Cardiovascular drugs Flashcards by R G

Describe the basis of hypertension treatment

Hypertension treatment options will be based on blood pressure reading(s), patients’ CVD risk and other co-morbidities.

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Describe ACEIs

The RAAS system

Regulates BP by ↑ or ↓ blood volume through modulating renal function
Renin secretion influenced by
- Reduced renal perfusion
- Reduced Na+ concentration in distal tubular fluid
Angiotensin II
- Potent vasoconstrictor
- Causes release of aldosterone
  - Na+ and water retention
ACE Inhibitors and Angiotensin II receptor blockers and aldosterone antagonists block this system at various points

ACEI
- Stop the renin-angiotensin pathway by inhibiting the conversion of angiotensin I (no appreciable activity) to angiotensin II (potent vasoconstrictor)
- Inhibit vascular tone
- directly lower BP
- Inhibit aldosterone release
- indirectly lower BP

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Describe AngII receptor antagonists or sartans

RAAS:
- Regulates BP by ↑ or ↓ blood volume through modulating renal function
- Renin secretion influenced by
- Reduced renal perfusion
- Reduced Na+ concentration in distal tubular fluid
- Angiotensin II
- Potent vasoconstrictor
- Causes release of aldosterone
- Na+ and water retention
- ACE Inhibitors and Angiotensin II receptor blockers and aldosterone antagonists block this system at various points

AngII receptor antagonists (sartans)
- Drugs that bind at the AT1 receptor to block action
- decreased vasoconstriction, increased salt excretion
- More direct as drug target so limited effect on serum K+ (v inc. in ACE use)
- No effect on bradykinin metabolism (cough physiology in ACEi use)

Reduced adverse effect profile

Advantages and disadvantages of ACEI/ARB

Recommended as first-line treatment of hypertension, especially those with DM, heart failure, CVD/IHD, or proteinuric chronic kidney disease
No rebound hypertension
Long-term benefits on cardiac remodelling and kidney disease with proteinuria

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Define and describe the consequences of the triple whammy

The ‘triple whammy’
of ACEI, NSAID, diuretics…leading to reduced renal perfusion and acute kidney injury (AKI).

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Describe calcium channel blockers

Increased concentrations of cytosolic calcium cause increased contraction in both cardiac and smooth muscle cells (↑ calcium = ↑contractions = ↑ BP)

Calcium channel blockers (CCB’s) all produce effects by binding to the alpha1 subunit of L-type-Calcium channels

Blocking inward movement of calcium through the slow channels of the cell membrane of cardiac and smooth muscle cells
Activity varies depending on the type of cardiovascular cells involved:
- Myocardium
  - Cardiac Conduction System (SA and AV nodes)
- Vascular Smooth Muscle
  - ↓ BP by ↓PVR
Two main classes of CCB’s
- Non-dihydropyridines (target vascular and myocardial cells)
  - diltiazem
    - effects:
      - Targets peripheral blood vesselsand cardiac calcium channels
        *Less effect on the heart compared to verapamil
        *↓ HR and mean arterial BP
      - DRUG INTERACTIONS (CYP inhibitor)
    - side effects:
      - bradycardia
      - constipation
      - AV block
      - worsening heart failure
  - verapamil (used as anti-arrhythmic)
    - effects:
      - targets primarily cardiac calcium channels
      - strong cardiac depressant effect: decreased heart rate and CO
      - reduces AV conduction and blocks SA node
      - decreased PVR and BP
      - drug interactions: CYP inhibitor
    - side effects:
      - bradycardia
      - constipation
      - AV block
      - worsening heart failure
- Dihydropyridines (target peripheral vascular smooth muscle)
  - amlodipine, nifedipine, felodipine
  - effects:
    *More selective as vasodilators and have less cardiac depressant effects (less effect on heart rate)
    *Produce reflex tachycardia by indirectly increasing sympathetic tone
    *Primarily work on vascular smooth muscle to reduce PVR
    *Increased incidence of peripheral oedema
  - side effects:
    - Peripheral oedema (non-responsive to diuretics
    - Hypotension
    - Reflex tachycardia and chest pain

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Describe SNS drugs

Adrenoceptors or catecholamines
- Act on adrenoceptors (alpha 1,2 and beta 1,2,3) to cause general physiological changes in the body that prepare for the “fight or flight” response
- 3 pharmacologically significant endogenous catecholamines in the body (all of which are available as therapeutic agents):
- Dopamine – metabolic precursor of noradrenaline and adrenaline
- Noradrenaline – neurotransmitter between sympathetic postganglionic nerves and organs they innervate (adrenergic transmission)
- Adrenaline – hormone secreted by adrenal medulla
- The various adrenorecpetors are pharmacological targets to alter physiological responses by agonism or antagonism.
- Used in acute treatment in an acute setting (for shock etc)

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Describe noradrenaline

Released as a result of sympathetic stimulation
- Responsible for peripheral vasoconstriction - mostly due to alpha 1 receptor agonist activity, but can be non-selective to alpha and beta receptors
- Used therapeutically for hypotensive states such as vasodilatory shock (administered intravenously)

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Describe adrenaline or epinephrine

Released as a result of sympathetic stimulation
Non-selective agonist for all alpha and beta receptors (choice and degree of activity is dose dependent)
Activity is related to which receptor is being agonised.
- As alpha agonist can cause vasoconstriction
- As beta agonist can increasechronotropy (rate of cardiac contraction) and inotropy (force of contraction) and can be used for low cardiac output (i.e. decompensated cardiac failure)

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Describe the mechanism of action of beta blockers

Mechanism of action:

Competitively block beta receptors in heart, peripheral vasculature, bronchi, pancreas, uterus, kidney, brain and liver.
Beta-blockers reduce heart rate, BP and cardiac contractility; also depress sinus node rate and slow conduction through the atrioventricular (AV) node, and prolong atrial refractory periods.
The affinity of individual beta-blockers for beta receptors varies (B1, B2 and B3)
- Beta 1 selective (eg metoprolol, bisoprolol, nebivolol)
- Beta non-selective (eg propranolol)
- Some beta blockers also have alpha blockade (carvediolol and labetalol)
- Some have anti-arrythmic effects through additional potassium channel blockade (eg sotolol)

Indications:

Myocardial infarction
Tachyarrhythmias
Angina
Chronic heart failure with reduced ejection fraction as part of standard treatment (eg with ACE inhibitor, diuretics)
Hypertension (not first line)
Prevention of migraine
Topical application (eye drops) for glaucoma (eg timolol)

Precautions:

Consideration of risk v benefit is very important when considering beta blocker treatment.
- Contraindicated in bradycardia (45–50beats/minute), second‑ or third-degree AV block, sick sinus syndrome, severe hypotension or uncontrolled heart failure.Beta-blockers may worsen first-degree AV block
- Asthma:Caution in severe or poorly controlled asthma as they may precipitate bronchospasm.Beta1-selective beta-blockers are preferred for patients with well-controlled asthma (on specialist advice).
- Treatment with drugs that cause bradycardia may further decrease heart rate and cause heart block and hypotension; avoid combination with verapamil (cardioselective CCB)

Side-effects
- cardiovascular: Decreased HR, hypotension, transient worsening of heart failure
- peripheral: cold extremities, exacerbation of Raynaud’s phenomenon
- respiratory: Bronchospasm, dyspnoea
- neurological or endocrine: Depression, fatigue, dizziness, altered glucose and lipid metabolism

recall also class II anti-arrhythmics

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Describe diuretics

**
List all

Proximal Tubule:

Leaky and allows passive flow in either direction – no big concentration gradient
Carbonic anhydrase inhibitors are important for Na+ andH+ exchange
- ↑excretion of bicarbonate with accompanying Na+, K+and water, resulting in an increased flow of an alkaline urine →metabolic acidosis

Loop of Henle

NaCl is actively reabsorbed in the thick ascending limb, causing hypertonicity→watermoves out (tubular fluid becomes more concentrated as it approaches the bend)
Theascending limbhas very low permeability to water →substantial concentration gradient across the wall of the tubule.
Active reabsorption of NaCl (not H20)→reducing the osmolality of the tubular fluid and making the interstitial fluid of the medulla hypertonic
Reabsorption of salt from the thick ascending limb is not balanced by reabsorption of water, so tubular fluid is hypotonic with respect to plasma as it enters the distal convoluted tubule (diluted)
Loop diuretics work at thick ascending limb:
- Most potent diuretic class
- InhibitNa+/K+/2Cl−carrier in the lumenal membrane by combining with its Cl−binding site.
- Increase Na+to the distal nephron→loss of H+and K+
- Loss Cl−(not HCO3−) in the urine→ ↑plasmaHCO3− as plasma volume is reduced (metabolic alkalosis)
- Loop diuretics ↑excretion of Ca2+and Mg2+and ↓ excretionof uric acid

Distal tubule

NaCl reabsorption and impermeability to water, further dilutes the tubular fluid.
Transport is driven by Na+-K+-ATPase→↓cytoplasmic Na+ →Na+enters the cell down its concentration gradient, accompanied by Cl− via Na+/Cl−co-transporter
Excretion of Ca2+is regulated in this part of the nephron, byparathyroidhormone(PTH) andcalcitriol→Ca2+reabsorption and phosphate excretion by increasing synthesis of several transporters
_Thiazide diuretics_ work here
Inhibits theNa+/Cl−co-transport system bybinding to the Cl−site→natriuresis with loss of sodium and chloride ions in the urine
Resulting contraction in blood volume stimulates renin secretion, leading to angiotensin formation and aldosterone secretion

Collecting ducts

Reabsorb Na+and secrete K+and two populations of intercalated cells, α and β, which secrete acid and base, respectively.
Impermeable to water and cations.
The movement of ions and water in this segment is under independent hormonal control:
- absorption of NaCl byaldosterone
- absorption of water byantidiuretic hormone(ADH)
Aldosterone antagonists
- Compete with aldosterone for its intracellular receptor inhibiting distal Na+retention and K+secretion.
- Limited diuretic activity
  - Distal Na+/K+exchange accounts for reabsorption of only 2% of filtered Na+

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List some commonly used anti-platelet medications

-P2Y12 antagonists
- Aspirin
- Dipyridamole
- Glycoprotein IIb/IIIa inhibitors
-

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Describe P2Y12 antagonsists

(oral):**

Clopidogrel
Prasugrel
Ticagrelor

Mechanism of Action:

Clopidogrel and Prasugrel: Irreversibly bind to the platelet P2Y12 receptor and inhibit platelet aggregation for the life of the platelet.
Ticagrelor: Binds reversibly to the P2Y12 receptor.

Indications:

Clopidogrel, Prasugrel, and Ticagrelor: Acute coronary syndrome (ACS) in combination with aspirin.
Clopidogrel: Alternative to aspirin for patients (Ticagrelor or Prasugrel arenot).

Adverse Effects:

Bleeding
Angioedema (specific to Ticagrelor)

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Describe aspirin

Aspirin (low doses 75-150mg DAILY)
Mechanism of Action:
Aspirin (COX inhibitor): Irreversibly inhibits cyclooxygenase (COX), reducing the synthesis of thromboxane A2 (an inducer of platelet aggregation) for the life of the platelet, thus inhibitig platelet aggregation

Indications:

Aspirin: PHistory of vascular event/s – secondary prevention of recurrent ischemic stroke and transient ischemic attack (TIA) ^[in combination with an antiplatelet agent?]

Adverse Effects:

GI irritation
Bleeding

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Describe dipyramidole

Mechanism of Action:

Inhibits platelet function by inhibiting phosphodiesterase, increasing platelet cAMP, and inhibiting endogenous adenosine reuptake, causing coronary vasodilation.

Indications:

prevention of recurrent ischaemic stroke and TIA in combo with aspirin

Adverse Effects:

Headache
GI upset
Hot flushes
Hypotension and tachycardia

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Describe glycoprotein IIb/IIIa inhibitors

(intravenous only):

Tirofiban
Eptifibatide

Mechanism of Action:

Prevent binding of fibrinogen to the platelet by occupying the glycoprotein IIb/IIIa receptor, blocking platelet aggregation.

Indications:

Unstable angina and non-STEMI in high-risk patients
Percutaneous coronary interventions (PCI)

Adverse Effects:

Bleeding
Thrombocytopenia

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List some commonly used anti-coagulants

There are three types of anticoagulants:
- NOACs
- Heparins
- warfarin

Describe NOACs

Examples of NOACs include
- Dabigatran
- Rivaroxaban
- Apixaban

Mechanism of Action:

Dabigatran: Direct thrombin inhibitor (oral)
Rivaroxaban and Apixaban: Xa inhibitors (oral)

Precautions:

NOACs: Renal impairment and extremes of body weight (need dose adjustment)
n.b. dabigatran more than rivaroxaban and apixaban

Extra Information and Indication:

For all: Therapeutic anticoagulation and VTE prophylaxis (usually post ortho surgery)

Monitoring:

NOACs: No monitoring

Reversal:

Dabigatran: Reversed by Idarucizumab (antidote)
Rivaroxaban and Apixaban: No reversal agent available

Side Effects:

NOACs: Bleeding, bruising, etc. (skin necrosis for rivaroxaban and apixaban)
- consider drug interactions

Describe heparin

Two main types of heparin
- Unfractionated heparin (UFH)
- Low molecular weight heparins (LMWH) - enoxaparin

Mechanism of Action:
- Heparins inactivate clotting factors ll(a) (thrombin) and Xa by binding to antithrombin III

Precautions for LMWH:

Heparins: Renal impairment and extremes of body weight (need dose reduction)

Extra Information and Indication:

UFH: Intravenous infusion for therapeutic anticoagulation
LMWH (enoxaparin): Therapeutic anticoagulation and VTE prophylaxis (usually post ortho surgery)

Monitoring:

Heparins: APTT for therapeutic anticoagulation, for LMWH: no montioring usually but can use anti-Xa levels

Reversal:

Heparins: UFH reversed by protamine, LMWH partially reversed by protamine

Side Effects:

Heparins: Bleeding, bruising, etc. Immune-mediated thrombocytopenia (HIT) - less than UFH

Describe warfarin

Mechanism of Action:

Warfarin: Vitamin K antagonist (oral) - reduces clotting factors II, VII, IX, X, and protein C and S

Precautions:

Warfarin: Poor compliance, alcoholism

Extra Information and Indication:

Warfarin: Therapeutic anticoagulation

Monitoring:

Warfarin: Monitoring INR (regular)

Reversal:

Warfarin: Reversed with vitamin K (phytomenadione)

Side Effects:

Warfarin: Bleeding, bruising, etc. Skin necrosis, GI ulceration and bleed (consider drug interactions)

Describe thrombolytics

Thrombolysis (Alteplase, tenecteplase, reteplase, urokinase)

Convert plasminogen to plasmin, which catalyses the breakdown of fibrin.

Indications:

Acute STEMI (where primary PCI is not possible)
Acute massive VTE (particularly PE) in patients who are haemodynamically unstable
Peripheral arterial thromboembolism
(alteplase is also used for ischaemic stroke in selected patients meeting strict criteria)

Adverse effects:

Bleeding, transient hypotension, allergic reactions, nausea and headache.

Describe class 1 anti-arrhythmics

Class 1a:
- Quinidine
- Procainamide
(not often used in practice)

Mechanism of Action:

Block Na+ channels by binding to sites on the alpha subunit. The effect on the action potential (AP) is reduced maximum rate of depolarization during phase 0. Action is use-dependent - the more frequently the channels are activated, the more block.

Class 1b:

Lignocaine (lidocaine)

Indication(s):

Ventricular dysrhythmia

Mechanism of Action:

Similar to Class 1a, but lignocaine associates and dissociates rapidly within the normal heartbeat. It dissociates in time for the next AP, provided cardiac rhythm is normal. Premature beats will be aborted due to channel block. Class 1b drugs bind selectively to inactivated channels and therefore block preferentially when cells are depolarized.

Side effects:

Headache
Dizziness
Confusion
Tremor

Extra info:

Proarrhythmic

Class 1c:

Flecainide

Indication(s):

Prevent paroxysmal AF, recurrent tachyarrhythmias associated with abnormal conduction.

Mechanism of Action:

Flecainide associates and dissociates slowly, reaching a steady state that does not vary appreciably during the cardiac cycle. It mostly inhibits the His-Purkinje system and suppresses ventricular beats.

Side effects:

GI upset
Paraesthesia
Ataxia
Dizziness
Drowsiness

**Extra information:
- Proarrhythmic

Describe class 2 anti-arrhythmics

Beta Blockers (e.g., Metoprolol)

Indication(s):

Tachyarrhythmias provoked by increased sympathetic tone

Mechanism of Action:

AV conduction depends critically on sympathetic activity; beta-adrenoceptor antagonists increase the refractory period of the AV node and can therefore prevent recurrent attacks of SVT. They are also used to prevent paroxysmal attacks of atrial fibrillation when these occur in the setting of sympathetic activation.

Side effects:

Bradycardia
Hypotension

Describe class 3 anti-arrhythmics

Amiodarone
Sotalol

Indication(s):

Amiodarone: Supraventricular and ventricular tachyarrhythmias
Sotalol: Paroxysmal supraventricular dysrhythmias, atrial and ventricular dysrhythmias

Mechanism of Action:

Amiodarone: substantially prolong the cardiac action potential, although the exact mechanism is not fully understood. They involve blocking some potassium channels involved in cardiac repolarization. The prolongation of the action potential increases the refractory period, accounting for their powerful and varied antidysrhythmic activity. Amiodarone also has weak beta blocker activity.
Note: drugs that prolong cardiac AP can be pro-arrhythmic
Sotalol: comibes class II snd III actions

Side effects:

Amiodarone: Prolonged QT interval, thyroid dysfunction, pulmonary toxicity, ocular effects
Sotalol: Prolonged QT interval, hypotension, bradycardia, drowsiness, dizziness

Extra information:

Amiodarone has a long half-life and complicated dosing. It also has negative inotropic effects and can be proarrhythmic. Sotalol combines class II (beta blocker) and class III actions.

Describe class 4 anti-arrhythmics

Class 4:

Verapamil
Diltiazem

Mechanism of Action:

Class 4 antiarrhythmics, known as calcium channel blockers, work by blocking voltage-sensitive L-type calcium channels. By doing so, they slow conduction in the SA (sinoatrial) and AV (atrioventricular) nodes, where action potential propagation depends on inward calcium current. This slowing effect on the heart can terminate supraventricular tachycardias (SVTs) by causing partial AV block. These medications also shorten the plateau phase of the action potential and reduce the force of contraction. By decreasing calcium entry, they can suppress premature ectopic beats by reducing after-depolarizations.
dilo\iazem works with more effects on smooth muscle and less bradycardia compared with verapamul

Side effects:

Both: Bradycardia, drug interactions, hypotension, constipation

Describe other anti-arrhythmic drugs

Digoxin:

Indication(s):
- Atrial fibrillation (AF) slow vebntriular rate
- Heart failure associated with arrhythmias
Mechanism of Action:
1. Cardiac slowing and reduced rate of conduction through the AV node, due to increased vagal activity.
2. Increased force of contraction.
3. Disturbances of rhythm, including block of AV conduction and increased ectopic pacemaker activity.
  Note: inhibition of the alpha subunit of the NA/K/ATPase in the cardiac myocytes.
  This increases na and ca.
  The molecular mechanis underlying increased vagal tone i.e. negative chronotoropy is unknown but could also be due to inhibitopn of the NA/K pump.
  Can slow AV conduction by increasing vagal outflow
Extra information:
Digoxin has a narrow therapeutic window and its effects are increased with reduced potassium levels dye to reduced compeptiion at K binfind site
Digoxin is renally cleared.
Plasma concentration can be used to monitor its therapeutic levels.

Adenosine:

Indication(s):
- Slow ventricular rate in acute supraventricular tachycardia (SVT) persisting after manoeuvres e.g. carotid artery massage to increase vagal tone
Mechanism of Action:
- A1 receptors are linked to the same cardiac potassium channel that is activated by Ach. Adenosine inhibits the A1 receptors in the cardiac tissue, causing hyperpolarization of the conducting tissue and slowing the rate of rise of the pacemaker potential i.e. depresses sinus node activity. This slows conduction through the AV node. Adenosine also produces peripheral and coronary vasodilation.
Side effects:
- Chest pain, shortness of breath, dizziness, and nausea.
- Contraindicated in 2nd or 3rd degree heart block or sick sinus syndrome.
  .
Extra information:
- lasts 20-30s i.e. transient and short-lived
- Once SVT has terminated, the patient usually remains in sinus rhythm, even though adenosine is no longer present in the plasma

Discuss prolongation of the QT interval

The QT interval in the ECG represents ventricular depolarisation and repolarisation. Most adults (about 90%) have a QTc (QT interval corrected for heart rate) of <440milliseconds; women generally have a longer QTc.

Prolongation of the QT interval can predispose to a potentially fatal ventricular arrhythmia known astorsades de pointes. Its risk increases gradually with increasing QT interval, especially when QTc >500milliseconds or if a contributing factor(s) (eg drug, electrolyte disturbance) causes an increase over baseline of >60milliseconds (see below).

QT interval can be prolonged by genetic abnormalities (congenital long QT syndrome) or by factors such as electrolyte disturbances (hypokalaemia, hypomagnesaemia, hypocalcaemia), testosterone suppression, bradycardia, structural heart disease (including heart failure, coronary heart disease) and drugs.Drugs that prolong the cardiac action potential (detected clinically as prolonged QT interval on the ECG can be pro-arrhythmic).

Describe class 1a anti-arrhythmics

Class 1a:
- Quinidine
- Procainamide
(not often used in practice)

Mechanism of Action:

Block Na+ channels by binding to sites on the alpha subunit. The effect on the action potential (AP) is reduced maximum rate of depolarization during phase 0. Action is use-dependent - the more frequently the channels are activated, the more block.

Describe class 1b anti-arrhythmics

Lignocaine (lidocaine)

Indication(s):

Ventricular dysrhythmia

Mechanism of Action:

Similar to Class 1a, but lignocaine associates and dissociates rapidly within the normal heartbeat. It dissociates in time for the next AP, provided cardiac rhythm is normal. Premature beats will be aborted due to channel block. Class 1b drugs bind selectively to inactivated channels and therefore block preferentially when cells are depolarized.

Side effects:

Headache
Dizziness
Confusion
Tremor

Extra info:

Proarrhythmic

Describe class 1 c anti-arrhythmics

e.g. Flecainide

Indication(s):
- Prevent paroxysmal AF, recurrent tachyarrhythmias associated with abnormal conduction.

Mechanism of Action:
Flecainide associates and dissociates slowly, reaching a steady state that does not vary appreciably during the cardiac cycle. It mostly inhibits the His-Purkinje system and suppresses ventricular beats.

Side effects:
- GI upset
- Paraesthesia
- Ataxia
- Dizziness
- Drowsiness

Extra information:
- Proarrhythmic

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Cardiovascular drugs Flashcards

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