Pharmacology Flashcards
What are the types and effects of adrenergic receptors?
Stimulate alpha-1 and beta-1 receptors.
Inhibit alpha-2 and beta-2 receptors.
What do alpha-1 receptors work on?
Alpha 1 receptors are adrenergic receptors.
GQ protein coupled to produce stimulatory effect
Found in:
- blood vessels –> Vasoconstriction
Certain smooth muscles of urogenital tract –> contraction e.g. oppose voiding bladder and ejactulation.
- glands –> secretion
- GI tract –> relaxation
Agonist: phenylephrine
Antagonist: prazosin
What do beta-1 receptors work on?
Found in:
- Heart
SA note –> increase rhythmicity increase heart rate
AV node –> increase conduction velocity
ventricular myocytes –> increase contractility
- Juxtaglomerular cells in kidneys –> increase renin release
Selective agonist: Dobutamine
Selective antagonist: metoprolol, atenolol, etc
What do Beta 2 receptors act on?
Found in:
Bronchi –> Bronchodilation
Blood Vessels –> vasodilation
uterus –> relaxation
GI tract –> relaxation
Pancreas –> glucagon secretion
Eye –> increase aqueous secretion
Detrusor muscle –> relaxation
Selective agonist: Salbutamol, terbutaline
Selective antagonist: alpha-methyl propanolol
What do beta 3 receptors act on?
Found in adipose tissue and detrusor muscle to cause relaxation
Selective agonist: mirabegron
What are the effects of the dopamine and its receptors when stimulated?
Dopamine is a catecholamine that has mixed adrenergic effects.
It has little alpha-adrenergic effects
lower doses (0.5-3mcg/kg/min): Dilate renal mesenteric coronary vascular beds. Useful in oliguric renal failure.
higher doses (5-13 mcg/kg/min): has beta-1 adrenergic agonist affects resulting in vasodilation. Can be used to improve cardiac output by decreasing afterload.
Dose range: 1-20mcg/kg/min. Discontinue if tachycardic or arrhythmic.
What are the effects of norepinephrine?
Norepinephrine is a mixed adrenergic agonist with a stronger effect on alpha-1 receptors than beta receptors.
It causes increased vasoconstriction.
It will commonly lower heart rate on account of baroreceptor reflex with increased blood pressure
Caution: Large dose of norepinephrine can cause profound bradycardia
Concern: to much vasoconstriction increases afterload causing decreased cardiac output.
Dose: 0.1 - 2mcg/kg/min
What are the effects of phenylephrine?
Phenylephrine is an alpha-1 agonist.
Indicated for hypotension when beta-adrenergic agonist effects are not desirable.
Can cause increased blood pressure and bradycardia.
too much vasoconstriction can increase afterload and decrease output. (Use with caution in patient with bradycardia or cardiac disease).
Dose: 0.1-2mcg/kg/min
What are the effects of vasopressin?
Vasopressin is also known as anti-diuretic hormone.
It causes vasoconstriction independent of adrenergic stimulation.
It is commonly used in conjunction with norepinephrine for refractory hypotension.
Vasopressin is not affected by pH making it ideal for use during prolonged CPR.
Dose: 0.01-0.04units/kg/min
Strength: 0.01units/ml
What are the effects of epinephrine?
Epinephrine is a mixed adrenergic agonist with both alpha 1 and beta one agonist properties
Low dose: beta-adrenergic effects predominate improving cardiac output and cardiac contractility
higher doses: more of an alpha-1 adrenergic agonist resulting in vasoconstriction.
CRI dose: 0.1-2.0mcg/kg/min
What do alpha-2 receptors work on?
Gi/Go coupled proteins acting on adenylyl cyclase cAMP pathway to produce inhibitory effects
receptors located prejunctional in nerve endings to inhibit transmitter release
Receptors in the brain decrease sympathetic flow
receptors in the pancreatic beta cells inhibit the release of insulin
Alpha 2 promotes platelet aggregation
receptors in the blood vessels induces vasoconstriction
results in profound sedative and analgesic qualities. Alpha-2 are effective emetics in cats
Agonist: Clonidine, dexmeditomidine, xylazine
Antagonist: Yohimbine
Cholinergic Muscarinic receptors
Involved in peristalsis, micturition, bronchoconstriction and several other parasympathetic reactions.
Muscarinic receptors are type of ligand-gated G-protein coupled receptor and are linked to second messenger systems.
Muscarinic receptor varies with the receptor subtype.
These receptors occur in the CNS and the autonomic parasympathetic division of the PNS.
Cholinergic receptors
Two types of cholinergic receptors: Nicotinic and muscarinic
Cholinergic nicotinic receptors
Found on skeletal muscles in the autonomic division of the peripheral nervous system and in the central nervous system.
Nicotinic receptors are monovalent cation channels through which both sodium and potassium can pass.
Nicotinic receptors divided into two subtypes:
N1 - peripheral neuromuscular junction - muscle contraction, if on adrenal glands - release adrenaline and norepinephrine
N2 - central nervous systemor neuronal
Adrenergic receptors
Are divided into two classes (alpha and beta) with multiple subtypes each.
Adrenergic receptors are linked to G proteins and initiate a second messenger cascade.
Glutaminergic Receptors
Metabotropic glutaminergic receptors act through G-protein-coupled receptors. Two types of glutaminergic receptors are receptor channels.
Glutamate
The main excitatory neurotransmitter in the CNS and also acts as a neuromodulator.
Action of glutamate at a particular synapse depends on which of its receptor types occurs on the target cell
alpha amino-3-hydroxy-5 methylisoxazole-4-proprionic acid)
AMPA receptors
Ligand-gated monovalent cation channels are similar to nicotinic acetylcholine channels.
Glutamate binding opens the channel, and the cell depolarizes due to net sodium influx.
N-methyl-D-aspartate
NMDA receptors
cation channels that allow sodium, potassium, and calcium to pass through the channel
Channel opening requires both glutamate binding and a change in membrane potential.
NMDA receptor channel is blocked by magnesium ions at resting membrane potentials.
Glutamate binding opens the ligand-activated gate, but ions cannot flow past the magnesium. If the cell depolarizes, the magnesium blocking the channel is expelled, and ions flow through the pores.
The NMDA receptor is a CNS receptor that ultimately has an excitatory effect CNS effect. Activation of NMDA receptors has been associated with altered modulation pathways and the formation of chronic pain including hyperalgesia, allodynia and reduced functionality of opioid receptors.
Ketamine is believed to be an NMDA antagonist that essentially shus off the NMDA receptor and believed to prevent and treat hyperalgesia and allodynia.
Hyperalgesia
phenomenon resulting in prolonged exposure of receptors to noxious stimuli, leading to stimulus that should cause mild pain producing an excessive sense of pain.
allodynia
a type of nerve pain that causes pain from stimuli that normally wouldn’t cause pain. e.g. a mild stimulus may feel more painful when sunburned or inflammed.
Gamma-aminobutyric acid type A (GABA A)
Ligand-gated ion channels that allow chloride ions to pass into cells.
one of the body’s main inhibitory transmitters. When stimulated will suppress excitability in the central nervous system.
Drugs that stimulate GABA A receptors: Avermectins, Benzodiazepines, propofol, Etomidate, Alfaxalone
Conditions that increase activity of GABA system: hepatic encephalopathy
Drugs that will decrease GABA: Metaldhyde, Lead interferes with GABA
What does ACEi stand for? What does it do?
Angiotensin-converting enzyme inhibitors that disrupt the renin-angiotensin-aldosterone system (RAAS).
Which organs does angiotensin II act on and what is the outcome of its mechanism of action?
Converted from Angiotensin I by angiotensin-converting enzyme (ACE)
Angiotensin II is a hormone that binds to receptors in various tissues to exert various effects.
Acts on the adrenal cortex, causing it to release aldosterone.
stimulates vasoconstriction in systemic arterioles
Promotes sodium reabsorption in proximal convoluted tubules of the kidneys.
In the CNS:
It acts on the hypothalamus to stimulate thirst and encourage water intake
It induces the posterior pituitary to release antidiuretic hormone
It reduces the sensitivity of the baroreceptors’ response to increase blood pressure
What is the role of angiotensin-converting enzyme?
It converts Angiotensin I to angiotensin II.
What are some effects of angiotensin-converting enzyme inhibition (ACEi)?
decrease proteinuria
promote vasodilation and ventilation
reduce plasma volume
All of the above sums to decrease systolic blood pressure
ACEi can also decrease the metabolism of vasodilatory agent bradykinin resulting in decrease in vascular tone.
What is first line of treatment for systemic hypertension in dogs?
ACE inhibitors
What are two of the most common ACEi?
Enalapril and Benazepril
Is ACEi a recommended first line treatment for SHT in cats? Why?
ACEi is not a recommended fist line treatment for cats as it does not sufficiently nor consistently lower blood pressure.
Benazepril may be beneficial in conjunction with calcium channel blocker.
What is the concern with ACEi in patients who are dehydrated or azotemic?
There is potential to worsen glomerular filtration rate and renal function through preferential dilation of the efferent arteriole that would thereby decrease glomerular filtration pressure.
Overall risk is low unless the patient also being treated with diuretic therapy or the patient has severe azotemia.
Which electrolyte imbalance might ACEi administration contribute?
hyperkalemia secondary to inhibition of aldosterone. However, this is unlikely to be clinically relevant event when given in conjunction with aldosterone antagonist such as spironolactone.
What effects do angiotensin receptor blockers (ARBs) exert?
Blocks the ability of angiotensin II to activate its receptors.
It does not affect the metabolism of bradykinin.
What is a contraindication for angiotensin receptor blockers (ARBs)?
Do not use in severely dehydrated or azotemic patients
What class of drug is Spironolactone?
aldosterone antagonist
How do aldosterone antagonist exert their effects?
Block the effects of aldosterone on the distal convoluted tubule and collecting duct.
Aldosterone
It is a steroid hormone produced by the adrenal cortex when stimulated by Angiotensin II.
It helps control the balance of water and salts in the kidney by keeping sodium and releasing potassium from the body.
What are the effects of chronic exposure to aldosterone?
Induces vascular remodeling in the glomerulus to retain sodium and water resulting in systemic hypertension.
Aldosterone also exerts proinflammatory effects promoting fibrosis.
What is a primary indication for use of spironolactone?
Hyperaldosteronism
When is it reasonable to suspect hyperaldosteronism in cats?
hypertension
hypernatremia
hypokalemia
mostly in chronic kidney disease
What is a potential adverse effect of spironolactone?
development of hyperkalemia. However, this is unlikely unless used with ACEi, ARBs or Beta blocker
Dihydropyridines
Dihydropyridines are a type of calcium channel blocker (CCB) that block calcium channels located in the muscle cells of the heart and arterial blood vessels, thereby reducing the entry of calcium ions into the cells. By blocking these channels, CCBs promote:
vasodilation
increase strength in contractility
minimal effect on cardiac conduction though the decrease in blood pressure may trigger a reflex tachycardia.
E.g. Amlodipine and Nicardipine
What is first line treatment for antihypertensives in cats?
Amlodipine because it has shown to be more effective than ACEi.
If the cat is refractory to amlodipine, then it may require an addition of ACEi or ARB
Side effects of CCBs
Reflex tachycardia
weakness, lethargy and decrease in appetite
intrarenal hemodynamics –> CCB promotes preferential afferent arteriolar dilation over the efferent arteriole, which may result in increased intraglomerular pressure, resulting in damage to the glomerulus and worsening proteinuria.
Adrenergic Antagonist
It can help manage SHT, especially if the underlying mechanism is sympathetically driven.
Prazosin
Selective alpha 1 antagonist to promote smooth muscle vascular relaxation.
Acepromazine
Dopamine antagonist with the potential to cause hypotension and GI upset
Atenolol
Beta 1 selective antagonist
Decreases heart rate and contractility
Reduces renin release and peripheral vascular resistance
Used more in cats with SHT and hypethyroidism
Used in dogs as adjunct for refractory SHT with reflex tachycardia
Propanolol
Non-selective beta antagonist
Decreases heart rate and contractility
Reduces renin release and peripheral vascular resistance
What is an adverse side effect of atenolol
Excessive bradycardia
Labetalol
Injectable mix of alpha and beta antagonists.
Used to manage severe acute hypertension
promotes vasodilation and prevents associated tachycardia
The use has been explored in dogs undergoing craniotomy or adrenalectomy
Hydralazine
Promotes vasodilation by altering smooth muscle intracellular metabolism.
works primarily on arteries
Causes vasodilation, afterload reduction and lowering of blood pressure
The mechanism is not entirely understood but the end result is smooth muscle relaxation and decrease in peripheral vascular resistance.
It is not used as a first-line drug but used as an adjunct in chronic management.
Injectable form used in urgent/emergent treatment due to its potent vasodilatory effects, and rapid onset.
What are adverse side effects to hydralazine?
Arteriolar vasodilator
excessive or irreversible hypotension
reflex tachycardia
sodium and water retention
GI upset
Sodium nitroprusside (SNP)
Arteriolar vasodilator
promotes potent vasodilation through release of nitric oxide.
Nitric oxide diffuses to vascular smooth muscle
decrease influx of calcium, activation of actin/myosin chains and overall contractile forces
Effects: smooth muscle relaxation and decreased vascular tone and peripheral vascular resistance
The injectable form has a short half-life and is easy to titrate, so it is ideally used for hypertensive crises. Administer as CRI.
Used to treat acute hypertensive crises or fulminant CHF
Contraindicated in hypotensive patients
IV nitroglycerine
promotes potent vasodilation through release of nitric oxide.
Nitric oxide diffuses to vascular smooth muscle
decrease influx of calcium, activation of actin/myosin chains and overall contractile forces
Effects: smooth muscle relaxation and decreased vascular tone and peripheral vascular resistance
The injectable form has a short half-life and is easy to titrate, so it is ideally used for hypertensive crises.
No risk of cyanide poisoning
What are the adverse side effects associated with sodium nitroprusside?
generation of cyanide and thiocyanate at high doses and prolonged use.
Patients with kidney and liver disease have decreased metabolism, therefore greater risk of cyanide toxicity.
Clinical signs of toxicosis: metabolic acidosis, depression, stupor, seizures
Fenoldopam
Selective agonist of dopamine 1 receptor. Promotes peripheral and renal vasodilation and natriuresis
Increases glomerular filtration rate
Injectable has a short half life.
Good potential for application in hypertensive crisis, but needs further investigation in vet med.
Class 1 Antiarrhythmics
Sodium channel blockers
Interferes intracellularly with sodium conduction through sodium channels
Subclassification determined by potency of effects on sodium channel, activated/inactivated blockade and effects on other channel receptors.
Class 1A antiarrhythmic agents
Quinidine and procainamide
Effective against ventricular and supraventricular arrhythmias.
fast sodium channel blocking effects and moderate blockade of rapid component of the delayed rectifier potassium current resulting in action potential elongation.
Procainamide
Class 1 A antiarrhythmic
Sodium channel blocker
Depresses conduction velocity and prolongs refractory period in a variety of tissues, including atrial and ventricular myocardium
Administer slowly IV over 5-10 minutes to prevent hypotension
Adverse effects more commonly associated with cats and humans; include anorexia, nausea, and vomiting
Class IB Antiarrhythmic
Inhibits fast sodium channels, primarily in the open and inactivated state, with rapid onset.
Sodium current is also inhibited, resulting in the shortening of action potential in normal myocardial tissue
Lidocaine and mexiletine
Lidocaine
Class IB antiarrhythmic
Sodium channel blocker.
The ability of lidocaine to block sodium currents is better during acidosis.
Benefit: minimal hemodynamic, SA, AVN affect at standard doses
Hepatic clearance determines serum concentration
Heart failure, hypotension, and severe hepatic disease can decrease lidocaine metabolism and predispose patients to lidocaine toxicity.
Adverse effects: higher incidence in cats
Nausea, vomiting, lethargy, tremors, seizure activity (usually symptoms stop when lidocaine is discontinued)
Dosing: Bolus 2mg/kg over 20-30 seconds; bolus can be repeated up to 8mg/kg within 10 minute period barring adverse effects
CRI: 25-75mcg/kg/min
Mexiletine
Class 1B antiarrhythmic
most common oral class in dogs
Highly protein-bound and excreted by the kidneys
Use and adverse effects similar to Lidocaine (rarely used in cats because of adverse effects)
Tocainide
Class 1B antiarrhythmic
Similar to lidocaine, rarely used in small animals because of high incidence of serious adverse effects including renal failure and corneal dystrophy
Class 1C Antiarrhythmic
Potent blockade of the open state fast sodium channel with greater effects as the depolarization rate increases
These agents prolong the refractory period in atrial and ventricular tissues
Propafenone and Flecainide
Propafenone
Class 1C antiarrhythmic
used to treat narrow complex tachyarrhythmias
usually combined with diltiazem
also has mild beta blocking properties
Flecainide
Class 1C antiarrhythmic
potent negative inotropic properties
Side effects include GI, but not commonly seen
Rarely used in veterinary medicine
Monitor heart rate, blood pressure and ECG when administering
Class II antiarrhythmic
Beta-adrenergic antagonists or beta-blockers are the most used cardiovascular drugs.
Must be cognizant of animals’ underlying disease when prescribing.
Beta-blockers contraindicated in patients with evidence of sinus nodal dysfunction, AVN conduction disturbances, pulmonary disease or CHF (must be evaluated for fluid retention and condition must be stabilized before implementing beta-blockade).
Reduces heart rate and myocardial oxygen demand and increases atrioventricular conduction time.
Inhibits pacemaker current I(f) that promotes proarrhythmic depolarization in damaged cardiomyocytes
Inhibits calcium current by decreasing tissue cyclic adenosine monophosphate levels ; the magnitude of effects depends on the sympathetic state. Greater effect with higher adrenergic states
Beta-adrenergic antagonists slow AVN conduction in SVT by slowing sinus discharge rate in inappropriate sinus tachycardia and suppresses ventricular tachycardia that may be exacerbated by increased sympathetic tone.
Used to treat supraventricular and ventricular arrhythmias.
Also used in HCM to control heart rate and decrease myocardial oxygen demand
Can cause hypotension due to decreased heart output.
Extremely low dosages must be used with patients with systolic myocardial dysfunction. Because of that, beta blockers are not generally first choice for acute anti-arrhythmic therapy because the amount required is not well tolerated.
Propranolol
Non-selective beta receptor antagonist (targets both beta-1 and 2 receptors).
Function: decrease heart rate and contractility. Decrease renin release and peripheral vascular resistance
Esmolol
Class II Antiarrhythmic
Short-acting Beta-1 blocker that can help control sympathetically driving ventricular tachycardia . Administered as a CRI on telemetry.
Side effects: Negative inotropic effects may be too pronounced in some patients and cause cardiovascular collapse. Requires blood pressure monitoring.
Atenolol
Class II antiarrhythmic.
The most common oral beta blocker in small animals.
Relative beta 1 selectivity and long half-life compared to propranolol.
Water soluble and eliminated by the kidney.
Metoprolol
Class II antiarrhythmic.
Common oral beta blocker in small animals.
Long half-life compared to propranolol.
Metabolized and eliminated through the liver.
Class III Antiarrhythmic agents
Block the repolarization of I(k) resulting in prolongation of action potential durations and effective refractory period.
Blocks rapid component of I(k) instead of the slow component – therefore effects are accentuated at slower heart rates rather than at the problematic tachyarrhythmic rates.
Puts patients at risk of early afterdepolarization (accounts of proarrhythmic effects of class III AA drugs) - risk is increased in patients with hypokalemia, bradycardia, intact females, increasing age, macrolide antibiotic therapy/other drug therapies
Amiodarone
Class III Antiarrhythmic
Alpha and Beta blocking properties.
Effects on sodium, potassium, and calcium channels.
Broadest spectrum exhibiting properties of all 4 AA classes.
Makes action potential durations more uniform throughout the myocardium and has the least reported proarrhythmic activity of any of the class III agents.
Used for refractory tachyarrhythmias, both atrial and ventricular
Significant side effects in dogs, including hepatopathy and anaphylaxis.
Monitor heart rate, blood pressure and ECG with administer.
Available as oral or injectable.
Major drawback: associated with a host of multi-systemic adverse side effects that do not occur with sotalol.
Adverse side effects (more common with higher maintenance doses): vomiting, anorexia, hepatopathies, thrombocytopenia
Two brands:
Cardarone IV, Nextarone
Cardarone IV
IV formulation of amiodarone
Serious side effects attributed to vasoactive solvents in the formulation.
Side effects include life-threatening hypotension, anaphylaxis, bradycardia, acute hepatic necrosis, and death.
Nexterone
Premixed aqueous solution of IV amiodarone.
No adverse hemodynamic effects of other adverse cllinical effects in healthy research dogs.
Class IV antiarrhythmic agents
Calcium channel antagonist
Slow AVN conduction and prolong the effective refractory period of nodal tissue
Effects are more notable at faster stimulation rates and in depolarized fibers.
Effective in slowing the ventricular response rate to atrial tachyarrhythmias and can prolong AVN’s effective refractory period to terminate AVN-dependent tachyarrhythmia.
It is mainly indicated to reduce the rate of arrhythmias passing through the AV node, such as supraventricular arrhythmias.
Major negative inotropic effects due to interactions with calcium in the smooth muscles.
Causes vasodilation
Limit amount of calcium available in cardiac contractility.
Diltiazem is the most widely used IV antiarrhythmic drug
Diltiazem
Class IV antiarrhythmic
Calcium channel blocker.
Minimal negative inotropic effects.
Used in dogs to immediately terminate a severe AVN-dependent tachyarrhythmia or slow ventricular response rate to an atrial tachyarrhythmia.
Adverse side effects: hypotension and bradyarrhythmia.
Administer IV slowly over 2-3 minutes.
Oral diltiazem administered TID.
Digoxin
Class V anti-arrhythmic (other)
Effects occur indirectly through the autonomic nervous system by enhancing central and peripheral vagal tone.
Used as an antiarrhythmic due to its ability to slow AV conduction time and have parasympathomimetic effects
Treats SVT to slow AV nodal conduction and reduce ventricular rate
Positive inotrope that will increase cardiac contractility in systolic disease
The risk of toxicity manifests as neurological, GI, and cardiac involvement.
Predisposed to toxicity if the patient has renal dysfunction, hypokalemia, elderly, chronic lung disease, hypothyroidism.
Magnesium Sulfate
1st line treatment for torsades de pointes
Used to treat hypomagnesemia
Administer slowly IV @ 30mg/kg over 5-10 minutes
Adverse effects: CNS depress, weakness, bradycardia, hypotension, hypocalcemia and QT prolongation
Adenosine
Used in humans to terminate AVN dependent tachyarrhythmias.
No study to date has shown effectiveness in dogs and cats.
Antiarrhythmic devices/procedures
Transvenous radiofrequency catheter ablation
Permanent pacemaker implantation
Implantable cardioverter defibrillators
Transverse radiofrequency catheter ablation
Identify reentrant circuit or automatic focus for ablation
Deliver radiofrequency energy via electrode causing thermal desiccation of small volume tissue to interrupt tachycardia circuit
Permanent pacemaker implantation
Manage bradyarrhythmias
Implantable cardioverter defibrillators
experimental in dogs
Anticholinergics
class of drugs taht block the action of acetylcholine (ACh), a neurotransmitter that sends signals between cells that affect a bodily function.
By blocking ACh at synapses in the central and peripheral nervous system, anticholinergics inhibit the parasympathetic nervous system.
Atropine
Anticholinergic
inhibit acetylcholine at muscarinic receptors
Clinical effects include increasing heart rate, resolving vagally mediated bradycardia, decreasing GI motility, pupillary dilation, bronchodilation, urinary retention and drying or secretion
Most commonly used to treat vagal-mediated bradycardias and toxicities
Able to pass the placental barrier.
Glycopyrrolate
Anticholinergic
inhibit acetylcholine at muscarinic receptors
Clinical effects include increasing heart rate, resolving vagally mediated bradycardia, decreasing GI motility, pupillary dilation, bronchodilation, urinary retention and drying or secretion
Most commonly used to treat vagal-mediated bradycardias and toxicities
Glycopyrrolate is associated with more stable cardiovascular system with fewer arrhythmias
Glycopyrrolate has a stronger anti-saliva secretion effect than atropine
It does not pass the placental barrier and, therefore, is the agent of choice for pregnant animals.
Diuretics (7 classes)
Loop diuretics
Osmotic Diuretics
Potassium sparing diuretics
Thiazide diuretics
Carbonic anhydrase inhibitors
Aldosterone Antagonist
Aquaretics (new)
Goals for diuretic therapy
Enhanced excretion of retained water, solutes and toxins
Promote urine flow
decrease urine concentration of solutes and toxins
Common indications for diuretic use
Oligoanuric acute renal failure
decompensated kidney disease
Congestive heart failure
ascites from liver failure
other fluid and electrolyte disorders
When it is justified to use diuretics to treat edema?
Only when fluid retention is caused by an increase in hydrostatic pressure.
When vascular permeability is increased, further depletion of vascular volume with diuretics is rarely indicated and often detrimental
Adverse effect of exaggerated diuresis
May activate RAAS by reducing intravascular volume and ventricular filling and may subsequently decrease tissue perfusion.
Therefore, diuresis requires therapeutic monitoring
Pathologic conditions that contribute to diuresis
pressure natriuresis
osmotic diuresis
pressure natriuresis
A negative feedback in hypervolemic hypertensive states
Diuretics operating on which part of the nephron is most effective and why?
Diuretics at the loop of Henle are the most effective because of the large amount of filtrate delivered to this site and the lack of efficient distal reabsorption region.
What triggers an increase to antidiuretic production?
Elevated plasma osmolality
hypovolemia
hypotension
(lesser extent) nausea
increased concentration of angiotensin II
Osmotic diuresis
passive mechanism due to abnormal urine concentration of osmotically active solutes such as glucose and sodium
What is required for antidiuretic hormone to function?
functional renal tubular system
medullary concentration gradient of sodium and urea
functional ADH receptor system
without any one of these factors will result in inappropriate diuresis
What may affect function of diuretics that work on proximal tubule?
Diuretics that work on proximal tubule can modulate a greater bulk of sodium, but their efficacy may be overcome by distal compensatory increases in sodium reabsorption.
What may limit efficacy of diuretics operating on distal tubule?
Diuretics operating on distal tubule may be limited by small amount of sodium reaching distal tubule
Osmotic Diuretics
hyperosmolality causes water shift from the intracellular fluid compartment to extracellular space, causing ECF expansion
Used to contract ICF in cases with cerebral edema associated with an increase in ICF and elevated intracranial pressure
Contraindicated for patients in or at risk of heart failure.
Effective in patients with anuric or oliguric rental disease, cerebral edema and increased intraocular pressure
eg. Mannitol
Mannitol
osmotically active non reabsorbed sugar alcohol
filtered by the glomerulus; does not undergo tubular reabsorption, thereby increasing tubular flow rate and osmotic diuresis
An increase in tubular flow rate reduces urea absorption, resulting in increased urinary clearance and serum urea concentration.
Potential benefits of mannitol:
Prostaglandin-induced renal vasodilation
reduced tendency of erythrocytes to aggregate
reduced renal vascular congestion
reduced hypoxic cellular edema
protection of mitochondrial function
reduced oxidative damage
renoprotectant when administered before toxic or ischemic event
*No data supports above benefits in renal failure cases
At high doses, mannitol can cause renal vasoconstriction and tubular vacuolization
Use cautiously with oliguric animals to avoid volume overload, hyperosmolality and further renal damage.
Carbonic Anhydrase Inhibitors
Clinical application of carbonic anhydrase inhibitors - mainly used to treat elevated intraocular pressure in glaucoma.
Work by suppressing the activity of carbonic anhydrase, an enzyme in red blood cells that converts carbon dioxide into carbonic acid and bicarbonate ions. CAIs can reduce secretion of H+ ions by the kidney tubule and can also impair the reabsorption of sodium, chloride and bicarbonate.
eg. Acetazolamide
Carbonic anhydrase also located on other organs.
Blockade of ocular and brain CA decreases the production of aqueous humor and CSF.
Blockade of red blood cell CA hampers carbon dioxide transport
Gastric CA - minimally affected by inhibitors.
Acetazolamide
Carbonic anhydrase inhibitor
Function: diuretic
Inhibits mostly the type II (cytoplasmic) and IV(membrane) proximal tubular carbonic anhydrases, decreasing the reabsorption of sodium bicarbonate.
Results in metabolic acidosis and natriuresis - minimal and self-limiting because progressively less bicarbonate is filtered as the proximal tubule becomes less responsive to carbonic anhydrase inhibition and the distal sodium reabsorption increases to compensate for the proximal losses.
Loop Diuretics
Binds to and inhibits Na+-K+-2Cl- cotransporters on the apical membrane of epithelial cells of the thick ascending loop of Henle.
Inhibition of reabsorption of both Na and Cl, ions remain in the tubular lumen and
water follows, resulting in diuresis and increased Na secretion
○ High sodium concentration later in the nephron results in increased sodium and
potassium exchange, which leads to increased potassium secretion as well
○ Increased calcium secretion also occurs
○ Also believed to decrease renal vascular resistance and increase renal blood
flow
Prototypical loop diuretic: furosemide
Torsemide
Furosemide
Loop diuretic
Improves renal parenchymal oxygenation by decreasing the energy expenditure of the secondary active Na-K-2Cl transporter
Mannitol + furosemide > synergistic in inducing diuresis in dogs with acute renal failure
Relative short half-life: 1-1.5 hours in dogs > can result in intermittent rebound sodium retention with loss of efficacy.
most commonly used in patients in heart failure.
Torsemide
potent loop diuretic of pyridine-sulfonylurea class
longer half-life (8 hours)
higher bioavailability (80%-100%)
strong diuretic effect than furosemide
Large scale study - effective in dogs with mitral valve disease, but high rate of renal adverse events.
Additional benefits observed in other species: vasodilation, improved cardiac function, reduction of myocardial remodeling, mineralocorticoid-receptor blockade with anti-aldosterone effect - has not been shown in small animals
Thiazide diuretics
exert their action by inhibiting the NaCl cotransporter on distal tubule.
Mainly used for anticalciuretic properties to prevent calcium-containing uroliths
Managing CHF in conjunction with other diuretics
treating ascites associated with right-sided heart failure
also used for treating polyuria of diabetes insipidus by inducing a mild hypovolemia and increasing proximal sodium conservation.
eg. Hydrochlorothiazide
Aldosterone Antagonist
Antagonize aldosterone by binding to its receptor in the late distal tubule and the collecting duct
increases sodium, calcium and water excretion and decreases potassium loss
e.g. Spironolactone and eplerenone
When to suspect hyperaldosteronism
concurrent hypernatremia, severe hypokalemia
Spironolactone
Aldosterone antagonist
potassium sparing diuretic
Best used in cases of hyperaldosteronism
Main clinical applications in liver and heart failure.
Also used as an antihypertensive in hyperaldosteron cases.
Usually, it is in combination with a more efficient loop diuretic.
Also seems to have a positive effect on myocardial remodeling and the reduction of cardiac fibrosis
Commonly added to other diuretics to reduce their potassium-wasting effects
Main adverse effect: development of hyperkalemia
potassium-sparing diuretics
Inhibit sodium reabsorption in the distal tubule and the collecting duct; suppressing the driving force for potassium secretion.
Only weak diuretic and natriuretic properties
Mostly used to counterbalance potassium-wasting effects of proximal diuretics.
e.g. Amiloride and triamterene
Aquaretics
New class of diuretics that antagonize the vasopressin V2 receptor in the kidney and promote solute-free water clearance
Vaptans - vasopressin receptor antagonist
Clinical use: free water rention in hypervolemic hyponatremia or normovolemic hyponatremic
drugs: conivaptan, tolvaptan and mozavaptan
Not used in small animals
Pimobendan
Function: positive inotropic and vasodilatory effects
Phosphodiesterase III inhibitor
Calcium sensitization
Used to treat congestive heart failure
Mechanism of Pimobendan via calcium sensitization
increase contractility via increasing binding affinity to the regulatory site on troponin C for calcium
sensitizes the myocyte contractile apparatus to calcium without increasing the amount of calcium within the cell.
Pimobendan is not dependent on catecholamines
Mechanism of pimobendan via phosphodiesterase III inhibition
increase contractility by increasing intracellular calcium levels.
PDE III inhibition increases cyclic adenosine monophosphate (cAMP), which in turn increases cAMP-dependent protein kinase.
Increase in calcium sequestration during diastole and increase in calcium influx during systole - both contribute to positive inotropy
PDE III and PDE V are found in vascular smooth muscle. Inhibition of PDE III and PDE V increases intracellular cAMP and cGMP - which facilitates calcium update through intracellular storage sites. Results in reduction of available calcium for contraction > greater vascular smooth muscle relaxation.
Elimination of Pimobendan
undergoes hepatic demethylation
bioavailability and duration of affect of Pimobendan
Pimobendan is highly protein bound with greater than 90% bioavailability.
Maximal cardiac effects at 2-4 hours following oral administration and persists up to 8 hours.
Clinical use of pimobendan
FDA approved to treat CHF with myxomatous mitral valve degeneration or DCM
Adverse effects of pimobendan
generally well tolerated but may cause GI upset - inappetence, vomiting, diarrhea and lethargy
Anti-hypertensives (7 mechanisms of action)
Angiotensin-converting enzyme inhibitor
Angiotensin receptor blocker
aldosterone antagonist
calcium channel blocker
alpha 1 antagonist
beta antagonist
arteriolar vasodilator
Angiotensin-converting enzyme inhibitor (ACE inhibitor)
Family of drugs designed to disrupt the renin-angiotensin-aldosterone system (RAAS).
Medications function by inhibiting the conversion of angiotensin I to angiotensin II.
ACE inhibitors can decrease proteinuria
promote vasodilation, venodilation and reduction in plasma volume with reduction in systolic blood pressure
ACE inhibitors can cause decreased metabolism of vasodilatory agent bradykinin –> further reduction in vascular tone
Clinical application of ACE inhibitors where systemic hypertension is caused by known or suspected increase in RAAS - most commonly related to chronic kidney disease and or glomerular disease.
Most commonly considered 1st line treatment for dogs (not cats).
Generally well tolerated.
Biggest concern: potential to worsen glomerular filtration rate and renal function through preferential dilation of the efferent arteriole (thereby reducing glomerular filtration pressure)
e.g. Enalapril, benazepril, lisinopril
Enalapril
Angiotensin Converting Enzyme Inhibitor
Benazepril
Angiotensin Converting Enzyme Inhibitor
Lisinopril
Angiotensin Converting Enzyme Inhibitor
Angiotensin receptor blockers (ARBs)
Class of drugs that block angiotensin II from its receptor.
Does not affect the metabolism of bradykinin
ARBs can decrease proteinuria
promote vasodilation, vasodilation and reduction in plasma volume with a reduction in systolic blood pressure
Side effects: similar side effects as ACEi; avoided or cautiously used in patients with severe dehydration or azotemia.
e.g. Telmisartan, losartan
Telmisartan
Angiotensin receptor blocker
Calcium channel blockers
decrease calcium influx into cardiac tissues (antiarrhythmic properties) and vascular smooth muscles (antihypertensive properties)
May cause reflex bradycardia
Other side effects could include weakness, lethargy, decreased appetite
CCBs promote preferential afferent arteriolar dilation over the efferent arteriole, which increases intraglomerular pressure, which could damage the glomerulus and worsen proteinuria.
Amlodipine
Belongs to the dihydropyridines family
Calcium channel blocker
Relative selectivity for vascular smooth muscles so promotes vasorelaxation and reduces systemic vascular resistance
An associated decrease in blood pressure may trigger reflex tachycardia.
First-line antihypertensive of choice for managing SHT in cats
Phentolamine
Alpha 1 adrenergic antagonist
used in hypertensive crisis, specifically as rescue therapy during pheochromocytoma surgery
phenoxybenzamine
Alpha 1 adrenergic antagonist
commonly used to stabilize patients with pheochromocytoma prior to surgical intervention
Vasopressor
Any drug specifically used to cause constriction to blood vessels
increase cardiac afterload, produce vasoconstriction, increase vasomotor tone and systemic vascular resistance
most common pathway is alpha 1 adrenergic agonism
positive inotrope
Any drug specifically used to increase cardiac contractility
most common pathway to achieve this is beta 1 adrenergic agonistm
Negative inotrope
decrease cardiac contractility
Dopamine
Catecholamine and sympathomimetic
Primary receptors: dopaminergic, beta-1 and alpha 1 adrenergic agonist
different doses = different effects
Low range - stimulate urine production in oliguiric or anuric AKI
Intermediate range: predominantly positive inotropic effects
High doses: vasoconstriction/increase in vascular resistance
Effects: increases renal blood flow
improves inotropy
increases heart rate
increases systemic vascular resistance
increases blood pressure
increases cardiac out put
Deliver as a CRI
Side effect: arrhythmias, tachycardia, hypertension
Continuous ECG, BP monitoring recommended
Dobutamine
Sympathomimetic
receptors: Beta-1 and Adrenergic-2 agonist
Effects: improves inotropy
+/- increase in heart rate
Increase in cardiac output
+/- increase in blood pressure
decrease systemic vascular resistance
Deliver as a CRI
Side effects: arrhythmias, tachycardia, hypertension, bradycardia
Monitoring: ECG/BP continuous
Norepinephrine
catecholamine and sympathomimetic
Receptors: Alpha-1 and beta 1 adrenergic agonist
Effects: increase in inotropy
decrease in heart rate
increase in systemic vascular resistance
increase in blood pressure
Deliver as a CRI
Side effects: arrhythmias, hypertension, bradycardia, excessive vasoconstriction
Epinephrine
Catecholamine
Receptors: alpha 1 and beta 1 adrenergic agonist
Lower doses have predominantly beta agonist effect: vasodilation, bronchodilation, increased cardiac contractility and cardiac output, increased heart rate
higher doses: more alpha 1 adrenergic effects: vasoconstriction
Used to treat anaphylaxis
Side effects: arrhythmia
Monitoring: continuous ECG/BP
Deliver as IV bolus, CRI, IM or intratracheally
Phenylephrine
sympathomimetic
receptor: alpha-1 adrenergic agonist
Effects: decrease in heart rate
increase in systemic vascular resistance (marked vasoconstriction) increase in blood pressure
May improve blood pressure, but the increase in cardiac afterload may decrease stroke volume and cardiac output
Deliver as a bolus or CRI
Side effects: arrhythmia, hypertension, bradycardia, excessive vasoconstriction
Ephedrine
Sympathomimetic
receptors: beta-1 agonist, and alpha 1 adrenergic agonist
effects: increase inotropy
increase in blood pressure
increase in cardiac output
+/- Heart rate
increase in systemic vascular resistance
deliver as a bolus (short duration of effect) or CRI
Side Effects: arrhythmias, tachyphylaxis (reduced sensitivity after repeated administration), hypertension, bradycardia, tachycardia
Vasopressin
receptors?
Effects?
Delivery method?
side effects?
Non-adrenergic hormone AKA anti-diuretic hormone
receptors: V1 vasopressin Agonist
effects: increase systemic vascular resistance
increase blood pressure
Increase in cardiac afterload may decrease stroke volume and cardiac output, resulting in decrease oxygen delivery to tissue
Alternative or conjunctive therapy to epinephrine in CPCR
More effective than epinephrine when patient in acidosis.
deliver as a bolus or CRI
Side effects: arrhythmias, hypertension, bradycardia, excessive vasoconstriction
What stimulates the release of vasopressin?
by which mechanisms?
- increases in plasma osmolality - central chemoreceptors detect systemic osmolality. Peripheral chemoreceptors in mesenteric and portal veins detect changes in osmolality of ingesta. Afferent impulses ascend via vagus nerve to stimulate vasopressin release. Plasma tonicity sened by hypothalamus to stimulate more vasopressin release.
- decreases in blood pressure - shifts osmolality. Baroreceptors in left atrium, aortic arch and carotid sinus sense drops in blood pressure and circulating blood volume. Allows for release of disinhibition of vasopressin release.
- drop in circulating blood volume
Vasopressin release can be inhibited by which drugs?
glucocorticoids
low dose opioids
atrial natriuretic factor
GABA neurotransmitter
Vasopressin receptors:
V1 receptor
location and mechanism of action
found primarily on smooth muscle cells
Activation of voltage gated calcium channels, increases intracellular calcium levels allowing for vasoconstriction.
V1-R in platelets - facilitates thrombosis because of intracellular calcium
V1-R in kidneys decrease blood flow to inner medulla and limit anti-diuretic effects; selective cause contraction of efferent arterials to increase GFR
There are species variations in V1R locations.
Vasopressin receptors:
V2 receptor
location and mechanism of action
Found primarily on basolateral membrane of distal tubule and principle cells of cortical and medullary rental collecting duct
triggers fusion of aquaporins with plasma membrane of collecting duct –> increasing water absorption.
stimulates release of platelets from bone marrow and enhances release of Von Willebrand’s factor and Factor VIII from endothelial cells
Role of vasopressin in homeostasis
regulating fast shuttling of aquaporin-2 to cell surface
stimulates synthesis of RNA encoding aquaporin 2
hereditary nephrogenic diabetes insipidus have V2-R gene mutations
Vasopressin metabolism and excretion
half life is 24 minutes
cleared by renal excretion and metabolized by tissue peptidases
Adverse effects of Vasopressin
contraction of bladder and gallbladder smooth muscles
increase peristalsis
decrease in gastric secretions
increase in GI sphincter pressure
Local irritation at injection site.
If extravasated, may cause skin necrosis
May increase liver enzymes and bilirubin levels
decrease platelet count
hyponatremia
anaphylaxis/urticaria
bronchospams
abdominal pain
hematuria
water intoxication reported with high dose treatment of diabetes
Terlipressin
selective for V1R
prolong duration - 6 hours half life
Used to manage hemorrhagic gastroenteritis
increase adverse effects - peripheral cyanosis/ischemia (use with caution)
Selepressin
V1R agonist
found to reduce risk of coronary ischemia
less adverse effects on mesenteric blood flow and gastric mucosal perfusion
effective substitute for maintaining MAP, reducing vascular leak, edema formation and shortening duration of shock.
Comparative study with norepi -> no improved outcome
Desmopressin acetate
synthetic vasopressin
intranasal and injectable form
binds primarily to V2R
more potent antidiuretic and procoagulant
Streptococcus
gram-positive cocci arranged in chains
Group A streptococci
It can cause pharyngitis, glomerulonephritis, and rheumatic fever in humans.
It rarely causes illness in dogs and cats, although dogs can carry the organisms.
Group C streptococci
rare causes of illness in healthy dogs and cats
Group G
common resident microflora and are the cause of most streptococcal infections in dogs and cats.
Streptococcus canis is the most common.
Streptococcus canis
The main source of infection in anal mucosa in dogs.
May be found in cats in abscesses, pyelonephritis, sinusitis, arthritis, metritis or mastitis
In dogs, it may be the cause of nonspecific infections including wounds, mammary tissues, urogenital tract, skin and ear canal.
May cause toxic shock syndrome in dogs.
Tx: Penicillin-G and ampicillin are effective for most infections
Group D streptococci
Enterococcal
Commensal bacteria that inhabit the alimentary tract of humans and animals
Most commonly see in post op wounds and urogenital infections.
Staphylococcal Infection
Gram positive bacteria, developing resistance to antimicrobials.
cephalosporins, penicillins and fluoroquinolones decreasing in effectivness.
Gram Negative
significant cause of morbidity and mortality in critically ill patients
Lipid A
known to be toxic
Induces proinflammatory responses and endothelial dysfunction
harmful effects of endotoxin include vasodilation, enhanced vascular permeability, tissue destruction, and activation of coagulation pathways
Apomorphine
Stimulates the chemoreceptor trigger zone to induce emesis as a non-selective dopamine agonist
Side effects: Failure to produce emesis, refractory vomiting, nausea, sedation
Adverse sedative effects can be reversed with an opioid agonist such as naloxone
Alpha-2 Adrenergic Agonist
Induces emesis
Thought to occur through the stimulation of the chemoreceptor trigger zone at least in part through the area of postrema of the medulla oblongata
Concerns include sedation, hyperglycemia, bradycardia, increased systemic vascular resistance, and increased cardiac afterload. Drug: dexmeditomidine
Xylazine
Alpha-2 adrenergic agonist
Dexmeditomidine
Alpha-2 adrenergic agonist
Peripheral acting emetics
most common include hydrogen peroxide, syrup of ipecac, and salt paste
syrup of ipecac no longer used due to potential for abuse and fatal cardiac arrhythmia.
Salt paste no longer clinically used due to risk of hypernatremia and questionable efficacy
Hydrogen peroxides: irritate oral, esophageal and gastric mucosa
Phenothiazine Derivatives
Acepromazine, chlorpromazine and prochlorperazine
Reduce emesis through blockade of dopamine receptors in CRTZ and emetic centers
No longer used because of potential side effects and availability of more effective agents
Produce an alpha-1 adrenergic antagonist which causes systemic vascular resistance and vasodilation; can result in hypotension
Metoclopramide
Prokinetic
Dopamine and serotonin antagonist and cholinergic agonist
Increases lower esophageal sphincter tone, facilitates gastric emptying
short half-life, thus usually prescribed as a CRI
contraindication: mechanical obstructions in the GI tract and intussusceptions
Ondansetron
Serotonin (5-HT3) Antagonist
Block serotonin receptors in the CRTZ and peripherally
Appear to be more effective than phenothiazine and metoclopramide
Side effects are rare
Maropitant
Neurokinin-1 (NK) antagonist
Blocks substance P at vomiting center in the brain
Proton Pump Inhibitors
Omeprazole, pantoprazole, esomeprazole
Inhibits Na/K ATPase pump activity
Recommended treatment for acid suppression; controls proton deposition in the gastric lumen and hydrochloric acid secretion
H2 Histageneric Antagonist
Famotidine, ranitidine, cimetidine
H2 blockers
Specific antihistamines that reduce the action of histamine at histamine receptors on gastric parietal cells; reduce stomach acid
Sucralfate
Sucrose sulfate-aluminum complex
Binds to locally injured GI lining and creates a physical barrier
Promotes bicarb production and may increase production of prostaglandin E2
Commonly used to treat GI or duodenal ulcers
Can also be beneficial in esophageal strictures
Misoprostol
Synthetic prostaglandin E1 analogue
It improves gastric blood flow, decreases gastric acid production, increases mucus production and bicarb secretion, and promotes cell turnover.
Specifically used to help prevent NSAID-induced GI injury and ulceration
Also has effects on myometrial contraction
Wear gloves when handling
Beta-2 adrenergic agonist
Bronchodilators and enhance mucus clearance via mucociliary system
Relaxes smooth muscle in respiratory passageways
May also cause vasodilation in muscles.
Commonly used to trat asthma in cats, chronic bronchitis in dogs or hyperkalemia
drugs: terbutaline, albuterol, salmeterol
Most common side effects: tachycardia, increased cardiac contractility and arrhythmia
Terbutaline
beta-2 adrenergic agonist
Bronchodilator
Commonly used to treat asthma in cats, chronic bronchitis in dogs or hyperkalemia
Administered orally or parenterally
Common side effects are tachycardia, increased cardiac contractility and arrhythmia
Albuterol
beta-2 adrenergic agonist
Bronchodilator
administered via inhaler
Common side effects are tachycardia, increased cardiac contractility and arrhythmia
I.e. albuterol toxicity
Methylxanthines
bronchodilator
Inhibit phosphodiesterase and blocking adenosine
believed to inhibit leukotriene synthesis and reduce inflammation
Narrow therapeutic range
Occasionally used to treat pulmonary hypertension and tracheal collapse.
adverse effects are tachycardia, arrhythmia and GI signs
examples of Methylxanthines:
Caffeine and theobromine - toxic to animals
Diphenhydramine
Antihistamine
Inverse agonist of H1 histagenergic receptor (produces opposite effect of histamine since its an inverse agonist)
influences muscarinic acetylcholine receptors, sodium channels and potentially reuptake of serotonin
Predominately used for:
- reducing signs of acute allergic reactions
- treat increase capillary permeability secondary to histamine release.
- reducing symptoms of histamine release from Mast cell tumors.
- crosses the blood brain barrier –> affect CNS; cause sedation or excitement (rare in dogs and cats)
Do not administer SQ because of irritating effects.
Meclizine
antihistamine
Used for patients with vestibular disease
Antiemetic and motion sickness
Cyproheptadine
antihistamine
serotonin agonist
Used as a mild appetite stimulant
Can also be used to treat serotonin syndrome –> evidence to support efficacy is limited
Mirtazapine
antihistamine
Has an effect on serotonin, adrenergic, dopamine and muscarinic receptors
weak appetite stimulant and antiemetic
Asprin
nonsteroidal anti-inflammatory drug
blocks platelet cyclo-oxygenase (COX)1 which causes inhibition of thromboxane A2 (TXA2)
Effect is irreversible
Primarily used to treat hypercoagulable states or states of increased platelet reactivity
Clopidogrel
Thienopyridine class drug
Blocks adenosine diphosphate (ADP) induced platelet aggregate through binding the platelet P2Y12 receptor
Primarily used to treat hypercoagulable states or states of increased platelet reactivity
Does not remove already formed blood clots
Heparins
Naturally occurring - stored within mast cells and released into vasculature at sites of tissue injury
Drug - Unfractionated heparin: heparin sulfate
can be reversed using protamine sulfate
Drug - low molecular weight heparins: Dalteparin and enoxaparin
Does not dissolve preexisting blood clots
Enoxaparin
Low molecular heparin
Associated with fewer bleeding events, more predictable absorption and can be given less frequently than UFH
Inhibits factor Xa
Incompletely reversed by protamine sulfate
Heparin sulfate
Unfractionated heparin
Binds to antithrombin and inhibits factors IIA, IXa, Xs, XIa, and XIIa
can be reversed using protamine sulfate
Direct Factor Xa Inhibitors
Rivaroxaban and apixaban
Does not require antithrombin for factor Xa inhibition and clinical effects
Does not dissolve blood clots that have already formed
Rivaroxaban
Trade name: Xarelto
Direct Factor Xa inhibitor
Oral anticoagulant used to prevent or treat thrombosis in high risk patients
Contraindicated in patient with uncontrolled pathologic bleeding, severe hepatic disease, hepatic disease associated with coagulopathy or with significant renal impairment
Thombolytics
Drugs: streptokinase, urokinase, tissue plasma activator (t-PA)
Not widespread in vetmed
Should be administered as early as possible to be most effective
contraindicated or inappropriate in situations of known coagulopathy, states of active bleeding, cardiac thrombi, neoplasia that invades the vasculature and infective endocarditis
Complication associated with thrombolytic agents: Bleeding
What are the two pathways in the arachidonic acid cascade?
1) 5-lipoxygenase (LOX)
2) Cyclo-oxygenase (COX)
What is the first thing that occurs when tissue is injured in the process of inlammation?
Arachidonic acid is released from the cell membranes, triggered by phospholipase A2
What occurs during LOX?
Arachidonic acid is metabolized into leukotrienes by LOX
What occurs during the Cox pathway?
arachidonic acid is metabolized into prostaglandins, prostacyclin and thromboxanes by COX
Two isoenzymes of COX
COX 1 and COX2
COX 1
Primarily responsible for basal prostaglandin production for normal homeostatic processes within the body, including gastric mucus production, platelet function, and, indirectly, hemostasis.
COX 2
found at sites of inflammation and some basal production of constitutive prostaglandins.
Ideally, selective inhibition of prostaglandins produced primarily by COX-2, however currently there are no pure COX2 inhibitors.
Arachidonic Acid
Present in phospholipid portion of plasma membrane.
It is an inflammatory mediator which causes vasodilation and vasoconstriction.
Inflammation = vasodilation
blood coagulation = vasoconstriction
Phospholipase A2 releases Arachidonic Acid.
Arachidonic Acid can then be broken down to prostaglandins or the leukotriens by COX or LOX respectively.
What inhibits phospholipase A2?
steroids
Therefore steroids are anti-inflammatory
NSAIDs function and adverse effects
NSAIDs inhibit COX enzyme, which inhibits formation of prostaglandins.
NSAIDs are metabolized by the liver and excreted by the kidneys.
Give with food.
Adverse side effects:
Because prostaglandins play a role in maintaining GI mucosal integrity, some of the side effects of NSAIDs are gastroenteritis, ulceration, and potentially GI perforation.
Use cautiously in patients with hypotension, hypovolemia, pre-existing renal disease (due to increased potential for renal vascular vasoconstriction which could lead to worsening of renal insufficiency)
use with caution perioperatively because of decreased platelet function –> may increase risk of operatie hemorrhage.
leukotrienes
Produced when lipoxygenase acts on arachidonic acid.
Lipid-like bronchoconstrictors that are released during the inflammatory response.
Asthma is treated with inhaled and oral medications that include beta-2 adrenergic agonist anti-inflammatory drugs and leukotriene antagonist
Prostaglandins
Produced when cyclooxygenase (COX) acts on arachidonic acid.
Many functions including:
Inflammation, Reproduction, gastric secretions, blood clotting
Two types of prostaglandins depending on tissue type.
Location: Platelets –> Thromboxane
Location: Endothelium –> Prostacyclin
Thromboxane –>vasoconstriction +bronchoconstrictor = procoagulation
Prostacyclin –> vasodilation + prevent platelet aggregation = anticoagulation
Prostaglandins protect GI mucosa from environment of stomach
Thromboxane (3 functions)
Vasoconstrictor
increases platelet aggregation
bronchoconstrictor
Prostacyclin
“keeps blood cyclin”
1. vasodilator
2. decreases platelet aggregation
Prostaglandin (PGE2) functions
- Promote fever
- promotes pain
Steroids
Inhibits Arachidonic acid
prostaglandins and leukotriens
What promotes Phospholipase A2?
tissue injury
thrombin
bradykinin
angiotensin II (stimulates vasoconstriction)
epinephrine (stimulates vasoconstriction)
meloxicam
NSAID
carprofen
Rimadyl, Carprovet, Truprofen
NSAID
firocoxib
Previcox or Equioxx
NSAID
deracoxib
Deramaxx
NSAID
grapiprant
Galliprant
NSAID
robenacoxib
Onsior
NSAID
Endogenous steroids are produced by which organ?
Adrenal gland, gonads and placenta
What are the two classes of corticosteroids?
Glucocorticoids and Mineralcorticoids
Function of Gluococorticoids
Increase carb, protein and fat metabolism
growth (specifically in utero)
increase contractile activity of left ventricle
signal kidneys to reabsorb sodium
inhibit activity of cells that are used to promote connective tissue production
alter turnover of bone
stop GI from absorbing calcium and promote calcium excretion from kidney
Inhibit formation of prostaglandins and bradykinins -> inhibit inflammation
suppress white blood cells (lymphocytes and eosinophils)
Antimicrobial stewardship and deescalation (3 key components)
- optimize antimicrobial use
- minimize the duration of prescription
- Re-escalating antimicrobial therapy when culture and susceptibility results have returned
Exceptions to 7 day administration of antimicrobials
- endocarditis
- prosthetic implants
- persistent neutropenia
Time dependent antimicrobials efficacy
only efficacious when [drug] in plasma is above the MINIMUM INHIBITORY CONCENTRATION (MIC) for that pathogens.
Note: in critically ill patients, ft>MIC may be 100%
ft>MIC
percentage of time drug concentration is above the minimum inhibitory concentration.
Concentration dependent antimicrobials
usually bind irreversibly to their target
their efficacy is usually predicted by comparing the maximum concentration (Cmax) to the MIC)
Critical illness Cmax:MIC should be >8
How might fluid overload affect antimicrobial pharmacokinetics?
Depending on if the antimicrobial is hydrophilic or lipophilic
Volume of distribution of the antimicrobial will be affected
e.g. If the antimicrobial is hydrophilic, the net effect of volume distribution is higher, decreasing [antimicrobial] in plasma –> decreasing [antimicrobial] in target tissue
Effects of AKI on antimicrobial elimination and considerations
AKI –> elimination via kidney is decreased therefore fT>MIC is increased.
However, must consider risk of toxicity is increased due to drug accumulation
Effects of augmented renal clearance (ARC) on antimicrobial elimination
Augmented renal clearance –> increased removal of substrate by the kidneys
Antimicrobials may remain at subtherapeutic levels resulting in worsening patient outcomes
Incidence not studied in VetMed.
Effects of hepatic dysfunction on antimicrobial administration
Antimicrobial clearance may be decreased for hepatically metabolized drugs.
(Usually takes reduction of 90% of liver) –> therefore patients in fulminant liver failure = consider dose reduction
Generally no change needed if biochem panel shows hepatic dysfunction.
What are the 4 classes of Beta-lactams?
Penicillins
cephalosporin
carbapenam
monobactam
Beta-lactams distinguishing feature and mechanism of action
beta lactam ring
effects exerted by disrupting the synthesis of the cell wall during bacterial replication by binding to the “penicillin-binding proteins” (PBP)
when beta lactam ring binds to PBP –> results in degradation of cell wall and imparis synthesis of new cell wall leaving bacteria exposed to local environment and resulting in bacterial lysis
Beta lactams are bactericidal
Four factors that influence resistance to beta lactams
alterations to PBP
development of antimicrobial efflux pumps
changes to porins in bacterial cell wall
inactivation by beta lactamases –> can be acquired or intrinsic resistance
Penicillins
Beta-lactam
Gram positive and anaerobic coverage
Minimal gram negative coverage
Able to kill enteric flora which can cause vomiting and diarrhea.
C
Penicillin excretion
Excreted unchanged in urine
highly effective in UTI
Penicillin Drugs
benzylpenicillin (Pen-G), phenoxymethylpenicillin (penicillin V), procaine penicillin, benzathine penicillin (pen B)
Cloxacillin, methicillin, oxacillin
Beta-lactamase resistant
Most effective against gram positive aerobes and anaerobes.
Cephalosporin
Beta-lactam
5 generations: grouped into generations based on their relative spectrum of activation
lower the generation, the better gram positive spectrum
the higher the generation, the better gram negative coverage
more stable against beta lactamases than penicillins
1st generation Cephalosporin
beta-lactam
effective against variety of gram positive
limited activity against anaerobic bacteria.
drugs: cefazolin, cephalexin, cefadroxil
2nd generation Cephalosporins
moderate gram positive and gram negative
increase spectrum against anaerobes
drugs: cefoxitan, cefotetan, cefuroxime
3rd generation cephalosporins
Broad spectrum activity with resistance to many beta lactamases
relies on normal plasma albumin for effective therapeutic serum levels
Good penetration of CSF
drugs: ceftiofur, cefotaxime, ceftazidime, cefovecin(Convenia - 1 injection for 14 days), cefpodoxime (only drug in this gen available as oral medication)
4th generation cephalosporin
excellent activity against enteric organisms
drugs: cefepime, cefpirome and cefquinome
5th generation cephalosproin
only 1 drug: ceftaroline
spectrum of action similar to 3rd gen - good gram positive coverage
retains efficacy to Staphylococcus spp. that are resistant to methicillin
Monobactams
Drug: Aztreonam
Gram Negative coverage
Not used much in vetmed
Carbapenems
broad spectrum
resistant to many beta lactamases
considered top tier antimicrobial goup and should not be used empirically
Drugs: imipenem, doripenem, ertapenem and meropenem
Imipenem
Carbapenem beta lactam antimicrobial
nephrotoxic - drug degrades in renal tubule by kidney enzyme dehydropeptidase 1
Administer with Cilastatin to prevent degradation
associated with seizures in humans
Meropenem
Carbapenem beta lactam antimicrobial
not nephrotoxic
Beta-lactamase inhibitors (3)
clavulanic acid
sulbactam
tazobactam
bind irreversibly to beta lactamases so when administered with a beta lactam, the beta lactam can bind to bacterial PBP.
Beta lactam adverse effects
Toxicity to beta lactam group considered very low.
Potential adverse reactions:
Type 1 hypersensitivity from urticaria to anaphylaxis - frequency unknown in small animals (occurs in 0.7%-10% of people receiving penicillin
Type 2 hypersensitivity can also occur – hemolytic anemia, thrombocytopenia and neutropenia reported
Type 4 reactions usually manifest as cutaneous disease
Can rigger immune-mediated reactions such as IMHA
Can kill neric flora which cause nausea, vomiting, diarrhea
High doses can result in seizures and other neurologic diseases (more likely if brain diseases already present)
Aminoglycosides
Antimicrobial used to treat gram negative infections
Rely on aerobic bacterial metabolism
parenteral administration only
requires monitoring of renal function
Exhibit synergistic bactericidal effects when administered in combination with beta lactams
Aminoglycosides mechanism of action (3 stage model theory)
Inhibit bacterial protein synthesis by binding to ribosome resulting in faulty protein.
further synthesis increases aminoglycoside uptake by the cell which eventually leads to complete cessation of ribosomal activity.
Stage 1: outer bacterial lipopolysaccharide membranes are negatively charged while aminoglycoside is positively charged. Ionic binding allows aminoglycoside entry into cell and increase cell wall permeability
Stage 2: Energy dependent phase Faulty protein synthesis inserted into cytoplasmic membrane of bacteria allowing for more aminoglycoside entry (slow process and relies on ATP hydrolysis –> therefore reduced activity in anaerobic conditions). This stage can be blocked by inhibitors of oxidative phosphorylation or electron transport
Stage 3: Aminoglycoside accumulate quickly after nonspecific membrane channels inserted –> increasing rate of mistranslation of protein synthesis
3 mechanisms of actions to aminoglycoside resistance + intrinsic resistance
- enzymatic mutation of aminoglycoside molecules
- target modification in ribosomal 30s subunit structure
- increase in aminoglycoside efflux
- intrinsic resistance to anaerobes
Aminoglycoside absorption, distribution, metabolism and elimination
Absorption: water soluble; poorly absorbed from GI tract therefore must be administered parenterally
Distribution: primarily extravascular - can reach bone, synovial fluids, peritoneal fluid (especially if inflammation present). Distribution to bronchial secretions is good. Does not penetrate cell membranes well because of positive charge. Not recommended for CNS, eyes or prostate.
Elimination: primarily through kidneys unchanged by glomerular filtration.
Aminoglycosides Adverse Effects
Aminoglycosides readily taken up by cells in proximal tubules and in ears
5-15% will suffer aminoglycoside induced nephrotoxicity (excreted through kidneys)
Nephrotoxicity:
dose dependent
majority of aminoglycoside is excreted but small amount is absorbed by renal tubules
Necrotic cells slough into tubular lumen which can result in obstruction
Underlying renal dysfunction predisposes patient to aminoglycoside induced nephrotoxicity
Often damage is reversible if caught early.
Ototoxicity:
hair cells update drug resulting in cell death and inflammation
dose and duration dependent
Ototoxicity is not reversible
Neuromuscular blockade
Rarely reported, but can be severe enough to cause respiratory depression
@ high doses - calcium release impaired at level of neuromuscular junction –> hypocalcemia. Concurrent use of neuromuscular blockade medications or myorelaxants may augment effets.
Aminoglycoside drugs
Amikacin
Gentamicin sulfate
Tobramycin sulfate
neomycin
Amikacin
aminoglycoside
Monitor for casts in urine and increases in BUN/Creat
dosage may need to be adjusted in critically ill patients
can be administered IV, IM, SQ q 24 hrs
Gentamicin Sulfate
Aminoglycoside
Monitor for casts in urine and increases in BUN/Creat
Can be administered IV, IM, SQ, q 24 hours
Tobramycin sulfate
Amino glycoside
Monitor for casts in urine and increases in BUN/Creat
Can be administered IV, IM, SQ q24 hours
Neomycin
Aminoglycoside
Used to treat hepatic encephalopathy
Minimal GI absorption
administer PO q 6-12 hrs
Fluoroquinolones
Mechanism of action
effectiveness and resistance
synthetic antimicrobials
Inhibit bacterial DNA gyrase which prevents bacterial DNA synthesis, replication and division, resulting in cell death
Bactericidal
Widest spectrum against gram-negative bacteria
Incomplete effectiveness against gram-positive and anaerobic bacteria
RESISTANCE TO FLUOROQUINOLONES CAN DEVELOP DURING THE COURSE OF THE TREATMENT
Fluroquinolones
metabolism and elimination
hepatic metabolism and excreted in bile +/- urine either unchanged or as metabolites
Most are eliminated by the kidneys
Half-life depends on renal elimination and dose
Resistance to fluroquinolones
increasing rate of resistance
attributed to widespread use of fluoroquinolones
Use of fluoroquinolones can lead to development of resistance to other antimicrobial classes
Fluoroquinolones should not be used as 1st line treatment. (exception - pyelonephritis, lower respiratory tract infections, bacterial prostatitis, hepatobiliary infections).
Adverse effects of fluoroquinolones
GI upset: V/D, nausea, abdominal cramping
Neurologic: rapid administration risk CNS adverse effects including seizures
It may lower the seizure threshold; therefore, do not use or use it with extreme caution in patients with seizure disorders.
Juveniles: cartilage defects - not recommended in growing animals
retinopathy: irreversible blindness in cats
Rapid IV administration may result in histamine release in dogs
Can chelate with positively charged ions - contains beta-keto acid group that can bind to and chelate with positively charged ions; most profoundly seen with aluminum and copper, but can also happen with magnesium and calcium
Cardiovascular signs can result in hypotension, bradycardia, prolonged QT
Rare reports of fluoroquinolones used in patients with necrotizing fasciitis resulted in activating bacteriophage, rapid bacterial cell lysis, and release of bacteriophage superantigen and the potential sequelae of toxic shock syndrome.
Enrofloxacin
2nd fluoroquinolone
only one available as injectable for dogs and cats
generally safe, though adverse effects can be permanent
Adverse effects can include:
- blindness in cats
- cartilage defects in juvenile animals
Max dose in cats if 5mg/kg q24hrs
primary metabolite of enrofloxacin is ciprofloxacin.
Marbofloxacin
2nd gen fluroquinolone
longest post-antibiotic effect and half-life
No clinical trials support the translation of long half-life to superior antimicrobial efficacy.
Pradofloxacine
3rd gen fluoroquinolone
Labeled for use in cats 12 weeks +, off-label for dogs (use in dogs associated with bone marrow suppression)
broad spectrum activity including many anaerobic bacteria
High potency with lower MIC values when compared with other fluoroquinolones
Ciprofloxacin
2nd gen fluoroquinolone
not labeled for veterinary use
Significantly higher doses needed in dogs than in humans and even so does not always achieve desired serum levels
Moxifloxacin
4th gen fluoroquinolones
improved activity against gram-positive and gram-negative
only used in human medicine
Metronidazole
drug class
Indications and mechanism of action
nitromidazole antimicrobial
Indicated to treat most gram-positive anaerobic and all gram negative anaerobic organisms
At higher dosages - effective against protoozoal diseases (giardia, amebiasis, trichomoniasis); however higher doses associated with CNS adverse effects
Concentration dependent
Within the bacteria: reduced and incorporates into bacterial DNA causing loss in helical structure
inhibits nucleic acid synthesis
results in cell death
Bactericidal
Metronidazole
Bioavailability, distribution, elimination
Good oral bioavailability
Excellent tissue distribution with good penetration to BBB and CSF
Elimination is dose dependent with renal and biliary routes
Hepatic metabolism –> dose reduction with liver dysfunction
Use with caution in patients with neurologic disease
Metronidazole
Adverse effects
GI upset
neurologic signs associated with higher doses and prolonged use
Clinical signs: vertical nystagmus, ataxia, paraparesis, tetraparesis, hypermetria, head tilt, tremors
Treatment: discontinue therapy and provide supportive care (IV fluids, antiemetics, sedatives PRN). Most patients improve within 3 days.
Chloramphenicol
drug class
mechanism of actions
Phenicol
Bacteriostatic
Inhibit protein synthesis by binding to 50S ribosomal subunit
In mammalian cells, can also inhibit mitochondrial protein synthesis (especially erythropoietic cells).
Chloramphenicol effectiveness
Gram-positive
Gram-negative
anaerobic
intracellular organisms such as: Chlamydia, mycoplasma and rickettsia
Not effective against pseudomonas aeruginosa
Chloramphenicol
bioavailability, metabolism and elimination
Good bioavailability through oral administration and tissue distribution
Penetrates CNS
Limited prostate
Hepatic metabolism –> dose reduction with liver dysfunction
Excreted in kidneys in mostly inactive form
Chloramphenicol
Toxicity
Dose-dependent bone marrow suppression in humans, dogs and cats (cats more sensitive)
DO NOT SPLIT
DO NOT PULVERIZE
Caretakers to wear gloves
Dogs: hind end weakness and GI signs
Chloramphenicol + drugs requiring CYP450 (phenobarbital)
Chloramphenicol is a potent inhibitor of CYP450.
Drugs that require CYP450 may need dose adjust to prevent toxicity.
Chloramphenicols + concurrent antimicrobials of other classes
Competitive inhibitors of 50S ribosomal subunits
Do not give chloramphenicols with lincosamides and macrolides
Tetracyclines bind to 30S subunit
Therefore Chloramphenicols may act synergistically with tetracyclines
Clindamycin
drug class
Mechanism of action
Lincosamide Antimicrobial
binds to 50S subunit of ribosome
Bacteriostatic and time dependent
Clindamycin effectivness
Effective against gram-positive aerobes and anaerobes
Effective against mycoplasma and toxoplasmosis
Clindamycin bioavailability
Distribution, metabolism and elimination
Good bioavailability after oral administration. Can also be administered SQ and IV
Good tissue distribution especially to skin and bone
penetrates CNS
penetrates blood prostate barrier –> good for gram-positive bacterial prostatitis
penetrates biofilms –> use for gingivitis, and peridontal disease
Clindamycin
Side effects
Overall rare
Humans: overgrowth of C. diff
Doxycycline
drug class
Mechanism of actions
Tetracycline
inhibits protein synthesis by binding to 30S ribosomal subunit
bacteriostatic
Lipid soluble –> greater bacterial penetration
Doxycycline
effectiveness
1st line therapy for tick borne rickettsial diseases
felin upper airway
canine respiratory
Gram-positive, gram-negative, mycoplasma, chlamydia, rickettsial, spirochetes
not considered effective against anaerobic infections
Doxycycline resistance
found in all bacteria secondary to presence of efflux pumps
alterations to binding sites
bacterial enzymatic destruction
Doxycycline
bioavailability
distribution, metabolism and elimination
high bioavailability
drug is lipophilic so will also distribute into placenta and milk
limited in prostate
highly protein bound
30%-40% CSF
elimination: mostly unknown with 16% in urine unchanged
predominance for intestinal elimination and enterohepatic recirculation
Doxycycline Adverse effects
Adverse effects more likely with decrease in rental function.
Give with food to decrease GI upset
Associated with ESOPHAGEAL EROSION - follow with 6ml water
Incorporates into bone and enamel resulting in discoloration
IV Doxycycline needs to be diluted and ideally given through central line to reduce risk of thrombophlebitis
Give over 1 hour as anaphylactic shock has been reported
Rarely hepatotoxic
Doxycycline
Concurrent administration of medications and fluids
should not be administered with antacids, aspirin or calcium containing fluids as it chelates with cations
May bind to cholestyramine because of its lipophilic nature
Sulfonamides and trimethoprim
individually - bacteriostatic
used together = bactericidal and time dependent
work on different stages of bacterial folic acid production
Combo therapy 1:5 trimethoprim: sulfonamide
Sulfonamides and trimethoprim
effectivess
broad spectrum
gram-positive, gram-negative and anaerobes
Ineffective against mycoplasma and rickettsial disease
Sulfonamides and trimethoprim
distribution, metabolism and elimination
goo tissue distribution to include CNS for sulfadiazine and prostate for trimethoprim
Both drugs undergo hepatic metabolism
metabolites thought to be responsible for allergic and idiosyncratic reactions
Both active drug and metabolites renally excreted
TMS highly concentrated in urine therefore considered 1st line therapy for bacterial cystitis
Sulfonamides and trimethoprim
Adverse effects
allogenic, immunogenic and toxic metabolites (Dobermans, Samoyeds and Mini schnauzers more sensitive)
hypersensitivity reactions: fever, polyarthritis, pancreatitis, hepatitis, glomerulonephritis, anemia, ITP, mucosal skin lesions.
KCS most common because of direct cytotoxic effects of sulfonamides on lacrimal gland
reversible with short treatments (<5 days), but may be irreversible with long term use.
decrease in thyroid hormone in dogs –> reversible
Macrolides
Drug examples
mechanism of actions
drugs: Erythromycin, azithromycin, clarithromycin
Mechanism of action: binds to 50S subunit inhibiting protein synthesis
Bacteriostatis
Macrolides effectiveness
Mainly effective against gram-positive bacteria and intracellular bacterial infections
limited effectiveness against Gram-negative bacteria
Not effective against anaerobic bacteria
Macrolides advantage
Alternative drug option for patients that cannot take beta-lactams (allergies)
Erythromycin
Macrolide
enteral and parenteral administration
rapid degradation by gastric acid when given orally
DO NOT CRUSH TABLETS b/c coating helps prevent rapid degradation
Drug of choice for Campylobacter jejuni
Azithromycin
Macrolide
Greater activity against gram-negative organisms
More stable in acid –> higher bioavailability when taken orally
Macrolides side effects
GI upset most commonly reported
also highly effective as a prokinetic when administered at subantimicrobial doses
Nitrofurantoin
Prescription based on culture and susceptibility and lack of any other viable alternative
treatment for multi drug resistant UTI
inhibits cell wall synthesis, bacterial protein and DNA synthesis
bactericidal
Gram Positive and gram negative
resistance is rare
side effects: irreversible peripheral neuropathies
use with caution in cats –> potential for hemolysis
Vancomycin
Prescription based on culture and susceptibility and lack of any other viable alternative
glycopeptide antibiotic
Reserved only for serious life-threatening multi-drug resistant gram-positive bacterial infections that cannot be treated with other agents (ie MRSA)
Mechanism of action: inhibits proper cell wall synthesis by binding to subunits preventing cross-link formation in peptidoglycan cell wall
Adverse effects: nephrotoxicity, ototoxicity
Rapid IV administration can be associated with histamine release
Extravasation can result in severe soft tissue damage
Rifampin
Prescription based on culture and susceptibility and lack of any other viable alternative
used to treat Methicillin-resistant staphylococcal pyodermas
Mechanism of action: inhibits RNA synthesis
Resistance develops in as short as 2 days when used as monotherapy
Use in combo with other drugs to decrease emergence to resistance
Rifampin + fluoroquinolone –> antagonistic
Fair to good oral bioavailability when fasted
Side effects: GI upset and hepatotoxicity
Pretreatment and weekly biochem monitoring for hepatotoxicity
Oxazolidinones
Prescription based on culture and susceptibility and lack of any other viable alternative
Linezolid - synthetic antibiotic
Treatment for multidrug resistant skin infections, pneumonia and bacteremia
Mechanism of action: binds to p-site of 50S ribsomal subunit –> inhibit protein synthesis
Bacteriostatic
effective against gram-positive, including methicillin and vancomycin resistant staphylococci
Anaerobic spectrum similar to clindamycin
Good bioavailability with tissue distribution to lungs, CSF , bones
well tolerated with dogs.
No studies on cat pharmacokinetics
Lipopeptides
Prescription based on culture and susceptibility and lack of any other viable alternative
Most recently discovered
Drug: Daptomycin
indicated for Gram-positive that are vancomycin resistant
effective against gram-positive and anaerobic
Mechanism of action: forms ion channels in cell membrane allowing it to depolarize and result in rapid cell death
Gram-negative organisms inherently resistant
Adverse effects: highly toxic, causes skeletal muscle damage
Antifungals (2 classes)
Polyene antibiotics
Azole derivatives
polyene antibiotics
two types
- amphotericin B
- lipid-complexed emphotericin B
