risk of ischaemic heart disease
What are the drugs of choice to reduce LDL?
What drugs reduce total and LDL cholesterol up to 60%, decrease triglycerides (up to 40%) and modestly increase HDL?
Give two examples of statins?
Simvastatin and artovastatin
What do statins act as a competitive inhibitor of?
(HMG-CoA) reductase or 3-hydroxy-3-methylglutaryl coenzyme A
What converts HMG-CoA to mevalonate?
What do statins do to hepatocyte cholesterol synthesis?
Drecrease it causing a compensatory increase in LDL receptor expression and enhanced clearanc of LDL
Are statins effective in familial hypercholesterolaemia?
No - LDL receptors are lacking
What are these 4 features other benifits of - decreased inflammation, reversal of endothelial dysfunction, decreased thrombosis, stabilisation of atherosclerotic plaques?
How are statins administered?
Orally at night
Give two side effects of statins?
2. Rhabdomyolosis - increased if statin combined with fibrate
Give two examples of Fibrates?
What drugs cause a pronounced decrease in triglycerides (50%) and modest decrease (up to 15%) and increase (up to 20%) in LDL and HDL, respectively?
What are the first line drugs in patients with very high triglyceride levels?
What do fibrates act as an agonist of to enhance the transctiption of several genes including that encoding LPL?
Nuclear receptor (PPARalpha)
What patients are you best to avoid fibrate use in?
Alcoholics predisposed to hypertriglyceridaemias
Give three adverse effects of fibrates other than myositis
1. GI symptoms
Name a type of drug that inhibits cholesterol absorption?
Bile acid binding resins
Name 3 bile acid binding resins
What drugs cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interupting enterohepatic recycling?
Bile acid binding resins
How are bile acid binding resins administered?
Ingested orally, not absorbed from GI tract, prevent the reabsorption of bile salts
What substances cause decreased absorption of triglycerides and increased LDL receptor expression?
Give one adverse effect of bile acid binding resins?
GI tract irritation
Name a drug used to inhibit Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol
What does ezetimibe do to LDL and HDL?
Little change to HDL
What is ezetimibe used in combination with, if the latter is not achieving a sufficient response?
How is ezetimibe administered?
Orally, metabolised to an active metabolite that undergoes enterohepatic recycling that contributes to a long half-life of approximately 22 hours
Give three adverse effects of ezetimibe?
What is exetimibe contraindicated in?
Breast feeding females
What is the term for arrest of blood loss from a damaged blood vessel?
What three things does haemostasis involve?
1. Local vasoconstriction
2. Adhesion and activation of platelets at site of injury
3. Formation of fibrin (blood coagulation)
What is the term for pathological haemostasis - a haematological plug in the absence of bleeding?
What are the predisposing factors (Virchow's triad) for thrombosis?
1. Injury to vessel wall (e.g. ruptured atheromatous plaque)
2. Abnormal blood flow
3. Increased coaguability of the blood
What is a white thrombus?
What is a red thrombus?
What is the name for - mainly platelets in a fibrin mesh?
What forms an embolus if it detaches from its site of origin (left heart, carotid artery) often lodges in an artery in the brain (stroke) or other organ?
White, arterial thrombus
What thrombus has a white head, jelly-like tail and is fibrin rich?
Red thrombus - venous thrombus
What thrombus type usually causes pulmonary embolism when it detaches as an embolus that lodges in the lung?
Red thrombus, venous thrombus
What are the three steps involved in platelet reactions to form a clot, after endothelial damage?
1. Adhesion, activation and aggregation of platelets
2. Secretion of preformed mediators (ADP) and synthesis of mediators (e.g. TXA2)
3. Further aggregation of platelets
What is the final substance in blood coagulation which leads to a fibrin clot?
What converts to fibrin, and what mediates this conversion?
Fibrinogen to fibrin
Mediated by thrombin IIa
What do thrombin IIa and fibrinogen cause?
Further aggregation of platelets
What forms thrombin IIa, and what mediates this reaction?
Prothrombin II to thrombin IIa
Mediated by Xa
What is converted to Xa?
In the vivo pathway for endothelial damage, what two substances are present that convert X to Xa?
Tissue factor and factor VIIa
In the contact pathway of endothelial damage, which two factors are present, which convert X to Xa?
XIIa and XIa
What are glycoprotein precursors of the active factors thrombin IIa, VIIa, IXa and Xa?
Clotting factors prothrombin II, VII, IX and X
What do thrombin IIa, VIIa, IXa and Xa act as?
Give an example of a post-translational modification that precursors require for subsequent function of the active factors?
Gamma-carboxylation of glutamate residues
What does the carboxylase enzyme that mediates gamma-carboxylation require?
Vitamin K in its reduced form as an esential cofactor
What does warfarin block?
Vitamin K reductase
What converts vitamin K oxidised form (epoxide) to vitamin K reduced form (hydroquinone)?
Vitamin K (quinone)
What converts - (oxygen + CO2 + glutamic acid residues [in II (descarboxyprothrombin), VII, IX, X]) to (gamma-carboxyglutamic acid residues [in prothrombin II, VII, IX, X])?
Conversion of vitamin K reduced form to vitamin K oxidised form
What drugs are used widely in the prevention and treatment of venous thrombosis and embolism?
What drugs can be used as treatment for DVT, post-operative thrombosis, patients with artifical heart valves and atrial fibrillation patients?
What do anticoagulants all carry the risk of?
What is a coumarin derivative structurally related to vitamin K, competes with vitamin K for binding to hepatic vitamin K reductase preventing the conversion of the epoxide to the active hydroquinone?
What drug renders factors II, VII, IX and X inactive?
What does warfarin block coagulation in?
In vivo and not vitro
How is warfirin administered and how long is its onset of action?
Why does warfarin have a slow onset of action?
Wait, whilst inactive factors replace active gamma-carboxylated factors that are slowly cleared from the plasma. Heparin may be added for rapid anticoagulant effect.
What can it be difficult to strike the balance with, when using warfarin?
Desired anticoagulant effect and haemorrhage - low therapeutic index
What must warfarin be monitored with?
Give two factors that potentiate warfarin action (risk of haemorrhage increased)?
1. Liver disease - decreased clotting factors
2. High metabolic rate - increased clearance of clotting factors
What 3 factors cause the risk of thrombosis to increase when using warfarin?
1. Pregnancy (increased clotting factor synthesis)
2. Hypothyroidism (decreased degradation of clotting factors)
3. Vitamin K consumption
What two things can be used to treat overdose of warfarin?
1. Vitamin K
2. Conentrate of plasma clotting factors
What is an important inhibitor of coagulation which neutralises all serine protease factors in the coagulation cascade by binding to their active site in a 1 to 1 ratio?
What binds to antithrombin III, increasings its affinity for serine protease clotting factors (particularly Xa and thrombin IIa) to greatly increase their rate of inactivation?
What is Xa inhibited by?
Antithrombin III and heparin
What inhibits thrombin IIa?
Antithrombin III and heparin
What must heparin bind to both of to inhibit thrombin IIa?
Both antithrombin III and thrombin IIa
What msut heparin bind to to inhibit Xa?
Only antithrombin III
What drug is a naturally occuring sulphated glycosaminoglycan of variable molecular size (unfractionated) and is also extracted from beef lung, or hog intestine?
Name two low molecular weight heparins?
What do LMWHs inhibit and not inhibit?
Inhibit factor Xa
Do not inhibit thrombin IIa
In what two ways can heparin be administered?
IV or subcutaneously
What is required to determine optimum dosage for heparin?
In vitro clotting test
What does elimination of heparin show?
Zero order kinetics whereas that of HMWHs is first order
How is LMWH eliminated from the body?
Via renal excretion, hence heparin is preferred in renal failure
Give 4 adverse effects of heparin and LMWHs?
1. Haemorrhage - discontinue drug and adminsiter protamine sulfate
2. Osteoporosis (long term treatment)
4. Hypersensitivity reactions
Give a drug which is a direct inhibitor of thrombin?
Give a drug which is a direct inhibitor of factor Xa?
What drugs are used to prevent venous thrombosis in patients undergoing hip and knee replacements?
Dabigatran and rivaroxaban
What does endothelial cell damage, or rupture of the cap of an atheromatous plaque lead to?
Platelet activation and aggregation, arterial thrombosis and potentially MI (heart attack)
How do platelets adhere to subendothelial molecules, revealed by vascular damage?
Via surface glycoproteins (GPIb receptors) with von Willebrand factor acting as a 'bridge'.
What happens to platelets once they have adhered to GPIb receptors with von Willebrand factors?
Change shape and subsequently aggregate.
What two platelet derived substances drive aggregation?
1. Secretion of adenosine diphosphate (ADP), 5-HT and coagulation factors from storage granules
2. Thromboxane A2 synthesis via the enzyme cyclo-oxygenase (COX)
What do ADP, 5-HT and TXA2 act on cell surface receptors of platelets to cause?
Expression of GPIIb/IIIa receptors that cross link platelets via fibrinogen.
What does exposure of acidic phospholipid on platelet surface promoting thrombin IIa formation stimulate?
Further aggregation, stabilised by formation of fibrin from fibrinogen.
What does tirofiban block?
Fibrinogen binding with GPIIb/IIa receptors
What does clopidogrel block?
Irreversibility of ADP
What mediates arachidonic acid generation to production of cyclic endoperoxides?
What does production of cyclic endoperoxidases lead to?
The synthesis of TXA2
What does aspirin block irreversibly?
What are used mainly in the treatment of arterial thrombosis?
What does aspirin's blockage of COX in endothelial cells inhibit?
The production of antithrombotic prostaglandin I2
What can endothelial cells synthesis, that new enucleate platelets cannot?
What drug is used orally, mainly for thromboprophylaxis in patients at high cardiovascular risk
Give two adverse effects of aspirin?
Which drug links to P2Y12 receptor by a disulphide bond producing irreversible inhibition?
Which drug, when administered orally and combined with aspirin has a synergistic action?
Which drug is given in short term treatment to prevent MI in high risk patients with unstable angina (along with aspirin and heparin)?
What exists endogenously and opposes the coagulation cascade?
A fibrinolytic cascade
Which class of drugs are used principally to reopen occluded arteries in acute MI or stroke, less frequently in life-threatening venous thrombosis or PE?
How should fibrinolytics be administered?
IV within as short a period as possible to the event
What is superior to fibrinolytic drugs when treating MI or stroke - but has to be available pronptly?
Percutaneous coronary intervention (PCI)
Which three fibrinolytic drugs activate plasminogen?
What is not an enzyme, but a protein extracted from cultures of streptococci?
What is the action of streptokinase blocked by after 4 days?
The production of antibodies
Which drug primarily reduces mortality in acute MI?
What two drugs are recombinant tissue plasminogen activator (rt-PA)?
Alteplase and duteplase
How are alteplase and duteplase administered?
IV - short half life