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Cardiology > pharmacology > Flashcards

pharmacology Flashcards

1
Q

what are fast action potentials?

A
  • present in atrial and ventricular muscle cells
  • eg purkinje fibres
  • In the diagram, the plateau phase is present
  • Sodium dependent
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2
Q

what are slow action potentials?

A
  • present in sinoatrial node, the normal pacemaker and atrioventricular node – this is the normal route of action potential conduction between atria and ventricles
  • In phase 4, there is a gradual depolarization, this is known as the pacemaker potential
  • Calcium dependent
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3
Q

what happens in phase 4 in ventricular cardiac muscle cells?

A
  • period between action potentials (diastolic potential)
  • There is a constanat movment of K+ ions out of the cel, resulting in a negative membrane potential of -90mV. Ion concentration across the membrane is mainained by the NA/K ATPase – if this is inhibited by digoxin, the cell will depolarize slightly
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4
Q

what happens in phase 0 in ventricular cardiac muscle cells?

A
  • action potential is stimulated by impulses from the SA node
  • involves rapid activation of voltage-activated Na+ channels at a threshold potential, generating an Na+ conductanced and an inward, depolarising Na+ current that drives Vm towards the Na+ equilibrium potential
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5
Q

what happens in phase 1 in ventricular cardiac muscle cells?

A
  • K+ efflux is dominant

- most evident in cells which has a prominent plateau phase, such as purkinje fibres and epicardial ventricular fibres

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6
Q

what happens in phase 2 in ventricular cardiac muscle cells?

A
  • influx of Ca+ is balanced by efflux of K+ - the plateau will last as long as this persists
  • influx of Ca+ vis voltage-activated Ca2+ channels (lL-type)
  • Ik1 channels open slow
  • Ical increases duration of plateau
  • drugs that block certain v potassium channels increase duration of ventricular action potentials - not good
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7
Q

what happens in phase 3 in ventricular cardiac muscle cells?

A
  • efflux of K+ is dominant

- Ica slowly decreases due to the inactivation of Ltype Ca+ channels

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8
Q

how does the slow response differ from the fast response in the nodal tissues of the heart?

A
  • Vm between action potential s(phase 4 ) is unsteady gradually shifting with a slope in the depolarising direction (pacemaker potential)
  • slope steepness in the SA node sets action potential interval and thus heart rate
  • upstroke (phase 0 ) is far less steep and is due to the opening of Ltype Ca2+ channels that mediate Ical
  • there is no distinct steady plateau (phase 2 ) but instead a more gradual repolarisation (phae 3 ) caused by the opening of delayed rectifier K+ channels mediating Ik
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9
Q

what happens in phase 4?

A
  • an effflux of K+
  • reduce influx of Ca2+
  • Na+ is increased, generating the pacemaker potential
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10
Q

what increases the intracellular conc of cycline AMP (cAMP)?

A
  • coupling through Gs protein alpha subunit stimulates adenylyl cyclase to increase the intracellular conc of cAMP
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11
Q

what does signalling though Gs, B1-adrenoceptor activation cause?

A
  • increased SA node action potential frequency and heart rate (positive chronotropic effect) due to:
    1. an increase in the slope of phase 4 depolarisation by inhanced If and Ical
    2. a reduction in the threshold for AP initiation by enhanced Ical
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12
Q

what are the impacts of sympathetic on cardiac rate and force?

A
  • higher contractility because more Ca+ comes into the cell during plateau = enhanced CICR
  • higher conduction velocity in AV node
  • increase in automaticity
  • decrease in duration of systole (due to increased uptake of Ca2+ into the sarcoplasmic reticulum)
  • increased activity of the NAKATPase
  • increased mass of cardiac muscle
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13
Q

parasympathetic: how does coupling through G1 protein work?

A
  • via alpha subunit inhibits adenylyl cyclase and reduces cAMP
  • via beta/gamma subunit dimer opens specific potassium channels
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14
Q

what does signalling through G1, M2 muscarininc recrptor activation cause?

A
  • decreased SA node action potential frequency and heart rate due to
  • a decrease in the slope in phase 4 depolarisation by reduced If and Ical
  • an increase in the threshold for AP initation by reduced hyperpolarisation during phase 4 via GIRKs
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15
Q

what happens if you block HCN channels?

A
  • a decrease in the slope of the pacemaker potential and a reduce in heart rate
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16
Q

summarise excitation contraction coupling in cardiac muscle relaxation

A
  1. repolarisation in phase 3 to phase 4
  2. voltage-activated l-type Ca channels return to closed state
  3. Ca influx ceases. Ca efflux occurs by the NA/Ca exchanger
  4. Ca release from the sacroplasmic reticulum ceases
  5. Ca dissociates form troponin C
  6. cross bridge between actin myosin break resulting in relaxation
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17
Q

what converts cAMP into 5’AMP?

A

phosphodiesterase enzyme (PDE)

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18
Q

what are catecholamines? (B-adrenoceptor ligands on the heart)

A
  • dobutamine
  • adrenaline
  • noradrenaline
  • they increase force, rate, cardiac output, O2 consumption
  • they decrease cardiac efficiency
  • can cause disturbances in cardiac rhythm
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19
Q

what are the effects of b-adrenoceptor agonists upon the heart?

A
  • adrenaline = reverse cardiac arrest, anaphylactic shock

- dobutamine = heart failure,

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20
Q

what are the effects of B-adrenoceptor ligands upon the heart? (antagonists)

A
  • thye may block B-adrenoceptors non-selectvely (propreanol) or selectively (atenolol)
  • may be non-selective and a partial agonist (alprenolol)
  • pharmacodynamic effects . of non selective blockers:
  • at rest = little effect on anything
  • during exercise, rate force and CO are depressed
  • cornonary vessel diameter reduced
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21
Q

what are the clinical uses of B-adrenoceptor antagonists (CVS actions only)?

A
  • treatment of disturbances of cardiac rhythm - B blockers decrease excessive sympathetic drive and healp to restore normal sinus rhythm
  • angina treatment
  • heart failure treatment-
  • hypertension treatment
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22
Q

what are the adverse effects of B-blockers (As a class)?

A
  • bronchospasm
  • cardiac failure
  • bradycardia
  • hypoglycaemia
  • fatigue
  • cold extremities
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23
Q

what are the effects of non-selective muscarinic ACh receptor antagonist upon the heart?

A
  • atropine = increases HR
  • first line treatment in bradycardia, esp in MI
  • used in anticholinesterase poisoning
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24
Q

what is digoxin?

A
  • a cardiac glycoside that increases contracility of the heart
  • binds to the a-subunit of NA/K ATPase in competition with K+
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25
Q

what are the indirecte actions that digoxin has on electrical activity?

A
  • increased vagal activity
  • slows SA node discharge
  • slows AV node conduction, increases RP
26
Q

what are the direct actions that digoxin has on electrical activity?

A
  • shortens action potential and RP in atrial and ventricular myocytes, toxin concentration causes membrane depolarisation and oscillatory afterpotentials likely due to Ca overload
27
Q

what are the clinical uses of digoxin?

A
  • Iv in acute heart failure
28
Q

what are the adverse effects of digoxin?

A
  • nausea
  • vomiting
  • diarrhoea
  • colour vision disturbances
29
Q

what does levosimendan do? (inotropic)

A
  • which is a calcium-sensitisers
  • binds to troponin C in cardiac muscles, sensitising it to the action of Ca
  • additionally it opens KATP channels in vascular smooth muscle causing vasodilation
30
Q

what do inodilators do?

A
  • eg amrinone and milrinone
  • inhibit phhosphodiesterase in cardiac and smooth muscle cells and hence increase cAMP
  • increase myocardial contractility, decrease peripheral resistance
31
Q

what drugs are used clinically to relax vascular smooth muscle?

A
  • organic nitrates

- calcium channel blockers

32
Q

what do organic nitrates do?

A

to treat angina/chest pain, used as prophylaxis to prevent angina, used to treat pulmonary oedema

33
Q

what do calcium channel blockers do?

A

to treat hypertension, in treatment of stable angina

34
Q

what are the 3 types of angina?

A
  • stable = due to fixed narrowing of coronary vessels following atherosclerosis
  • unstable = due to platlet-fibrin thrombus in association with atheromatous plaque
  • variant = associated with coronary artery spasm
35
Q

what are non-polar lipids and how are they transported?

A
  • eg cholesterol esters

- they are transported in blood by lipoproteins eg HDL, LDL

36
Q

what is the structure of a lipoprotein?

A
  • hydrophobic core containing estrified cholesterol and triglycerides
  • hydrophilic coat comprising a monolayer of amphipathic cholesterol, phospholipids and one or more apoproteins
37
Q

what is the role of ApoB-containing lipoproteins?

A
  • they deliver triglycerides to the muscle for ATP biogenesis and to adipocytes for storage
38
Q

what do apoproteins do?

A
  • they are recognised by receptors in liver and other tissues allowing lipoproteins to bind to cells
  • then chylomicros are formed in interstitial cells and transport dietry triglycerides (exogenous pathway)
  • VLDL particles are formed in liver cells and transport triglycerides synthesised in that organ (endogenous pathway)
39
Q

how can the life cycles of ApoB-containing liposomes be summarised?

A
  • assembly (with apoB100 in the liver and apoB48 in the intestine)
  • intravascular metabolism (involving hydrolysis of the triglceride core)
  • receptor mediated clearance
40
Q

describe the assembly of apoB-containnig lipoproteins to form VLDL?

A
  • VLDL particles containing triglycerides are assembled in liver hepatocytes from free fatty acids derived from 1) adiopose tissue (during fasting) and 2) de novo synthesis
  • MTP lipidates APOB100 forming nascent VLDL that coalesces with triglyceride droplets
41
Q

describe the assembly of apoB-containing lipoproteins to form chylomicrons?

A
  • monoglyceride combines with free fatty acid (dietry fat) to form triglyceride
  • cholesterol combines with NPC1L1 and undergoes estification to form a cholesteryl ester
  • a chylomicron is formed when the triglcyeride undergoes lipidation by MTP in the endoplasmic reticulum and a cholestryl ester is formed
  • APOB48
42
Q

how are chylomicrons and VLDL particles activated?

A
  • by the transfer of apoCLL from HDL particles
43
Q

describe intravascular metabolism of ApoB-containing lipoproteins

A

once apoCLL has been added to the LDL, the apoCLL allows particles to react with an enzyme (lipoprotein lipase) which is on the surfaces of capillaries

44
Q

what are chylomicron and VLDL remnants?

A
  • particles depleted of triglycerides (but still containing cholestryl esters)
45
Q

describe the clearacne of apoB-containing lipoproteins?

A
  • LPL causes chylomicrons and VLDL particels to become enriches in cholesterol due to triglyceride metabolism
  • chylomicrons and VLDL dissociate from LPL
  • apoCLL is tranfered to HDL particles in exchnage for apoE which is a high affinity ligand for receptor mediared clearnace, particles are now remnants
  • remnants return to the liver and are further metbaolised by hapatic lipase
  • all apoB48-containing remnants and 50% or apo100 contianing-remnants are cleared by receptor-mediated enocytosis into hepatocytes
  • remaining apoB100-containing remnants loose further triglyceride thorugh heapitic lipase, become smaller and enriches in cholestryl ester and via intermeidate density lipoproteins (IDL) become LDL particles lacking apoE and retaining solely apoB100
46
Q

what is clearnace of LDL particles dependant on?

A
  • the LDL receptor expressed by the liver
47
Q

what does cellular uptake of LDL particles occur via?

A
  • receptor-mediated endocytosis
48
Q

how is cholesterol released from cholestryl ester?

A

by hydrolysis

49
Q

what does released cholesterol cause?

A
  • inhibition of HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
  • down regulation of LDL receptor expression
  • storage of cholesterol as cholesterol ester
50
Q

what is the disease progression of atherosclerosis?

A
  1. uptake of LDL from the blood into the intima of the artery - LDL subsequently oxidised to atherogenic oxidised LDL
  2. migration of monocytes across the endothelium int the intima where they become macrophages
  3. uptake of OXLDL by macrophages converts them to cholesterol-laden foam cells that form a fatty streak
  4. release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
  5. the formation of atheromatous plaque consisting of a lipid core and a fibrous cap
51
Q

what does HDL do?

A
  • removes excess cholesterol from cells by transporting it in plasma to the liver
  • known as reverse cholesterol transport
52
Q

where is HDL made?

A
  • in the liver, initially as ApoA1 in association with a small amount of surface phospholipid and unestrified cholesterol
  • disc-like pre-B-HDL matures in the plasma to spherical a-HDL as surface cholesterol in enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
53
Q

how do statins work?

A
  • inhibit HMG CoA reducatase, causing decrease in de novo cholesterol synthesis + increase in LDL receptor expression to enhance cholesterol clearance
54
Q

when are statins useless?

A
  • in homozygous famlial hypercholesterolaemia where LDL receptors are lacking
55
Q

when are statins administrated?

A
  • orally at night
56
Q

what are the other beneficial effects of statins?

A
  • decreased infalmmation
  • reversal of endothelial dysfunction
  • decreased thrombosis
  • stabilisation of athersclerotic plaques
57
Q

what happens when a statin is combined with a fibrate?

A
  • myositis

- rhabdomyolosis

58
Q

what is the role of fibrates?

A
  • decrease in triglycerides (up to 50%)

- increases LDL and HDL (20%)

59
Q

give examples of fibrates?

A
  • beafibrate and gemfibrozil
60
Q

how do fibrates work?

A
  • as an agonist of a nuclear receptor toenhance the transcroption of several genes, including that encoding LPL
61
Q

when should you avoid fibrates?

A

in alcoholics

Cardiology (40 decks)

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