Dobermans (dilated cardiomyopathy)

King Charles cavaliers (endocardiosis)

What occurs during the P wave?

What occurs during the T wave?

How can class I Congestive Heart Failure be classified?

Only limited during strenuous exercise

How can class II Congestive Heart Failure be classified?

Fatigue, shortness of breath, and coughing on exercise

How can class III Congestive Heart Failure be classified?

Comfortable at rest, exercise minimal, symptoms get progressively worse

How can class IV Congestive Heart Failure be classified?

Clinical signs at rest, no capacity for exercise

Classes II, III, IV

Digoxin, Pimobendan, ACE inhibitors, and other inotropic drugs.

What substance is derived from the Digitalis species of plant (Foxclove)?

Glycoside 

What are the three components of the structure of cardiac glycoside?

Lactone – (5 member)

 Steroid

Sugar residues 

The lactone and Steroid portion

What is the structural difference between Digitoxin and Digoxin? How does this effect therapeutic outcome?

Digitoxin: Y = H

Digoxin: Y = OH

Digoxin is more readily used in clinical settings because it doesn’t hang around in the body as long as digitoxin does.  Digoxin is more ionized and therefore more readily excreted by the kidneys. 

What effect does Glycoside have on Ca when administered?

How do glycosides cause an increase in cytosolic calcium?

What is positive inotropic action?

What is negative chronotropic action?

What is negative chronotropic action?

What is negative dromotropic action?

Slowing the conduction at the AV node, by raising its threshold. Can cause a complete AV block. 

What are some deleterious effects of digoxin on the heart?

Auricular arrhythmias/tachycardia

AV block

Ventricular arrhythmias/pulus bigemini/ventricular fibrillation 

What are some symptoms of Digoxin toxicity?

Disturbances in heart rhythm (extrasystole, coupled beats),

GI disturbances (anorexia, vomiting, diarrhea) 

How do you treat digoxin toxicity?

Stop giving the drug

Treat ventricular arrhythmias with lidocaine, propranolol, phen

Maximize renal clearance by administering IV fluids

Digoxin immune Fab or cholestyramine

What drug is an inodilator?

Pimobendan

What is an inodilator?

What is the function of Troponin I?

It inhibit actin and myosin combination until calcium is bound to troponin C.  The calcium sensitizer increases the calcium binding to troponic C. 

What is the function of the Phosphodiesterase inhibitor in Pimobenden?

Dopamine D5 receptors

Dobutamine Beta 1 agonist 

Amrinone phosphodiesterase III inhibitor 

23 - 39 hours 

Steady state in 7 days

25-78 hours - very variable 

Steady state in 10 days 

13 - 23 hours 

steady state in 3-5 days

Increase in cardiac output 

Decrease in heart rate 

Decrease in venous pressure 

Reduced heart size

Water loss and reduced body weight 

In cardiac electric activity, what is the zero phase?

This is the upswing of cardiac potential.

This is carried by the opening of the sodium ion channels.

They bind to sodium channels in a state dependent manner. 

Channel opened by drugs like local anesthetics (lidocaine) - this is the "refractory" state and then acts as a "gate" and swings closed, this only allows a certain amount of sodium in. 

This reduces depolarization rise. (0 phase refractory period) 

These drugs only bind to depolarized/damaged muscle cells. 

These are used to block high frequency excitation dysrhythmias 

Ie. Lidocaine 

These associate and dissociate rapidly 

selectively bind to sodium channels during depolarized, ischemic cardiac muscle. 

Used to control ventricular dysrhythmias after myocardial infarction.  

What are class 1c antidysrhythmic drugs?

ie. Flecainide

Associate and dissociate less rapidly - steady state block (no variation with stage of cycle) 

Used for general reduction (less effect of premature beats) and help with re-entrant rhythyms. 

ie. Quinidine and Procainamide

This is the oldest group - kinetics between class b and c 

(middle of the road on speed of associating and dissociating) 

This reduce the excitibility of the heart (if being overstimulated sympathetically).  

Also reduces AV conduction, thus slowing ventricular rate.

**Cat = parathyroid hyperplasia

ie. amiodarone

Prolongs cardiac action potential and increases refractory period. 

Extensively bound to tissues - long half life. 

Dose given IV in life threatening arrhythmias

ie. verapamil and dilitiazam

Block voltage sensitive Ca channels, shorten plateau of action potential and reduce force of contraction.  

Reduction of Ca prevents premature beats and inhibits "slow response"

Conduction that occurs in depolarizing myocardium that may sustain re-entrant rhythms.  

This can be inhibited by Class IV antidysrhythmic drugs.

used to reverse superventricular arrhythmias (esp atrial fibrillations) in horses. ORAL 

ACTION: prolongs artial refractory period, vagolytic (atropine like) -- Class Ia antidysrhythmic drug. 

Side effects: Diarrhea, tachycardia, allergic responses, ataxia, nasal mucosal swelling

Used to treat ventricular arythmias or ventricular tachycardia.

Class Ia drug (blocks sodium channels) 

DO NOT use in conduction blocks. 

Given orally to dogs, and give half if renal compensation.

Used IV without epinephrine

Used to treat severe acute ventricular arrhythmias

Undergoes efficient first pass effect, no oral admin

Side effects: Seizures, hypotension

NOT effective if there is hypokalemia

Dose should be reduced in hepatic dz and congestive heart failure.

Prevent reflex tachycardia, lower blood pressure, reduce ventricular hypertrophy form cardiomyopathy and hyperthyroidism

1.2 hour half life

Side effects: Bronchospasms (administer slowly for 3 days to full dose) 

Can cause bronchial muscle spasms - 

administer at lower dose over 3 days to full dosage

Beta 1 antagonist - long acting

Can be used in the treatment of hypertrophic cardiomyopathy and supraventricular arrhythmias.  

Prolongs refractory period (class III)

Used to treat supra-ventricular & ventricular arrhythmias

Side effects: Can cause pulmonary fibrosis, intestinal disturbances, corneal deposits

IV or Oral 

Class III antidysrhythmic drug 

used to treat supraventricular or ventricular arrhythmias 

- Inhibits slow Ca channels (damaged myocytes) 

depress AV conduction in supraventricular tachycardias

- dilate capillaries and coronary arteries (hypotension)

given IV 

Verapamil is given IV, but Diltiazem is given orally and is better for long term use.

Both are Class IV anti-dysrhythmic drugs that inhibit slow Ca channels. They also dilate coronary artery and can cause hypotension.

Inhibits slow Ca channels (class IV) 

and causes dilation of coronary artery - can cause hypotension

Favored for long term use orally 

Verapamil and Diltiazem can treat Atrial tachycardia by blocking slow Ca channels

Quinidine and Procainamide is used to treat atrial fibrillations by blocking Na channels

Class II Beta antagonists - reduce AV conduction in atrial tachycardias

propanolol (Class II) can treat reflex tachycardia and atrial premature depolarizations. 

Flecainide (vet use is unlikely) 

Quinidine and Procainamide - blocks Na channels 

Propanolol - stress induced tachycardias that act as beta antagonists.

Which of the following conditions can be treated using cardiac glycosides? There may be more than one right answer.

A) Subcutaneous edema

B) Congestive heart failure 

C) Atrial arhythmias

D) Ventricular arhythmias

E) Cardiac bradycardia

Common use: B) treat congestive heart failure

also can be used to treat atrial arhythmias

What is the site of action of the cardiac glycosides?

A) The sodium channel 

B) The calcium channel 

C) The endoplasmic reticular release mechanism of calcium

D) The Na/K ATPase 

E) Actin-myosin contraction coupling mechanism 

Answer: D) 

The Na/K ATPase is inhibited causing an increase in intracellular Na which in turn causes an increase in Ca.

Stop administration of digoxin

Give fluids that can raise serum K 

Use an antidysrhythmic if high risk condition

Increased arterial blood pressure 

Increased cardiac output 

What is the mode of action of lidocaine?

A) blocks sodium channels 

B) blocks calcium channels 

C) acts as a beta-blocker

D) increases refractory period of the heart

E) Speeds the uptake of cytosolic calcium

What is the mechanism of the anti-dysrhythmic effect of propanolol on heart?

A) Blocks sodium channels 

B) Blocks calcium channels

C) Beta blocker

D) Alpha- blocker

E) Speeds the uptake of calcium 

Which of the following are true about diltiazem?

A) It inhibits sodium channels 

B) It inhibits calcium channels 

C) Depressant effect on AV node - favored for supraventricular arrhythmias

D) Depressant effect on ventricular muscle - favored for ventricular arrhythmias

E) It inhibits beta-receptors

Answer: B and C

it inhibits calcium channels and has a depressant effect on the AV node and it used to treat supraventricular arrhythmias.

Class IV anti-dysrhythmia

What are some properties of amiodarone?

A) Blocks calcium channels

B) Prolongs refractory period 

C) Toxic side effects include corneal deposits 

D) Contra-indicated for supra-ventricular arryhthmias

E) Toxic side effects at the kidney

Answer: B and C 

Prolongs refractory period and cause corneal deposits 

What are some indications for diuretic use?

Edema (generalized and local) 

Hypertension

Others

Congestive heart failure 

Nephrotic syndorme

Hepatic disease 

Decreased cardiac output  -> renal hypoxia and decreased function -> renin-angiotensin system activated -> retention of Na and H20 

= edema

Backup of blood from decreased cardiac output will cause Extracellular fluid to shift from arterial to venous and cause pulmonary and peripheral edema.

Protein is lost in the urine -> causes a decrease in oncotic pressure -> fluid released into interstitial tissue 

=edema

Liver not making enough plasma proteins -> decreased oncotic pressure = edema

Decreased aldosterone metabolism by liver -> increased Na+ retention = edema

Causes:

cardiogenic: cardiomyopathy, valve defects, septal defects and arrhythmias

Treatments: loop diuretics, Oxygen, aminophylline, morphine 

Pulmonary edema 

Lymphdema

cerebral edema

ocular edema 

mammary edema 

essential (no apparent cause) 

Renal hypertension (renin-angiotensin activated)

Primary aldosteronism (increased aldosterone causes increased Na retention

Symptomatic hypercalcemia

recurrent renal calcium urolithiasis 

glaucoma

hypokalemic and hyperkalemic disorders 

drug and mineral intoxication - increases elimination

metabolic alkalosis 

nephrogenic diabetes insipidus

proximal renal tubular acidosis 

Osmotic diuretics 

loop diuretics 

Thiazides

Ca inhibitors 

K+ sparing diuretics

Methylxanthines

acidfying salts

Prevent reabsorption of water and ions in the proximal tubule and descending loop

It does this by mannitol increasing prostaglandin this increasing renal medullary flow 

Mannitol - used as IV short term (canine)

Glycerol - oral - treatment for glaucoma

Glucose - IV (rarely used) 

Avoid chilling - forms crystals

Use IV filter 

use warm water to dissolve crystals

Dont use with generalized or acute pulmonary edema 

Dont use with cerebral hemorrhage 

**monitor electrolyte balance**

Acute glaucoma 

Renal failure (in conjunction with furosemide)

cerebral edema 

Poisonings

INhibits Na/K/2Cl transporter - in the luminal membrane of ascending loop of henle.

Inhibits Ca2+ and Mg2+ reabsorption 

Furosemide (lasix) 

can increase Na+ 17 fold at 1.0 mg/kg

Furosemide

Bumetanide (25-40 times more potent than furosemide)

Torsemide (twice as potent as furosemide) 

Ethacrynic acid (not in Small Animals) 

What are the pharmokinetics of loop diuretics?

(absorption, onset of action, excretion)

Absorption: well orally - bound to plasma proteins, doesnt pass into the glomerular filtrate 

action: rapid onset (within 5 minutes) 

Excretion: 60-80% unmetabolized in urine, 20-30% as glucuronide in bile

Edema - esp pulmonary edema 

Heart failure - MOST EFFECTIVE class 

Acute renal failure - (with mannitol) 

Hypercalcemia - increased elimination 

EIPH - exercising horses 

Ascites 

anti-hypertensive

Post parturient udder edema - APPROVED

Electrolyte imbalance - esp hypokalemia

Ototoxicity - deafness from innner ear imbalance

Avoid prolonged use:

dehydration, muscle weakness, CNS depression, volume depletion

Drowsiness, confusion, irritbility, loss of sensation, dizziness, muscular weakness, tetany, cardiac arrhythmias, respiratory arrest, coma

TREAT WITH POTASSIUM 

Loop and thiazide diuretics

ulcerative colitis 

pyloric obstruction 

chronic laxative ingestion 

severe diarrhea

Inhibition of Na/Cl symporter

increases reabsorption of Ca2+ - by stimulating Na+/Ca2+ countertransporter

Benzothiadiazide

Chlorothiazide (Diuril)

Hydrochlorothiazide (Hydrodiuril)

Trichlormethiazide (naquasone - dairy cattle) 

Chlorthalidone - long acting

What are the pharmokinetics of Thiazide diuretics?

(absorption, onset, excretion) 

Absorption: absorbed well orally in cats and dogs, IV/IM in cattle

Onset: 3 hours, lasts 6-12 hours

Excretion: non metabolized - excreted in urine 

Long term diuretic therapy 

Approved treatment of post parturient udder edema 

nephrogenic diabetes insipidus 

Ca-Oxalate uroliths

Fluid / electrolyte imbalance 

hypokalemia and hypochloremia 

hyperglycemia and glucosuria

corticosteroids or amphotericin B - hypokalemia

Sulfonamides - potentiate activity 

Administration of Vitamine D or Calcium salts - increase hypercalcemia

Na+ channel blockers (like triamterene, amiloride)

Aldosterone antagonists (like spironolactone, potassium canrenoate) 

Principal cells - Na+, K+, H20 transport

intercalated cells - H+ secretion 

This drugs (amiloride and triamtrene) block Na+ channels, which decreases the driving force for K+ secretion.

It also decreases H+ secretion in intercalated cells. 

= Increased Na, decreased K+, decreased H+ in urine

(K sparing class of drugs) 

These K sparing drugs (like Spironolactone) competitively inhibit binding of aldosterone to receptors - redcued aldosterone induced proteins 

THUS inhibiting: Synthesis of Na/K channels and Na/K ATPase. 

= increased NaCl, decreased K and H in urine

Absorption: Orally 

Onset: Na channel blockers have rapid onset, 

aldosterone antagonists are slower (2-3 days)

Excretion: metabolized in liver - excreted in urine and bile

Congestive heart failure 

Primary and secondary aldosteronism

Treatment of ascites 

Potentiation by other diuretics 

Hyperkalemia - DO NOT MIX K+ sparing diuretics

Metabolic acidosis - from H+ inhibition

male sexual dysfunction 

GI disturbances 

amemia in patients with cirrhosis 

Inhibition of Carbonic anhydrase - reduces hydrogen ion - not enough for Na/H exchange 

= increased excretion of NaHCO3, K, Cl

Absorption - oral 

onset - 30 minutes, lasts 6-12 hours

Excretion - metabolized and excreted in the urine  

Tx of glaucoma - inhibits ciliary body CA = decreased humo production 

Tx of metabolic alkalosis - controls hyperkalemic periodic paralysis 

GI disturbances 

CNS effects (sedation or excitation) 

Bone marrow suppression 

* dont use with liver disease 

can have tertaogenic potential

Ammonium chloride -> lowers pH of Extracellular fluid and urine.  Liver converts NH4Cl to NH3, H+, Cl-

H+ buffered by Bicarb in plasma = acidosis 

increased Cl- = urinary loss of Na and Cl

Severe, uncompensated acidosis 

nausea and gastric irritation

For FUROSEMIDE what is:

- site of action 

- mechanism of action 

- therapeutic uses 

- adverse effects 

- drug interactions 

Loop Diuretic

Site of action: loop of henle 

Mechanism: inhibits Na/K/2Cl cotransporter

therapeutic uses: edema, heart failure, renal failure, hypercalcemia, EIPH, hyperkalemia, ascites

Adverse effects: HYPOKALEMIA, ototoxicity

Drug interactions: aminoglycosides and cisplatin

Class: Osmotic diuretic  

Site of action: Proximal tubule, and descending loop

Mechanism: prevents water and ion resorption

Therapeutic uses:Glaucoma, renal failure, cerebral edema, poisonings

Adverse effects: dont use with edema or cerebral hemorrhage

Drug interactions: ??

Class: Na+ channel blocker, Potassium sparing diuretic

Site of action: late distal tubule, collecting duct

Mechanism: block Na channels = increased Na in urine

Therapeutic uses: Chronic uses, aldosteronism, ascites

Adverse effects: Hyperkalemia, metabolic acidosis 

Drug interactions:ACE inhibitors, Aspirin

Proinflammatory (chronic) 

Vasoconstriction (necrosis) 

platelet aggregation (thrombosis) 

Bronchoconstriction of allergies = asthma

septic and anaphylatic shock 

pancreatitits 

Antagonists to receptors

Prevent synthesis of PAF

Rupatadine - (also H1 receptor antagonist)

Lexipafant - used against septic shock

Ginko biloba - has PAF-R antagonist in it 

Reversible infertility - because uterine implantation (inflammation) 

to prevent Lissencephaly  

this is where one quadrant of the brain doesnt get developed.

It is an ADP receptor antagonist - 

receptors are located on platelets and ADP and causes platelet aggregation. 

So this PREVENTS coagulation

heparin

warfarin

NSAIDS

(factor x?)

ADP-receptor antagonists (clopidogrel)

Prostacyclin (PGI2) receptor agonist (beraprost) 

It is an H1-R, PAF-R antagonist 

Used against allergies 

adverse: can cause reversible infertility 

PAF-R antagonist 

Used against septic shock 

Adverse: can cause reversible infertility 

Pro coagulant 

Activates clotting factors - required for hepatic modification of factors 2, 7, 9, 10

Recycled!

Anticoagulant 

Activates antithrombin III - thus inactivating thrombin

Procoagulant 

physically interacts with and inactivates heparin 

Used against severe heparin overdose 

Anticoagulant 

ADP receptor antagonist 

ADP causes platelet aggregation (released from damaged cells)

Anticoagulant 

inhibits the biochemical recycling of vitamin K 

Anticoagulant 

Prostacyclin (PGI2) receptor agonist 

Used against peripheral occlusive arterial disease

These systems add to the PLA2 normally present causing an over production of PGs and LTs

Rickettsiae infections – inserts its own

Envenomation (honey bee venom and snake venom)

Androgen-related neoplasia causes overactive endogenous PLA2 (prostate, ovarian, mammary cancers) 

That have oprin which is a protease that can degrade PLA2 

(because it is a protease it would not make a good drug- would cleave the wrong proteins) 

Why might sponges be used to develop drugs?

(the kind in the sea, not the kind in your sink...) 

(Singulair) Leukotriene receptor antagonist

Used for rhinitis, asthma, CGPD, non-responding chronic processes

luteolysis in animal reproduction 

open angle glaucoma / ocular hypertension (latanoprost) 

Gastroprotection (misoprostol) 

All are anti-thrombotic 

VSM receptors

If PGE2 were to bind, it would inhibit actin-myosin and cause vasodilation.  But if PGF2 were to bind, it would promote actin-myosin and cause vasoconstriction.

There could be platelet aggregation (thrombosis) - if PGE2-R-E were to bind 

= calcium influx -> clot formation 

There could be anti-thrombosis - if PGI2-R-E were to bind 

= calcium stasis -> no clot 

It is a PG-Receptor agonist 

It is used to promote luteolysis, increase uterine contractions, and induce parturition or abortion in ruminants.  

Dont used in horses to induce parturition because it causes colic, but can be used to induce estrus.  

Misoprostol is a PGE1-Receptor agonist

It can be used to promote gastric secretions when NSAIDS are being used to prevent gastric ulcers. 

It can also be used to cause luteolysis, myometrial contractions, abortions. 

DO NOT ADMINISTER IV!!

DO NOT administer IV - can cause bronchospasms 

Dont use dinoprost in horses to induce parturition

Make sure clevix is open during pyometra - or uterine rupture. 

- modulate blood flow 

- regulate secretory processes in specific tissue 

- alter smooth muscle function 

- participate in inflammation, pain, anaphylaxis, allergies, and types of drug reactions. 

Biogenic amine autocoids

Phosopholipid derived autocoids 

Polypeptides 

cytokines 

others 

Epinephrine - first line of drug 

Aminophylline & corticosteroids - secondary treatment 

What are H1 receptors associated with:

Allergy or GI hyperacidity?

What are H2 receptors associated with:

Allergy or GI hyperacidity?

INcreases bronchial smooth muscle contraction in many mammals 

in cats and sheep - bronchial smooth muscle relaxation 

Vagus nerve activated by sight/smell of food-> Ach acts on patietal cells (that have muscarinic receptors) which produce gastric acids 

Also ECL cells are acted on by the vagal nerve and containa lot of histamine that they release. this works on the stomach and also stimulates gastric acid production

What are physiological antagonists to histamine?

How do they work?

Epinephrine, ephedrine, and isoproterenol 

The act opposite physiologic effects - 

epi stimulates alpha and beta adrenoreceptos to elevate BP and relax bronchi 

Cromolyn sodium, nedocromil, theophylline aminophylline.

Cromolyn and nedocromil - inhibit degranulation of mast cells

Theophylline and aminophylline - block degradation of cAMP -> decreased histamine 

They are steroid nasal sprays that are used in humans 

acts by reducing nasal inflammation and secretion by decreasing level of histamine and prostaglandins

Diphenhydramine, promethazine, pyrilamine, chlorophenarimine

block autonomic receptors, have strong sedative effects 

What are some second generation antihistamines?

How do they work ?

Fexofenadine (allegra), Cetirizine (Zyrtec), and Loratadine (Claritin) 

Minimal sedative effects, less distribution to CNS.

Urticaria, pruritis, pulmonary emphysema, drug allergies

motion sickness

pre-op for spenic mass surgery 

tx of reverse sneeze

tx of organophosphate/ carbamate poisoning

tx of acute laminitis in horses/founder in cattle

insect stings 

angioedema 

bovine asthma 

sedation 

antimuscarinic effects (dry mouth, fluid retention, tachycardia) 

*1st generations readily enter the brain readily - can cause convulsions, hyperpyrexia, even death at high doses 

What are some H2 receptors inhibitors?

What is their function?

Cimetidine, ranitidine, famotidine, and nizatidine 

competitively inhibit H2 receptors in parietal cells = decreased gastic acid production 

orally administered, mostly metabolized by liver 

GI: ECM cells in stomach and small intestine = 90% 

Cns and platelets too

the serotonin in plants, animals, and insect venoms produce pain.  

5HT also stimulates sensory nerves during pruritus

This is a serotonin agonist that stimulates GI movement!

Used in constipation, megacolon, esophageal reflux

Also used in post-operative ileitis in horses 

D2 antagonist/serotonin agonist

Used to treat vomiting, constipation, and gastritis, has anti-emetic effect 

anti-serotonin and antihistamine

used as an appetite stimulant, anti-asthmatic in dogs and cats, treatment of atopic dermatitis, controls photic head shaking in horses 

How is bradykinin formed?

How is it inactivated ?

cleavage of plasma alpha globulin kininogen by kallikrein (enzyme) 

inactivated by kininase 1 and antiotensisn-converting enzymes (ACE) 

Causes vasodilation 

this is done by generating more nitric acid and prostaglandins

How do ACE inhibitors effect the renin-angiotensin system?

What are some examples?

It blocks the conversion of angiotensinI to angiotensinII 

and cascade is prevented - thus no increase in blood pressure 

ie. captopril, enalapril, lisinopril

AT1 receptors in vasculature linked to phospholipase C - DAG causes increase in PKC = contraction of smooth muscle

- IP3 causes increase in Ca = contraction of smooth muscle 

====Increased blood pressure====

Decreased Na and water retention (by decreased aldosterone amounts) 

increased bradykinin (vasodilation) 

decreased blood pressure

Bradykinin produces ACE which is responsible for cleaving Angiotensin I into Angiotensin II thus activating the pathway to increased blood pressure?

True or false?