Cardiovascular Pharmacology Flashcards by Jess Hebron

Dyslipidaemia: Statins

Inhibit the enzymatic action of HMG CoA reductase, decreasing cholesterol synthesis. Prevents the conversion of HMG-CoA to mevalonate. ↓↓↓ LDL, ↑ HDL, ↑ TGs Increased expression of LDL receptors ADRs: GI disturbances, insomnia, rashes, rhabdomyolysis CAUTION: Metabolised by CYT P450S Examples: Simvastatin, atorvastatin, fluvastatin, pravastatin

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Dyslipidaemia: Fibrates

PPAR, increases lipoprotein lipase activity. Agonists of PPAR alpha, lipid-controlled regulatory elements. Increase transcription for lipoprotein lipase, increase hepatic LDL uptake, reduce plasma CRP and fibrinogen. ↓ LDL, ↑ HDL, ↑↑↑ TGs ADRs: Rhabdomyolysis, GI disturbances Examples: Bezafibrate, fenofibrate

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Dyslipidaemia: Resins

MOA: Bind to cholesterol-holding bile acids to create an insoluble complex. Leads to secretion in faeces. Increased expression of LDL receptors on hepatocytes, leading to decreased levels of plasma

LDL. ↓↓ LDL, ↑ slightly HDL, ↑ slightly TGs

ADRs: GI disturbances (constipation), decreased absorption of other drugs, fat soluble vitamin deficiency

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Dyslipidaemia: Ezetimibe

MOA: Acts at the brush border, upon enterocytes. Prevents absorption of cholesterol, without affecting absorption of fat soluble vitamins, triglycerides and bile acids.

↓↓ LDL, - HDL, - TGs Increased expression of LDL receptors

ADRs: GI disturbance, headache, rhabdomyolysis (if alongside statins) Example: Ezetimibe used in conjunction with statins

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Arrhythmia: Class I

Sodium channel blockers/membrane stabilisers. Bind Sodium channels, in the open state, and some K channels. Decrease the availability of channels for binding, increases the threshold for depolarisation and increases the refractory period. Example: Flecamide, lidocaine ADRs: Visual impairment, dizziness, dyspneoa Subtype III only used for severe ventricular arrhythmia - risk of cardiac arrest

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Arrhythmia: Class II

Beta-blockers. Affect rate Decrease automaticity (inotropic and chronotropic) and AV conduction velocity. Refractory period is increased. ADRs: Bradycardia, cold extremities, GI disturbances - Not to be used in heart failure, 2nd/3rd degree heart block Example: Atenolol (relatively selective for B1), propanolol, labetolol (+ vasodilation)

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Arrhythmia: Class III

K+ channel blockers Bind potassium channels and prevent movement of potassium back into cells, for repolarisation. Prolongs the refractory period. Delays repolarisation. ADRs: Bradycardia, GI disturbances, corneal deposits Example: Amiodarone, defetilide, sotalol

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Arrhythmia: Class IV

Calcium channel blockers Bind calcium channels and prevent the inward movement of calcium. Decrease contractility, automaticity and AV conduction. ADRs: Constipation, flushing and headaches Example: Verapamil, diltiazem

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Heart failure: Digoxin

Inhibit the ATPase enzyme, disrupts NA/K exchange. Increases intracellular calcium concentration, increases [calcium] in the SR, increases calcium available for contractile activity. Increased inotropy ADRs: Dizziness, visual distrubances, nausea Indications: AF

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Arrhythmia: Adenosine

Opens K+ channels –> Hyperpolarization. Decreases calcium currents. Short and rapid action

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Hypertension: ACE inhibitors

Inhibit angotensin converting enzyme (ACE), preventing conversion of angiotensin I to angiotensin II. Ultimately prevents aldosterone release and any subsequent water and salt retention, prevents MAP increase. Examples: Ramipril, captopril, enalopril, lisinopril, perindopril ADRs: Dry cough, hypotension, hyperkalaemia

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Hypertension: Renin inhibitors

Inhibit renin preventing the conversion of angiotensinogen to angiotensin, inhibiting the whole of RAAS. No alderosterone release and no rise in MAP. Examples: Aliskiren ADRs: Dry cough, hypotension, hyperkalaemia

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Hypertension: Beta-blockers (B1)

Bind and blocks beta 1 receptors, preventing Noradrenaline binding. Blocks the action of the the Gs G protein, Gs –> adenylate cyclase –> cAMP –> PKA and increased Calcium. Decreased calcium means decreased contraction. Examples: Atenolol, bisprolol ADRs: Bronchoconstriction (nonspecific binding), hypotension, cold hands and feet, fatigue Contraindications: Not to be used by severe asthmatics, severe PAD, bradycardia > 50

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Hypertension: Alpha-blockers (a1)

Bind to alpha 1 receptors, preventing the binding of noradrenaline to the receptors. Binding to A1 receptors inhibits the Gq G protein, prevents PLC activity and production of DAG and IP3. Decreases calcium concentration. Also acts upon A2, as an agonist. Creates negative feedback loop for noradrenaline. Also acts alpha 2 related Gi proteins. Sees inhibition of adenylate cyclase, preventing cAMP production. Examples: Doxazosin, indoramin, prozosin *Used for benign prostatic hypertrophy* ADRs: Postural hypotension, fatigue, dizziness

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Hypertension: Calcium channel inhibitors

Block calcium channels, prevents influx of calcium and therefore reduces muscle contraction. Act on L-voltage gated calcium channels, act on the alpha subunit. Dihydropyridines: Lower BP through vasodilation, more specific for smooth muscle channels (Hypertension, angina, supraventricular arrhythmia, not heart failure) Nondihydropyridines: Act on vascular and also cardiac calcium channels. Also have an effect upon AV and SA nodes. (Hypertension, angina with a beta blocker, not heart failure)

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Hypertension: Angiotensin II receptor inhibitors (AT1)

Block the angiotensin II receptors, AT subtype 1 receptor. This prevents vasoconstriction and also prevents secretion of aldosterone, any water and salt retention and therefore an increase in MAP. Examples: Candesartan, losartan, valsartan ADRs: Orthostatic hypotension, hyperkalaemia, less common dry cough Contraindications: Not to be used in pregnancy

Diuretics: Loop diuretics

MOA: Act on the thick ascending limb through inhibition of the Na+/K+/Cl- transporter. Decreases the reabsorption of Sodium, Potassium and H+ ions. Calcium and Magnesium absorption is also decreased. Water follows.

Most effective. Site of 25 % sodium resorption

ADR: Ototoxicity, hypokalaemia, hypocalcaemia, hyperglycaemia

Examples: Furosemide, butemide

Diuretics: Thiazides

MOA: Act on the Na+/Cl- symporter within the distal convoluted tubule. Increased secretion of Na+, K+. Cl-, H+ and H2O is seen. Decreased secretion of Ca2+ is seen.

Examples: Bendraflumethazide, chlortalidone, indapamide.

ADRs: Gout, hypokalaemia, hypercalcaemia, hyperglycaemia, orthostatic hypertension

Diuretics: Potassium sparing diuretics

Can take 2 mechanisms 1.) Inhibit sodium channels: Decrease absorption of sodium and increase water secretion. K+ and H+ are retained. ADR: Hypernaturiesis, hyperkalaemia, hypotension 2.) Aldosterone receptor antagonists: Increase Na+ secretion and K+ absorption. ADRs: Menstrual changes, gynaecomastica Example: Spironlactone

Heart failure: Digoxin

MOA: Act on Na/K ATPase, increase intracellular calcium levels as the Na/Ca symporter is upregulated, increase calcium in the SR, increase calcium available for release during contractile activity, positive inotropic effects ADRs: GI upset, heart block, confusion Indications: Heart failure associated with AF

Heart failure: Inotropic sympathomimetics

Those acting on beta 1/2 and alpha 1 receptors. Agonists which increase heart rate and vasodilation

Heart failure: Phosphodiesterase inhibitors

Prevent degradation of cAMP, increase mobilisation of calcium. ADRs: Headache, nausea, vomiting, diarrhoea

Heart failure: Neprilysin inhibitor

Inhibits degradation of signalling peptides, such as ANP (atrial natriuretic factor) ANF is released by the atrium in response to increased distension.

Heart failure: Vasodilators - NO

MOA: Nitrates administered are concerted to NO, which acts to increase cGMP levels, which decreases calcium levels and increases vasodilation (in veins and large coronary vessels) ADRs: Headache, postural hypotension Indications: Angina, congestive heart failure

Anticoagulants: **Unfractioned Heparin**

**MOA:** Acts through increasing the activity of antithrombin III leading to increased deactivation of clotting factors **Uses:** Thromboprophylaxis, DVT, to prevent coronary events, bridging therapy for oral anticoagulants **Monitoring:** PTT (aim for PTT of 1.5 - 2.5 x the patient baseline) * Reversed by protamine **ADRs:** Haemorrhage, osteoporosis \*Administered parenterally

Anticoagulants: **LMWH**

**MOA:** Increases the action of antithrombin III on factor Xa, but not IIa **Advantages:** Longer half life (administered twice daily), no monitoring, causes less thrombocytopenia **Disadvantages:** More difficult to reverse effects - not metabolised by protamine **Uses:** Thromboprophylaxis, DVT, PE, prevent coronary events **Monitoring:** Non-required, effects are more predictable **ADRs:**

Anticoagulants: Warfarin

**MOA:** Inhibits Vitamin K reductase, reducing the regeneration of Vitamin K. This in turn reduces the synthesis of Vitamin K dependnent clotting factors (II, VII, X and IX) **Uses:** AF, DVT, PE **Disadvantages:** _Slow_ to act (due to the half life of clotting factors), metabolised by _CytP450_ (multiple interactions), _teratogenic_ and has a _narrow therapeutic window_ **Monitoring:** PT - normalised to give INR. INR or around 2-3 **ADRs:** Haemorhage * **Reversal:** Fresh frozen plasma, administer Vitamin K

Anticoagulants: **Thrombin inhibitors**

MOA: Bind thrombin preventing action Used for HIT patients (Heparin Induced Thrombocytopenia)

Anticoagulants: **Activated factor Xa inhibitors**

**MOA:** Rivaroxaban

Factors/molecules stimulating platelet adhesion

* Trauma * ADP, 5HT * **↑ Calcium** allows GPIIIa/IIb receptor activation

Antiplatelets: Aspirin

**MOA:** Prevents synthesis of TXA2, through **irreversible** inhibition of COX. This prevents TXA2 binding to the TXA2 receptor, stimulating _Gq_ signalling and _raising intracellular calcium_ levels. **Inhibits Gq signalling.** * Effects are irreversible as platelets are unable to reprodice COX, due to having no nucleus **Uses:** Secondary prevention of MI, prevent vascular events in PVD **ADRs:** Bleeding, GI disturbance, _Reyes in children_

Antiplatelets: **ADP receptor inhibitors (P2Y₁₂)** - Clopidogrel

**MOA:** Bind to ADP receptors. Prevent binding of ADP, subsequent Gi activity, PKA activation and platelet activation. * **Inhibit Gi activity:** Cause ↑ cAMP, ↑ PKA activity, decreased platelet activation

Antiplatelets: **PDE inhibitors** Dipyridamole

**MOA:** Prevent conversion of cAMP to AMP. cAMP levels remain high, PKA activity persists and platelet activation is prevented **and** inhibits cellular uptake of adenosine. * Less effective than aspirin **Uses:** Prosthetic heart valves

Antiplatelet: **GPIIIa/IIb inhibitors**

**MOA:** Bind to the GPIIIa/IIb receptor, preventing the cross linking of platelets via fibrin. **Uses:** _Specialist use only._ NSTEMI and heart surgery * IV only

Antiplatelet: **Epoprostenol**

**MOA:** Bind prostacyclin receptors, increase cAMP, decrease platelet aggregation

**Fibrinolytics: 4 named examples**

1. **Streptokinase:** Activates **plasminogen to plasmin.** Dissolves the clot. 2. **Alteplase: Ativates plasminogen** bound to fibrin 3. **Urokinase:** Converts **plasminogen to plasmin** 4. **Anistreplase:** Human plasminogen + bacterial streptokinase **Uses:** Acute stroke, arterial thrombosis **ADRs:** Bleeding, allergic reactions