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BIOL2049 S2 > Cardiac pharmacology > Flashcards

Cardiac pharmacology Flashcards

1
Q

LO

A
  • Cardiac intrinsic excitability - Action Potential
  • Electrocardiogram - ECG / EKG
  • Excitation / Contraction coupling
  • Autonomic regulation – sympathetic / parasympathetic
  • Inotropic / Chronotropic effects
  • Vascular smooth muscle tension – load / resistance
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2
Q

Tell me about the circulation of blood around the body?

A
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3
Q

Tell me about cardiac AP and ECG?

A
  • Heart muscle is myogenic, excitation originates from muscle as opposed to nerve impulses
  • Sinoatrial node in the right atrium initiates the contraction
  • Breadth of AP is to do with voltage gates calcium channels, and these determine the length of the contraction
  • Muscle cells are built so there AP are long, allow for long period of contraction which matches the hydrodynamics of pushing the blood out
  • Ca2+ pumped back into SR after contraction (ATP dependent process)
  • Some flux and pumping across membrane
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4
Q

Excitation/ contraction coupling

A
  • Gap junctions between cells allow the spread of excitation
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5
Q

What are the steps to excitation-contraction coupling and relaxation in cardiac muscle?

A
  • DHR = Dihydropyridine receptor Aka voltage gates Ca2+ channel
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6
Q

Tell me some HVA/ “L” type calcium channel agents

Tell me about them and their action

A
  • DHP has 4 regions with TMD which controls heart contraction as is where Ca2+ passes through
  • Verapamil slows flux of Ca2+ through channel- antagonist, channel blocker, wouldn’t want to use too much as would kill person. Want to just give enough to correct the problem
  • Diltiazem is an antagonist and a channel blocker
  • Nifedipine is an antagonist- DHP receptor got its name from this drug. This isn’t a proper antagonist
  • All the drugs don’t block site of agonist they just slow the flux of the Ca2+ through the channels. Bind to points on Cav1.2 and modify tis behaviour e.g., change flux (Cav1.2 isn’t just found in the heart)
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7
Q

Tell me an agonist and antagonist to the ryanodine receptor?

Tell me about them?

A
  • Ryanodine named after alkaloid
  • Ryanodine: rigid molecule, push up binding affinity if it will match what it will bind to (increase chance of binding effectively), dantrolene is an antagonist to the ryanodine receptor
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8
Q

Autonomic innervation of the heart

A
  • The heart is innervated by vagal and sympathetic fibers. The right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node; however, there can be significant overlap in the anatomical distribution.
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9
Q

Tell me about autonomic regulation- sympathetic/ parasympathetic

A
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10
Q

G-protein couples receptor super-family

A
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11
Q

Tell me about adrenergic receptors: G-protein coupled receptors

Tell me their roles, levels of NAdr and Adr

A
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12
Q

Name some adrenergic drugs

A
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13
Q

Draw adrenaline

A
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14
Q

Draw noradrenaline

A
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15
Q

Draw atenolol

A
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16
Q

draw phenylephrine

A
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17
Q

Draw propanolol

A
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18
Q

Draw Prazosin

A
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19
Q

The following the Beta1 adrenoreceptor structure (cardiac role)

A
  • Schematic representations of the turkey β1AR structure
  • (A) Diagram of the turkey β1AR sequence in relation to secondary structure elements. Amino sequence in white circles indicates regions that are well ordered, but sequences in grey circles were not resolved in the structure. Sequences on an orange background were deleted to make the β1AR construct for expression. Thermostabilising mutations are in red and two other mutations C116L (increases functional expression) and C358A (eliminates palmitoylation site) are in blue. The Na+ ion is in purple. Numbers refer to the first and last amino acid residues in each helix (blue boxes), with the Ballesteros-Weinstein numbering in superscript. Helices were defined using the Kabasch & Sander algorithm49, with helix distortions being defined as residues that have main chain torsion angles that differ by more than 40° from standard α-helix values (−60°,−40°)
  • (B) Ribbon representation of the β1AR structure in rainbow colouration (N-terminus blue, C-terminus red), with the Na+ ion in pink, the two disulphide bonds in yellow and cyanopindolol as a space-filling model. Extracellular loop 2 (EL2) and cytoplasmic loops 1 and 2 (CL1, CL2) are labelled
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20
Q

Sequence differences alter pharmacology

A
  • Figure 2. Subtype specific ligand binding in the b2AR. Amino acids that differ between b1AR and b2AR are shown in yellow. The inverse agonist carazolol is shown with green carbons.
  • The binding pocket of the human b2AR. Only 1 of the 15 amino acids that constitute the antagonist binding pocket (defined as being within 4A°of the inverse agonist carazol) differs between b1AR and b2AR. Tyr308 at the top of TM7 in the b2AR is Phe in the b1AR.
  • The extracellular surface of the b2AR.
  • The interior surface of the b2AR that has been split along the plane of the binding pocket, TM1–TM5 on the right and TM6 and TM7 on the left.
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21
Q

Whats meant by an inotropic effect?

A

modifying the force or speed of contraction of muscles.

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22
Q

Give an example of a positive inotrope?

A

Noradrenaline

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23
Q

Tell me about NorAdrenaline - Sympathetic B1 adrenergic R stimulation and what it leads to…

A
  • GPCR Activation–>Gs–> Adenylate cyclase–> cAMP–> PKA

Leads to:

  • PKA phosphorylation of CaV1.2 increases ICa influx
  • PKA phosphorylation of phospholamban produces more Ca++ATPase activity of SR so more Ca++loading

HENCE:

  • Systole- increases Contraction for any given Excitation AND
  • Diastole- increases Relaxation and SR loading
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24
Q

Adrenergic and cholinergic

A
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25
Q

Name some cholinergic drugs

A
26
Q

M2 receptor structure (cardiac role)

A
27
Q

Summary

A
  • Cardiac intrinsic excitability - Action Potential
  • ElectroCardioGram - ECG / EKG
  • Excitation / Contraction coupling
  • Autonomic regulation – sympathetic / parasympathetic
  • Inotropic / Chronotropic effects
28
Q

Pharmacological interventions

LO

A
  • Hypertension (cf. diuretic lectures)
  • Dysrhythmias
  • Angina- transient ischemia
  • Heart Attack- ischemia / infarct
  • Heart Failure (cf. diuretic lectures)
29
Q

Adrenergic receptors on smooth muscle e.g. vasculature

A
30
Q

Tell me about vasculature and blood pressure

A

Smooth muscle tension controls load/ flow/ resistance

  • Smooth muscle tension controlled by intracellular Ca++ ions
  • β2 AdrR activation relaxes smooth muscle of vessels to skeletal muscles and of Bronchioles/ block causes bronchoconstriction
  • β1 AdrR activation or block little effect on peripheral resistance as few β1 AdrR
  • α1 AdrR activation strong vasoconstriction increased peripheral resistance and BP. Antagonists reduce peripheral resistance
31
Q

Name an Alpha1 AdrR antagonist?

A
32
Q

Tell me about alpha1 AdrR activation?

What do antagonists reduce?

A
  • α1 AdrR activation strong vasoconstriction increased peripheral resistance and BP
  • Antagonists reduce peripheral resistance
  • BUT initially get HR and BP elevation due to response to reduced peripheral resistance ALSO loss of regulation of BP in orthostatic hypotension (lie-to-stand transition)
33
Q

What can cardioactive drugs reduce the effect of?

Give an example

A

Cardioactive drugs can reduce effects of excess sympathetic activation– but substantial reductions of cardiac output would compromise tissue perfusion

β-blockers e.g. Propranolol

34
Q

Drugs that relax arterial smooth muscle reduce what?

What can this improve?

Give an example of a drug

A

Drugs that relax arterial smooth muscle reduce peripheral resistance – can improve perfusion

Dihydropyridines e.g., Nifedipine

35
Q

Tell me about HVA/”L” type calcium channel agents

A
36
Q

Anti-hypertensive drugs: beta-blockers and dihydropyridines

A
37
Q

Give an example of blockade of INa

A

Blockade of INa e.g., Lignocaine fast kinetics Flecainide slow kinetics

38
Q

What do beta-blockers reduce

Tell me about them and provide an example

A

β- blockers- reduce sympathetic effects NA

  • cAMP increases pacemaker current
  • If / HyperpolCyclicNucleotide sensitive channel HCN
  • e.g., Propranolol
39
Q

Give an example of voltage-gated Ca channel blockers

A

e.g., Verapamil, diltiazem

40
Q

Membrane conductance of ions and potential

A
41
Q

What does a reduction in INa result in?

A

reduces excitability

42
Q

Provide examples of anti-arrhthymic drugs and what is their target?

A

These are also local anesthetics

43
Q

What does a high affinity block of the open/ inactivated state of the V-gated Na channel lead to?

A

leads to a use-dependent block- reduces repeat excitability- hence anti-arrhythmic

44
Q

Whats Anginal pain?

A

when coronary blood flow is inadequate for metabolic demands of cardiac muscle

45
Q

Tell me about usual blood flow in the heart and how this is affected by angina (transient ischemia of heart muscle)

A
  • Flows occur during diastole from aorta to ventricles through coronary arteries
  • Restricted flow due to atheroma can produce angina on exercise
46
Q

Whats the blood supply of the heart?

A
47
Q

Tell me the pharmacological intervention of angina

give an example

A
  • Organic nitrates produce Nitric Oxide NO (physiologically from endothelium NO synthase)
  • eg. CH2ONO2-CHONO2-CH2ONO2 Glyceryl trinitrate
48
Q

What does NO activate?

A

NO activates soluble Guanylate Cyclase produces cGMP

49
Q

Whats does cGMP activate?

A

cGMP activates Protein Kinase G etc.

50
Q

What does PKG cause the relaxation of?

What does PKG enhance?

A
  • PKG causes relaxation of coronary artery smooth muscle – increased gK+ (IKCa++)
  • Relaxation produces better Perfusion
  • PKG - enhance opening of I K Ca++ chs and reduces effect of Phospholipase C so less IP3 – so hyperpol and Ca++i reduced
51
Q

Tell me about the anti-angina NO donors

What do they target

A
52
Q

What is coronary heart disease?

Whats it caused by?

What does it lead to?

A
  • Coronary artery disease (atherosclerosis) occlusion of vessels
  • Reduced perfusion causes ischemia and infarct – cell depolarisation and death
  • Can lead to dysrhythmias
  • Can lead to heart failure
53
Q

Tell me about PREVENTIVE PHARMACOLOGY against athero-sclerosis

A

Statins - reduce cholesterol synthesis – reduce atheroma/atherosclerosis

54
Q

Tell me about ACUTE TREATMENT of Coronary Artery Occlusion

A
  • Clot busters - TPA (tissue plasminogen activator)
  • Physical interventions e.g. Stenting
55
Q

Heart failure: history

A
56
Q

Tell me about the possible causes of heart failure

A
  • Failure Associated with Coronary Disease
  • Heart Failure Associated with Valvular Lesions
  • Idiopathic Dilated Cardiomyopathy
  • Inflammatory Diseases of the Myocardium
  • Hypertrophic Cardiomyopathy

  • Cardiac output becomes insufficient – failure of adequate tissue perfusion – progressive*
  • Decreased excitation-contraction coupling*
57
Q

Heart failure can be treated with cardiac glycosides

Tell me about the actions and side effects

A

ACTIONS

  • Cause slowing of AV conduction and cardiac slowing – Via effect on autonomic NS
  • Direct action is increased contractility via effect of Na/K pump

SIDE EFFECTS

  • Nausea, vomiting, cardiac arrhythmias, confusion

nb. OLDER THERAPY now largely replaced – cf. diuretic lectures

58
Q

Provide examples of cardiac glycosides and what do they target?

A
59
Q

Tell me about the actions of the cardiac glycosides digoxin/ ouabain

A

Cardiac Glycosides

e.g., digoxin, ouabain

  • Inhibit Na/K pump 3:2
  • Nai accumulates
  • Reduces Na/Ca exchange 3:1
  • Increased Cai (and SR loading)
  • Increased force of contraction
60
Q

Summary: cardiac pharmacology

A

Cardiac properties

  • Cardiac intrinsic excitability - Action Potential
  • ElectroCardioGram - ECG / EKG
  • Excitation / Contraction coupling
  • Autonomic regulation – sympathetic / parasympathetic
  • Inotropic / Chronotropic effects
  • Vascular smooth muscle tension – load / resistance

Pharmacological Interventions

  • Dysrhythmias
  • Hypertension (cf. diuretic lectures)
  • Angina- transient ischemia
  • Heart Attack- ischemia / infarct
  • Heart Failure
61
Q

Basic mechanisms to remember

A
  • Cardiac intrinsic excitability - Action Potential
  • ElectroCardioGram - ECG / EKG
  • Excitation / Contraction coupling
  • Autonomic regulation – sympathetic / parasympathetic
  • Inotropic / Chronotropic effects
  • Vascular smooth muscle tension – load / resistance
62
Q

Whats atheroma?

A

An atheroma, or atheromatous plaque (“plaque”), is an abnormal accumulation of material in the inner layer of the wall of an artery

The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount of fibrous connective tissue.

BIOL2049 S2 (10 decks)

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