CARDIO

CARDIAC ACTION POTENTIALS

There are two types of main types of action potentials in the heart:

 Nodal (SAN and AVN)

 Non-nodal (atrial and ventricular myocytes)

Non nodal Nodal

  Phase 0 = Rapid depolarisation – due to the opening of voltage gated sodium channels
 Phase 1 = Initial Repolarisation – as sodium channels close, potassium channels open, to start repolarising
 Phase 2 = Plateau – calcium channels open, so as potassium leaves, some calcium enters, this results in a
balance of voltage.
 Phase 3 = Eventually more voltage gated slow potassium channels open, resulting in a rapid efflux of
potassium ions, causing the voltage gated calcium ions to close
 Phase 4 = Resting potential – the cell is waiting for the next action potential- a few of the potassium ion
channels remain open to allow for slow potassium permeability

KEY POINTS:
a) In Nodal action potentials there are no phases 1 or 2
b) The refractory period (the period where no other action potentials can take place) is between Phase 0 and 3

The refractory period is an important concept when it comes to discussing the mechanism of action of certain anti-
arrhythmic agents. If we increase the refractory period  increases the amount of time between depolarisations 
increase the amount of time between heart beats = slow the heart rate

ANTI-ARRHYTHMIC AGENTS

CLASS 1 – SODIUM CHANNEL BLOCKERS (THIS HAS 3 SUBCLASSES)

Class Examples Mechanism of action Used to treat Side effects
 Disopyramide Lengthens the overall action potential  Ventricular  Nausea and
1a  Quinidine  Moderate blocker of sodium ion arrhythmias vomiting
 Procainamide channels (therefore depolarisation  Prevention of AF  Dry mouth
takes longer)  Wolff Parkinson  Blurred vision
 Also blocks Potassium Ion channels White Syndrome  Urinary retention
(therefore repolarisation takes (procainamide)  Hypotension
longer)  Precipitation of
 The refractory period is longer Lupus
(procainamide)
1b  Lidocaine, Shortens the overall action potential  Ventricular  Convulsions
 Phenytoin,  Mild blocker of Sodium ion tachycardia-  Nausea and
 Mexiletine channels (Depolarisation takes especially after vomiting
longer) MI
 Blocks Sodium ions in a later phase
(which decreases repolarisation
time)
1c  Moricizine No significant change in the time of  Prevents AF  Further
 Flecainide, action potential arrhythmias
 Propafenone  Most potent blocker of Sodium Ions  Dizziness
(Depolarisation takes longer)
 Does not affect repolarisation
CLASS 2 – BETA BLOCKERS
 Preferentially acts on the nodal tissues (SAN and AVN)
 Beta 1 receptors are important in sensing sympathetic
stimulation
 So beta blocker reduces the amount of sympathetic tone to the
heart
 This increases the depolarisation time
 Also there is prolonged repolarisation time in the AV node
(which reduces the amount of impulses that go to the ventricles)

Examples: Propranolol, Metoprolol, Atenolol, Bisoprolol

Used to treat: Tachyarrhythmias
Side effects: Tiredness and some provoke asthma

CLASS 3 – POTASSIUM CHANNEL BLOCKERS

 Blocks potassium channel
 This causes a sustained plateau period (phase 2) and a longer
repolarisation
 This means the refractory period is longer

Examples: Amiodarone (also has Class 1a,2 and 4 properties), Sotalol

(also a beta blocker), Ibutilide, Dofetilide, Dronedarone
Used to treat: Wolf Parkinson White syndrome, AF, atrial flutter
Side effects: Liver damage, Thyroid disorders, neuropathy, interstitial
lung disease

CLASS 4 – CALCIUM CHANNEL BLOCKERS

 Preferentially acts on nodal tissues (SAN and AVN)
 Decreases the rate of depolarisation (phase 0 takes longer)
 So this decreases the firing rate of the SAN and the conduction
rate of the AVN (this will help prevent re-entry tachycardia)

Examples: Non-dihydropyridines (Verapamil, Diltiazem)

Used for: Prevention of Supraventricular tachycardia, AF
Side effects: Precipitation of cardiac failure, Atrioventricular block

DIGOXIN
 Inhibits the sodium potassium pump
 This means there will be a slower rate of depolarisation- slower heart rate
 Also increases vagus nerve activity- which slows the rate of depolarisation especially in the AVN

Used for: Supraventricular arrhythmias

Side effects: irregular heart rate, dizziness, visual disturbances, other arrhythmias, yellow green vision, toxicity (reverse tick)

ADENOSINE
 Binds to adenosine receptors in pacemaker cells which opens potassium ion channels leading to
hyperpolarisation.
 Also inhibits calcium ion channels
 Causes a decreased heart rate and reduces conduction velocity especially in the AVN
 Very short half-life of 10 seconds
Used for: terminating supraventricular tachycardias visual disturbances,
Side effects: metallic taste, transient asystole, nausea
RESP

ASTHMA

SHORT ACTING BETA AGONIST

Drug name: Salbutamol Dose: 100mcg Route: Inhalation
Frequency: 2 puffs when needed Indication: Asthma Class: Bronchodilators
Mechanism of action: Salbutamol is a short beta2-adrenergic agonist and stimulate Beta2-receptors.
Beta2-receptors are found in smooth muscle of bronchi and stimulation of this receptor increases cAMP
production. Increased intracellular cyclic AMP increases the activity of cAMP-dependent protein kinase A,
which activates myosin light chain phosphatase, therefore inhibits the phosphorylation of myosin and
lowers intracellular calcium concentrations.
Side effects: Tachycardia, Tremor, Anxiety, Palpitation, Hypokalemia
Contraindication: Beta blockers, NSAIDs (including Aspirin)

Step 1 of asthma management. It is a blue inhaler known as “the reliever” to the patient. They only take it when they
need it to relieve breathlessness. Onset of action is 15 minutes and a duration of action of 4-6 hours. Drugs can be
delivered via aerosol (Metered dose inhaler MDI) or dry powder. Inhaler technique and compliance should be
checked at every session. Need to explain to the patient that this only treats the symptoms and not the disease
itself. Also used for hyperkalaemia due to the side effect.

When medications like NSAIDs or aspirin block the COX-1 enzyme, production of thromboxane and some anti-
inflammatory prostaglandins is decreased, and in patients with aspirin-induced asthma this results in the
overproduction of pro-inflammatory leukotrienes to causes severe exacerbations of asthma.

Patients need to be able to monitor the disease severity so this can be done with Peak flow. They may be able to
adjust their own treatment with the guidance of their action plan.

INHALED CORTICOSTEROIDS
Drug name: Beclometasone Dose: 100mcg Route: Inhalation
Frequency: 2 puffs OD Indication: Asthma Class: Corticosteroid
Mechanism of action: Passes through the plasma membrane and interact with receptors in the cytoplasm.
Pro inflammatory ILs, cytokines and chemokines are downregulated, while anti-inflammatory proteins are
upregulated. This reduces the mucosal inflammation, widens the airways and reduces mucus secretion.
Side effects: Oral candidiasis, hoarse voice, growth retardation (children)

Step 2 of asthma management. It is a brown inhaler known as “the preventer” to the patient. They take this
everyday even if they aren’t experiencing symptoms and does not provide immediate relief. Need to stress to the
patient to clean out the inhaler after every use as it can cause fungal infections like oral candidiasis.

If using a spacer, then they cannot dry the spacer after cleaning as it causes static and the medication will stick to the
sides.

Inhaled steroids should be considered with any of the following features:

• Using inhaled β2 agonists three times a week or more

• Symptomatic three times a week or more
• Waking one night a week
• Exacerbation of asthma requiring oral corticosteroids in the last two years
LONG ACTING BETA AGONIST
Drug name: Salmeterol Dose: 50mcg Route: Inhalation
Frequency: BD Indication: Asthma Class: Bronchodilators
Mechanism of action: Binds to exosites near beta2-receptors in the lungs and on bronchiolar smooth
muscle, allowing the active portion of the molecule to remain at the receptor site, continually binding and
releasing. Beta2-receptor stimulation in the lung causes relaxation of bronchial smooth muscle,
bronchodilation, and increased bronchial airflow.
Side effects: Dizziness, sinus infection, migraine headaches (all due to vasodilatory properties)
Contraindication: Beta Blockers

Step 3 of asthma management. LABA should always be taken with an ICS. They are usually prescribed as a
combination inhaler to ensure co administration. Should be careful when prescribing beta agonists to cardiovascular
patients, in whom tachycardia may provoke angina or arrhythmias. It is long acting (12 hours) but the duration is also
long acting.

Formoterol – short onset and long duration

THEOPHYLLINE
Drug name: Aminophylline Dose: 225mg then 450mg after 1week Route: Oral
Frequency: BD modified release Indication: Asthma Class: Xanthine
Mechanism of action: After ingestion, theophylline is released from aminophylline, and theophylline
relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway
responsiveness to histamine, methacholine, adenosine, and allergen.
Side effects: Hypokalaemia, Toxicity – vomiting, agitation, sinus tachy
Contraindication:

Theophylline is metabolised in the liver.

LEUKOTRIENE RECEPTOR ANTAGONIST

Drug name: Monteleukast Dose: 10mg Route: Oral
Frequency: BD modified release Indication: Asthma Class: Leukotriene antagonist
Mechanism of action: Selective leukotriene receptor antagonist so blocks cysteinyl leukotriene to bind to
receptors and therefore reducing airway oedema, smooth muscle contraction and inflammatory process.
Side effects: Abdominal pain, Thirst, Headache
Contraindication:
ACUTE ASTHMA – O SHIT ME

Oxygen

Salbutamol 2.5-5mg neb – continue until 5-10mg/hour

O SHI = administer all
Hydrocortisone 100mg IV together

Ipratropium 500mcg neb

Theophylline 1g in 1L saline 0.5ml/kg/h

Magnesium sulphate 2g IV over 20mins T ME = need senior advice

Escalate care (intubation and ventilation – later change asthma plan)

SHORT ACTING ANTI MUSCARINIC
Drug name: Ipratropium Dose: 500mcg Route: Nebulised
Frequency: QDS Indication: Asthma Class: Short acting Antimuscarinic
Mechanism of action: Bind to muscarinic receptor where they act as a competitive inhibitor for
acetylcholine. This results in a decrease in the formation of cGMP on intracellular calcium and therefore
decreased contractility of smooth muscle
Side effects: Dry mouth, Constipation, Diarrhoea
Contraindication:

Nebulised medication comes as a liquid and then oxygen is passed through it to, vaporising it so the patient can
inhale. COPD patients usually have medical air passed through instead to prevent CO2 retention. Need to explain to
the patient that you are treating the symptoms and not the disease. Advise then to chew gum, suck sweets and keep
a bottle of water with them if they develop a dry mouth. To check if there is an improvement, ask the patient and
perform peak flow readings.

MAGNESIUM SULPHATE
Drug name: Magnesium sulphate Dose: 2g over 20 mins Route: IV
Frequency: Indication: Asthma Class: Sulphates
Mechanism of action: Magnesium inhibits Ca2+ influx through dihydropyridine-sensitive, voltage-
dependent channels (calcium antagonist). Therefore, stops calcium binding to troponin C so actin cannot
bind to myosin and there is vascular smooth muscle relaxation
Side effects: Hypomagnesaemia – nausea, vomiting, thirst, hypotension

ACUTE ASTHMA – CATEGORIES

Life threatening  Altered conscious level  PEFR <33% best or predicted

 Exhaustion  SpO2 <92%
 Arrhythmia  PaO2 <8kPa
 Hypotension  Normal PaCO2 (4.6-6.0 kPa)
 Cyanosis
 Silent chest
 Poor respiratory effort
Severe  PEFR 33-55% best or predicted
 RR >25/min
 HR >110/min
 Inability to complete sentences
Moderate  Increasing symptoms
 PEFR >50-75% best or predicted
 RR <25
 HR <110

COPD

LONG ACTING ANTI MUSCARINIC

Drug name: Tiotropium Dose: 18mcg (if used alone) Route: Dry powder inhaler
Frequency: OD Indication: COPD Class: Long acting Antimuscarinic
Mechanism of action: Bind to muscarinic receptor where they act as a competitive inhibitor for
acetylcholine. This results in a decrease in the formation of cGMP on intracellular calcium and therefore
decreased contractility of smooth muscle
Side effects: Dry mouth, Constipation, Diarrhoea
If used in adjunction with ICS and LABA for maintenance treatment of patients with asthma who have suffered one
or more exacerbation in the last year, then it is used as a regular inhaler with 5mcg OD. Another example includes
Glycopyrronium bromide (Seebri).

LABA + ICS if evidence of

asthma or eosinophils

PULMONARY FIBROSIS

ANTI FIBROTICS
Drug name: Nintedanib Dose: 150mg Route: Oral
Frequency: BD Indication: Fibrosis Class: Anti-fibrotic
Mechanism of action: Tyrosine protein kinase inhibitor. Targets growth factor receptors and inhibits
platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular
endothelial growth factor receptor (VEGFR) so therefore reduces disease progression in IPF.
Side effects: Abdominal pain, decreased appetite, diarrhoea
Tolerated: Reduced to 100md BD if it is not tolerated

Nintedanib can be used only if:

 The person has a forced vital capacity (FVC) between 50% and 80% of predicted and
 The company provides nintedanib with the discount agreed in the patient access scheme

Treatment is stopped if disease progresses (a confirmed decline in percent predicted FVC of 10% or more) in any 12-
month period.

Drug name: Pirfenidone Dose: 801mg Route: Oral

Frequency: TDS Indication: Fibrosis Class: Anti-fibrotic
Mechanism of action: Reduces fibroblast proliferation, inhibits stimulated collagen production and
reduces the production of fibrogenic mediators
Side effects: Abdominal discomfort, anorexia, arthralgia
Contraindication: Cigarette smoking
Dosing: Initially 267 mg 3 times a day for 7 days, then increased to 534 mg 3 times a day for 7 days, then
increased to 801 mg 3 times a day
Pirfenidone can be used only if:

 The person has a forced vital capacity (FVC) between 50% and 80% predicted and
 The manufacturer provides pirfenidone with the discount agreed in the patient access scheme

Treatment is stopped if disease progresses (a confirmed decline in percent predicted FVC of 10% or more) in any 12-
month period.

DVT AND PE

HEPARIN
Drug name: Heparin Dose: Route: IV
Frequency: Indication: PE/DVT Class: Heparin (LMW/UF)
Mechanism of action: Accelerates action of antithrombin III (ATIII) increasing its inactivation mainly of
factors IIa (thrombin), Xa, IXa, XIa and XIIa. Intrinsic pathway.
Side effects: Bleeding, Thrombocytopenia, hypersensitivity reactions, osteoporosis
Contraindication: Clotting disorders, Severe uncontrolled hypertension, Recent surgery or trauma

Destroyed by gastric acid, so oral administration not

possible. Two main types in common use:

• Unfractionated heparin (UFH) e.g.

• Low molecular weight heparins (LMWH) e.g.
tinzaparin, Dalteparin, enoxaparin – more
commonly used

Dosage is adjusted according to the activated partial

thromboplastin time. Overdose treated with
protamine sulphate. Elimination half-life 40–90min;
renal excretion

Unfractionated heparin (UFH) activates antithrombin

that, in turn, inactivates clotting factor Xa and
thrombin. Low molecular weight heparins such as
Dalteparin and enoxaparin have a similar mechanism
of action but preferentially inhibit factor Xa.

Low molecular weight heparins have a more

predictable effect and, unlike UFH, do not usually
require laboratory monitoring. Consequently,
LMWHs are now preferred in most indications. Heparin induced thrombocytopenia is less likely to occur with LMWH
rather than UF.

In patients with renal impairment, LMWH and fondaparinux may accumulate and should be used at a lower dose or
unfractionated heparin is used instead. UF heparin is also used in haemodynamically unstable patients (abnormal
blood pressure, suggesting inadequate arterial blood flow).

In major bleeding associated with heparin therapy, protamine can be given to reverse anticoagulation. This is
effective for UFH but much less so for LMWH. It is ineffective against fondaparinux. Both unfractionated and low-
molecular weight heparin can cause hyperkalaemia. This is thought to be caused by inhibition of aldosterone
secretion.
LMWH vs UFH

Standard UF heparin LMWH

Administration Intravenous Subcutaneous
Duration of action Short Long
Mechanism of action Activates antithrombin III. Forms a Activates antithrombin III. Forms a complex
complex that inhibits thrombin, that inhibits factor Xa
factors Xa, IXa, Xia and XIIa
Side-effects Bleeding Bleeding
Heparin-induced thrombocytopenia
(HIT) Lower risk of HIT and osteoporosis with
Osteoporosis LMWH
Monitoring Activated partial thromboplastin time Anti-Factor Xa (although routine monitoring
(APTT) is not required)
Useful in situations where there is a Now standard in the management of
Notes high risk of bleeding as venous thromboembolism treatment and
anticoagulation can be terminated prophylaxis and acute coronary syndromes
rapidly

WARFARIN
Drug name: Warfarin Dose: 5-10mg Route: Oral
Frequency: OD Indication: PE/DVT Class: Coumarin
Mechanism of action: Inhibits the reduction of vitamin K and thus prevents vitamin K co-factors II, VII, IX
& X for their synthesis by the liver. Extrinsic pathway.
Side effects: Dry mouth, Constipation, Diarrhoea
Contraindication:

Vitamin K converts the precursor coagulation forms into complete forms  last stage. Therefore, if block then less
coagulants produced. Competitively antagonises vitamin K, necessary for production of clotting factors II, VII, IX, X

Given orally and well absorbed from gut. Slow onset of action. Several days until therapeutic action kicks in and
therefore you use heparin after a DVT for 5 days or until INR is below 5. Plasma half-life of 35 hours. There is inter-
patient variation, so monitor with International Normalised Ratio (INR). INR is calculated from the prothrombin
coagulation test. Formula:

INR = (PT patient / PT control)

INR system allows INR results to be compared from different laboratories using different reagents. Target INR: 2.5
(range 2-3) is the standard intensity. Some indications have a higher target INR range. Higher INR means bleeding
more and it takes longer to thin the blood. Incidence of haemorrhage proportional to INR – BUT can occur within
target range.

Come in different strengths: 1mg = brown, 3mg = blue, 5mg = pink and regular monitoring needed. Patients are
given a yellow book

Factors affecting INR:

• Individual variation/genetic
• Drugs (including alcohol) can potentiate the effects of warfarin (check INR within 5 days of starting/stopping
new drug) – increase INR (ciprofloxacin, aspirin) and decrease INR (rifampicin)
 • Diet e.g. vitamin K content (cranberry juice)
• Intercurrent illness
• Mistake e.g. elderly, visually impaired

Offer a warfarin to patients with confirmed proximal DVT or PE within 24 hours of diagnosis and continue the
warfarin for 3 months. Offer beyond 3 months to patients with an unprovoked PE, taking into account the patient's
risk of VTE recurrence and whether they are at increased risk of bleeding.

Management of high INR

Situation Management
Major bleeding Stop warfarin
Give intravenous vitamin K 5mg
Prothrombin complex concentrate - if not available then FFP*
INR > 8.0 Stop warfarin
Minor bleeding Give intravenous vitamin K 1-3mg
Repeat dose of vitamin K if INR still too high after 24 hours
Restart warfarin when INR < 5.0
INR > 8.0 Stop warfarin
No bleeding Give vitamin K 1-5mg by mouth, using the intravenous preparation orally
Repeat dose of vitamin K if INR still too high after 24 hours
Restart when INR < 5.0
INR 5.0-8.0 Stop warfarin
Minor bleeding Give intravenous vitamin K 1-3mg
Restart when INR < 5.0
INR 5.0-8.0 Withhold 1 or 2 doses of warfarin
No bleeding Reduce subsequent maintenance