Pharm 2: Exam 2 HW Prevention, Glucocorticoids, Drug Interactions

Animals with MDR1 (ABCB1) mutations

What mammals can be hypersensitive to heartworm preventatives at a normal dose?

Macrocyclic lactone

All veterinary labeled Dirofiliria immitis preventatives belong to what drug class?

-Drugs: Ivermectin, Selamectin, Eprinomectin, Milbemycin oxime, Moxidectin

L3, L4

What HW life cycle stage are killed with heartworm preventatives?

*Retrograde kill

True

True or False: The Exact MOA of macrocyclic lactones in heartworm disease prevention is unclear.

Ivermectin

Oral HW preventative that's safe for dogs

-Extra label for microfilaricides

*Can have impaired drug elimination in dogs with ABCB1 mutations

-Susceptible to ↑ neurological side effects

Eprinomectin

Topical or combo HW preventative in cats

-Neurological toxicosis reported in cats with MDR1 mutations

Moxidectin

Is ivermectin or moxidectin a longer lasting HW preventative with a higher tissue distribution?

*Due to lipophilic molecules within medication

Moxidectin

Proheart6 and Proheart12 contain what macrocyclic lactone?

-SQ injections for dogs only

Concurrent with vaccines, pre-existing allergic diseases, unstable weight

What are 3 reasons for concern/caution when administering Proheart to dogs?

*Review Client Information Sheet pre-injection

Anaphylactic reactions

What reactions can occur after ProHeart injections by itself or when given with vaccines?

Echinococcus granulosus, Echinococcus multilocularis

What are the 2 extremely tiny tapeworms that are being seen in dogs more recently & are zoonotic?

Topical

Do oral or topical moxidectin products for dogs kill whipworms?

Microfilaria

Advantage multi is the only topical moxidectin that's approved to kill .... in heartworm disease

Moxidectin

What macrocyclic lactone has the greatest efficacy against ML resistant HW larvae?

False (still 99% efficacy in MS delta despite emerging resistance)

True or False: Year-round HW preventatives have 50% efficacy in MS Delta due to macrocyclic lactone resistant HW strains.

increase Dose frequency, change formulation (to ↑bioavailability)

What are 2 ways to optimize the current macrocyclic lactone products to fight HW resistance?

*No new HWP products with novel MOA

Improve HWP compliance (giving prevention on time!)

What can pet owners do to combat HW resistance?

Melarsomine

AHS recommended & only FDA approved adulticide for HW treatment in DOGS ONLY

*Brand name: Diroban

Contains arsenic

Why is melarsomine not approved for HW adulticide treatment in other countries?

2 injections

How many melarsomine injections are needed to achieve 90% efficiency in canine HW adulticide treatment?

3 injections (1 dose, wait 30 days, then 2 doses 24 hrs. apart)

How many melarsomine injections are needed to achieve 98% efficiency in canine HW adulticide treatment?

*AHS recommended treatment protocol

2 months

How many months prior to giving melarosomine injections should ML be administered in HW positive dogs?

*Use with caution in dogs with high microfilarial counts

Prevents new infections, kills larvae < 60 days old

Why are macrocylic lactones given 2 months prior to melarosomine tx in HW+ dogs?

-Allow > 60 d.o. worms to mature so they're more susceptible to melarsomine

-Stunts adult HW development

Doxycycline

Antibiotic with a 30 day course that should be administered 2 months prior to melarsomine injections

Wolbachia

What rickettsial gram (-) intracellular bacteria in heartworms is killed with doxycycline?

-HW require this bacteria for protein synthesis, energy metabolism, repro.

True

True or False: Heartworms and Wolbachia have a symbiotic relationship.

Reproduction

What physiologic process in heartworms is disrupted by eliminating Wolbachia?

Decreased fertility and circulating microfilariae (female HW can't produce viable MF)

How are adult female HW affected by Wolbachia being eliminated?

Makes them non-infective to new hosts

How does doxycycline affect HW microfilariae to block transmission of heartworm infection?

Surface proteins

What are released from Wolbachia when they're killed?

*Leads to an inflammatory response (pulmonary inflam, arteritis)

Doxycycline

Do macrocyclic lactones or doxycycline reduce the release of Wolbachia surface proteins?

*Decreases pro-inflammatory response

Doxycycline + moxidectin (Moxi-Doxy)

Melarosomide is an FDA approved adulticide for "fast-kill" HW TX. What combo products can be used for "slow-kill" HW treatment (non-arsenical)?

Prednisone

Oral steroid used in HW treatment to ↓ pulmonary inflammation from dead & dying heartworms post-melarsomine tx

-Minimizes reaction to ML in a symptomatic patient

No (bc this steroid causes PU/PD/PP)

Should prednisone be used in diabetic patients with HW disease?

Prednisone

What is the HW treatment for cats?

-Doxycycline & melarsomine are not approved for HW tx in cats

Cats

Do dogs or cats have a lower inflammatory response from HW treatment due to a lower worm burden?

False (only melarsomide = 1st line, can use slow kill when melarsomide is unavailable)

True or False: The AHS recommends fast kill (melarsomide inj) or slow kill (non-arsenic products) as 1st line HW treatment in dogs.

Slow kill (Non-Arsenical)

Are fast kill (melarsomide inj) or slow kill (non-arsenic products) strategies more likely to extend the length of HW treatment?

*Has the potential for selection of resistant HW subpopulations

Older

Can younger or older worms be less susceptible to slow kill (non-arsenical) HW treatments?

Activity restriction

Both fast kill (melarsomide) & slow kill (doxy + moxy) HW treatments require what?

Oral (Injectable- proheart & topical- advantage multi both have high concentrations)

What moxidectin formulation doesn't have well known pharmacokinetics in slow kill HW treatment?

Anabolic

What type of steroid are androgens?

-Used to increase muscle mass & protein synthesis

Catabolic

What type of steroid are glucocorticoids?

-Decrease muscle mass & protein synthesis

-Ex: Cortisol, prednisone

True

True or False: Anabolic steroids approved as drugs (not growth implants) are now DEA Schedule 3 drugs.

Adrenal cortex

What general part of the adrenal gland produces cortisol & aldosterone?

Glomerulosa, fasiculata

Adrenal Cortex Hormones:

-Zona _____ = produces aldosterone

-Zona _____ = produces cortisol

Catecholamines (norepinephrine, epinephrine)

What "fight or flight" hormones does the adrenal medulla produce?

-Increases metabolic rate, BP, cardiac contractility, & myocardial excitability

Glucocorticoids

Synthetic hormones that mimic cortisol

-Ex: Prednisone, cortisone, dexamethasone

Mineralcorticoids

Synthetic hormones that mimic aldosterone

-Ex: DOCP (Desoxycorticosterone pivalate)

Gluconeogenesis, insulin

Glucocorticoids increase blood glucose through _____ and have an anti-_____ effect.

Glucocorticoids

Synthetic hormones that:

- Suppress immune system

- Aid in fat, carb, and protein metabolism

- Reduce bone formation

- Promote Ca elimination at kidney

- Stress leukogram

Cushing's, Addison's

Giving an excess of glucocorticoids can cause ____ disease, while abruptly stopping steroids can cause _____ disease.

Enhance or inhibit gene transcription (& protein translation)

Glucocorticoids MOA:

Free hormone diffuses into cell → binds to cytoplasmic receptor → translocates to nucleus → binds to DNA to....

Lipocortin

Inhibitory protein that's produced when glucocorticoids are given

*Useful for anti-inflammatory & antipruritic therapies since it inhibits phospholipase A2

Anti-inflammatory/Antipruritic

Knowing this mechanism occurs, what therapy could glucocorticoids be used for?

Glucocorticoid given → lipocortin produced → Phospholipase A2 inhibited → no arachidonic acid → no prostaglandins & leukotrienes released → no swelling, redness, pain, or itching

COX (Cyclooxygenase), LOX (Lipoxygenase)

Glucocorticoids prevent arachidonic acid release which indirectly prevents the activation of what 2 pathways?

Only prevent COX pathway activation

Why are NSAIDs not as effective in certain therapies as glucocorticoids?

Impair MPS (occurs hours after administration)

Glucocorticoids cause immunosuppression by causing the following changes. Which change occurs the fastest?

A) Decrease antibody synthesis

B) Decrease antibody-cell binding affinity

C) Impair mononuclear phagocytic system (MPS)

Fc receptors

Glucocorticoids impair the MPS by down regulating the expression of what macrophage receptor?

-Reduces phagocytosis of opsonized cells

Anti-inflammatory properties

Which of these is an advantage to glucocorticoid use?

A) Decrease egress of cells from the blood

B) Suppress macrophages & neutrophil bactericidal functions

C) Inhibit amplification pathways of the complement cascade

D) Decrease antigen presentation to Th cells

E) Anti-inflammatory properties

2-6 hours

How many hours after glucocorticoid administration does improvement in an airway inflammation, edema, & bronchoconstriction occur?

Physiologic

Clinical effect from a low dose of glucocorticoids that mimics baseline endogenous cortisol

-Good for Addisonian dogs

Anti-inflammatory

Clinical effect from a moderate dose of glucocorticoids that controls signs of acute inflammation, allergies, & hypersensitivity reactions

Immunosuppression

Clinical effect from a high dose of glucocorticoids that's used to treat severe diseases

*Increases risks of side effects & secondary infections

Dexamethasone

Which of the following steroids has the greatest glucocorticoid potency?

A) prednisolone

B) dexamethasone

C) methylprednisolone

*Relative to hydrocortisone (1.0)

False (Dex 7x more potent)

True or False: Prednisolone is ~7 times more potent than dexamethasone.

0.5-1 mg/kg (less potent = give more drug to reach full affect)

Knowing that dexamethasone is more potent than prednisolone, which anti-inflammatory dosage likely belongs to prednisolone?

-0.15 mg/kg

-0.5-1 mg/kg

False (cats require 2x more)

True or False: Dogs may require 2X dose as cats for same the anti-inflammatory effects.

Cats

Any animal receiving glucocorticoids is at risk of developing diabetes mellitus. Which animal is the most at risk despite being more resistant to other side-effects?

Cats, horses

What 2 domestic animals don't absorb prednisone well & should be given prednisolone instead?

Laminitis

What disease are horses on steroids predisposed to?

Cattle

What animal is more prone to abortion / induction of parturition from certain steroids in the last 1/2 of gestation?

-Less risk with prednisolone & isoflupredone

True

True or False: A 10 day regimen of dexamethasone can cause abortion/fetal reabsorption in dogs.

Potency

Which of the following should NOT be used as a factor for selecting a steroid?

A) Route of administration

b) Interference with diagnostic testing

C) Drug Potency

D) If mineralocorticoid effects are needed/not

Reduce systemic side effects

What is a major advantage of local acting steroids?

-Ex: Respiratory inhaler (fluticasone, ciclesonide), Budesonide (nasal spray)

Depo-Medrol (methylprednisolone)

What repository steroid injection in dogs & cats can cause more adrenal suppression & too high highs & too low lows?

*Beneficial for owners that don't want to pill their animals

Minimal to none

What are the adverse effects of giving glucocorticoids for a physiologic use?

PU/PD/PP (increased thirst, urination, hunger)

What are the adverse effects of giving glucocorticoids for a anti-inflammatory use?

Immunosuppression

General consequence of giving high doses of glucocorticoids

-Adverse effects: PU/PD/PP , muscle wasting, predisposed to infections, thin skin, etc.

Dehiscence, delayed wound healing

What surgical risks could arise in animals taking glucocorticoids?

-Don't want to operate on animals taking steroids (short acting H20 soluble steroid is best if it must be used)

Bacterial

Are bacterial or fungal infections more common in animals receiving long term immunosuppressive therapy?

Hypoadrenocorticism (Addison's)

Caused by deficient cortisol production from the adrenal cortex

-Why: Cortex is not responsive to typical stimuli

Cortisol and aldosterone (mineralocorticoid)

What 2 steroids are deficient in Typical Addison's Disease?

Cortisol

What steroid is deficient in Atypical Addison's Disease?

Decreased blood volume, increased K

What 2 conditions stimulate the release of aldosterone from the adrenal cortex?

Na, water, Cl

What ions does aldosterone primarily reabsorb?

K, H

What ions does aldosterone primarily excrete?

Principal cells (in distal tubules & collecting ducts)

What is the site of action of aldosterone?

-↑ activity of basolateral Na+/K+-ATPase

- ↑ transcription of luminal Na+ channels

Mineralcorticoids

Are the following mainly glucocorticoid or mineralcorticoid products:

-Fludrocortisone

-DOCP

True

True or False: Prednisolone has incidental or additive mineralocorticoid effects.

Pharmaceutical, pharmacodynamic, pharmacokinetic

What are the 3 categories of drug interactions?

Pharmaceutical

What drug interaction occurs when drugs are chemically incompatible with each other?

-Ex: Mixing 2 clear drugs into 1 syringe & the syringe becomes cloudy

Pharmacodynamic

What drug interaction occurs when 1 drug alters another's molecular, biochemical, or physiologic effects?

Pharmacokinetic

What drug interaction occurs when 1 drug alters the absorption, distribution, metabolism or excretion of another drug?

Incompatible pH (between drugs)

Why does a precipitate form in Pharmaceutical Interactions?

*Most common reason for this type of drug interaction

True

True or False: Diazepam sticking to the walls of plastic & glass containers is an example of a pharmaceutical interaction.

Enrofloxacin

What fluoroquinolone is incompatible with essentially everything you can dilute it in?

-Risk of pharmaceutical interactions

Diazepam

What benzodiazepine can't be mixed with anything except NaCl or Ketamine?

-Risk of pharmaceutical interactions

True

True or False: Pharmacodynamic Interactions can be beneficial or harmful.

Synergistic (or additive)

What beneficial pharmacodynamic interaction occurs with these antibiotics:

-TMS

-Beta-lactams + aminoglycosides