Drug class 9: Cardiac glycoisides-Digoxin

Digoxin (Does not reduce mortality but reduces morbidity and hospitalisation for heart failure)

9.1 Mechanism of action:

1. ***Potent inhibitors of the active transport of Na+/K+ across cell membranes. 

-Reversible binding to subunit of Na+, K+ ATPase.

-Both sodium and calcium ions enter cardiac muscle cells during each depolarisation.

Normally, Calcium entry triggers contraction. It is then taken into the Sarcoplasmic reticulum via SERCA (S.R. calcium ATPase)

-It is also removed from the cell via Na+/Ca2+ exchanger (NCX) and sarcolemmal Ca2+ ATPase.

∴Inhibition of Na+/K+ ATPase by digoxin results in a reduction in rate of Na+ removal (dump out of cell). Na+ accumulates in cell.

-Reduces ability of NCX ability to remove Calcium ions during myocyte repolarisation.

-As Ca2+ accumulates (due to repeated entry of ions) and reduced efflux of Calcium ions, the calcium ion intake into the SR is increased.

Ultimately, the calcium present in the SR increases and more is released during the next ECC (excitation-contraction coupling). Increases myocardial contractility!!!

2. Increases force of myocardial contraction (Positive inotropic)

3. Decreases AV nodal conduction (predominantly by its vagotonic effect on the heart). Decreases automaticity.

4. Increases diastolic resting membrane potential in atrial and AV nodal tissues (Easier to reach threshold) ??? ASK JOE WOULDN’T THAT INCREASE AUTOMATICITY?

Vagontonic: hyperexcitability of the vagus nerve, producing bradycardia, decreased heart output, and faintness.

4. Modulates ANS (autonomic nervous system). This contributes to their efficacy in the management of CHF. Decreases sympathetic tone.

5. May increase excitability of cardiac muscle (particularly at higher doses)–>Atrial and Ventricular arrhythmias (AT HIGHER DOSES).

-This simultaneous non-uniform increase in automaticity and depression of conduction in Purkinje fibres and ventricular muscle fibres can cause serious ventricular arrhythmias.

9.2 Clinical Indications

(a) Atrial and AF flutter (Decrease heart rate)

(b) Heart Failure

9.3 Precautions

1. Hyperthyroidism and fever. Both of these conditions increase sympathetic tone thus making digoxin relatively ineffective (Since digoxin affects ANS too)

Solution: Treat underlying cause and use larger doses or another agent.

2. Hypothyroidism. May increase sensitivity to digoxin

Solution: Require smaller doses.

3. Hypokalemia, Hypomagnesemia, Hypercalcemia (i.e. lack of electrolytes) and Hypoxia (lack of oxygen)

-Increase risk of digoxin toxicity

-Increases risk of digoxin toxicity due to electrolyte imbalance and oxygen imbalance.

Solution: Correct electrolyte imbalance.

4. Cardiac Issues

-Contraindicated in second or third degree heart block (without pace-maker)–>Arrhythymias

-Contraindicated in SVT (sino-ventricular tachycardia) involving accessory pathway–>Wolff-Parkinson-White syndrome (Bundle of Kent affected)

*Second-degree heart block may result in the heart skipping a beat or beats. This type of heart block also can make you feel dizzy or faint.

*Third-degree heart block limits the heart’s ability to pump blood to the rest of the body. This type of heart block may cause fatigue (tiredness), dizziness, and fainting. Third-degree heart block requires prompt treatment because it can be fatal.

-Contraindicated in Ventricular tacycardia and filbrillation

-Contraindicated in Hypertrophic obstructive cardiomypopathy or cor pulmonale (acute and chronic)

*Cor Pulmonle-Enlargement of the right ventricle of the heart as a response to increased pressure in lungs (Pulmonary hypertension)

-Contraindicated in constrictive pericarditis

Use cautiously in the following cardiac conditions:

In acute MI, ischemic heart disease or myocarditis. Digoxin incresaes risk of arrhythmias.

-Sick Sinus Syndrome. Increases risk of severe bradycardia or sinoatrial block.

-Severe aortic stenosis. Digoxen may worsen cardiac function because it increases force of myocardial contraction (Positive inotropic)

5. Renal Issues (Impaired)

-Digoxin is mainly renal cleared (70%)

Solution: Reduce dose in renal impairment.

6. Elderly-Reduce dose.

7. Pregnancy-Safe to use, dose requirement is not predictable. Safe to use when breastfeeding.

Solution: Depending on circumstance, increased dose may be required. ***Used to treat fetal arrhythmias (CAT A-AUS)

9.4 Adverse effects/ Side effects

***Potential to worsen arrhythmia/Proarrhythmic effect

VERY VERY VERY VERY IMPORTANT: DIGOXIN HAS A NARROW THERAPEUTIC INDEX (Side effects may occur at <1 nanomol/L)

1. Effect on ECG. Digoxin results in prolonged PR interval, ST depression or T-wave inversion.

-Apart from the effect on PR interval, which is a sign of toxicity, these ECG changes do not necessarily mean digoxin toxicity or MI.

-In children, arrhythmias (including sinus bradycardia) are the earliest and most frequent indicator that digoxin dosage is too high.

2. Blurred vision (Xanthopsia Yellow)

3. Arrhythmias (mentioned above)

4. Nausea

5. Confusion

6. Depression

7. Psychosis (acute)

Acronym: BAN CARDIAC DIGOXIN PLANTS!!!

8. Vomitting, diarrhoea, anorexia, drowsiness, dizziness, nightmares, agitation

Infrequent side effects: Delirium, amnesia, shorterned QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or filbrillation, heart block, Gynaecomastia (prolonged use)

Rare: Rash, thrombocytopenia, seizures

9.5 Pharmacokinetics

-t1/2 for digoxin is 36 hours in patients with normal renal function.

-Steady-state blood levels achieved in around 5 days-1 week after initiation of maintenance therapy

-Digoxin excreted via kidneys (mentioned previously) at a clearance proportional to GFR. This means that if anything that alters GFR (e.g. renal insufficiency/renal arterial stenosis will potentially affect clearance of digoxin.

-It is a CYP3A4 substrate [Note and remember all the CYP3A4 substrates]. Potential drug interactions.

9.6 Practice Points + Counselling

1. ADJUST DOSAGE ACCORDING TO PATIENTS RENAL/HEPATIC/CARDIAC CONDITION!!! 

Adjust/Tailor dosage according to renal function, clinical response and therapeutic drug monitoring.

-Digitalisation with loading dose is needed only to treat arrhythmias and is usually not required for heart failure.

-IV administration is seldom required and offers little therapeutic advantage over oral dosage.

What is a loading dose?

-Loading dose is Maximum possible dose given at the start/initial part of treatment course before dropping down to a lower maintenance dose (to maintain steady levels)Loading doseSteady state levels

e.g. Adult loading dose, oral/IV 250-500 mcg/ every 4-6 hours. Max 1.5 mg

compared to

Maintenance dose, oral 125250 mcg/ once daily  (Rarely increased up to 500 mcg daily)

*The above dosages are from AMH 2012.

2. MONITOR DIGOXIN SERUM CONCENTRATIONS!!!

*Careful concentration monitoring is required!!!

-Take blood sample at least 6 hours after a dose to allow for redistribution.

-Steady state is reached in about 5 days if renal function is normal (half life is 36 hours). Renal impairment t1/2 increases.

-Manufacturers recommend a therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml). However, do note that toxic effects (e.g. anorexia, nausea, vomitting) occur at this range.

*Strike a balance between clinical benefit and the occurance of clinical side effects. Reduce dose if necessary.

-Remember that (look at precautions) that we said that the elderly, electrolyte imbalanced individual, hypoxia or hypothyroidism individuals are more susceptible to digoxin toxicity. 

-Interpret the results of concentration monitoring in relation to clinical condition (DON’T JUST ASSUME ONE SIZE FITS ALL e.g. PATIENT MAY APPEAR TO have normal levels but has hepatic impairment.

3. USE IN HEART FAILURE!!!

-Consider using lower concentrations of 0.5-0.8 micrograms/L for patients with Heart Failure who are in sinus rhythm (normal beating of the heart, as measured by an electrocardiogram (ECG)). 

-Higher concentrations of digoxin within the therapeutic range may be associated with increased rates of mortality and hospitalisation.

4. ADVICE/COUNSEL/INFORM PATIENTS ON ADMINISTRATION!!!

*Administration: Give IV over at least 5 mins, compatible fluids are sodium chloride 0.9%, glucose 5% and glucose/sodium chloride solution

*DO NOT GIVE INTRAMUSCULARLY (unpredictable absorption, local irritation)

*Counselling-Check if the patient is taking any OTC or herbal products.

*Practice points: 

-Always check the renal function and electrolyte concentration before starting digoxin

-OAA: 4-6 hours after initial dose

-Regularly assess patients for evidence of digoxin toxcitiy (including resting heart rate) , Routine measurement of pulse rate before giving next dose of digoxin is not needed.

-Assume that any arrhythmia that occurs in a child taking taking digoxin is due to the drug until proven otherwise. (GUILTY UNLESS PROVEN OTHERWISE)

-Stop Digoxin if patient reverts to sinus rhythm. *DOES NOT HAVE ANY PREVENTIVE ROLE IN PAROXYSMAL AF OR FLUTTER.

Paroxysmal-Sudden attack or incidence of symptoms

-If another arrhythmic agent (e.g. Verapamil, Diltiazem) is combined with digoxin, try to reduce and stop digoxin once patient is stable.

Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml) [Manufacturer recommended]

Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml)

Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml)

 

9.7 Drug Interactions

1. Digoxin is a CYP3A4 substrate. SO ANYTHING THAT CAN INHIBIT OR A SUBSTRATE OF CYP3A4 WILL AFFECT METABOLISM!!!

-Remember list of CYP3A4 SUBSTRATES AND INHIBITORS.

2. Anti-arrhythmic agents used in combination (e.g. amiodarone)

3. Care with drugs that lower K+ levels (ARBs, ACE-inhibitors–>Refer to acronym…Captain Ace….)(Loop diuretics also will affect) or

4. Care with drugs that  lower Mg2+ levels

 

*Note: There are drugs out there that can reduce digoxin toxicity (e.g. DIGIBIND-Digoxin specific antibody/Fab fragments)

 

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Respiratory Diseases-Pharmacotherapy (Asthma and COPD)

Summary Diagrams:

Asthma and COPD drugs 3Asthma and COPD drugs 2Asthma and COPD drugs

(SABA, LABA and AMA)                                                    (Steroids)                                                                        (Other prophylatic agents)

Refer to them!!!

Class 1 and 2: SABA and LABA

SABA (selective short acting beta-2 receptor agonist)

SalbutamolSalbutamol

-Indicated for management of astham exacerbations or other Chronic obstructive airway diseases.

-Very similar in structure to terbutaline (+ Unlike terbutaline, salbutamol exhibits less cardiac stimulation and more prolongefd bronchodilation than isoproterenol or metaproterenol).

 

(a) Salbutamol

Mechanism of action: Stimulates B2 receptors found in uterus, blood vessels, and lungs–>Bronchodilation (Reduced airway resistance and facilitates mucous drainage). Prevents mast cell degranulation

*Use as an adjunct for the treatment of hyperkalemia (Stimulates Na+/K+ ATPase pump and thus K+ excretion via kidneys).

-Levabuterol/R-Salbutamol is commonly administered, Similar to Terbutaline structure (but exhibits less cardiac stimulation)

-Comes in the form of oral tabs and oral inhalation [More common form] (90% swallowed and goes into GIT)]

*Onset of action (oral inhalation)-5-15 mins and DOA: 2-6 hours

-If SABA is required more than 2 days a week or if significant symptoms reoccur, then start to treat persistant asthma with ICS

-ACUTE SYMPTOM CONTROL!!!

 

(b) Terbutaline

*Indications: (a) Bronchospasm in asthma, COPD (b) Premature labour

 

Note: More than 12 months use will lead to tolerance and decreased lung function

-May stimulate B2 receptors found on the heart (Affect Cardiac-Causes stimulation)

-Terbutaline is less cardiostimulatory than other B2 agonists

Note: May cause hyperglycemia, stimulate uterine relaxation and dilation of arterioles

 

2. LABA (Long acting B-agonists)

 

(a) Salmeterol (Sell me to all)

Mechanism of action: Lipophilic side chain increases hydrophobicity and side chain appears to only bind to exosite (site near B2 receptor). Binding to this exosite allows the the continuous engagement and disengagement with the receptor, thus increasing duration of action. Exosite binding contributes to salmeterol’s inhibition of late phase antigens.

Highly selective to B2

*Indications: Maintenance treatment of asthma, Prevention of bronchospasm in COPD

-Long DOA, thus twice a day dosing is possible. However OAA of salmeterol is prolonged, thus therapeutic effect is limited.

*Never use Salmeterol for Acute asthma attacks (OAA too long). Useful for prophylatic therapy.

-Administered by oral inhalation.

-Onset of therapeutic effects is measured by 15% improvement in FEV1 within 14 mins.

 

(b) Eformoterol

(c) Indacaterol

 

3. Anti-muscarinic agents

(a) Ipratropium

-Synthetic quaternary compound that is similar in structure to atropine

-Administration via nasal spray or oral inhalation (most commonly used as a bronchodilator for cholinergic mediated bronchospasm associated with COPD)

*Much less effective than B2 agonists in reducing exercise induced asthma.

Mechanism of action: Antagonises the action of Acetylcholine on muscarinic receptors in the cholinergic neurons. In airways, this ultimately reduces contractility of smooth muscle. It is not muscarinic selective!!!

Intranasal adminstration of ipratropium produces a localised parasympatholytic effect which reduces watery hypersecretion from mucosal glands (Alleviates rinnorrhea associated with rhinitis or common cold)

(BAD) *Since it is quaternary (charged), it is not readily absorbed into systematic circulation. After intranasal dosing, less than 20% ipratropium dose is absorbed from the nasal mucosa into systemic circulation.

 

(b) Tiotropium

-Long acting N-quaternary structure, selective anti-muscarinic agent (Highly SELECTIVE TO M3 receptors in smooth muscles)

-Very slow dissociation from receptors, long DOA, long half life

-improved lung function (FEV1 and FVC) significantly within 30 mins after first dose administered and improvement was maintained for 24 hours.

 

4. Inhaled Corticosteroids (ICS)

-Anti-inflammation effect. MOST POTENT AND EFFECTIVE CLASS FOR ASTHMA TREATMENT!


-Administration as a MDI with spacer (Metered dose inhaler+Spacer). *Remember to wash and rinse mouth with water, gargle and spit out after each inhalation. *Oral candidasis is a common side fungal infection due to prolonged ICS use. 

Mechanism of action: Inhibits PLA2 which prevents the conversion of Arachidonic Acid to Prostaglandins, Leukotrienes, PAF etc. Thus inflammatory mediators are reduced and downstream effects inhibited.

-Inhibits both late phase (Recruitment of eosinophils, inflammatory cells) and intermediate phases (Bronchospasm, Production of leukotrienes, chemotaxins by mast cells) of asthma.

 

Glucocorticoid comparion table (DOA, minero-effects) (Refer to slide 21 of notes)

(a) Beclomethasone

-Synthetic halogenated glucocorticosteroid

Indications: Treatment of steroid-dependent asthma, Relieves symptoms associated with asthma and non-asthma rhinitis, Prevention of nasal polyps after surgical removal

-When used intranasally, the anti-inflammatory and vasoconstrictive effects are 5000x more potent than hydrocortisone

Mechanism of action:

1. Naturally occuring hormones that suppress inflammation and immune responses when administered at pharmacological doses.

2. At the molecular level, unbound glucocorticoids readily cross into cell (lipid soluble) and binds to nuclear receptors present on the nuclear membrane. Steroid-Receptor complex taken into nucleus and gene transcription is altered. New proteins are formed and released into systemic circulation. [TIME CONSUMING-SLOW PROCESS]

3. Protein alteration: Inhibition of leukocyte infiltration at the site of inflammation (less adhesion molecules made), Less inflammatory mediators made, Suppression of humoral response (Innate)

 

*Oral inhaled corticosteroid hormones reduce the intermediate and late phase allergic response associated with chronic bronchial asthma.

4. Decreased IgE synthesis

5. Increased number of B-adrenergic receptors on leukocytes

6. Decreased Arachidonic Acid production, Downstream effects of prostaglandin and leukotriene production inhibited (Refer to top)

 

Pharmacokinetics:

-Nasal inhalation absorption. Minimal amounts absorbed systematically.

-Oral inhalation absorption. After oral inhalation, drug is absorbed rapidly from the lungs and GIT. Some absorbed into systemic circulation but not sufficient to exert systemic effects.

OAA:  Occurs in a few days but may take 1-4 weeks to reach full, maximum effect

-Without spacer, approx 10-25% of orally administered dose enters the respiratory tract. The rest is deposited into mouth and is swallowed. Thus the use of spacer increases the amount of drugs that is deposited into the lungs.

 

(b) Budesonide

-Administered either intranasally or oral inhalation. Oral dosage form (tablets) usually for symptom management in Crohn’s diasease, allergic rhinitis and asthma

-Potent glucocorticoid and weak mineralocorticoid activity.

-Intranasal budesonide allows 1x daily dosage but has a less desirable side effect profile than the other intranasal steroids

*High anti-inflammatory effect when applied topically and has low systemic effect!

Pharmacokinetics:

-After nasal inhalation, approx 20% of the dose reaches systemic circulation

-After oral inhalation or nebulisation, approximately 6-13% and 6% of dose respectively reaches systemic circulation.

 

(c) Fluticasone

-Might cause a significant decrease in adrenal cortex production of glucocorticoid.

-Medium-potency corticosteroid

Indications: Used topically to relieve the inflammatory and pruritic (itching) symptoms of dermatoses and psoriasis. Used intranasally for symptom management of allergic and non-allergic rhinitis. Oral inhalation for asthma. Used clinically in some patients for COPD.

 

Pharmacokinetics:

-Administered by intranasal inhalation.

-Most of a dose following intranasal administration of fluticasone is swallowed with metabolism in gut and partial absorption with extensive first pass-metabolism in the liver. Thus, the systemic effect is negligible.

-Absorption following topical administration is minimal.

-Oral inhalation aerosol has a systemic bioavailability of about 3% of delivered dose. Bioavailability of the oral inhalation is roughly 14%.

 

 

(d) Ciclesonide

-Non-halogenated corticosteroid

*Beneficial in treating inflammatory conditions allergic rhinitis and asthma. May be beneficial in treatment of COPD.

-Low systemic bioavailability (Intranasal and oral inhalation). This limits systemic effects such as cortisol suppression.

*Administered by intranasal or oral inhalation. Oral bioavailability is negligible.

 

Pharmacokinetics:

-Ciclesonide is a produg drug with an active metabolite des-ciclesonide (100x-120x more potent)

-Esterases in the nasal mucosa hydrolyse ciclesonide to a biologically active des-ciclesonide

-Des-ciclesonide undergoes furthur metabolism in the liver via CYP3YP (MAJOR) and CYP2D6 (Minor)

-OAA: (Intranasal) 24-48 hours, with additional effects observed in 1-2 weeks for those with seasonal allergic rhinitis and 5 weeks in those with perennial allergic rhinitis.

 

 

(e) Hydrocortisone/Cortisol

(f) Prednisolone (Active metabolite), Prednisone (Prodrug)

-Prednisolone, including derivatives, are synthetic glucocorticoids used as an anti-inflammatory or immunosuppressive agent.

-(Opthalmic solutions) Can be used to treat allergic various inflammatory eye conditions.

*Can be administered with systemic corticosteroids for the maintainence treatment of uncontrolled persistant asthma

-Once stablisation of asthma is achieved, dose should be reduced or eliminated due to side effects associated with chronic use.

 

 

 

5. Cromones

(a) Sodium cromoglycate

Mechanism of action: Inhibits antigen induced bronchospasm. Prophylatic agent in the treatment of mild to moderate asthma. Intranasal inhalation to treat seasonal allergic rhinitis. Opthalmic solution to treat allergic and vernal conjunctivits.

Oral treatment for mastocytosis (too many mast cells in the body) and ulcerative collitis.

*Approved for use in adults and children as young as 2 years of age.

*An alternative to ICS in the treatment of mild persistent asthma.

  • Mechanism of action: Cromolyn works at the surface of the mast cell to inhibit its degranulation (Mast cell stabilisation occurs). This prevents release of histamine, slow reacting substance of anaphylaxis (SPS-A) and mediators of Type 1 allergic reactions.

-May reduce the release of inflammatory leukotrienes. However, it does not interfere with the binding of IgE to the mast cells or antigen to IgE.

-They can reduce hypersensitivity of the bronchi and asthmatic responses to environmental triggers.

-It is not a bronchodilator. Largely prophylatic actions.

 

  • Pharmacokinetics:

-Systemic bioavailability of oral cromolyn is 1%. However, it is still administered orally to treat systemic mastocytosis and ulcerative collitis. 

-Minimal systemic absorption occurs after intranasal and opthalmic use.

-Roughly 5%-10% of an inhaled dose reaches lungs [Amount that reaches lungs depends on extent of bronchoconstriction present]

-Several weeks of therapy may be required before improvement is obvious (hence 1 month wait to see improvements when administered ocularly)

 

 

(b) Nedocromil Sodium

*Mast cell stabiliser

-Available as opthalmic solution (For allergic conjunctivis). Available as oral inhalational aerosol (Respiratory anti-inflammatory agent for the long-term treatment of mild-moderate asthma).

*Nedocromil is an alternative to ICS in the treatment of mild persistent asthma in children 5 years of old.

-Actions similar to cromoglycate.

  • Mechanism of action:

-Although both nedocromil and cromoglycate works similarly (inhibits mast cell degranulation), nedocromil PREVENTS BRONCHOCONSTRICTION primarily (at lower doses than cromoglycate)

-Interferes with mast cell degranulation thus histamine not released. However it does not inhibit chemotaxis of eosinophils by PAF and LTB4.

-Inhibits the activation and release of PAF, leukotriene B4 and histamine from mast cells.  ***NOTE: PAF and Leukotriene B4 causes acute bronchoconstriction and increased vascular permeability (late phase of allergen-induced asthma).

-Prevents migration and recruitment of eosinophils, neutrophils, macrophages and platelets that causes airway inflammatory changes.

Does not interfere with binding of antigen to IgE or IgE to mast cells.

 

  • Pharmacokinetics

-Administered via oral inhalation or by ocular administration.

-Systemic bioavailability of inhaled nedocromil is approximately 6% to 9%

-After ocular administration, less than 4% of the total dose of 2% is systemically absorbed [Absorption is mainly through the nasolacrimal duct]

 

 

6. Leukotriene antagonists

(a) Montelukast (Prophylatic agent)

-Prophylatic agent and chronic treatment of asthma and allergic rhinitis.

-Alternative but not preferred substitute for ICS in treating mild persistent asthma.

-Efficacy shown in children as young as 12 months old and infants as young as 6 months old for allergic rhinitis.

*Available in tablet form (chewable tablet) and oral granule formulations.

 

  • Mechanism of action: Potent and selective antagonist of the receptor CYSLT1 receptor found in airways.

-Mast cells and eosinophils release LTD4, LT4, LTE4 (Bronchoconstrictors). Montelukast inhibits LTD4 from binding.

-Leukotrienes cause increased endothelial membrane permeability, peripheral edema, smooth muscle contraction and hypersecretion of viscous mucus

.-They are also associated with symptoms of allergic rhinitis (e.g. sneezing, nasal itching, rhinitis and late-stage congestion)

Montelukast inhibits both early and late-phase bronchoconstriction due to antigen challenge. Also helps in alleviating the above symptoms.

 

  • Pharmacokinetics

-Administered orally. Chewable tablet has an oral bioavailability of 63% (after being reduced by food). However, the clinical efficacy is not affected!

*ALL ORAL FORMS OF MONTELUKAST MAY BE TAKEN WITHOUT REGARD TO FOOD (i.e. taking after, before, during food is allowed)

-It is 99% bound to serum albumin.

-Undergoes extensive first pass metabolism in the liver via CYP3A4 and CYP2C9. Half life is 2.7-5.5 hours in average healthy, young adults.

(b) Zirfirlukast

 

 

7. Anti-IgE antibodies

 

Omalizumab

-First monoclonal humanised (chimaeric) antibody directed against IgE. Treats moderate to severe allergic asthma (i.e. due to allergens)

-Addition of this drug to patient’s drug regimen reduced the frequency of allergic asthma exacerbations. More patients can also discontinue or reduce dosage of corticosteroids.

*Anaphylatic shock may/may not develop after first dose or during ongoing treatment.

  • Mechanism of action:

-Binds to human IgE antibody (Fc-Constant region). This prevents the binding of IgE to various cells (BUT NOT ANTIGEN). Antigen can still bind to IgE.

-Omalizumab thus lowers free serum IgE concentrations (more than 90% decrease)

-Avoiding the bridging between IgE and cells prevents Ag-Ab induced cross-linking or receptors. No degranulation of mast cells occur, no inflammatory mediators produced.

-Suppresses eosinophil induced sputum and blunt both early and late phase allergic responses.

 

  • Pharmacokinetics:

-Administered by subcutaneous (SC) injection. Every 3 weeks, 1 injection.

-Serum free IgE levels are reduced in a dose-dependent manner within 1 hour of the first dose of omalizumab and are maintained between doses.

 

Pros: The IgE levels do not return to pre-treatment levels after discontinuation of Omalizumab (up to 1 year)

-Slow elimination t1/2 is 22+/- 9 days

 

 

8. Methylxanthine derivatives

(a) Theophylline

-Used both orally and IV to treat asthma and bronchospasm.

*Narrow therapeutic range-Thus careful monitoring of serum levels is required!

  • Mechanism of action:

1. Believed to inhibit PDE 3 and PDE 5 in smooth muscle cells. Thus, cAMP levels increase and less Ca2+ is formed–>Vasodilation.  However, other PDE inhibitors (e.g. dipyridamole, papaverine) don’t have a bronchodilating effect…(suggests an alternative mechanism)

2. Adenosine antagonism. Adenosine is a CNS stimulant, thus antagonising it will stimulate the medullary respiratory centre (increases sensitivity to carbon dioxide)

3. Inhibition of histamine release

4. Can stimulate cardiac and skeletal muscle (Opposite effect to smooth muscles)

 

  • Pharamokinetics:

-Children more than 1 years of age and adults metabolise theophylline hepatically via CYP1A2, 2E1 and 3A4

-Forms active metabolites (caffeine and 3-methylxanthine)

 

***Monitoring Parameters

-Monitor heart rate, CNS effects (insomnia and irritability), respiratory rate

-Patients often have elevated respiratory rates (due to increased sensitivity to Carbon dioxide)

 

Reference Range– Asthma (5-15 mcg/ml)–>Therapeutic Range                   >20mcg/ml–>Toxic

(b) Aminophylline

Drug Class 8: Vasodilators (Hydralazine, Minoxidil, Diazoxide, Sodium nitoprusside)

Types of Vasodilators: Hydralazine, Minoxidil, Diazoxide and Sodium nitroprusside (Detailed in alphabetical order)

8.1 Diazoxide (May cause ‘Diabetes’/Hyperglycemia)

  • Mechanism of action: Predominantly an arteriolar vasodilator with little effect on venous smooth muscle.

-Arteriolar vasodilation results in reflex sympathetic stimulation, leading to tachycardia and fluid retention.

  • Clinical indications:

(a) Hypertensive emergency. (b) Intractable hypoglycaemia due to hyperinsulinemia (oral)

  • Precautions:

-(a) Subarachnoid, Subdural, intracerebral, postoperative bleeding and dissecting aortic aneurysm CONTRAINDICATED!

Image

(b) Hypertension with pulmonary edema, aortic coarctation or atrioventricular shunt CONTRAINDICATED!

(c) Heart Failure- May exacerbated by reflex tachycardia and fluid retention induced by diazoxide CAUTION!

(d) Cerebral or coronary artery disease-May be exacerbated by excessive drop in BP CAUTION!

(e) Diabetes-Diazoxide causes hyperglycemia. *Monitor blood glucose closely

-Diazoxide may act directly to increase glucose production and inhibit glucose uptake

(f) Gout-May be exacerbated

(g) Pregnancy-Use with extreme caution, may cause fetal bradycardia, hyperglycemia has been observed in neonates (Cat C-AUS) *DON’T USE IN PREGNANCY!

  • Side effects/Adverse effects

*Common side effects (Oral)

1. Flushing, headache, nausea

2. Tachycardia

3. Hyperglycemia

4. Edema (retention of salt and water retention)

*Infrequent side effects:

1. Hyperuricemia

2. Fever

3. Rash

4. Lymphadenopathy (swollen/enlarged lymph nodes)

5. Loss of taste

6. Hypertrichosis (chronic use)-Abnormal amount of hair growth over body

7. Constipation

8. Dizziness

9. Burning sensation at injection site

*Rare side effects:

-Diabetic Ketoacidosism, Hyperosmolar non-ketotic coma, pancreatitis, neutropenia, eosinophilia, thrombocytopenia

*IV side effects

-Hypotension, bradycardia, angina, arrhythmias, cerebral ischemia, confusion, seizures, loss of consciousness

  • Administration advice/Therapeutic points

*Avoid extravasation during IV administration since cellulitis and pain may results. If extravasation occurs, treatment with cold packs is recommended.

  • Practice points

*Infusion regimens are preferred to minimise risk of precipitous fall in BP

*Diazoxide is often given with a B-blocker and diuretic to obtain maximum anti-hypertensive effect and to prevent tachycardia and fluid retention.

*Diazoxide is given orally to treat intractable hypoglycemia, it is not used orally in chronic treatment of hypertension (poorly tolerated)

  • Drug Interactions

-Diazoxide can increase blood glucose concentration (so any drug that can affect blood glucose concentration can interact)

-Diazoxide causes hypotension. *Administration with other anti-hypertensive drugs (reduce BP) may enhance its hypotensive effect. Take particular care if the hypotensive agents are given IV.

8.2 Hydralazine

Mechanism of action: Predominantly an arteriolar vasodilator with little effect on venous smooth muscle. Arteriolar vasodilation results in reflex sympathetic stimulation leading to tachycardia and fluid retention.

Clinial Indication: (a) Hypertensive emergency (Not for chronic treatment) (b) Refractory hypertension (in combination with a B-blocker and diuretic) (c) Heart Failure, with a nitrate (Accepted clinical indication)

Precautions:

1. Idiopathic systemic lupus erythematosus (ISLE) or related diseases-Contraindicated

2. Cerebral Artery disease (*May be worsened by excessive drop in BP)

3. Cardiovascular

-Contraindicated in dissecting aortic aneurysm, Severe tachycardia and Heart Failure with high cardiac output (e.g. due to hyperthyroidism).

-Contraindicated in heart failure due to mechanical obstruction (e.g. aortic stenosis) or corpulmonale (enlargement of the right ventricle of the heart as a response to increased resistance or high blood pressure in the lungs (pulmonary hypertension)

-Angina may be exacerbated by reflex tachycardia.

*Avoid using hydralazine after myocardial infarction until condition has stabilised.

*Coronary artery disease may be worsened by excessive drop in BP.

4. Renal impaired (Reduce dose if necessary)

5. Hepatic impaired (Reduce dose if necessary).

*Note: People with the slow acetylator phenotype have a greater risk of adverse effects (i.e. lupus-like syndrome). Approx 50% of Caucasians and 10-20% of Asians are slow acetylators.

 N-acetyltransferase gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide (antiarrhythmic)

6. Pregnancy-Associated with fetal distress and fetal arrhythmias following IV administration in the last trimester of pregnancy. (CAT C-AUS)

7. Breastfeeding-Safe to use

  • Side effects/Adverse effects

*Common side effects:

1. Flushing, headache, dizziness

2. Tachycardia, Palpitations (Arrhythymias)

3. Edema (Sodium and water retention)

*Infrequent side effects:

Angina, Nasal congestion, lupus-like syndrome (fever, arthralgia, myalgia, malaise)

*Rare

Blood dyscrasia (‘Bad mixture’), rash, paraesthesia

  • Counselling

*This medicine may cause dizziness especially at the start of treatment. If affected, do not drive or operate machinery.

*Important Practice points:

1. Prolonged treatment (>6 months) may induce a lupus-like syndrome. Check antinulcear factor before starting and during prolonged treatment.

2. Beta-blockers and thiazides are often used with hydralazine to prevent tachycardia and fluid retention.

3. Combination of hydralazine and isosorbide dinitrate has been shown to reduce mortality in heart failure. Although it is not as effective as ACE-inhibitor, consider this combination in people unable to tolerate an ACE-inhibitor or ARB.

  • Drug Interactions

-Drug causes hypotension, administration with other anti-hypertensive drugs that also reduce BP may enhance hypotensive effect. Take particular care if the hypotensive agents are given IV.

8.3 Minoxidil

  • Mechanism of action: Predominantly an arteriolar vasodilator with little effect on venous smooth muscle. Arteriolar vasodilation leads to sympathetic stimulation causing tachycardia and fluid retention.
  • Clinical indications: (a) Severe refractory hypertension (use with other anti-hypertensives) (b) Alopecia (loss of hair from body)
  • Precautions

1. Pheochromocytoma (Tumour in the adrenal gland). Overproduction of adrenaline which may increase risk of tachycardia, effective use of B-blockers is crucail before starting treatment with minoxidil.

2. Cardiac

-Contraindicated in pulmonary hypertension secondary to mitral stenosis.

-Increased risk of excessive tachycardia if mitral regurgitation is present.

-Heart failure may worsen due to fluid retention. Angina may worsen due to reflex tachycardia (*Avoid using minoxidil post-MI until condition has stabilised)

3. Pregnancy

-Oral administration may cause hypertrichosis in neonate (CAT C-AUS)

4. Breastfeeding-Use with caution

  • Adverse Effects

Systemic side effects occur mainly with oral minoxidil and can sometimes occur with topical use.

Common:

1. Edema (Sodium and water retention)

2. Cardiospecific-Tachycardia, Pericarditis, Pericardial effusion, ECG changes (ST depression, T wave inversion), Palpitations

3. Headache, Flushing, Dizziness

4. Hypertrichosis (as facial hair 3-6 weeks after starting treatment, may become generalised, resolves 1-6 months after stopping the drug)

Infrequent of rare:

-Breast tenderness, gynaecomastia, menstrual disturbances, changes in skin pigmentation, hypotension, increased angina, intermittent claudication (muscle pain which occurs during exercise), paraesthesia, thrombocytopenia

  • Practice Points

Diuretics and beta-blockers are often used with minoxidil to prevent fluid retention and tachycardia.

8.4 Sodium nitroprusside

Mechanism of action: Non-selective arteriolar and venous dilator

Clinical Indications: (a) Hypertensive emergency (b) Controlled hypotension during surgery to reduce bleeding (c) Acute Heart Failure

Precautions (All of them are contradicated for sodium nitroprusside use)

1. Compensatory hypertension (e.g. atrioventricular shunt or coarctation of the aorta- congenital condition whereby the aorta narrows in the area where the ductus arteriosus insets)

CONTRAINDICATED!!!

2. Vitamin B12 deficiency-CONTRAINDICATED!!! Refer to Vitamin Metabolic Biochemistry Lecture (Increased plasma homocysteine levels and increases damage to vessels. Adding nitroprusside will increase risk of thrombosis.)

3. Cerebral or coronary artery disease-CONTRAINDICATED!!!

4.  Congenital (Leber’s) optic atrophy-CONTRAINDICATED!!!

5. Tobacco amblyopia-CONTRAINDICATED!!!

6. Hypovolemia-CONTRAINDICATED!!!

7. Uncorrected anemia-CONTRAINDICATED!!!

Not contradicated but take extra caution

8. Increased intra-cranial pressure, encephalopathy-Risk of aggration

9. Hypothyroidism-Thiocyanate (degradation product of sodium nitroprusside). Inhibits both uptake and binding of iodine.

10. Hypothermia-Risk of aggravation

11. Pulmonary mpairment-May worsen hypoxemia

12. Renal impaired-Reduced excretion of thiocyanate concentrations during prolonged treatment.

13. Hepatic-Avoid use in severe impairment

14. Elderly-May require lower doses

15. Pregnant-Reserve for use in patients with hypertension not controlled by other agents. Short-term use for control of hypertensive crises may be safe provided that the pH and thiocyanate concentrations in maternal blood are monitored. Cat C-AUS

  • Side effects/Adverse effects

-Excessive hypotension or excessive cyanide accumulation

-Thiocyanate toxicity may also occur, especially with renal impairment

Common:

1. Nausea, Vomiting, Headache

2. Sweating, apprehension (Fear)

3, Restlessness

4. Muscle twitching

5. Retrosternal discomfort

6. Palpitations

7. Dizziness

8. Abdominal pain (with too rapid reduction in BP)

Infrequent:

-Postural hypotension, Hypothyroidism, Paraesthesia, feeling of warmth, rash, flushing, increased intracranial pressure

Rare:

-Thrombocytopenia, Methaemoglobinemia, Phlebitis (inflammation of veins usually in legs)

Toxicity:

-Toxicity may occur, particularly with prolonged infusion or higher than recommended maximum dose. Toxicity is due to accumulation of thiocyanate or cyanide.

*Sodium nitroprusside slowly breaks down to release 5 cyanide ions, especially upon exposure to UV light

*In normal renal function, cyanide accumulates with infusion rate of >2 micrograms/kg/min.

-Risk of toxicity is greater in renal impairment because of reduced excretion of thiocyanate.

-Thiocyanate toxicity causes confusion, psychosis, tinnitus, blurred vision, nausea, dyspnea, hypothyroidism and ataxia (lack of voluntary coordination of muscle movements)

Cyanide toxicity causes tachycardia, sweating, hyperventilation, headache, arrhythmias, metabolic acidosis, areflexia, coma, hypotension, pink colour of skin and mucous memranes, shallow breathing, dilated pupils and death.

  • Administration advice

-Dilute with glucose 5%, do not administer by direct injection!

-Infusion solution should be protected from light, e.g. with aluminium foil

-Final infusion concentration should be 50-100micrograms/ml (i.e. 50mg of sodium nitroprusside in 500-1000ml glucose 5%)

  • Practice points

-Monitor intra-arterial BP continuously during infusion and titrate infusion rate carefully to avoid excessive hypotension

-Abrupt withdrawl of sodium nitroprusside may cause rebound hypertension. Withdraw over at lesat 10-30 mins to avoid rebound.

-Usual duration of treatment should not exceed 72 hours because of cumulative thiocyanate toxicity and the possibility of cyanide toxicity; monitor thiocyanate concentrations.

  • Drug Interactions

-Nitrates (including sodium nitroprusside) as well as amyl nitrite causes hypotension. *Additional hypotensive effects may occur if administered with other anti-hypertensive agents.

*Administration with phosphodiesterase-5-inhibitors and nitrates is contraindicated.

Drug class 7: Calcium Channel Blockers (CCBs)

Calcium Channel Blockers

7.1 Subtypes

1. Dihydropyridine/DHPs (Amlodipine, Felodipine, Nimodipine, Nifedipine)

2. Benzothiazepine (Diltiazem)

3. Phenylalkylamine (Verapamil)

7.2 Mechanism

1. Block inward current of calcium into cells in vascular smoth muscle, myocardium and cardiac conducting system via L-type Ca2+ chns.

2. Dihydropyridines– Act mainly on vascular smooth muscle to reduce peripheral vascular resistance (Decrease TPR), minimal effect on normal myocardial cells at therapeutic doses.

3. Nimodipine and Flunarizine (Not used in australia-Treatment of migraine headaches or vertigo)– Prevent cerebral ischemic damage from reactive vasospasm after subarachnoid hemorrhage by dilating cerebral vessels and increasing blood flow.

4. Verapamil-Mainly cardiac effects, reducing contractility, heart rate and almost negligible effect on vascular smooth muscle.

5. Diltiazem (Partial)– Acts on both cardiac and vascular smooth muscle but it has less effect on cardiac cells than verapamil.

*CCBs differ in their chemical nature, sites of action and therapeutic effects (Not all CCBs are born equal)

7.3 Clinical Indications

1. Hypertension

2. Angina

*Clinically decreased afterload and reflex increases in heart rate compensate for CCB-induced negative inotropic effects except in patients with impaired left ventricular function (e.g. CHF).

7.4 Precautions

1. Myasthenia-like neuromuscular disease (muscle weakness) -CCBs may increase risk of muscle weakness and respiratory depression (mostly with verapamil)

2. Cardiovascular

-Contraindicated in cardiogenic shock. In heart failure or significantly impaired left ventricular function, there is a risk of furthur depression of cardiac function (greatest risk with verapamil-Cardio-specific, followed by diltiazem, least risky would be DHPs)

*Even though Diltiazem is less risky in LVF failure, exercise caution regardless.

-Angina symptoms may worsen when starting a DHP (due to reflex cardiac stimulation/Baroreceptor reflex-Tachycardia, Increased contractility occurs). May occur if CCBs stopped abruptly.

-Aortic stenosis. DHRs may cause coronary hypoperfusion and systemic hypotension.

3. Hepatic Impaired (Dose reduction may be required)

4. Elderly. *Start treatment at a lower dose

5. Pregnancy

-Maternal hypotension, primarily caused by short-acting products, may cause fetal hypoxia (CAT C-AUS)

However, nifedipine is used for pre-term (premature) labour

6. Breastfeeding

-Limited data is available for Nifedipine, Diltiazem and Verapamil but Nifedipine seems safe to use. *Avoid breastfeeding in on any CCBs.

7.5 Side effects/Adverse effects

-Adverse effect profile varies between specific CCBs according to relative effects on vascular, myocardial and conducting tissue. Check each CCB.

-DHPs especially cause headache, flushing peripheral edema and palpitations.

1. Rash

2. Constipation (Verapamil)

3. Cough, Wheezing

4. Nausea, Headache, Flushing (Hypotension related)

5. Pulmonary edema

6. Peripheral edema

7. Arrhythmias-Bradycardia (Diltiazem, Verpamil)

8. Fatigue

9. Gingival Hyperplasia

10. Abdominal pain (Not in Joe’s notes)

*All the above are common side effects.

Infrequent side effects:

DHPs-Pulmonary edema, hypotension, tachycardia, chest pain, dyspepsia (Indigestion, impaired digestion), Constipation (General-Not Verapamil), Paraesthesia (Abnormal Sensation of tingling), Muscle Cramps, Polyuria (Excessive urine produced), Rash

Diltiazem: AV-block

Verapamil: Elevation of hepatic enzymes, AV-block, developing or worsening of heart failure

Rare:

Parkinson’s disease

DHPs:Cerebral and myocardial ischemia (Following excessive fall in BP)

Diltiazem:Hypersensitivity reactions including Stevens-Johnson syndrome (SJS) and exfoliative dermatitis, hepatitis, gingival hyperplasia

Verapamil: Gynaecomastia, hepatitis, gingival hyperplasia

7.6 Comparative information

For hypertension:

-Effect of CCBs on arterial pressure is similar to that of other antihypertensives e.g. diuretics, B-blockers and Ace-inhibitors

*Diltiazem and verapamil had no advantage over diuretics or beta-blockers in terms of overall prevention of cardiovascular events (however specifically, there is less occurance of stroke and more MI with diltiazem)(More heart failure with  verapamil)–>Increased incidence of adverse effects.

*Long-acting Nifedipine and Felodipine are as effective as diuretics or beta-blockers in the elderly (difference in preventive efficacy cannot be ruled out)

For Heart Failure:

*Verapamil and Diltiazem are contraindicated with patients with CHF and can be combined with B-blockers only under close surveillance and only in patients without ventricular dysfunction.

*Amlodipine and Felodipine have been shown to not increase deaths/morbidity in CHF.

For Prevention of angina:

-Their symptomatic efficacy is similar to that of B-blockers. However, only controlled release verapamil has been shown to decrease the incidence of cardiovascular events in stable angina and reduce risk of re-infarction and death after MI.

For other indications:

*Verapamil is useful for the prevention and treatment of Sino-ventricular tachycardias (SVTs) and for ventricular rate control in Atrial Filbrilation and atrial flutter.

*Nimodipine is used to prevent and treat ischemic neurological deficits after subarachnoid hemorrhage (CROSS BBB)

*Nifedipine used for pre-mature labour.

7.7 Duration of action

-Duration of action of DHPs differ depending on pharmacokinetics and formulation used.

-Nifedipine and Felodipine absorbed rapidly and have relatively short half-lives. Controlled release products are available to prolong their duration of action and facilitate once daily dosage.

*Amlodipine and Lercanidipine have a longer half life and can be administered once daily. *Note: They have slower onset of action, which may take longer to reach maximal response.

7.8 Practice Points

*DHP-induced peripheral edema does not require treatment with diuretics, which may put patient at risk of volume depletion.

7.9 Types of CCBs

1. Amlodipine

Indications: (a) Hypertension (includes combinations with olmesartan, telmisartan, valsartan, valsartan + Hydrochlorothiazide combination)  (b) Angina

  • Combination with atorvastatin (Cholesterol lowering class)
  • Combination with perindopril (ACE-inhibitor) (For Hypertension if already maintained on perindopril and amlodipine) or (For stable coronary heart disease if already maintained on perindopril and amlodipine)

2. Felodipine

Indications: Hypertension (includes combination with ramipril) [Rf]

***Counselling: Swallow tablet whole, do not crush or chew. Avoid grapeful juice as it may increase the risk of side effects with felodipine.

3. Lercanidipine

Indications: Hypertension (Includes combination with enalapril) [El]

Precautions: Treatment with cyclosporin (Immunosuppressant) (manufacturer contraindicates combination)

  • Renal impaired-Contraindicated if Creatinine Clearance <12ml/min
  • Hepatic impaired-Contraindicated in severe hepatic impairment

4. Nifedipine

Indications: (a) Hypertension (b) Angina (c) Pre-term labour/Premature Labour (Accepted indication)

*Counselling-Swallow controlled release tablet whole, do not crush or chew.

*Practice points:

  • When treating angina, controlled release tablets may be more appropriate than conventional tablets as they do not increase heart rate to the same extent.
  • Stop nifedipine if marked hypotension or dyspnea (shortness of breath) occurs.

5. Nimodipine

Indications: Prevention and treatment of ischemic neurological deficits following subarachnoid hemorrhage

*Precautions:

  • Ethanol content (infusing at 2mg/hour for 24 hours will deliver about 50g of ethanol)
  • Cerebral edema or severly raised intra-cranial pressure (Caution: Use with close monitoring)
  • Hypotension-Risk of aggravation
  • Other drug interactions: Manufacturer contraindicates use of oral nimodipine with rifampicin, phenobarbitone, phenytoin or carbamazepine (Treatment with drugs that affect CYP3A4 may affect nimodipine’s clearance and activity)
  • Treatment with disulfiram (treatment of alcohol disorders) or metronidazole (antibiotic) may cause reactions with ethanol as nimodipine infusion contains ethanol (about 25%)
  • Hepatic impaired: Requires lower dosage in hepatic impairment, monitor BP and pulse rates

*Adverse effects:

Rare: Bradycardia, Paralytic ileus (Paralysis of the intestine)

*Administration advice

-Give infusion via a central catheter using an infusion pump.

*DO NOT use PVC giving sets because of loss of nimodipine and contamination by plasticisers; use polyethylene sets instead.

*Counselling: (For Tablets) Avoid grapefruit juice as it may increase the risk of side effects with nimodipine.

*Practice Points: High morbidity and mortality after aneurysmal subarachnoid hemorrhage is associated with neurological damage from bleeding (initial and recurrent) and cerebral ischemia due to reactive vasospasm. Early medical treatment aims to prevent vasospasm and re-bleeding and to stablise the patient for surgery.

6. Diltiazem

Indications: (a) Angina (b) Hypertension (controlled release) (c) Atrial Filbrilation (Ventricular Rate control-Accepted Indication)

Precautions:

1. Cardiovascular-Contraindicated in severe bradycardia and sick sinus syndrome (SSS), second or third-degree AV block (without pacemaker) or hypotension (systolic BP <90mmHg)

-Diltiazem may cause hypotension, bradycardia and shows cardiac conduction.

-Treatment with drugs that can cause bradycardia will worsen heart rate and cause hypotension. *Monitor cardiac function.

*Diltiazem is metabolised by CYP3A4. It also inhibits CYP3A4, thus Diltiazem may increase the concentration of other drugs metabolised by this enzyme–> Leading to toxicity

7. Verapamil

Indications: (a) SVT with atrioventricular nodal re-entry (b) Atrial Filbrilation or atrial flutter (Ventricular rate control) (c) Hypertension, including combination with trandolapril [Tv] (d) Angina

Precautions:

1. Cardiovascular

-Contraindicated in severe bradycardia, sick sinus syndrome, 2nd or 3rd degree AV block (without pacemaker), hypotension (systolic BP<90mmHg), AF or atrial flutter complicating Wolff-Parkinson-White syndrome or wide complex ventricular tachycardia (IV use).

-Verapamil may worsen first degree AV block (greater risk than with diltiazem)

2. Other drugs

(a Treatment with anti-arrhythmics. Increase risk of heart failure, bradycardia may furthur decrease heart rate and cause hypotension. Use of beta-blockers is not recommended, unless under specialist supervision. *Monitor cardiac function.

(b) Contraindicated with Dabigatran (anti-coagulant). Combination not allowed.  Dabigatran can however be used with conventional and controlled released verapamil.

*Administration advice: 

-Give IV injections slowly under continuous ECG monitoring over 2-3 minutes. Rapid IV administration may result in hypotension, bradycardia, heart block and asystole (flatline, no cardiac electrical activity)

*Counselling

-Swallow controlled release products whole. DO NOT CRUSH OR CHEW if necessary, capsules may be opened and the contents can be sprinkled onto apple sauce and taken immediately.

-Verapamil may increase the effects of alcohol so that patients may be more easily affected and the effects last longer. Limit alcohol intake until you know whether you are affected like this. 

*It is metabolised by CYP3A4. Administration with drugs that inhibit this enzyme may increase its concentration and risk of adverse effects. Combination with inducers may decrease its concentration and possibly its efficacy.

*Verapamil also inhibits P-glycoprotein. If given with one of the enzyme’s substrates, the substrate’s concentration and risk of adverse effects may increase.

7.10 Drug Interactions

  • Amlodipine, Felodipine, Lercanidipine, Nifedipine , Nimodipine, Diltiazem and Verapamil  Acronym: (AFL, Not Now Damn Vexing)
  • CCBs also cause hypotension. Thus, administration with other drugs that can decrease BP can result in additional hypotension!!!
  • Amlodipine specific

-Cyclosporin

-Ritonavir (Ritonavir with indinavir increases amlodipine concentration and possibly risk of adverse effects. Monitor for adverse effeects and reduce amlodipine dose if neccessary.

  • Diltiazem specific

*Diltiazem is metabolised by CYP3A4. It also inhibits CYP3A4, thus Diltiazem may increase the concentration of other drugs metabolised by this enzyme–> Leading to toxicity

1. Alfentanil

2. Atorvastatin

3. Atazanivr (Increases concentration of diltiazem and its metabolite, increasing the drug’s therapeutic and adverse effects. Both drugs also increase the PR interval)

4. Buspirone (Anti-anxiolytic)

5. Calcineurin inhibitors (e.g. Tacrolimus, Sirolimus, Cyclosporin)

6. Carbamazepine (Anti-epileptic)

7. Cilostazol (Improves walking speed in patients with intermittent claudition/Muscle pain)

8. Cimetidine (Anti-histamine)-Inhibit diltiazem’s metabolism, increasing its concentration, therapeutic and adverse effects. Monitor clinically and decrease diltiazem dose if necessary.

9. Cisapride

10. Colchichine (Anti-Gout)

11 Cyclosporin

12. Digoxin

13. Efavirenz (May decrease the concentration of diltiazem and its metbaolites, possibly decreasing its efficacy, monitor clinical effects and increase dose of Diltiazem if necessary)

14. Eplerenone

15. Impiramine

16. Ivabradine

17. Methylprednisolone

18. Midazolam

19. Phenytoin

20. Rifampicin (Increase metabolism of diltiazem, possibly decreasing its therapeutic effects; monitor clinical effects and incresae dose if necessary)

21. Ritonavir (Combination with Indinavir may incresae diltiazem concentration and possibly risk of adverse effects. Monitor adverse effects and reduce diltiazem dose if neccesary.)

22. Simvastatin

23. Tigacrelor (ADP inhibitor)

24. Triazolam

  • Felodipine specific

1. Erythromycin (inhibits felodipine metabolism, increasing its concentration, with possible increase in adverse effects)

2. Itraconazole (Decreases metabolism of felodipine increasing its concentration and risk of adverse effects. The risk of heart failure may also increase as they both have a negative inotropic effect.)

*Avoid combination or monitor for adverse effects. Reduce felodipine dose if necessary.

3. Tacrolimus

  • Lercanidipine specific

1. Cyclosporin

2. Ketoconazole (Markedly increases concentration and activity of lercanidipine). *Avoid combination or monitor BP and reduce dose if required.

3. Metoprolol-Decreases lercanidipine concentration and may reduce its activity. *Monitor BP and adjust dose if necessary.

  • Nifedipine specific

1. Cimetidine (Cimetidine incresaes nifedipine concentration and risk of adverse effects). Use an alternative H2 antagonists or monitor for adverse effects and reduce nifedipine dose if necessary.

2. Fluconazole (Inhibits nifedipine metabolism, increasing its concentration and risk of adverse effects). *Monitor BP and for adverse effects of nifedipine (e.g. ankle swelling and decrease dose if necessary)

3. Indinavir (Combination with ritonavir may increase nifedipine concentration. It increases the risk of adverse effects. *Monitor BP and for adverse effects of nifedipine-Ankle swelling)

4. Itraconazole

4. Magnesium sulfate

5. Rifampicin (May increase metabolism of nifedipine and reduce its efficacy. Monitor BP and increase nifedipine dose if necessary-May need to be substantial)

6. Tacrolimus

  • Nimodipine

-Causes bradycardia. Administration with other drugs that slow down the heart rate may result in additional bradycardia.

-Use of oral nimodipine with rifampicin, phenobarbitone, phenytoin or carbamazepine (Contraindicated)

  • Verapamil

-Combining verapamil with dysarrhythmics increases risk of heart failure, bradycardia and proarrhythmic effect. 

*Avoid such combinations with anti-arrhythmics unless there is no alternative (Refer to pg 195 of extra CCB notes for specific interactions)

*Verapamil slows cardiac conduction and causes bradycardia. Administration with other drugs that also decrease heart rate may cause additive bradycardia and hypotension. *Monitor Cardiac function.

*Avoid combination of verapamil with beta-blockers, including eye drops (unless under specialist supervision)

*It is metabolised by CYP3A4. Administration with drugs that inhibit this enzyme may increase its concentration and risk of adverse effects. Combination with inducers may decrease its concentration and possibly its efficacy.

*Verapamil also inhibits P-glycoprotein. If given with one of the enzyme’s substrates, the substrate’s concentration and risk of adverse effects may increase. 

1. Buspirone

2. Carbamazepine

3. Colchicine

4.  Cyclosporin

5. Dabigatran

6. Digoxin

7. Eletriptan

8. Eplerenone

9. Erythromycin

10. Everolimus

11. Sirolimus and derivatives

12. Ivabradine

13. Midazolam

14. Phenobarbitone (increases metabolism of verapamil. Decreases its concentration and therapeutic effect. *Monitor clinical effect and increase dose of verapamil if necessary)

16. Rifampicin (Increases metabolism of verapamil, decreasing its concentration and therapeutic effect–>IV verapamil seems unaffected). *Avoid combination if possible, otherwise monitor clinical effect and increase verapamil dose if necessary.

17. Simvastatin

 

7.11 Important Clinical Points

For hypertension:

*CCBs are effective in any age group (including children), White or Black populations with low renin levels (as monotherapy or combined with other antihypertensive agents including diuretics, B-blockers or ACE-inhibitors).

-As monotherapy, the CCBs that have been used to treat hypertension to be equally effective, controlling BP in approx 60%-80% of patients with mild to moderate hypertension.

Safe to use in patients with COPD, peripheral atherosclerotic disease or Raynaud’s phenomenon. 

-Additional benefits in hypertensive patients with concomitant angina pectoris, supraventricular tachycardia (verapamil) or peripheral vascular disease (nifedipine).

*CCBs Not Recommended as first line anti-hypertensive therapy.

*In patients with diabetic nephropathy, diltiazem is the CCB (but not the drug) of choice. It reduces proteinuria. Nifedipine should not be used in patients as it increases proteinuria.

 

For Angina:

In chronic stable agina and unstable angina, CCBs are the second or third line agents after Beta-blockers and oral nitrates. CCBs appear to be as effective as B-blocker

(This means that oral nitrates is first line therapy in stable, unstable angina followed by beta-blockers and CCBs)

*In prinzmetal angina, CCBs are the drug of choice (particularly diltiazem and verapamil).

 

 

 

 

 

 

 

Immunology: Anti-histamines and Immunosuppressant drugs

Part 1: Anti-histamines

What is histamine?

-Naturally occuring amine that is found in most body tissues in a inactive bound form (histamine+heparin+protein)

-Important component of mast cell granules and released in response to stimuli such as physical trauma or antigen-antibody reactions.

-Various chemicals such as tubocurarine, morphine, some anti-histamines,  snake venome and proteolytic enzymes can cause release as well.

-The triple response of Lewis is a cutaneous response that occurs from firm stroking of the skin, which produces an initial red line, followed by a flare around that line, and then finally a wheal. [Subtypes involved: H1 and H2 receptors]

Physiological function of histamine:

1. In body epithelia, it is released in repsonse to invasion by foreign substances.

2. In glands, mediates part of the normal secretory process.

3. In most cells near blood vessels where it plays a role in regulating microcirculation.

Action of histamine

Smooth muscles: Cause smooth muscles to contract (not including arterioles but larger arteries). Stimulation of human uterus is insignificant. Brisk attack of bronchospasm may be induced in subjects who have allergy esp. asthma.

1. Dilate arterioles, with a consequent fall in blood pressure.

2. Dilate capillaries

3. Pruritic (Cause itchiness)

4. Gastric secretion (Increased acid and pepsin concentration in gastric juices)

5. Metabolism (Formed from the amino histidine and metabolised minaly by deamination and by methylation)

  • Types of Histamine receptors (H1, H2, H3)

h1: Anti-histamine usually refers to H1-receptor antagnoists (which is affects various allergic and inflammatory mechanisms)

h2: Recently developed, main effect is on gastric secretion (e.g. cimetidine)-‘Cement ti dine’

h3: Experimental and investigational tools.

1.1 H1 antagonists (Anti-histamines)

-Considerable structural similarity to histamine, adrenaline, serotonin and acetylcholine. Thus, may affect or block one another.

-H1 anti-histamines have sedative, antimuscarinic or even alpha antagonist effects.

-As such, H1-anti-histamines can be used as hypnotics, antitussives, expectorants, in motion sickness and in parkinson’s disease.

-if used for its anti-histamic effect, the above uses will become adverse effects.,

1. 2Mechanism of action: 

  • Decrease histamine-mediated contraction of smooth muscles in the bronchi, the intestine and in the uterus.
  • Reduce the increased vascular permeability caused by histamine.
  • Sedation
  • Prevent motion sickness

1.3 Clinical Uses/Indications:

-For allergic reactions including hay fever, urticaria, insect bites, drug hypersensitivities. Drugs that lack sedative effect are preferred (e.g. fexofenadine-(Fatso fiend-a dine) or cetirirzine)

-Used as anti-emetics for the prevention of motion sickness or other causes of nausea, especially those with associated with vertigo (e.g. labyrinthine disorders) [Loratadine]

-For sedation (e.g. promethazine found in Phenergen)

1.4 Side effects

-Depends on the effects that the drug is prescribed for. This means that if a drug is used for peripheral actions, the CNS activity is unwanted and vice versa.

-When used for their sedative or anti-emetic actions, some of the CNS effects are dizziness, tinnitus and fatigue are unwanted.

Precautions: Excessive doses may cause excitation and convulsions in children. (!st generation anti-histamines) For children, sedation may be induced and learning ability will be affected. Severe effects are unusual following ovedoses of 1st generation anti-histamines.

-Altering the structure of some drugs may prevent them from entering BBB and less unwanted Adverse effects (e.g. loratadine)—>More polar

Loratadine

*Peripheral actions on CNS activity is always unwanted!!! When used for sedative or anti-emetic actions (eg. dryness of the mouth, blurred vision, constipation, retention of urine)

*Gastrointestinal disturrbances and Allergic dermatitis can follow after application

1st generation anti-histamines: Hydroxyzine, Bromazine, Mepyramine

2nd generation anti-histamines (Agents with no sophoric effect): Loratadine, Cetirizine, Mizolastine, Terfenadine, Astemizole (Terfenadine and astemizole are non-sedating alternatives to first-generation compounds, inhibits several ion channels) *Disturbing arrhythmias were described for these two drugs.

3rd generation anti-histamines (Non-cardiotoxic, non-sedative agents): Fexofenadine (Children who have overdose can be managed at home)

Part 2: Immunosuppressant drugs

2. 1Generabl Mechanism of action:

1. Inhibits IL-2 production or action (e.g. cyclosporin, tacrolimus, sirolimus/rapamycin)

2. Inhibitors of cytokine gene expression (e.g. corticosteroids)

3. Act by cytotoxic mechanisms (e.g. cyclophosphamide, chlorambucil)- Prevents cell proliferation

4. Inhibits purine or pyrimidine synthesis (e.g. azothioprine, myclophenolate mofetil)

5.  Blocks cytokines and receptors mediating immune responses (e.g. antibodies)

2.2 Clinical Indications

1. To suppress tissue regection after transplant

2. To suppress graft versus host disease in bone marrow transplant.

3. To treat autoimmune diseases (psoriasis, ulcerative colitis, systemic lupus erythematosus/SLE, idiopathic thrombocytopenic purpura/ITP)

2.3 Types of immunosuppressant drugs

1. Cyclosporin

-Fungal peptide (cyclic 11 amino acids, invaluable role in organ transplant)

Mechanism of action:

  • Decreased clonal proliferation of T cells, primarily by inhibiting IL-2 release and decreasing expression of IL-2 receptor
  • Reduced induction of and clonal proliferation of cytotoxic T-cells from precursor CD8+ cells
  • Reduced function of effector T-cells that mediate cell-mediated responses
  • Some reduction of T-cell dependent responses

***Main effect by preventing IL-2 transcription

Antigen binds to T-cell receptor–>Increase in intracellular Ca2+–>Ca2+ plus calmodulin stimulates phosphatase, calcineurin, that activates various transcription factors–>Transcription of IL-2 genes–>Cyclosporin binds with a cystolic protein called cyclophilin–> The resulting complex inhibits calcineurin–>Inhibits IL-2 production and T-cell proliferation does not occur.

Unwanted effects:

1. Nephrotoxicity (probably due calcineurin inhibition)-Limiting factor in certain patients (Esp with renal failure)

2. Hypertension

3. Hepatotoxictiy

4. Less crucial side effects (Anorexia, lethargy, hirsuitism, tremor, parasthesia, gingival hyperplasia, gastrointestinal disturbances)

+No depressant effects on bone marrow

2. Tacrolimus

Mechanism of action: Macrolide antibiotic with a similar mode of action to cyclosporin but the internal receptor is not cyclophilin but immunophilin known as FKBP/FK binding protein. The complex inhibits calcineurin in the same way. 

Side effects:

-Similar to cyclosporin. Hypertension and Nephrotoxicity not that serious here.

-Thrombocytopenia and hyperlipidemia may occur but reversible by reducing the dose.

3. Glucocorticoids-Discusssed previously

4. Azathioprine

-Interfers with purine synthesis and is cytotoxic. Used widely for the control of tissue rejection in transplants. Drug is metabolised to give mercaptopurine (analogue which inhibits DNA synthesis)

-Both cell-mediated and antibody-mediated immune reactions are depressed by this drug since it inhibits clonal proliferation in the induction phase of the immune response by cytotoxic effects on dividng cells. Main unwanted effect is depression on bone marrow.

5. Alkylating agents

-Two alkyl groups which can form covalent bonds with cell substituents. Can cross link two nucleophilic sites such as N7 of guanine in DNA.

Mechanism of action: During DNA replication, the result is base substitution, base excision or chain breakage. Eventually, cell dies by apoptosis.

(a) Cyclophosphamide-Cytotoxic agent with powreful immunosuppressive effects. Particular action on lymphocytes during the clonal proliferation phase and inhibits both anti-body and cell-mediated immunity

(b) Chlorambucil-Similar in action and effects to cyclophosphamide

6. Mycophenolate mofetil

-Derivative of fungal antibiotic.

-Metabolised into mycophenolic acid in the body which inhibits proliferation of both T and B lymphocytes by inhibiting inosine monophosphate dehydrogenase (enzyme needed for purine biosynthesis)

-T-cells and B-cells need this pathway. So inhibiting this pathway has rather specific effects.

*When used with cyclosporin and steroids, it is effective in suppressing kidney transplant rejection.

7. Immunoglobulins

-Antibodies against human lymphocytes or their surface proteins.

-When derived from animal sources, the antibodies themselves are potent antigens which limits their usefulness.

-Using genetic engineering, the antibodies can be humanised to combine the Fab region to the Fc region.

8. Polyclonal

-Anti-lymphocyte immunoglobulin and anti-thymocyte immunoglobulin are obtained from horses which are immunised against human lymphocytes or feotal thymus tissue respectively.

-Binding of the antibodies cause complement activation and lysis of target cells.

-Unwanted effects: Due to the presence of foreign proteins and subsequent immune response. Anaphylaxis can occur and immune complexes can lodge into kidney causing nephritis.

9. Monoclonal

-Directed against surface components of T-cells.

CD3-Group of peptides responsible for epxression of T-cell receptors at the cell surface.

CD4-Essential co-receptor on T-helper cells

IL-2 receptor-Needed for clonal proliferation of T-cells

-Initial doses of anti-CD3 can cause severe side effects. Fever, hypotension, pulmonary edema, nephropathy and encephalopathy which is thought to be due to cytokine release can occur. Pre-treatment with steroids is required to mitigate these effects.

10. Anti-TNF humanised antibodies

Clinical uses: Ankylosing Sponylitis, Crohn’s disease, Psoriasis, Psoriatic arthritis, Rheumatoid arhritis

-Very effective though the vary in effectiveness with different disease, adverse reactions are unusual but as they inhibit immunity some increase in infections have been noted.

*It is advised that a patient suffering from infections to stop Adalimumab (Humira) treatment.

*Increased in liver enzymes (AST and ALT) and formation of autoantibodies similar to early SLE have been reported.

(a) Infliximab (Remicade): Mouse-Human antibody to TNF-a

(b) Etanercept (Enbrel): Construct of human TNF receptor and IgG which binds to TNF-a and prevents its action. Effectiveness may decrease over time, perhaps due to antibody formation and less effective in obese patients, maybe due to adipocytes being a source of TNF-a.

(c) Adalimumab (Humira): Fully human monoclonal antibody to TNF-a. Slightly more effective than Enbrel in psoriasis and injections are once a fortnight as compared to once a week with Enbrel.

(d) Efalizumba (Raptiva): Recombinant humanized monoclonal to CD11a. Part of the integrin molecule LFA-1 involved in immune cell extravsation. Withdrawn from market due to progressive multifocal leukoencephalopathy (PML)

11. Rapamycin (Sirolimus)

-Macrolide antibiotic like tacrolimus

Mechanism of action: Binds to intracellular immunophilin, FKBP. However, complex does not bind to calcineurin nor does it affect IL-2 gene transcription. Interferes with IL-2 signal transduction pathway, blocking the cell cycle of activated T cells in G1 phase.

-It also competes with tacrolimus for FKBP but their effects are additive.

-Nephrotoxicity and hypertension not serious problems. Hyperlipidemia and ITP responds to reduction in dosage.

12. Future drug developments 

a) Sulphated polysaccharides

-Sulphated glycosaminoglycans (GAGs) such as chondroitin sulphate and heparan are major constituents of cell membranes and extracellular matrix (ECM)

-GAGs represent the endogenous ligand for the sulphated polysaccharide receptors on cells.

*Sulphated polysaccharides, phospho-sugars and the oligosaccharide-processing inhibitor castanospermine represent promising new drugs with a novel mode of action.

Mechanism of action of drugs above: Inhibition of migration across vascular endothelium and entry into tissue parenchyma at sites of inflammation. Prevents the accmuluation of leukocytes in inflammatory foci. The drugs may halt the progression of inflammatory dieases such as rheumatoid arthritis.

b) Immunosuppressants

Brequinar sodium: An anti-metabolite that inhibits de-novo (on the spot) pyrimidine synthesis

Mizoribine: An inibitor of purine synthesis

-Monoclonal antibodies: To cytokines, cytokine receptors and adhesion molecules. There is also the possiblity of inducing specific tolerance to donor antigens by blocking T-cell activation and inducing T-cell apoptosis.

c) Anti-rheumatoid agents

-Cytokine-targeted therapies including anti-TNF-a antibodies, soluble TNF receptor to remove TNF-a.

d) 5-lipooxygenase inhibitors

-Prevents the conversion of arachidonic acid to 5-HPETE. Thus, they prevent leukotriene production. Useful for asthma treatment.

e) Phosphodiesterase inhibitors

-To increase cAMP concentrations in cells thus reducing activation.

Anti-hypertensives Part III (Adrenergic Receptor Antagonists)

*This section will be expanded upon. 

Part 1: Alpha receptor antagonists

(a) Non-selective

Phenoxybenzamine

Phentolamine

(b) alpha 1 selective

Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin, Indoramin, Urapidil, Bunazosin

(c) a2 selective-Yohimbine

1.1 Alpha 1 Receptor antagonists

Mechanism of action: Blockade of alpha 1 adrenergic receptors inhibits vasoconstriction induced by endogenous catecholamines. This results in a decrease in BP due to decreased TPR. The magnitude depends on the activity of the sympathetic nervous system. Decreases in BP is smaller in supine position than in upright subjects. Decreases also enhanced by low blood volume.

  • For most a-receptor antagonists, fall in BP is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention.
  • These compensatory reflexes are worsened if the antagonist also blocks alpha 2 receptors on periperal sympathetic neurons which leads to enhanced release of NAdr. Increased stimulation of B1 postsynaptic receptors in the heart and on JGA cells.
  • Since a1 receptors are blocked, the endogenous catecholamines will bind to other receptors (B2 receptors). This triggers vasodilation which means that Adr now becomes a vasodepressor (presor responses are inhibited).

Drug 1: Prazosin (Potent and selective a1 receptor antagonist)-Used frequently in hypertension  

-The affinity for a1 adrenergic receptors is 1000x that for a2 adrenergic receptors.

Mechanism of action:

1. Major effect is that due to the blockage of a1 receptors in arterioles and veins, leading to a fall in TPR and venous return to the heart.

2. Also acts in CNS to suppress sympathetic outflow. ***Prazosin appears to depress baroreceptor reflex in hypertensive patients.

3. *Prazosin and related drugs tend to have favourable effects on serum lipids in humans–>Decreases LDL and triglycerides while increasing concentrations of HDL 

-Decreases cardiac preload and thus have little tendency to increase cardiac output and heart rate (compared to vasodilators which have minimal dilatory effects on veins)

Pharmacokinetics of Prazosin:

-Well absorbed with bioavailability of 50-70% and peak plasma concentration is 1-3 hours after oral dose.

-Prazosin binds with greatest affinity a1-acid glycoprotein (only 5% of the drug is free). Diseases may change the free fraction.

-Extensively metabolised in the liver (plasma half life, 2-3 hours, may be prolonged to 6-8 hours in CHF)

-In treatment of hypertension, the duration of action is 7-10 hours.

Adverse effects:

*First dose effect (marked postural hypotension and syncope which may occur 30-90 mins after initial dose)

-Risk is minimised by limiting the initial dose (e.g. 1mg at bedtime, increasing dosage slowly and introducing additional anti-hypertensive drugs cautiously)

1.2 Alpha 2 Receptor agonists (+)

Mechanism of action: Activation of alpha 2 receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a decrease in BP

Drugs that are a2 receptor agonists: Clonidine and methyldopa (CAT A-AUS) [Methyldopa can be used during pregnancy!]

Note: Yohimbine is an a2 receptor antagonist (Just good to know)

1.3 Non-selective Alpha antagonists

-Phentolamine (‘Non’-Friend told amine). Competitive alpha receptor with similar affinities for a1 and a2 receptors.

Clinical indications: (a) Short term control of hypertension in patients with pheochromocytoma (adrenal tumour producing Adr and NAdr) (b) Useful for treatment of hypertensive cases that follow the abrupt withdrawl of clonidine (c) Sexual dysfunction-Can be administered bucally, orally or intracavernously (injection at the base of the penis) into penis 

1.4 Alpha 1 selective

Part 2: Beta Receptor antagonists [B-blockers can be distinguished by relative specificity of B1 over B2, intrinsic sympathomimetic activity, capacity to block B-receptors, differences in lipid solubility, capacity to induce vasodilation, pharmacokinetic properties] 

(a) Non-selective (first generation)

Propranolol, Pnebutolol, Pindolol, Nadolol, Timolol (3P NoT)

(b) B1 selective (Second Generation)

Atenolol, Acebutolol, Bisoprolol, Metroprolol, Esmolol (ABME) 

(c) Non-selective with additional cardiovascular actions (Third Generation)

Carteolol, Carvedilol, Bucindolol, Labetalol

(d) B1 selective additional cardiovascular actions (Third Generation)

Betaxolol, Celiprolol, Nebivolol

-Additional features of certain b-blockers: 

Carteolol (NO production, beta 2 receptor agonism), Labetalol (A1 receptor antagonist), Carvedilol (Ca2+ entry blockade and antioxidant activity), Betaxolol (Ca2+ channel blockade)

2.1 Mechanism of action: Antagonists inhibits interaction of NAdr, Adr and sympathomimetic drugs with B receptors. Effects of B-adrenergic antagonists may be predicted from the consequences of B-receptor stimulation (due to effects of elevated cAMP) 

*Note: Beta-blockers generally do not reduce blood pressure in patients with normal BP but lower BP in patients with hypertension.

***Reduction of B1-stimulated renin release from JGA cells is a contributing mechanism!!!

-Long term administration of B-blockers to anti-hypertensive patients decresae peripheral vascular resistance.

2.2 Comparison of various B-blockers

-Propranolol interacts with B1 and B2 with equal affinity. No ISA and doesn’t block a receptors.                                               *Hepatic metabolism CYP 1A2, 2C19, 2D6, 3A4. Individual variation in                                                                                                                                                                                                                           hepatic clearance of propranolol contributes to variability in plasma                                                                                                                                                                                                                           concentration (20x) after oral administration. Propranolol readily enters                                                                                                                                                                                                                     the CNS.

-Pindolol is a weak partial B-agonist (ISA). ISA drugs preferred when diminished cardiac activity or bradycardia.                    *Hepatic metabolism by 2D6.

-Metoprolol is a B1-selective antagonist.                                                                                                                                            *Extensive first pass metabolism. Wide variability in t1/2 based on genetic                                                                                                                                                                                                                  differences in 2D6 activity. t1/2 (normally 3-4 hrs) can double in CYP2D6                                                                                                                                                                                                                    poor metabolisers, who have 5x higher risk for adverse effects compared                                                                                                                                                                                                                  to normal metabolisers.

-Atenolol is a B1-selective antagonist.                                                                                                                                                 *Largely excreted by kidneys; dosage should be reduced when creatinine                                                                                                                                                                                                                   clearance is <35ml/min

2.3 Adverse effects and precautions

1. Exacebate heart failure 

2. Bradycardia (life-threatening bradycardia with partial or complete AV conductoin defects). Caution in patients taking other drugs (e.g. verapamil or various anti-arrhythmic agents which may impair sinus node function or AV conduction)

3. Raynaud’s syndrome-Cold extremities while taking B-blockers

4. Increased response after abrupt B-blocker withdrawal

5. Blunt recognition of hypoglycemia and delayed recovery from insulin-induced hypoglycemia

6. Depression, sleep disturbances, fatigue

7. Bronchoconstriction

Anti-Hypertensives Part II (Diuretics)

Thiazides/Benzothiadiazides (Not to be confused with benzodiazepines and benzothiazides)

3.1 Mode of action

-Moderately potent diuretics, they inhibit absorption of sodium and chloride in the proximal segment of the DCT and produce a corresponding increase in potassium excretion.

-Essentially blocks Na+/Cl- symporter

-They also promote vasodilation directly at low doses (e.g. open Ca2+/activated K+ channels, leading to hyperpolarisation of vascular smooth muscle cells–>Relaxation–>Vasodilation)

-When used in recommended low doses for hypertension, they lower BP mostly by vasodilator effect.

3.2 Clinical Indications

1. Mild to moderate hypertension

2. Edema associated with heart failure or hepatic cirrhosis

3. Nephrogenic diabetes insipidus (a form of diabetes insidipus but not due to lack of ADH but due to a lack of sensitivity of kidneys or nephrons to ADH)

*Diabetes insipidus (DI) is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. Insufficient ADH produced.

3.3 Precautions

1) Gout. Diuretic induced rise in serum uric acid concentration may precipitate gout (more likely with higher doses)

  • Urate reabsorption from the tubular fluid into the cell is mediated by urate transporter 1 (URAT1), OAT4, and OAT10, located on the luminal membrane, and from the cell back to the peritubular capillary blood through glucose transporter 9 (GLUT9) located on the basolateral membrane.
  • Loop and thiazide diuretics decrease urate excretion by increasing net urate reabsorption; this can occur either by enhanced reabsorption or by reduced secretion
  • A direct effect of diuretics on promoting urate reabsorption by the proximal tubule.
  • An indirect effect of diuretic-induced volume depletion on increasing urate reabsorption by the proximal tubule.

2) Heart Failure (with significant edema). Hyponatremia may occur, particularly if higher doses are used with a salt-restricted diet and/or potassium sparing diuretics and excess water intake.

3) K+ excreting drugs. Amphotericin (Anti-fungal)-Increases risk of hypokalemia

*Monitoring blood K+ levels is neccesary.

4) Renal patients

-Contraindicated in severe renal impairment or anuria (less than 45 ml urine per day)

-Thiazides are relatively less effective as diuretics in significant impairment (Creatinine Clearance <24ml/min), however they are still effective (at low doses where they reduce BP by direct vasodilation)

Normal Creatinine Clearance

    1. Men
      1. Average: 120 ml/min/1.73 m2 (+/-25) or 175 Liters/day
      2. Range: 97-137 ml/min/1.73 m2 (0.93-1.32 ml/sec/m2 IU)
    2. Women
      1. Average: 95 ml/min/1.73 m2 (+/-20) or 135 Liters/day
      2. Range: 88-128 ml/min/1.73 m2 (0.85-1.23 ml/sec/m2 IU)

-When used with loop diuretics in heart failure, thiazides may reduce renal perfusion and precipitate uremia (urea accumulated in urine).

5) Hepatic impaired

-Contraindicated in hepatic precoma and coma (refers to alterations in behaviour in parenchymatous hepatic disorder).

-In cirrhosis, diuretic-induced volume depletion and/or electrolyte disturbance may precipitate hepatic coma or hepatic enchephalopathy (accumulation of toxic substances in the brain which leads to confusion)

6) Elderly

-More susceptible to electrolyte imbalance (e.g. hypokalemia) and orthostatic/postural hypotension.

7) Pregnant women

-AVOID USE. May cause electrolyte disturbances or neo-natal thrombocytopenia (lack of platelets in newborn), reduction in maternal blood volume may diminish uteroplacental perfusion.

*They are not allowed or not permitted in treatment of pregnancy associated hypertension/Gestational hypertension (CAT C-Aus).

-Placental Hypoperfusion and transient volume depletion.

8) Breastfeeding

-Unlikely to suppress lactation. Thiazides appear in breast milk, should be avoided by nursing mothers.

3.3 Adverse Effects/Side Effects

1. Glucose tolerance, plasma lipid levels and male sexual function impaired/Erectile dysfunction (minimal with low doses)

2. Dizziness and Weakness

3. Muscle Cramps

4. Polyuria

5. Orthostatic hypotension

6. Hyponatremia (low sodium)

7. Hypokalemia (low potassium)

8. Hyperuricemia (High uric acid)–>Leading to Gout

9. Hypochloremic alkalosis (Low chloride)

10. Hypomagnesaemia (Low magnesium)

11. Hypercalcemia (Ca2+ excretion inhibited)

Way to remember: 2 Highs (Ca2+, Uric acid), 4 Lows (Na+, K+, Cl-, Mg2+), Hypertension related effects, Glucose+lipid metabolism, Erection

*Other infrequent side effects: Rash, hyperglycaemia, hypercalcemia, blurred vision, impotence, dyslipidemia (increase in total lipid cholesterol), LDL and triglyceride concentrations increase and reduced LDL concentration.

*Rare side effects: Nausea, vomitting, constipation, diarrhoea, parasthesia (tingling sensation with no long term physical effect), intrahepatic cholestatic jaundice,  cholecystitis, pancreatitis, agranulocytosis, aplastic anemia, hemolytic anemia, thrombocytopenia, epidermal necrolysis, purpura, necrotising vasculitis

3.4 Comparative Information

-At equipotent doses, all thiazides and related diuretics are effective in reducing BP. Indapamide is no less likely than ther others to cause hyponatremia and hypokalemia.

-Often, thiazides are used in combination with ACE-inhibitors, ARBs, other potassium-sparing diuretics (triamterene and amiloride)

*Indapamide is available alone or as a combination product with an ACE inhibitor (Perindopril)

*Do Not start treatment with combination products. Reserve them for patients stabilised on similar doses of single ingredient products.

3.5 Counselling AND Practice Points 

-Patient may feel dizzy on standing when taking this medication.

-Get up gradually from sitting/lying down to minimise this effect. Sit or lie down if necessary.

*Practice Points

-May be given with loop diuretics in severe heart failure to increase diuresis. Use small, intermittent doses with careful monitoring, seek specialist advice.

-Use low doses (e.g. up to 25 mg hydrochlorothiazide). High doses increase the likelihood of metabolic adverse effects without an additional anti-hypertensive effects.

*Diuretic Induced Hypokalemia

Reduce risk by minimising dose of thiazide or related diuretic

-Less likely when also taking an ACE-inhibitor or ARB (because ACE-inhibitors/ARBs retain potassium)

-May be difficult to correct if hypomagnesemia is present

-When potassium levels <3.5mmol/L, consider using potassium supplements (not preferred since each 600mg tablet contains only 8mmol of K+, daily requirement 20-60mmol daily) or potassium-sparing diuretics (easier to use)

3.6 Types of Thiazide Diuretics

  • Chlorthalidone/Chlortalidone

Indications: (a) Hypertension, (b) Edema associated with Heart Failure or hepatic cirrhosis (c) Nephrogenic Diabetes Insidipus (accepted)

-Counselling: Taken once a day usually in the morning (qd am)

  • Hydrochlorothiazide

Indications:

(a) Hypertension: (in combination with amloride, triamterene) (in combination with ACE-inhibitors: enalapril, fosinopril, quinapril) (in combination with ARBs: Candesartan, Olmesartan, Eprosartan, irbesartan, telmisartan, valsartan) (in combination amlodipine and valsartan)

(b) Edema associated with heart failure

(c) Hepatic cirrhosis or nephrotic syndrome (includes combination with amiloride and with triamterene) 

(d) Accepted indications: Prevention of renal calculi associated with hypercalciuria

Precautions: High doses of hydrochlorothiazide may cause hypokalemia. If there is a history of kidney stones, avoid using triamterene or potassium chloride.

Counselling: Taken once daily in the morning. If patient is taking it twice a day, take the first dose in the morning and the second dose before 6pm.

  • Hydrochlorothiazide + Triamterene

Mechanism of action: Triamterene inhibits sodium absorption in the distal tubule by blocking sodium channels. As a result, it interferes with sodium/potassium exchange and reduces urinary potassium excretion

Indications: (a) Hypertension (b) Edema associated with heart failure, hepatic cirrhosis or nephrotic syndrome

-Precautions: Hyperkalemia (contraindicated), Treatment with drugs that can increase potassium concentration (ACE-inhibitors-Avoid combination and avoid monitoring potassium concentration–>contraindicated). Kidney stones (avoid use-increased risk of triamterene stones). Contraindicated in renal and hepatic impairment.

Adverse effects specific to this combination:

1) Hyperkalemia, hypomagnesemia (Common)

2) Kidney stones (usually with high doses), megaloblastic anaemia (inhibition of dihydrofolate reductase), blood dyscrasias, photosensitivity (Rare)

*Counselling points: Taken once a day in the morning. If patient is taking it twice a day, take the first dose in the morning and second dose before 6pm. DO NOT TAKE POTASSIUM SUPPLEMENTS WHILE ON THIS MEDICATION UNLESS TOLD OTHERWISE BY DOCTOR!!!

-Practice points: Maximum dose in the manufacturer’s product information leads to an unnecessarily high dose of hydrochlorothiazide (100mg) however,no more than 25 mg required daily to treat hypertension

  • Indapamide

Indication: Hypertension (in combination with perindopril)

Practice points: Although still common, the risk of hypokalemia is less than 15mg controlled release tablet than with 2.5mg conventional tablet, their anti-hypertensive is similar.

Acronym: CHITs

3.7 Drug Interactions

Hydrochlorothiazide:

1) Bile acid binding resins (Bile acid binding resins may decrease hydrochlorothiazide absorption and its therapeutic effect. Give resin at least 1 hour before or 4-6 hours after hydrochlorothiazide.

Thiazides:

1) ACE-inhibitors

2) Loop Diuretics

3) NSAIDs-May reduce renal function, reduce diuretic (inhibits synthesis of renal prostaglandins, thus reducing the anti-hypertensive effects) and hypotensive effect and increase risk of nephrotoxicity. *Avoid combination or monitor BP, renal functoin and weight. Adjust dosage accordingly. Low-dose aspirin is unlikely to be a problem.

4) Lithium (All diuretics decrease the clearance of LI+, increases risk of toxicity. *Thiazide diuretics are often prescribed with lithium for lithium-induced diabetes insipidus. Close monitoring required.

*******************************************************************************************************************************************

Potassium Sparing Diuretics

4. 1 Mechanism of action

-Inhibits sodium absorption in the collecting tubules by blocking sodium channels.

-Thus, this interferes with sodium/potassium exchange and reduce urinary potassium excretion.

-Weak diuretics when used alone, may cause severe hyperkalemia especially in the presence of renal impairment or if used with ACE-inhibitors, ARBs, Aldosterone antagonists or potassium supplements.

4.2 Comparative information

  • Amiloride: used to prevent diuretic induced hypokalemia, reduces magnesium loss. It is preferred over potassium supplements because of greater convenience and tolerability.

-Also used in combination with hydrochlorothiazide. The combination products have an unnecessarily high content of hydrochlorothiazide (no more than 25mg needed for hypertension)

  • Triamterene: Similar to amiloride but does not reduce magnesium loss. It also inhibits dihydrofolate reductase and may cause megaloblastic anemia.

-Triamterene only used in combination with hydrochlorothiazide.

4.3 Types of K+ sparing diuretics

1. Amiloride (A milo ride)

Indications: (a) Prevention of diuretic induced hypokalemia. (b) Edema due to heart failure (c) Hepatic cirrhosis or nephrotic syndrome, as an adjunct (used in combination to potentiate effects of other drug) to thiazide or loop diuretic (d) Primary hyperaldosteronism (Accepted indication)

*Can be used in combination with hydrochlorothiazide for hypertension and edema due to heart failure or hepatic cirrhosis.

Precautions:

1) Hyperkalemia (potassium >5mmol/L)-contraindicated

2) Debilitated patients with cardiopulmonary disease or uncontrolled type 1 Diabetes-Increased risk of hyperkalemia and respiratory or metabolic acidosis

3) Treatment with drugs that can increase potassium concentration, e.g. ACE inhibitors (increases risk of hyperkalemia-avoid combination)

4) Contraindications: Renal impaired, Hepatic impaired (Hepatic cirrhosis, hyperchloremic metabolic acidosis, hepatic encephalopathy)-Risk is incresaed when amiloride is used with other diuretics.

5) Elderly. More susceptible to postural hypotension and hyperkalemia.

6) Pregnancy. Avoid use, treatment during pregnancy may result in electrolyte disturbances in fetus (CAT C-AUS)

7) Breastfeeding. Safe to use.

***Always monitor potassium concentration

Adverse side effects associated with amiloride

1) Hyperkalemia

2) Hyponatremia

3) Hypochloremia (especially when combined with thiazide diuretics)

4) Nausea, vomitting, Constipation

5) Impotence

6) Dizziness

7) Muscle cramps

*Listed above are the common side effects

*Infrequent side effects: Diarrhea, anorexia, dry mouth, abdominal pain, flatulence, polyuria, postural hypotension, palpitations (due to hyperkalemia), rashes, joint/muscle pain, increased plasma creatinine

*Rare side effects: Jaundice, eosinophilia, itching, encephelopathy, paraesthesia, increased intraocular pressure

Counselling and Practice Points

-Patient may feel dizzing on standing when taking this medication. Get up gradually from sitting or lying to reduce this effect, sit or lie down if necessary. DO NOT TAKE POTASSIUM SUPPLEMENTS WHILE ON THIS MEDICATION UNLESS TOLD TO DO SO BY DOCTOR!!!

-Amiloride is not required routinely in patients taking thiazide or loop diuretics (Reserve for use if hypokalemia occurs, serum potassium <3.5mmol/L)

-Amiloride is preferred to potassium supplements to prevent diuretic induced hypokalemia because of greater convenience and tolerability

*Can be used in combination with hydrochlorothiazide

4.4 Drug Interactions

1) [Amiloride Specific] NSAIDs-May cause or increase risk of hyperkalemia. Also, it reduces renal function. *Monitor serum potassium and creatinine, particularly in the elderly and patients with renal impairment. Low dose aspirin is unlikely to be a problem\

2) [Triamterene] NSAIDs-Same as above but  appears to be an increased risk of renal impairment when indomethacin is used concurrently. *Monitor serum potassium and creatinine, particularly in the elderly and patients with renal impairment.

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 Class 5: Loop diuretics

5.1 Mechanism of Action

-Inhibits reabsorption of sodium and chloride in the thick ascending limb of the loop of Henle.

-This site accounts for retention of approximately 20% of filtered sodium. Therefore, they are potent diuretics.

*Produce a rapid and intense diuresis and have a short duration of action (4-6 hours). They are effective over a wide dose range with a dose-related response.

5.2 Clinical Indications

1. Edema associated with heart failure

2. Hepatic cirrhosis

3. Renal impairment

4. Nephrotic syndrome (a nonspecific kidney disorder characterised by a number of diseasesproteinuriahypoalbuminemia and edema. It is characterized by an increase in permeability of the capillary walls of the glomerulus leading to the presence of high levels of protein passing from theblood into the urine)

*NOTE NOT INDICATED FOR HYPERTENSION !

5.3 Precautions

1. Allergy to specific loop diuretics -Contraindicated

2. Gout- May be aggravated by diuretic induced hyperuricemia (too much uric acid)

3. Treatment with ototoxic  drugs (damage to the ear)-Use combinations cautiously, especially in renal impairment

4. Electrolyte imbalance

-Contraindicated in severe sodium and fluid depletion

-Concurrent treatment with potassium lowering drugs (hypokalemia may occur) *Careful potassium monitoring required

5. Renal impaired

-Contraindicated in anuria (lack of urine <45ml of urine per day)

-Higher doses of loop diuretics are usually required in impairment. Renal function may worsen. *Careful monitoring of creatinine clearance and electrolyte levels is required.

-Treatment with nephrotoxic drugs (e.g. lithium, cyclosporine) increases risk of nephrotoxicity with loop diuretics.  Use combinations carefully, especially in renal impaired.

6. Hepatic impaired

-In patients with Hepatic impairment, diuretic induced electrolyte imbalance may lead to hepatic encephalopathy.

7. Elderly

-Elderly are more susceptible to electrolyte imblance (e.g. hypokalemia) and postural hypotension.

8. Children

Frusemide is used most commonly. Limited information for ethacrynic acid and bumetanide.

9. Pregnancy *AVOID USE, may cuase electrolyte disturbances in fetuses, possible neonatal thrombocytopenia (CAT C-AUS)

10. Breastfeeding

-Use with caution (unlikley to usppress lactation) ??? Meaning control doses?

5.4 Adverse Effects/Side Effects (Usually dose-related)

1. Electrolyte imbalance (Hyponatremia, hypokalemia, hypomagnesemia)

2. Dehydration (Loss of too much water)

3. Uric Acid accumulation (Hyperuricemia), Gout (may occur)

4. Dizziness, Postural hypotension, Syncope (Associated with rapid loss of blood volume)

*Above are the common ones.

*Infrequent side effects: Dyslipidemia, Increased creatinine concentration, hypocalcemia, rash

*Rare: Tinnitus, vertigo, deafness (especially with rapid IV administration), acute pancreatitis, jaundice, thrombocytopenia, hemolytic anemia, agranulocytosis, interstitial nephritis, exfoliative dermatitis, Stevens-Johnson syndrome, bullous eruptions.

5.5 Comparative information

-Frusemide is the only loop diuretic available in oral and IV formulations

-Bumetanide may be used in patients allergic to furosemide/Frusemide but cross-reactivity may occur.

-Ethacrynic acid can be used in patients allergic to both frusemide and bumetanide but has a greater risk of ototoxicity and other adverse effects

5.6 Counselling points and Practice points

-Medicine should be taken once daily in the morning. If patient is taking it twice a day, take the first dose in the morning and the second dose during lunchtime.

-Patient may feel dizzy upon standing when taking this medicine. Sit down or lie down if necessary.

-Role of loop diuretics in hypertension is limited (thus not indicated) to the management of excess salt and water retention inadequately controlled by other anti-hypertensive treatments.

*Treatment Heart Failure patients

-Start with a low dose then adjust according to clinical response! Use the lowest effective maintenance dose.

-Combine with an ACE-inhibitor

-If hypotension occurs, decrease dose of diuretic before that of the ACE-inhibitor (i.e. Ace-inhibitor prioritised)

-Usually given once daily in the morning although there may be better clinical response if drug is given twice daily (Second dose is midday and diuresis may interfere with sleep if given after 6pm)

-Higher doses necessary in refractory heart failure (defined as symptoms of CHF at rest or repeated exacerbations of CHF despite “optimal” triple-drug therapy)

Consider:Trial of IV frusemide may be more effective than increasing oral doses

Consider: Increase diuretic effect by adding a thiazide diuretic (use small intermittent thiazide doses with careful monitoring, seek specialist advice)

*Monitor weight and electrolytes

-Hypokalemia is less likely when diuretics are used with ACE-inhibitors or ARBs (K+ retention) than when used alone.

5.7 Types of Loop diuretics

  • Bumetanide

Indications: (a) Edema associated with heart failure (b) Hepatic cirrhosis (c) Renal impairment and nephrotic syndrome

*Adverse effects: Myalgia (Rare)

*Note: 1mg bumetanide has a diuretic effect equivalent to 40mg oral furosemide

  • Ethacrynic Acid

Indications: (a) Edema associated with heart failure (b) Hepatic cirrhosis (c) Renal impairment and nephrotic syndrome

*Precautions: Renal Impaired Patients (due to increased risk of ototoxicity, accumulation of ethacrynic acid may occur because of reduced excretion)

*Adverse effects: GI toxicity (nausea, vomitting, diarrhea, GI hemorrhage), hallucinations, inapprorpiate behaviour, mania [All rare adverse effects]

  • Furosemide/Frusemide

Indications: (a) Edema associated with heart failure (b) Hepatic cirrhosis (c) Renal impairment and nephrotic syndrome (d) Severe hypercalcemia (with adequate rehydration) [Accepted indication]

Note: The high ceiling effect of furosemide (substantial diuresis-up to 20%)  makes treatment of edema associated with CHF appropriate but not hypertension.

-Dose equivalence: Oral bioavailability of frusemide is about 50%. However, it may be lower in severe heart failure and renal disease. Thus, individualise dose according to clinical response.

-Administration advice: Avoid ototoxicity by giving IV no faster than 4mg/min.

-Practice points: In acute decompensated heart failure, continuous and bolus infusions appear to be equally effective.

*Bolus infusion:  administration of a medicationdrug or other compound that is given to raise its concentration in blood to an effective level

5.8 Drug Interactions

-Loop diuretics are potentially ototoxic and nephrotoxic. Administratoin with other drugs may add to toxicity.

1) NSAIDs

-Reduce Renal function and may reduce diuretic effect.  Also increases risk of nephrotoxicity, monitor BP, renal function and weight. increase diuretic dose accordingly if NSAID cannot be avoided. Low-dose aspirin is unlikely to be a problem

2) Li+

3) ACE-inhibitors

4) ARBs

5) Thiazide diuretics-Synergistic effect with loop diuretics which may cause profound diuresis and serious electrolyte disturbance. Monitor BP, electrolytes and renal function closely and use small/intermittent thiazide doses.

6) Glucocorticoids- Can amplify hypokalemia produced by loop diuretics.

6) Furosemide Specific Drug Interactions: Sevelamer (drug used to treat high levels of phosphate in blood). Reduce frusemide’s absorption, decreasing its efficacy. Monitor for its clinical effect. Giving it 1 hour before, or 3 hours after sevelamer may minimise interaction. Continue to monitor carefully if trying this approach.

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Class 6: Aldosterone antagonists

Spironolactone

Eplerenone

6.1 Mechanism of action

-Inhibits sodium absorption in distal tubule/collecting tubule by antagonising aldosterone.

-Increases sodium and water excretion. Reduces potassium excretion, weak diuretics (only 0.1-2% of Na+ reabsorbed)

-Aldosterone may contribute to pathophysiology of heart failure by reducing its activity (using Aldosterone antagonists may help)

6.2 Clinical Indications

1) Heart Failure. Aldosterone antagonists improve survival and decrease hospitalisations for heart failure when used with standard treatment

-Spironolactone has been studied in severe (NYHA class III or IV) heart failure and eplerenone in mild heart failure (NYHA class II). No direct comparison trials exist.

-Spironolactone is less expensive than Eplerenone (More appealing to patients?) 

2) Primary Hyperaldosteronism and Refractory edema (Only Spironolactone approved)

-Only spironolactone approved for these indications. Refractory edema associated with secondary hyperaldosteronism (e.g. ascites)

3) Acne and Hirsutism treatment in women.

-Anti-androgenic effects.

6.3 Adverse Effects/Side effects

1) Hyperkalemia (K+ sparing diuretic) especially in renal impairment or if used with ACE inhibitors, ARBs, potassium sparing diuretics or potassium supplements.

2)Endocrine adverse effects (Only for spironolactone, NOT eplerenone) -Gynaecomastia (develop of breasts in men), menstrual abnormalities and sexual dysfunction/impotence.

6.4 Drug Interactions

*Eplerenone is more likely than spironolactone to be affected by drug interactions

*Eplerenone is metabolised by CYP3A4. Thus any drug which inhibits this enzyme will increase eplerenone’s concentration. Any drug which induces CYP3A4 will decrease its concentration, thus decreasing efficacy.

*Consider using spironolactone if necessary or monitor/alter eplerenone doses appropriately.

(A) Spironolactone drug interactions

  • Digoxin (Spironolactone increases digoxin concentration)
  • Low dose spironolactone is used with ACE-inhibitors in patients with severe heart failure but careful K+ level monitoring is necessary.

(B) Eplerenone drug interactions

  • Itraconazole (Anti-fungal) (Inhibits CYP3A4)-Contraindicated
  • Amiodarone (Increases eplerenone’s concentration)
  • Diltiazem (Increases eplerenone’s concentration)
  • Erythromycin (Increases eplerenone’s concentration)
  • Fluconazole (Increases eplerenone’s concentration)
  • Ketoconazole (Greatly Increases eplerenone’s concentration)-Combination is contraindicated, use spironolactone instead
  • Saquinavir (Increases eplerenone’s concentration)
  • Verapamil (Increases eplerenone’s concentration)

6.5 Types of Aldosterone Antagonists

6.5.1 Spironolactone

Indications: (a) Primary hyperaldosteronism (b) Refractory edema associated with secondary hyperaldosteronism (e.g cirrhosis of the liver) (c) Hirsutism in females (d) Heart failure (Accepted clinically)

Precautions

1. Hyperkalemia (potassium <5mmol/L) Contraindicated

2. Debilitated patients with cardio-pulmonary disease or uncontrolled type 1 diabetes (increased risk of hyperkalemia and of respiratory or metbaolic acidosis)

3. Treatment with drugs that increase potassium concentration (e.g. ACE-inhibitors, ARBs) *Avoid combination or monitor potassium concentration.

4. Renal impaired (Contraindicated in renal failure, avoid use in severe impairment)

5. Hepatic impaired (Patients with cirrhosis, spironolactone may cause the following if metabolic derangements occur: Renal failure, hyperchloraemic metabolic acidosis, hepatic encephalopathy).  Risk is greater when spironolactone is used with other diuretics.

6. Pregnancy *Avoid use, may cause feminisation of male fetus (CAT B3-AUS)

7. Breastfeeding-Seems to be safe to use

  • Adverse effects (Spironolactone specific)

– Hyperkalemia, hyponatremia, hypochloremia (especially when combined with thiazide diuretic), weakness, headache, nausea, vomitting, mastalgia (breast pain) [Common]

-GI cramps, diarrhoea, ataxia, drowsiness, confusion, impotence, gynaecomastia, menstrual irregularities, mild acidosis, renal impairment [Infrequent]

-Agranulocytosis, hepatotoxicity, rash, lichen planus, lupus-like syndrome, cutaneous vasculitis, urticaria (hives), alopecia (loss of hair from the head or body), chloasma (facial pigmentation), osteomalacia [Rare]

  • Practice points

*Reserve the use of spironolactone for hirsutism in females for whom other treatments are not suitable.

-In heart failure, spironolactone is used with an ACE-inhibitor, loop diuretic and in some cases Digoxin. 

*Monitor potassium levels each week for the first month, then each month for 2 months, then every 3 months and when indicated clinically.

6.5.2 Eplerenone

Indications: (a) Reduces Risk of cardiovascular death in patients with heart failure and left ventricular impairment within 3-14 days of an acute MI (in combination with standard therapy) (b) Mild heart failure (Accepted indication)

-Special Precautions: Hyperkalemia (potassium levels >5.5 mmol/L)-Contraindicated 

Diabetes and/or proteinuria-Increased risk of hyperkalemia

Important drug interactions  (eplerenone-specific):

1) Ketoconazole, Itraconazole (Contraindicated-CYP3A4 inhibitors)

2) Treatment with drugs that can increase potassium concentration (e.g. ACE-inhibitors, increases risk of hyperkalemia). Potassium-sparing diuretics (Contraindicated)

*Monitor K+ Concentrations

3) Renal impairment (If Creatinine Clearance is <50ml/min, it is contraindicated). (Creatine clearance 30-50ml/min, can be used at lower doses)

*Carefully Monitor K+ Concentrations

4) Hepatic impairment (Contraindicated in severe hepatic impairment)

5) Pregnancy (CAT B3-AUS)

Adverse effects associated:

-Hyperkalemia, hypotension, angina, weakness, vomitting, altered renal function, increased creatinine concentration (Common)

-Orthostatic hypotension, angina, weakness, vomitting and hyponatremia (Infrequent)

Practice points:

-Check potassium concentration at baseline, within 1 week, then 1 month after starting treatment. Adjust dosage accordingly. Then check every 3 months and when clinically indicated.

*Stop treatment or reduce dose if hyperkalemia occurs

***Underutilising or omitting a diuretic is a frequent cause of Resistant hypertension (a type of high blood pressure that does not respond well to traditional medical therapy)