MIDTERM II - Topic 29, 30, 31 and 32

Question 1

29: ANTIARRHYTHMIC DRUGS:

Action potential of the cardiac muscle

1. When is the action potential more specific?
2. You can influence which ion to block that specific channel?
3. What do we call that specific phase?
4. Explain the graph

Answer 1

The development of the action potentials is more specific through the presence of a plateau phase.

• 0 =Opening of Na+ channels, large inward Na+ current.
  
  • This will cause depolarization and initiation of an action potential.
• 1= Opening of K+ channels
• 2= Opening of L-type Ca2+ channels
  
  • A calcium influx and a potassium efflux will then occur (plateau phase).
• 3= Ca2+ channels close, but delayed K+ channels remain open.
  
  • You can influence the potassium ions which are usually released i.e.
    
    • you have an opportunity to block the potassium channel which is why you can influence the refractory phase, this is the effective refractory phase of the heart muscle.
• 4= Na+ and Ca2+ channels closed, Open K+ leak changel

Question 2

29: ANTIARRHYTHMIC DRUGS:

When you have a case of arrhythmia, you can influence ?

Answer 2

• The ion influx or ion efflux.
• We can have a sodium blocker and a potassium channel blocker.

Question 3

29: ANTIARRHYTHMIC DRUGS:

What are the 3 different causes of arrhythmia?

Answer 3

1. Ectopic impulse
2. Cardiomyopathy
3. Re-entry.

Question 4

29: ANTIARRHYTHMIC DRUGS:

What are the 3 different causes of arrhythmia?

1. ECTOPIC IMPULSES

Answer 4

• When there is a problem with impulse initiation i.e.
  
  • SA-Node
  • AV-node,
  • Bundle of his
  • Trabecular fibres.
• Initiation disturbances of the heart could be
  
  • homotropic or
  • heterotropic impulse initiation disturbances.
• Ectopic impulse means that the
  
  • Normal cardiac rhythm will be disturbed via heterotropic impulse disturbance.
    
    • Something stimulates and disturbs the normal automacy of the heart
      
      • leading to an
        
        • extra beat
        • systole
        • possibly ventricular fibrillation.

Question 5

29: ANTIARRHYTHMIC DRUGS:

What are the 3 different causes of arrhythmia?

2. CARDIOMYOPATHY

Answer 5

• This can be
  
  1. Congestive
  2. Hypertrophic.
• Boxers and German shepherds (large breeds) are examples of breeds that are usually affected by this.

1. Congestive myopathy,
   
   1. the ventricular node is very thin i.e.
      
      1. there will not be enough contractility.
2. Hypertrophic cardiomyopathy,
   
   1. the ventricular wall is very thick i.e.
      
      1. there is no room for saturation.

• These are usually accompanied by developmental arrhythmia.

Question 6

29: ANTIARRHYTHMIC DRUGS:

What are the 3 different causes of arrhythmia?

3. RE-ENTRY

Answer 6

• This means that in the normal rhythm of the heart
  
  • ​Initiated by either SA or AV node,
  • Impulse will go down
  • When they meet each other, they will DIE OUT
    
    • This is the refractory period.
• When there is a re-entry,
  
  • There will be a necrotic myocardial part which means the
    
    • impulse propagation or
    • initiation will suffer i.e.
      
      • conductance will not be appropriate.
  • After this refractory period, there will be
    
    • re-excitation,
      
      • meaning another impulse will occur
      • which can cause arrhythmia.

Question 7

29: ANTIARRHYTHMIC DRUGS:

Additional causes for arythmia is

Answer 7

1. Drugs
2. Electrolyte balance
3. Primary causes

Question 8

29: ANTIARRHYTHMIC DRUGS:

Additional causes for arythmia is

1. Drugs causing arrythmia

Answer 8

• Drugs that can cause arrhythmia include
  
  • ADRENALINE or
  • Antiarrhythmic agents e.g.
    
    • AMIODARONE can cause arrhythmia itself because it is proarrhythmogenic.
• If you use certain antiarrhythmic agents with normal patients, then they can
  
  • induce arrhythmia i.e.
  • you must be careful when diagnosing arrhythmia patients.

Question 9

29: ANTIARRHYTHMIC DRUGS:

Additional causes for arythmia is

2. ELECTROLYTE IMBALANCE

Answer 9

• You must pay attention to the potassium and calcium imbalances before you apply the antiarrhythmic agents.
• In the case of LIDOCAINE, potassium supplementation is necessary

Question 10

29: ANTIARRHYTHMIC DRUGS:

Additional causes for arythmia is

3. PRIMARY CAUSES

Answer 10

. There are also a number of primary causes which can cause arrhythmia as well.

Question 11

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

Answer 11

Question 12

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP I

Answer 12

Group I.

• These are sodium channel blockers
• Stabilise the membrane.
• These are broken up into:

1. I.A.
   
   1. QUINIDINE,
   2. PROCAINAMIDE
2. I.B.
   
   1. LIDOCAINE,
   2. MEXILETINE
3. I.C.
   
   1. FLECAINIDE

• The difference between these groupings is that the
  
  • ERP (effective refractory period) will be different.
    
    • For group I.A.,
      
      • it can enhance the ERP.,
    • I.B.
      
      • can shorten the ERP and
    • I.C.
      
      • will not influence the ERP.
  • There is also a difference in the amplitude of the action potentials

Question 13

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP I

IA

QUINIDINE

Species?

Treatment of?

Effect?

Contra indications?

Side effects?

Route of administration?

Side effects in a particular species?

Answer 13

Quinidine:

• This is usually applied to horses to treat supraventricular/atrial arrhythmia.
• This is important because the horse will have a huge atrium.
• Quinidine has a vagal effect i.e.
  
  • atropine-like effect and
  • it will have a negative inotropic effect i.e.
    
    • contractility of the heart will be weakened.
• This is why this drug should not be applied in heart failure.
• The side effects include
  
  • gastrointestinal and
  • cardiovascular problems e.g.
    
    • hypertension
      
      • because it will dilate the blood vessels.
  • Atropine can also cause tachycardia.
  • It has a short half-life i.e. it is applied frequently.
• It can be administered i/v or orally.
• When used in the horse, various side effects can occur e.g.
  
  • mucosal membrane swelling,
  • laryngeal oedema,
  • excitation as a CNS effect or it can also
  • rarely cause hypertension.

Question 14

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP I

IA

2. PROCAINAMIDE

1. Administration route
2. Side effect
3. Quinidine vs Procainamide

Answer 14

Procainamide:

• This can be administered orally or parenterally.
• Its side effect is a
  
  • negative inotropic effect i.e.
    
    • cannot be administered to heart failure patients.
    • It has similar side effects.
• The difference is that
  
  • QUINIDINE is used for supraventricular arrhythmia in horses
  • PROCAINAMIDE is used in cases of ventricular arrhythmia when LIDOCAINE is not working.

Question 15

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP I

IB

LIDOCAINE

Used in?

Advantageous due to

Supplementation especially In which cases

1st choice due to?

Route of administration

Species sensitive to Lidocaine?

Side effects?

Side effect treated with witch drug?

Answer 15

Lidocaine:

• This is used in ventricular arrhythmia.
• Its advantage is that it does NOT have a negative inotropic effect i.e.
  
  • can be given in case of heart failure patients.
• Because hypercalcemia will reduce its effect,
  
  • Potassium supplementation is necessary.
  • This means that you have to use potassium infusion.
    
    • This is important as in the cases of life-threatening arrhythmia,
• First choice is due to the fact that the muscle will react to lidocaine when it is damaged.
• It is not administered orally but i/v.
• Cats are very sensitive to lidocaine, this is why they have a different dose (0.25-0.75 mg/kg i/v then continuous infusion) to dogs (2-4 mg/kg loading dose, then continuous infusion).
• The side effects include (especially in the case of cats)
  
  • CNS effects,
    
    • as lidocaine can penetrate the BBB
      
      • Cause:
        
        • dizziness,
        • excitation,
        • tremors and
        • convulsion i.e.
          
          • it is treated with DIAZEPAM.

Question 16

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP I

IB

MEXILETINE

1. Substitute to which drug?
2. Administration route makes it possible to?
3. Used in?
4. Bioavailability?
5. Side effects?
6. Used in combinations with?

Answer 16

Mexiletine:

• This drug is an oral substitute to LIDOCAINE i.e.
  
  • they are very similar.
• Due to the fact that this drug can be administered orally, it is used as long-term therapy.
• It is used in:
  
  • Ventricular arrhythmia,
  • Congestive myopathy
  • Hypertrophic cardiomyopathy.
• It can be given orally with a very good bioavailability of more than 80%.
• Side effects are similar to that of lidocaine however this drug is superior in that respect.
• It is combined with beta-blockers frequently.

Question 17

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP II

1. Type of blocker
2. Selectivity
3. Effect
4. Used as
5. Heartrate effect in case of beta-blockers
6. Poisoning
7. Overstimulating adrenal gland
8. Chronic?
9. The Final result of these drugs?
10. Impulse propagation problems and contraindications

Answer 17

• These are beta-blockers.
• These can be selective or non-selective i.e.
  
  • Difference in specificity.
• They have a negative chronotropic effect i.e.
  
  • they slow down the heart (bradycardia).
• These can be used as
  
  • Anti-hypertensive agents
    
    • to decrease the blood pressure
  • Against arrhythmia (class II. beta-blockers).
  • Applied in connection to ventricular and supraventricular arrhythmia, in HCM in order to counteract the high blood pressure,
  • Good in cases of hyperthyroidism which is due to excessive sympathetic tone (usually seen in older cats) and we recognize this through a fast heart rate.
• When we use beta-blockers, we can slow down the heart. We can also use these in cases of methylxanthine poisoning e.g.
  
  • Theobromine presence in chocolate.
• In dogs and cats, the half-life of theobromine is much longer than that in humans.
• It can also be used in cases of pheochromocytoma, which is mainly seen in dogs.
  
  • It originates from an overstimulation of the adrenal medulla and a lot of adrenaline and noradrenaline will be present, leading to a hypertonic crisis.
• They can also be used in chronic hypertension.
• The final result of these drugs is severe bradycardia.
• It also causes impulse propagation problems in connection with the AV-node i.e.
  
  • When the impulse is not conducted appropriately from atrium to ventricle, do not use these drugs.

Question 18

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP II

1. Generations
2. Name of drugs
3. Which to preffer
4. Influence which receptor
5. Causing which effect?
6. Combinations?

Answer 18

1. The 1st generation is BETA-1 and BETA-2 blockers
   
   1. ​PROPRANOLOL
      
      1. This means that they will influence beta-2 receptors also, causing
         
         1. bronchoconstriction i.e.
            
            1. they cause asthmatic attacks.
2. We prefer to use 2nd generation beta-blockers
   
   1. METOPROLOL
   2. ATENOLOL
   3. ESMOLOL
      
      1. As they only influence beta-1-receptors.
      2. These can be used in combination with MEXILETINE.
3. The 3rd generation beta-blockers
   
   1. CARVEDILOL
      
      1. ​ Have a slowly developing effect i.e.
         
         1. Begin with a low dose that we slowly begin to elevate.
         2. These are also used as an antioxidant agent.

Question 19

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP III

What type of blocker

ERP

How to avoid excitation due to Re-entry?

Name drugs

Answer 19

Group III.

• These are potassium channel blockers.
• The ERP will be influenced i.e.
  
  • these can be used in cases of re-entry
    
    • ​Can cause arrhythmia.
      
      • By prolonging the ERP, we can avoid the excitation brought on by re-entry.

1. SOTALOL
   
   1. This can be used for a longer period in cases of
      
      1. boxer cardiomyopathy.
   2. It is mainly used in ventricular arrhythmia.
2. AMIODARONE:
   
   1. This can be used in connection with
      
      1. ventricular and
      2. supraventricular arrhythmia.

Question 20

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP III

AMIODARONE:

1. Used in connection with
2. Effect on the
3. Technically it belongs to which group, but….?
4. Side effect
5. Class II effect
6. Class I effect

Answer 20

AMIODARONE:

• This can be used in connection with
  
  • ventricular
  • supraventricular arrhythmia.
• This drug has an effect on the
  
  • Sodium channels (I effect)
  • Beta receptors (II effect)
  • Calcium channels (IV effect) i.e.
    
    • it technically belongs to groups I-IV however, its most significant effect is on the potassium channels (III effect).
• Liver toxicity can occur.
• In connection to its class II effect,
  
  • it can cause a decrease in blood pressure and
• in connection with its class, I effect,
  
  • it will have an anti-vagal effect.

Question 21

29: ANTIARRHYTHMIC DRUGS:

Vaughan-Williams conductance GROUPING

GROUP IV

1. Type of blockers
2. Cause
3. Effect
4. Used in
5. If we block channel, what happens?
6. When to use it?
7. Dihydropyridine type?
8. Non-dihydropyridine?

Answer 21

Group IV.

• These are calcium channel blockers and
  
  • they can cause bradycardia.
• They have a negative chronotropic effect.
• They are used in supraventricular arrhythmia.
• If we block the calcium channel,
  
  • There will be no calcium influx i.e.
    
    • The contractability will be decreased.
  • The blood vessels will be dilated (vasodilation).
  • This is why these can be used
    
    • in cases of high blood pressure.
• If we have dihydropyridine type,
  
  • The blood vessels will be affected
  • Vasodilation will occur

1. AMLODIPINE
2. NIFEDIPINE
   
   • These can be used as an anti-hypertensive agent.
   • AMLODIPINE is used to treat hypertensive in cats orally.

• Non-dihydropyridine type arrhythmia affects the heart

1. VERAPAMIL
2. DILTIAZEM

• Are not used to decrease blood pressure but in cases of arrhythmia.
• Verapamil and diltiazem are negative inotropic drugs i.e.
  
  • Cannot be used in cases of heart failure.

Question 22

30: HEART FAILURE

Congestive heart failure (CHF) can be broken up into?

Answer 22

1. Acute heart failure or
2. Chronic heart failure.

Question 23

30: HEART FAILURE

Congestive heart failure (CHF)

The cause of Acute heart failure

Answer 23

• Sudden deterioration of the heart pump function e.g.
  
  • myocardial infarction,
  • ventricular fibrillation.

Question 24

30: HEART FAILURE

Congestive heart failure (CHF)

The cause of Chronic heart failure

Answer 24

Chronic heart failure can be brought about by gradual and slow deterioration in the heart pump function and performance.

1. The first reason for chronic heart failure is endocarditis which is the
   
   1. degeneration of the valves in the heart and is mainly seen frequently in
   2. small breeds of dogs or cats.
2. The other reason for chronic heart failure is cardiac myopathies,
   
   1. either dilated or
   2. hypertrophic.
3. These diseases affect the heart morphology and anatomy.
4. Another cause of chronic heart failure, because of the
   
   1. enlargement of the heart = > arrhythmias.
   2. This affects large dogs.

Question 25

30: HEART FAILURE

Congestive heart failure (CHF)

1. Final effect
2. Drugs help to
3. What can we do pharmacologically

Answer 25

1. The final effect is that the heart performance is decreased.
2. The drugs applied can affect contractility to help.
3. Pharmacologically,
   
   1. Increase contractility
   2. Decrease preload

INCREASE CONTRACTILLITY

DECREASE PRELOAD

• Burden that falls onto the heart as water i.e.
  
  • Water amount that flows onto the heart will put a
    
    • Burden on the heart,
    • Expand it and
    • Decrease performance
      
      • if the heart is not healthy and able.

Question 26

30: HEART FAILURE

Congestive heart failure (CHF)

Decreasing preload

Answer 26

• Decreasing preload means that we
  
  • decrease the expansion.
• For this purpose, we use diuretics (FUROSEMIDE)
  
  • Because they remove excess water from the body via
    
    • Urination.

Question 27

30: HEART FAILURE

1. Preload and afterload effect on the heart
2. In addition, we can also influence?
3. What will happen?
4. Why would we do that?

Answer 27

• The preload and afterload do not usually affect the heart.
• In addition, we can also
  
  • INFLUENCE the FREQUUENCY. but this will
    
    • Not significantly increase performance
      
      • Increase this, filling the heart with blood will not be as efficient.
  • This will increase oxygen consumption which is not good for the heart and this is only used in life-threatening situations e.g.
    
    • ADRENALINE,
    • NORADRENALINE or
    • DOPAMINE
  • to increase frequency to save the animals life.

Question 28

30: HEART FAILURE

Congestive heart failure (CHF)

After load as a affecting factor

Answer 28

• This is the other burden on the heart.
• It is the vasoconstriction of the blood vessels
  
  • Forces the heart to pump against a resistance
    
    • which causes peripheral resistance.
• For the purpose of preventing this afterload,
  
  • we use VASODILATORS

Question 29

30: HEART FAILURE

Factors affecting HEART PERFORMANCE?

Answer 29

1. CONTRACTILITY
2. AFTER-LOAD - Peripheral resistance
3. PRELOAD - Blood inflow into ATRIA

+ FREQUENCY

Question 30

30: HEART FAILURE

How to treat Congestive heart failure (CHF)

Answer 30

Several options!!

1. In life-threatening cases, we can
   
   1. increase the FREQUENCY of the heart
      
      1. This will exhaust the heart.
      2. It is only helpful for a handful of minutes but after that it deteriorates the heart.
2. ​A better way includes
   
   1. Increasing the CONTRACTILLITY.
   2. This is done through digitalis glycosides
      
      1. Plant-origin toxic substances
3. Decrease the PRELOAD and AFTERLOAD with the
   
   1. Angiotensin-converting enzyme (ACE) inhibitors
4. ​The most effective drugs for CHF
   
   1. PHOSPHODIERTERASE (PDE) inhibitors
      
      1. ​. These affect
         
         1. contractility,
         2. preload
         3. afterload
5. The last group are the vasoactive substances.
   
   1. These are the VASODILATORS i.e.
      
      1. they only decrease AFTERLOAD.
      2. They are used very infrequently
         
         1. e.g. NITROGLYCERIN which is a very potent vasodilator,
         2. mainly decreasing the AFTERLOAD.
6. We can also use DIURETICS,
   
   1. mainly FUROSEMIDE.
   2. These are used very frequently to
      
      1. decrease the PRELOAD of the heart

Question 31

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Answer 31

Positive inotropic drugs, cardiotonics:

• In cases of acute heart failure, we administer I/V

1. ​EPINEPHRINE,
2. ADRENALINE,
3. DOBUTAMINE,
4. DOPAMINE

• Only used in life-threatening situations.
• In chronic heart failure,

1. CARDIOTONICS such as
   
   1. DIGITALIS GLYCOSIDES
   2. PIMOBENDAN (PDE inhibitors).

• Cardiotonics reduce contractility, this is why they are also known as positive inotropic drugs.

Question 32

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

Answer 32

Digitalis glycosides:

• These are very old drugs derived from plants.
• Cardiac glycosides.
• Very active and very toxic.
• The two plants that we know of are

1. DIGITALIS PURPUREA (which contains digitoxin) and
2. DIGITALIS LANATA (which contains digoxin).

Question 33

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGITOXIN VS DIGOXIN

Answer 33

• DIGITOXIN is mainly used in human medicine because of pharmacokinetic problems e.g.
  
  • too short or
  • long of a half-life.
• DIGOXIN is used in the veterinary field but very
  
  • infrequently because of its toxicity.
  • It is used only in a special case

Question 34

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGITOXIN VS DIGOXIN

Mechanism of action!

1. Inhibition of which enzyme
2. Inhibition of the action lead to
3. Lead to what in the heart
4. Increasing what

Answer 34

• DIGOXIN and DIGITOXIN inhibits the
  
  • Na+/K+ ATPase enzyme
  • Responsible for sodium efflux and potassium influx.
• If this action is inhibited,
  
  • Sodium will remain inside the cell
    
    • Pump that allows a
      
      • Sodium influx
      • Calcium efflux,
    • will NOT function.
  • This means that calcium will also remain in the cell
    
    • Leads to an increased calcium level in the heart muscle i.e.
      
      • increased myofibrillar action and an
      • increased myofilament contraction of the heart that will, in turn,
        
        • increase CONTRACTILLITY

Question 35

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGITOXIN VS DIGOXIN

Side effect is that if you inhibit the Na+/K+ ATPase pump

Answer 35

• Then potassium cannot enter the heart muscle
  
  • which leads to hypokalemia.
• If hypokalemia is already present in the blood,
  
  • Enhance the side effects of the digitoxin/digoxin.
• This is why it is necessary to measure the potassium levels prior to application.

Question 36

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGITOXIN VS DIGOXIN

The pharmacological effects

Answer 36

• Include positive inotropic effect i.e.
  
  • Cardiac output will increase
    
    • Improve the renal blood flow which in turn,
      
      • increases water and Na+ excretion i.e.
        
        • Mild diuretic action.

This is why we can also see a small decrease in preload.

• These toxins are NOT used for their positive inotropic effect due to their toxicity
  
  • They also have an alternative effect
    
    • increase the vagal tone
      
      • which leads to a
        
        • negative chronotropic and
        • dromotropic effect.
  • This means that they
    
    • slow down the heart
    • increase the threshold of the heart.

This is why it is used as an antiarrhythmic

• Against atrial fibrillation (a very significant increase in the frequency of the atria).

Question 37

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGOXIN

1. Administration
2. Protein binding
3. Absorbtion
4. Similar to which drugs
5. Excreeted in? Contra indication?!
6. Safety?
7. Before and after administering

Answer 37

• Digoxin is given orally as a tablet.
• It has a high protein binding
  
  • Leads to interactions with other drugs.
  • NSAIDs, glucocorticoids or FUROSEMIDE have very high protein binding which means that,
    
    • if administered with digoxin, will compete for the binding of the protein albumin i.e.
    • they will show toxic interactions.
• Digoxin is accumulated in myocytes and heart muscle cells
• Has a very large individual difference in connection to absorption.
• Similarly to PHENOBARBITAL and POTASSIUM BROMIDE,
  
  • individual differences were large i.e.
    
    • taking blood and measuring the plasma content of digoxin is
      
      • recommended after 3-5 days.
• Excreted by the urine so it is not recommended in renal failure cases.
• The drug has a small therapeutic index
  
  • ​making it very toxic.
  • This toxicity is enhanced by the pre-existence of hyperkalemia in the blood.
• Before administering this drug, we take blood from the animal to check
  
  • renal function,
  • potassium levels and
  • plasma levels
    
    • after 3-5 days i.e. monitoring of the animal is necessary.

Question 38

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGOXIN

Side effects

Answer 38

The side effects of this drug include arrhythmias and bradycardia (due to its negative chronotropic effect). If you give too much digoxin, the heart will slow down very significantly. If this happens, the heart tries to escape and put in an ‘escape beat’.

These escape beats can be so frequent that they can lead to arrhythmias which can be treated with LIDOCAINE. The antidote to digoxin overdose is called DIGIBIND. It is used mainly in humans. Digoxin is used for atrial arrhythmias but if you overdose it, the heart will slow down so significantly that it will cause ventricular fibrillation which can be life threatening. This drug also causes significant vomiting i.e. extracardiac side effects are also very frequent.

It is used to prolong the survival time in heart failure but this use is very infrequent. It is used mainly in supraventricular (atrial) tachyarrhythmias (very frequent contractions of the atria) because of its negative chronotropic and dromotropic effect.

Question 39

30: HEART FAILURE

Positive inotropic drugs, cardiotonics:

Digitalis glycosides:

DIGOXIN

Contra indications

Answer 39

Its contraindication, as well as hyperkalaemia, is outflow obstruction of the heart which means that when the blood cannot leave the heart normally e.g. in cases of hypertrophic cardiomyopathy (HCM) or aortic stenosis. This is because if you increase the contractility yet the blood is unable to leave the heart, exhaustion of the heart will occur. This obstruction can be seen in an ultrasound i.e. as well as monitoring the blood concentrations, we must also take an ultrasound before digoxin administration. Its dose is 5-10 μg/kg orally BID. Because of the accumulation in the heart muscle cells, we have the option to give digoxin 6 days a week with 1 day rest to eliminate this unnecessary amount via the kidney. This aids in maintaining the safety when given this toxin.

Question 40

30: HEART FAILURE

PDE Inhibitors for the treatment of heart failure?

Name of drug?

Answer 40

PDE Inhibitors:

1. PIMOBENDAN (NB NB NB)

• This is the most important heart failure treatment drug for companion animals.
• It is commercially known as VETMEDIN.

Question 41

30: HEART FAILURE

PDE Inhibitors:

PIMOBENDAN (NB NB NB)

Mechanism of action

Answer 41

• This has multiple mechanisms of action.
  
  • Firstly, it inhibits the PDE3 enzyme in the heart muscle which will cause an
    
    • accumulation of cAMP in the myocardial cells which will cause an
    • Increase in calcium concentration,
    • Leading to a positive inotropic effect.
• This is the most important effect of this drug.
• We have a large amount of PDEs in the body,
  
  • the blood vessels included as PDE4 and 5.
• These have different function of vasodilation.
• This arterial and venous dilation will lead to a
  
  • decrease in preload, due to dilation in vessels,
  • causing a peripheral resistance and this
  • dilation will decrease the amount of water in the vessels i.e.
    
    • water in the heart, and
    • afterload.
• This means that all 3 attack points in heart failure are affected;

1. Increase in contractility
2. Decrease in preload
3. Decrease in afterload.

• In addition, in the heart muscle, it also acts as a
  
  • calcium sensitizer which means that the
    
    • myofilaments have a higher affinity to calcium than before
    • Bind calcium better
    • leading to a positive inotropic effect
    • as well as an increase in calcium.
• It is much more effective and much safer than digoxin.
• It is known as an inodilator due to its positive inotropic effect and vasodilator.
• This is the only inodilator we use and is the
  
  • most effective drug in cases of heart failure.
• Frequency is not affected as vasodilation will not increase the oxygen consumption by the heart i.e.
  
  • exhaustion will not occur.

Question 42

30: HEART FAILURE

PDE Inhibitors:

PIMOBENDAN (NB NB NB)

Contraindication

Answer 42

• This drug is contraindicated in outflow obstruction (HCM, stenosis) i.e.
• must perform an ultrasound before administration.

Question 43

30: HEART FAILURE

PDE Inhibitors:

PIMOBENDAN (NB NB NB)

Route of administration

Answer 43

• We administer this drug orally and
  
  • must be given one hour before meal
    
    • ​as feeding decreases its absorption
    • but can also cause vomiting.
• It also has an extensive protein binding like digoxin, so
  
  • must not be administered with other high protein binding substances e.g.
  1. FUROSEMIDE,
  2. NSAIDs or
  3. digoxin etc.

Question 44

30: HEART FAILURE

PDE Inhibitors:

PIMOBENDAN (NB NB NB)

Side effects

Answer 44

• Its side effects are very rare which are mainly
  
  • gastrointestinal
    
    • vomiting,
    • diarrhea.

Its dose is 0.1-0.3 mg/kg BID orally.

It is given twice a day due to its relatively short half-life.

Question 45

The most effective drug in cases of heart failure?

Answer 45

PIMOBENDAN

Question 46

31A: PHARMACOLOGY OF VOLUME REGULATION:

ACE Inhibitors:

1. Saafety
2. Prototype of these drugs
3. Mechanism of action
4. Indication

Answer 46

ACE Inhibitors:

• These are very safe but not as effective as PIMOBENDAN.
• The prototype of these drugs is CAPTOPRIL
  
  • Isolated from snake venom.
• Its mechanism of action is the
  
  • RAAS = renin-angiotensin-aldosterone system.
  • If the renal blood flow decreases (due to dehydration or blood loss),
    
    • System is stimulated that help maintain homeostasis and retain water in your body.
    • This happens through the release of renin from the kidney.
    • The enzyme will convert angiotensin to angiotensin-I.
    • Angiotensin is produced in the liver.
    • Angiotensin-I will be converted by the angiotensin-converting enzyme (ACE) to angiotensin-II
      
      • ​which will help to maintain a water balance in the body.
  • This happens by causing vasoconstriction to stabilise the blood pressure.
  • Aldosterone retains sodium,
  • ADH (antidiuretic hormone)
    
    • retains water and the
    • salt hunger and
    • thirst
      
      • ​will force you to find water and sodium ions.
  • The same thing happens if you are suffering from heart failure as if the heart cannot pump properly, the renal blood flow will be decreased and this mechanism will be stimulated.
• The indications for these drugs are
  
  • heart failure (species specific),
  • hypertension
  • proteinuria.

Question 47

31A: PHARMACOLOGY OF VOLUME REGULATION:

ACE Inhibitors:

In heart failure, if this system is stimulated,

ACE

Answer 47

• Vasoconstriction will cause an increased afterload,
• Aldosterone and ADH will retain water,
• Thirst will keep water in the body

All increase the preload.

• This is why, in heart failure,
  
  • ACE inhibitors are used to counteract these effects.

ACE inhibitors will cause arterial vasodilation

• which leads to Peripheral resistance and a
• Decrease in afterload.
• It also causes venous dilation which
  
  • Decreases the central venous pressure (CVP) to decrease the afterload.
• They also have a diuretic effect of increasing water excretion
  
  • ​which, again, decreases the preload.

These drugs do not alter contractility but their actions are still excellent at increasing heart performance as well as decreasing blood pressure.

Question 48

31A: PHARMACOLOGY OF VOLUME REGULATION:

ACE Inhibitors:

EXPLAIN PICTURE

Answer 48

1 = RENIN

2 = ACE

A = VASOCONSTRICTION (20x ephinephrine)

B= ALDOSTERONE

C= ADH

D= Salt hunger, thirst

E= BRADYKININ

Question 49

31A: PHARMACOLOGY OF VOLUME REGULATION:

Pharmacokinetics

1. Route of administrtation, with one exeption
2. Metabolism
3. Most important drugs
4. Requirement for activation
5. Onset of action
6. Contraindications
7. Duration of action
8. Side effects
9. Safety

Answer 49

Pharmacokinetics:

• Oral administration of these drugs leads to good absorption, the exception being
  
  • CAPTOPRIL which has a bad absorption that is why it is an out-of-date drug and is no longer used.
• They are metabolized in the liver and are prodrugs i.e.
  
  • Need to be activated in the liver.
• Our most important drugs are

1. ENALAPRIL,
2. BENAZEPRIL,
3. RAMIPRIL

​ and they are activated in the liver into

1. ENALAPRILAT,
2. BENAZEPRILAT,
3. RAMIPRILAT.

• In order for this activation to occur, we require a well functioning liver.
• Because of this activation, onset of action is slow (approx. 4-6 hours).
• This means that these are not administered in life threatening cases i.e.
  
  • Acute heart failure,
• Used for chronic heart failure.
• The duration of action is relatively long (12,14 even 24 hours).
• This is why these drugs are given once or twice a day.
• BENAZEPRIL and LISINOPRIL have a longer duration of action and are usually given SID
• RAMIPRIL and ENALAPRIL are given BID.
• Lisinopril is not a prodrug and does not require activation in the liver i.e.
  
  • it can be used in patients who suffer from liver patients.
  • Those patients who have proteinuria for treatment but are in
    
    • hepatic failure, are treated with lisinopril.
• Excretion is via the kidney
  
  • ​but BENAZEPRIL is also excreted by the bile.
• In renal failure cases,
  
  • benazepril’s dose should not be decreased as it can escape from the bile.
• Other drugs need the kidney as their primary excretion route i.e.
  
  • if the patient has chronic renal failure, these drugs require a dose decrease.
• The side effects of these drugs are very rare i.e.
  
  • these are very safe drugs.
  • A very important side effect is AZOTAEMIA
    
    • which is when urea creatinine levels rise.
    • This is because, in the case of proteinuria, these drugs decrease the glomerular pressure and the efficacy of filtration will be lowered.
    • This is beneficial for proteinuria but for other substances it might not be.
    • This is how azotemia can occur.
• This means that the kidney parameters must frequently be checked for this issue.
• The LD50 is very high (100-200 mg/kg) and the normal dose of these drugs is 0.25-0.5 mg/kg i.e. it is very difficult to overdose these drugs.
• Blood biochemistry is critical to monitor, especially in the first few weeks.
• Hypotension is also a side effect, resulting in
  
  • tiredness and
  • faintness.
• Humans are much less sensitive than dogs.
• This side effect is what allows for vasodilation and water excretion.
• This tiredness and faintless leaves within a few days.
• GI disturbances (anorexia, diarrhea, vomiting) can occur but this is extremely rare.
• In humans, a dry cough can occur due to a lack of bradykinin inactivation.

Question 50

31A: PHARMACOLOGY OF VOLUME REGULATION:

Pharmacokinetics

Drugs

Answer 50

1. Captopril:
2. Enalapril:
3. Ramipril:
4. Benazepril:
5. Lisinopril:

Question 51

31A: PHARMACOLOGY OF VOLUME REGULATION:

Pharmacokinetics

Drugs

• Captopril:

Answer 51

This drug is no longer used as it has a short half-life bad absorption.

Question 52

31A: PHARMACOLOGY OF VOLUME REGULATION:

Pharmacokinetics

Drugs

1. Enalapril:
2. Ramipril:

Answer 52

• Enalapril: 0.5 mg/kg.
• Ramipril: 0.125 mg/kg BID or SID.
• These two drugs are excreted mainly via the urine.
• When we are treating cases of proteinuria, there is usually a deficiency in the kidney i.e.
  
  • renal failure.
• This is why these dosages should be decreased in these drugs.

Question 53

31A: PHARMACOLOGY OF VOLUME REGULATION:

Pharmacokinetics

Drugs

Benazepril

Answer 53

Benazepril: 0.25-0.5 mg/kg.

• This drug is also excreted in the bile i.e.
  
  • Dose should not be decreased in renal insufficient patients.
  • This is the preferred substance for these cases.
  • SID administration is preferred.

Question 54

31A: PHARMACOLOGY OF VOLUME REGULATION:

Pharmacokinetics

Drugs

Lisinopril:

Answer 54

Lisinopril:

• This drug is not activated in the liver
  
  • Preferred drug in cases of hepatic failure patients
    
    • Require ACE inhibitors e.g.
      
      • proteinuria with liver failure,
      • Hypertension with liver failure etc.

Question 55

31A: PHARMACOLOGY OF VOLUME REGULATION:

Angiotensin II receptor (AT II) antagonists:

Answer 55

Angiotensin II receptor (AT II) antagonists:

• These drugs do not involve enzymatic activity i.e.
  
  • They do not inhibit ACE.
  • Instead, they directly antagonise angiotensin II
    
    • Pharmacological effects are the same
      
      • because ACE inhibitors also decrease angiotensin II levels.
• These drugs are more specific and do not affect bradykinin levels i.e.
  
  • coughing is much less frequent.
• They are more active and more effective and are used much more frequently in cases of
  
  • hypertonia (elevated blood pressure) and
  • proteinuria.

Question 56

31A: PHARMACOLOGY OF VOLUME REGULATION:

Angiotensin II receptor (AT II) antagonists:

Drugs

Answer 56

These drugs are known as

1. LOSARTAN,
2. VALSARTAN in human medicine and for us,
3. TELMISARTAN.

• These drugs are also administered orally.
• If proteinuria does not vanish and foam is seen on top of the urine (protein),
  
  • then these can be administered in combination with ACE inhibitors.
  • However, when these drugs are combined, there is a higher risk of azotaemia to occur.
    
    • This is because, when combined, these drugs are more active against proteinuria i.e.
      
      • they are also more active against a glomerular pressure decrease.

This is why we regularly check the kidney parameters.

Question 57

31B: PHARMACOLOGY OF VASOREGULATION:

Answer 57

• Calcium channels are allowing for a Ca2+ influx which will bind to calmodulin which will then activate the MLCK (myosin light chain kinase).
  
  • This enzyme phosphorylates the MLC which allows for muscle contraction.
• If you require a drug that causes vasodilation
  
  • (usually the case in heart failure),
  • then we must inhibit this process.
• We use CA2+ channel inhibitors to do this.

The other side of relaxation is

• Modulated by nitrogen monoxide which elevates cGMP levels
  
  • which will increase MLCP (myosin light chain phosphatase)
    
    • which will remove the phosphate group from the activated MLC to inactivate it.
• This causes vasorelaxation (vasodilation).
• In order to cause vasodilation,
  
  • we can administer Ca2+ blockers or NO donors.

Question 58

31B: PHARMACOLOGY OF VASOREGULATION:

Organic nitrates:

Answer 58

Organic nitrates:

• These donors are organic nitrates e.g.

1. NITROGLYCERINE
   
   • Which causes a nitrogen monoxide release,
   • Resulting in very good arterial and venous dilation
   • Which then decreases the afterload and preload.
   • There will be a very pronounced dilation in the mesenteric veins and the blood can flow from the lungs to the mesenterial veins i.e.
     
     • Life threatening effect of pulmonary oedema in patients of acute heart failure will vanish and this is why these drugs are used in those patients.

• This drug decreases preload, afterload, and myocardial oxygen consumption and dilates the coronary arteries.
• This helps the oxygen and energy supply of the heart.
• This drug is applied topically usually.
• Orally, it has a very pronounced first pass effect i.e.
  
  • has bad absorption via destruction in the liver.
• ​ We can give it i/v or sublingually but it is very infrequent.
• It is usually given as a transdermal patch and topically on very thin skin layers e.g.
  
  • ear,
  • thoracic wall and
  • abdomen.
• It has a very short half-life i.e.
• Used infrequently in life threatening cases such as acute heart failure or a chronic heart failure that has been decompensated e.g.
  
  • Patient of heart failure that exercises in heat.

Question 59

31B: PHARMACOLOGY OF VASOREGULATION:

Ca2+ channel blockers:

Answer 59

Ca2+ channel blockers:

Dihydropyridines

1. AMLODIPINE,
2. NIFEDIPINE), which are mainly acting on the vessels by vasodilation (antihypertensive agents), Nifedipine used in humans. Its dose is -.625 mg/kg. These calcium channel blockers are very important in cases of hypertonia and can decrease the blood pressure by dilating the vessels.

Non-dihydropyridines

1. VERAPAMIL,
2. DILTIAZEM,

• which mainly act on the heart as antiarrhythmic agents.

Question 60

31B: PHARMACOLOGY OF VASOREGULATION:

Ca2+ channel blockers:

AMLODIPINE

DILTIAZEM, VERAPAMIL

Answer 60

Amlodipine:

• This drug causes a very potent arterial vasodilation,
  
  • also in the coronary arteries.
• It is given orally and is very safe.
• It is our first choice of drug in feline hypertension
  
  • Used frequently in canine hypertension.

Diltiazem, Verapamil:

• These are antiarrhythmic agents
  
  • Lower vessel/heart selectivity.

Question 61

32: DIURETICS

Types of DIURETICS

Answer 61

1. Diuretics due to cardiac failure
2. Cardiac Diuretics - have the side effect of diuresis
3. Osmotic diuretics
4. Natriuretics

Question 62

32: DIURETICS

Diuretics due to cardiac failure

Answer 62

• The performance of the heart can be affected by
  
  • Increasing the contractility,
    
    • mainly through PIMOBENDAN,
  • Decreasing the preload and afterload via
    
    • ACE inhibitors or AD II antagonists.
  • The best drugs for decreasing the preload of the heart i.e.
    
    • decreasing the water amount or
    • blood amount flowing into the heart,
    • = are the DIURETICS.
  • However, these are not only used in heart diseases, they have other functions too.

Question 63

32: DIURETICS

2. CARDIAL Diuretics

Answer 63

• Diuretics can be CARDIAL DIURETICS,
  
  • which have the side effect of diuresis e.g.
  1. DIGOXIN,
• Xanthine derivatives such as
  
  1. CAFFEINE,
  2. THEOPHYLLINE,
  3. THEOBROMINE
  4. ACE inhibitors.
• This diuresis is not so significant as it is not their main pharmacological effect but their side effect

Question 64

32: DIURETICS

3. OSMOTIC DIURETICS

Answer 64

1. MANNITOL,
   * these are much more effective.

Question 65

32: DIURETICS
3. NATRIURETICS

Answer 65

• These inhibit the
  
  • Reabsorption of sodium in the kidney tubules,
    
    • Causes water to be passively passed.
  • Normally, there is a huge amount of water that enters the tubules
    
    • which is significantly reabsorbed and if this is influenced,
      
      • we can induce significant diuresis i.e.
        
        • we do not affect the filtration as it is already very high.

Question 66

Osmotic diuretics:

Answer 66

• These are filtered through the glomerulus into the tubules.
• After this, they cannot be reabsorbed and because of this,
• They osmotically retain water and prevent reabsorption i.e.
  
  • These diuretics act everywhere in terms of the kidney

1. MANNITOL
2. GLYCERINE

Question 67

Osmotic Diuretics

MANNITOL and GLYCERINE

Answer 67

MANNITOL

• This is a sugar alcohol.
• These canNOT move through biological membranes
  
  • (no absorption)
  • I/V administration is required.
• They can be filtered through the fenestrated capillaries of the glomerulus
  
  • Then they can be filtered into the kidney tubules.
• They are used mainly in life threatening situations e.g.
  
  • brain or lung edema
  • Acute renal failure
    
    • Kidney function stops, and there is significant azotemia in the body.
• Acute renal failure occurs in cases of:
  
  • Antifreeze (ethylene glycol) poisoning,
  • Babesiosis in the kidney,
  • Shock.

In this case, the kidney practically:

• Stops working
  
  • Causes oliguria initially
  • Eventually anuria
    
    • No urine production,
  • Azotemia will follow
  • Most significantly, hyperkalemia.
• This will eventually kill the patient
  
  • because it can stop the heart.
• It can also be used in ophthalmology
  
  • as mannitol is retaining the water
  • Can be useful in glaucoma
    
    • (can decrease the intraocular pressure in the eye).
• The dose is 0.5-1 g/kg i/v every 4-6 hours.
• We require masses of mannitol in the circulation and urine.

GLYCERINE:

• This drug has good oral absorption.
• It has a much less pronounced effect as mannitol,
• it is not usually used.

Question 68

NATUIRETICS

Answer 68

Natuiretics:

• These prevent sodium reabsorption
  
  • which prevents water to be reabsorbed.
• They are broken up into four groups and
  
  • these different types have different sites of action.

1. Carboanhydrase inhibitors
2. Loop diuretics:
3. Thiazides:
4. Potassium sparing diuretics:

Question 69

NATUIRETICS

Carboanhydrase inhibitors

Drugs

Answer 69

1. Carboanhydrase inhibitors:
2. ACETAZOLAMIDE,
3. DORZOLAMIDE,
4. BRINZOLAMIDE.

Question 70

NATUIRETICS

Carboanhydrase inhibitors

1. Drugs
2. Where do they act
3. Reabsorbtion
4. Diuretic?
5. Responsible for producing?
6. REquire?
7. 2 main effects
8. Contraindication
9. Indication
10. Side effects
11. ACETAZOLAMIDE
12. DORZOLAMIDE, BRINZOLAMIDE

Answer 70

1. Carboanhydrase inhibitors:

ACETAZOLAMIDE, DORZOLAMIDE, BRINZOLAMIDE.

• These act in the proximal convoluted tubule and
• Reabsorption is approx. 5-15% at this site of the kidney i.e. if carboanhydrase is inhibited,
  
  • You will not induce a significant diuretic effect.
• Carboanhydrase inhibitors are very mild diuretics.
• These are usually used for other indications
  
  • ​rather than as diuretics.
• Carboanhydrase is responsible for producing
  
  • carbon dioxide and
  • Water
  • from carbonic acid
• The consequence is that protons and hydrocarbonate ions cannot be reabsorbed in the cell
  
  • ​because they are ionised.
• If we would like to reabsorb hydrocarbonate ions,
  
  • we require carbonic acid.
  • This acid can be absorbed and produces carbon dioxide and water.
• ​ If we inhibit carboanhydrase,
  
  • this process will not work and
  • hydrocarbonate ions cannot be absorbed into the cells
  • This is why hydrocarbonate ions will be eliminated by the urine i.e.
    
    • the urine will have an alkaline pH.
• In addition, this proton will enter inside the cells via the sodium/proton antiport mechanism.
  
  • This pump allows for a sodium influx and pumps protons into the urine where it can react with hydrocarbonate ion.
  • If this enzyme is inhibited, the pump is inhibited and sodium will remain in the urine and act as an naturieticand protons will stay inside the cell and vanish from the urine.

These are the two main effects:

1. Sodium excretion and
2. Hydrogencarbonate excretion.

• These are not used as diuretics
• Not in cases of heart failure
• Used in patients with glaucoma.
• There can be systemic and local (preferred) administration
  
  • as eye drops.
• Because these also cause an alkaline production in the urine,
  
  • they are used in the prevention of cystine stones.
  • These cystine uroliths are produced in acidic urine
    
    • and that is why this is helpful.

The side effects include

• Acidosis,
• other urolith production (uroliths that require an alkaline pH urine e.g. struvite stones).

ACETAZOLAMIDE:

• This carboanhydrase inhibitor is administered:
• orally in cases of cystine stones.

DORZOLAMIDE, BRINZOLAMIDE:

• These are used locally in cases of glaucoma as eye drops.

Question 71

NATUIRETICS

2. Loop diuretics:

Answer 71

2. Loop diuretics:

1. TORSOMIDE
2. FUROSEMIDE

• These act in the loop of henle in which 70-80% of the water is reabsorbed i.e.
  
  • Site of action is inhibited,
    
    • Induce a very significant diuretic effect and are life-saving diuretics in some cases..

FOROSEMIDE and TORSOMIDE = The most significant diuretic we use.

• These inhibit the NKCC2 channel
  
  • Responsible for the reabsorption of
    
    • 1 sodium ion,
    • 1 potassium ion,
    • 2 chloride ions.
  • If this is inhibited,
    
    • sodium will retain in the tubule and will not allow the reabsorption of water i.e.
      
      • Large amount of sodium will leave in the urine and prevent the reabsorption of water.
      • Potassium will also be lost when we use this drug.
      • Magnesium and calcium will also be excreted i.e.
        
        • when this drug is used for a long time,
          
          • magnesium-containing uroliths (struvite stones) or calcium-containing uroliths (calcium oxalate stones) can be produced however, this is very rare.
• This drug significantly increases a diluted urine production and stones are not usually present in a diluted urine so this is more so a theoretical side effect.

Question 72

NATUIRETICS

2. LOOP DIURETICS

TORSEMIDE

Answer 72

• Torsemide is much more active (requires a lower dose)
• Longer half-life i.e.
  
  • it is given once a day as opposed to furosemide which must be given two to three times a day.
• If we use these diuretics,
  
  • the body will become dehydrated.
  • The body will not allow this and releases aldosterone which will try to retain sodium and water.
  • Aldosterone is unable to fight against furosemide or torsemide.
    
    • Body will release an increasing amount of aldosterone = Aldosterone escape.
    • When aldosterone is present in this high dose
      
      • Bad affect on the heart.
      • Aldosterone will act on the myofibroblasts, especially in the heart,
        
        • These will produce collagen.
    • When collagen is present in the heart, it
      
      • Prevents its expansion = Remodelling.
    • Remodelling of the heart
      
      • ​ muscle tissue of the heart is infiltrated with collagen and connective tissue
        
        • process is irreversible.
  • ​​This is why we would like to inhibit this aldosterone escape via aldosterone antagonists.
    
    • This is how aldosterone antagonists aid in the treatment of heart failure and they are usually administered in combination with these drugs.
• Torsemide has a mild aldosterone antagonising effect
  
  • ​Advantage as to why we use it in preference to furosemide.

Question 73

DIURETICS

NATUIRETICS

2. LOOP DIURETICS

FUROSEMIDE

Answer 73

Furosemide:

• This is a very important primary drug for the treatment of heart failure.
• It can be used in
  
  • dogs,
  • cats,
  • horses
  • humans.
• They are used in:
  
  • All types of oedema
  • Oliguria and
  • Polyuria i.e.
  • Acute renal failure
    
    • but, in this case, MANNITOL is always the first choice.
    • If mannitol is not working, we can administer furosemide
    • When treating renal failure with furosemide you must ensure rehydration.
• These drugs are very safe
  
  • but they have various side effects e.h.
    
    • Hyperkalaemia,
    • Alkalosis, and
    • Hypertension.
      
      • Hypertension = as they excrete water.
      • Humans and cats are very sensitive to this hypertension which is why their dose is lower (Fe: 4 mg/kg max.) than that of dogs (8 mg/kg max.) who are relatively resistant to this side effect.
    • The last side effect is OTOTOXICITY i.e.
      
      • Toxic to the eye and ear.
      • This is rare however, if they are combined with other ototoxic drugs e.g. antibiotic groups of aminoglycosides (GENTAMICIN), the ototoxicity of furosemide will be significantly enhanced.
• The dose is usually 1-5 mg/kg i/v, i/m, orally BID or TID (TID is preferred).
• Furosemide also has very good oral absorption.
• In life threatening situations, we administer the maximum dose i/v (4 mg/kg in cats, 8 mg/kg in dogs, 1-2 mg/kg in horses, 0.2-0.4 mg/kg in humans).

Question 74

DIURETICS

NETUIRETICS

3. THIAZIDES

Answer 74

3. Thiazides:

• These act in the distal convoluted tubule
  
  • Reabsorption is 10% i.e.
  • these, similarly to carboanhydrase inhibitors,
    
    • Only mild diuretics.
• These inhibit another pump called NCCT
  
  • Leads to sodium and water excretion.
  • Potassium excretion is increased
  • Calcium excretion is decreased.
• ​This is why these drugs are useful in the treatment of calcium oxalate stones.
• These are rarely used in the veterinary field but are frequently used in human medicine.
• We use these if furosemide is not working e.g.
  
  • if we have an animal with hydrothorax
    
    • with a lot of water inside the cavities
    • and furosemide is not working,
    • then we can combine it with thiazides.
• In humans, they are used mainly for the treatment of hypertension.
• An example of its use is in combination with LOSARTAN which is an AT II receptor blocker or in combination with ACE inhibitors either in the human field.

CHLOROTHIAZIDE, HYDROCHLOROTHIAZIDE (HCT):

HCT is more frequently used.

• Drugs in the human field that can be seen are Enalapril-HCT, Ramipril-HCT etc.

Question 75

DIURETICS

NETUIRETICS

4. Potassium sparing diuretics:

Answer 75

4. Potassium sparing diuretics:

• These act in the collecting duct
  
  • ​where there is only 1-2% water reabsorption
  • Little to no diuretic effect,
  • Usually used for a different function.
• In these kidney tubules, we have two types of ion channels.

1. Sodium is reabsorbed via the electrogenic sodium channels
2. Released via a sodium ATPase pump on the other side.

• From the urine,
  
  • the tubules reabsorb sodium and water.
  • AMILORIDE and TRIAMTERENE inhibit this pump.
• On the blood side,
  
  • sodium-potassium channels are releasing sodium into the blood.
  • Aldosterone antagonists decrease the expression of the ENaC pump as well as decrease the expression of the sodium potassium ATPase pump i.e.
  • The Na/K-ATP-ase protein expression will decrease.
  • These drugs do not directly inhibit the pump itself.
  • By doing this, these drugs increase sodium excretion
    
    • Cannot be reabsorbed by the urine,
    • which leads to diuretics,
    • and they also cause potassium to remain in the blood.
    • This is how they obtained their name.
• We use these drugs as aldosterone antagonists (rather than diuretics) in cases of heart failure.

​SPIRONOLACTONE

Question 76

DIURETICS

NETUIRETICS

4. Potassium sparing diuretics:

SPIRONOLACTONE

Answer 76

SPIRONOLACTONE

• Aldosterone antagonist
• Used for the long-term treatment of heart failure.
• It is combined with
  
  • ACE inhibitor in the product Cardalis,
  • Can also be combined with furosemide.
• ​It can also be used in hyperaldosteronism
  
  • ​(this is extremely rare).
• These inhibit potassium excretion
  
  • but do not cause hyperkalemia.
• These are extremely safe drugs.
• Their dose is 1-2 mg/kg orally BID.
• Its main indication is to fight the effect of aldosterone in CHF.

In the dog, to treat HCF, we can combine:

1. PIMOBENDAN with FUROSEMIDE and SPIRONOLACTONE.

• The pimobendan is
  
  • used to provide a longer survival time.
• The others are only used to decrease the clinical symptoms.
• In cats and horses, we usually only use furosemide.