inhibits fungal cell sterol synthesis

fungistatic

•Aspergillus

Dermatophytes

•

Yeasts (Malassezia)

•

Systemic fungi

Itraconazole

what effects absorption of capsules?

enhanced by food

decreased by anti-acid drugs

interactions do not affect oral solution

highly lipophillic

concentrates in tissues for 2-4 weeks

allows for pulse dosing

cats

dermatophytes

dogs

blastomycosis

dermatophytosis

capsule

suspension

increased liver enzymes

hepatotoxicosis

anorexia

vomiting

Fluconazole has less activity on Aspergillus

less active against systemic fungi

less active against dermatophytes

greater hydrophilicity

water soluble

higher concentrations in urine, CSF, aqueous humor

high oral absorption

disintegration

dissolving

membrane barriers

tablets

suspension

injection

Pharmacokinetics of Fluconazole in horses?

half life?

volume of distribution?

clearance rate?

%F

where are there high concentrations

42 hour half life

1.2 L/kg volume of distribution

clearance is 0.02 L/kg/hour

%F is greater than 100%

high concentrations in tissues, eyes, urine

14mg/kg oral loading dose

5mg/kg q24hr, oral maintenance dose

Voriconazole

Posaconazole

humans

(limited experience in animals)

fungicidal

decreases synthesis of ergosterol in the cell membrane

mediastinal lymphoma

alimentary lymphoma

multicentric lymphoma *

cutaneous lymphoma

lymphocytic leukemia

cure-kill and remove all cancer cells

remission-reduce the tumor burden so that there are no clinical signs

palliation-to improve the well being of the patient

surgery

radiation

hyperthermia

chemotherapy

cryotherapy

gene therapy

immunotherapy

C=cyclophosphamide

H=doxorubicin (hydroxydaunomycin)

O=Vincristine (Oncovin)
P= prednisone

-G1=normal cellular events; synthesis of cellular components for DNA, RNA, and protein synthesis

S=synthesis phase (DNA synthesis)

G2=spindle and microtubule synthesis

M=mitosis

anticancer drug toxicity?

other cells in the body that are affected?

-GI tract (epitheilum)
-bone marrow suppression (granulocytes)

-hair growth

-drug specificy toxicity

cardiotoxicosis with doxorubicin

neurotoxicosis with vincristine

renal toxicosis with cisplatin

vomiting

diarrhea

neutropenia (leading to increased infections)

-granulocytes affected most severely

-nadir of toxicity in 7-10 days

-recovery (dogs) in 21-28 days

-stem cells are usually spared

-RBCs are less affected than WBCs

1. use combination drugs

2. monitor fot toxicity (CBC, renal function, cardiac toxicity)

3. administer fluid therapy prior to nephrotoxic drugs

4. administer anti-emetic drugs when nausea or vomiting is anticipated

5. dose selection (surface area versus body weight)

when drug clearance is determined by:

hepatic function

hepatic blood flow

protein binding

-alkylate bases of DNA

-disrupts DNA base pairing, synthesis, and replication

-causes cell death

-binds alkyl group to cellular macromolecules (nucleic acids, enzymes)

-bifunctional alkylating agents: Cross link DNA molecule

(example:N-7 of guanine, N-3 of cytocine, N-3 of adenine)

What are these:

nitrogen mustards (cyclophosphamide)

nitrosoureas (BCNU carmustine)

busulfan (Myleran)

Dacarbazine (DTIC)

platinum compleses (cisplatin)

What are these?

cyclophosphamide

chlorambucil

melphalan

lymphosarcoma

carcinomas

immunosuppressive therapy (Pemphigus vulgaris, IMHA, systemic lupus)

-dose dependent bone marrow suppression

-nausea, vomiting, diarrhea

-sterile hemorrhagic cystitis

-direct injury from cytotoxic metabolites (acrolein)

-in dogs more so than cats

-mechanisms to decrease toxicity:

1. promote dilute urine

2. corticosteroids

3. furosemide diuretic

4. mesna (mercaptoethanesulfonate)

carcinomas, sarcomas

osteosarcoma

TCC

give the group about once a month

most dose limiting effect

fluid loading with saline prior to therapy

vomiting is common (pre treat animals with antiemetic)

toxicity and death reported in cats

myelosuppression (but minor compared to other drugs)

What are these?

Vincristine

Vinblastine

Vinca Alkaloids:

derived from?

action

-derived from plants

-"spindle poison"

-binds tubulin proteins

-blocks polymerization of microtubules

-arrests cells in m phase

-interrupts mitotic spindle formation

combination therapy for LSA

treats TVT

local vesicant action

peripheral neuropathy (attributed for affinity for tubulin proteins)

constipation

causes very little myelosuppression compared to other drugs

increases release of functional platelets from bone marrow

inhibits platelet destruction in IMT

What kind of drugs are these:

Doxorubicin

Danorubicin

Mitoxantrone

inhibits topisomerase II-dependent DNA synthesis

forms free radicals causing oxidative injury to cancer cells

-intercalates between DNA base pairs

-inhibits DNA, RNA, protein synthesis

-generate oxygen radicals in cancer cells

-cell membrane toxicity

Sarcomas

carcinomas

lymphoma

osteosarcoma

-bone marrow suppression (nadir at 7-10 days, recovery in 21-28 days after IV dose)

-cardiotoxicity (dose limiting effect, acutely arrhythmias, chronically cardiomyopathy) DOGS

-alopecia

-GI (vomiting, diarrhea_

-histamine reaction

-oxidative stress from redox cycling procedures (mitochondrial injury, changes in sarcoplasmic reticulum Ca channels)

-mechanism:complex with iron to produce oxygen radical formation

-prevention: Dexrazoxane chelates the iron and may be used to reduce toxicity

What is Toceranib?

-new cancer drug: approved in dogs in 2009

-first anticancer approved by the FDA for animals

-indication: mast cell tumors

-cytotoxic to malignant lymphocytes

-antiemetic

-decreases inflammation associated with cancer

-decreases the synthesis of TNF

-improves appetitie

-prednisone

-dexamethasone (antiemetic)

-utilize services of a qualifies pharmacist

-avoid handling if you have a risk factor

-wear protective gloves, eye protection

-mix drugs in ventilated hood

-observe proper recommendations for disposing of drugs and materials

-synergisism with other drugs increases tumor cell kill

-decreased toxicity

-optimize tumor cell killing by using drugs that affect different phases

-delay drug resistance

acupuncture

physical therapy

chiropractic

dietary supplements

chondroprotective agents

anti-inflammatory/analgeic drugs

opioids

NSAIDS

local anesthetics

corticosteroids

benzodiazepines

muscle relaxants

antidepressants

antianxiety agents

meloxicam

tepoxalin

carprofen

etodolac

firocoxib

dercoxib

phenylbutazone

meclofenamic acid (not marketed)

Salicylates

flunixin meglumine

naproxen

ketoprofen

piroxicam

telfenamic acid

vedaprofen

carprofen

tepoxalin

meloxicam

aspirin

dercoxib

inexpensive

analgesic and anti-inflammatory

no tolerance or dependence with chronic administration

few drug interactions(compatible with antestheitics and opioids)

GI effects

renal perfusion

bleeding (platelet inhibition)

adverse reactions

current labels

client information sheets

What can you find at http://www.usp.org?

with the use of NSAIDS

indications

dosing information

off-label uses

inhibits COX-2 expression

which prevents the formation of PGE

which prevents edema, swelling, pain

(biological effects in brain, spinal cord, kidney, GI mucosa, bone, cartilage, lung)

aid in ulcer healing

promotes angiogenesis

contributes to bone remodeling

preserves renal function

gastritis

vomiting

diarrhea

GI ulcaration and hemorrhage

renal injury

hepatic injury

platelet inhibition and bleeding

allergic reactions

non selective drugs (COX1 and COX2 inhibitors) cause ulcers at high doses

even selective COX2 inhibitors can cause ulcers

no

all animals respond differently

increased ALP

increased ALT

increased Bilirubin

side effects

intrinsic reactions

idiosyncratic reactions

allergic reactions

elevated liver enzymes

depression, lethargy

elevated bilirubin

death

diarrhea

the second most common advese event

70% of adverse effects were seen in dogs that were 6 years old or older (but this may not really be relevant due to the fact that dogs under 6 probably wouldn't need Carprofen anyway)

What defines a side effect?

examples?

undesirable, but unavoidable effects

expected reactions, usually related to the drug's pharmacolgocial effect

usually does not require treatment

examples are antihistimines that cause drowsiness or glucocorticoids that cause Pu/Pd

What classifies an intrinsic reaction?

What are some examples?

dose related

predictable

can be reproduced in experimental animals

examples are renal injury caused by aminoglycosides, gastric ulceration with high doses of NSAIDS, enrofloxacin induced blindness in cats

high theraputic ratio=wide gap between the safe dose and the toxic dose

low therapeutic ratio=small gap between the safe dose the the toxic dose

unpredictable

not dose related

difficult to demonstrate in experimental animals

may represent 3-25% of reactions

may be under genetic control

examples include:

carprofen=hepatotoxicosis in dogs

phenobarbital=hepatotoxicosis

diazepam=hepatotoxicosis in cats

azathioprine=bone marrow injury

sulfonamides=keratoconjunctivities sicca

not dose related

reaction is unrelated to the drug's pharmacological action

minimal reaction from initial exposure but more serious reaction from subsequent exposure

can be minimized or treated with antihistimines, glucocorticoids, or epinephrine

examples include=penicillins causing skin reactions, and sulfonamides causing joint injury or hepatic injury

(S-Adenocylmethionine)

hepatic anti-oxidant

glutathione conjugation reactions

sulfation of bile acids

reduces hepatocyte apoptosis

may be beneficial in hepatitis and hepatotoxicosis

mixture of anti-hepatotoxic flavonolignans

phosphatidylcholine formulation that are important for oral absorption

hepatic anti-oxidant

may increase hepatic gluthathione content

S-Adenosyl methionine (SAMe)

silymarin (milk thistle)

Vitamin E

benefits of restoring liver function are unknown for sure

chrondroprotective agents

dietary supplements

omega 3 fatty acids

opioids (morphine like drugs)

corticosteroids

benzodiazepines

muslce relaxants

antidepressants

anti-anxiety agents

glycosaminoglycan

glucoasmine+chrondroitin sulfate (cosequin)

polysulfated glycosaminoglycans (adequan)

tetracyclines (DOXY)

green lipped mussel powder (Glyco-flex)

Na or Ca pentosan polyphosphate

Hyaluronic acid

benefits of Glucoasmine+Chondroitin sulfate

and risks?

stimulates cartilage matrix synthesis

decreases enzyme activity in joints

risks

minor changes in hematologic and hemostatic variables

Hill's diet that is used for nutritional management of dogs with osteoarthritis

contains optimum ratio of omega6 and omega 3 fatty acids, plus glucosamine and chondroitin

Trichophyton spp

and

Microsporum spp

are examples of what?

Enilconzole (Clinafarm)

Miconazole (Conofite)

Clotimazole (Lotrim)

Terbinafine (Lamisil)

Griseofulvin (Fulvicin)

Ketoconazole (Nizoral)

Itraconazole (Sporanox)

Fluconazole (Diflucan)

Terminafine (Lamisil)

microsporum spp

trichophyton spp

incorporates into keratin of the skin and nails

inhibits mitosis of fungal cells

treatment of Dermatophyte infection

for a duration of > 4 weeks

bone marrow suppression, especially in cats with viral infection (FIV)

tertogenic in pregnant animals

do not administer during pregnancy

binds to sterols in the fungal cell membrane

cell membrane becomes more permeable

fungal cell death (fungicidal)

Blastomyces

Histoplasma

Cryptococcus

Coccidioides

Candida

Aspergillus

Leishmania

systemic fungal infections

given IV

fever

thrombophlebitis

nausea, vomiting, anorexia

anemia

renal injury (acute injury, chronic injury)

pretreatment fluid administration

slow IV infusion

SQ administration

liposomal formulations

Characteristics of the lipid formulations of

Amphotericin B?

-modify rate of transfer of drug from lipid carrier to cholesterol containing mammilian membranes

-increased uptake by mononuclear phagocyte system (increases clearance)

release at the site of infection from monocytes

higher theraputic index so you need higher doses

Amphotec

ABCD

Ketoconazole

Enilconzole

Clotrimazole

Fluconazole

Itraconazole

Voriconazole

inhibits fungal P450 enzyme responsible for synthesis of fungal cell sterols

inhibits ergosterol synthesis

fungistatic

yeasts (malassezia pachydermatis)

dermatophytes (Trichophyton, Microsporum)

Systemic fungi (Bastomyces, Coccidiodies, Histoplasma)

enhanced by food

inhibited by stomach antacids

pooryly absorbed in horses

GI (nausea, vomiting, diarrhea)

Hepatotoxicosis (increased liver enzymes ALT and ALP, idiosyncratic hepatic injury)

This anti-fungal drug inhibits the metabolism of these drugs:

cyclosporine

prednisolone

digoxin

warfarin

What is P-glycoprotein?

Where is it located?

transmembrane protein that is associated with multi-drug resistance

ATP-dependent pump producing drug efflux out of cells

sites:

liver bile canaliculus

intestinal epithelial cells

placenta

kidney (proximal tubule)

endothelial cells (brain)

treats dermatophytes

predominantly treats Microsporum canis

salicylates (aspirin)=acidosis

acetaminophen =hepatic injury, blood cell injury

aspirin

ketoprofen

meloxicam

piroxicam

firocoxib

phenylbutazone

flunixin

ketoprofen

ibuprofen

naproxen

meclofenamic acid

firocoxib

if contaminated

if there is tissue perfusion

increased time of surgery increases risk of infection

depends of prognosis

is there a high likelihood of postoperative infection

bactericidial

broad spectrum

IV route

must be compatible with anesthetics

use appropriate timing of administration

select a drug that is active against the bacteria

select a drug that reaches the site of infection

consider local factors that affect drug activity

select a drug that can be administered conveniently

consider drug safety

cefazolin

ampicillin

ceftazidime (3rd generation)

cefoxitin (2nd generation)

opioids

nsaids

local anesthetics

muslce relaxants

alternative therapy

drug infusions

opioid agonist (IV, IM)

transdermal opioid

opioid agonist/antagonist

oral opioids and NSAIDS

20-30 minutes prior to surgery

may need to redose every 90-120 minutes

post operative regimen is not necessary in most cases

compatibility with anesthetics

potential adverse effects on the heart and blood pressure

effects on coagulation and bleeding

effects on the kidney

avoid oral medications

meloxicam

tepoxalin

carprofen

etodolac

firocoxib

deracoxib

phenylbutazone

meclotenamic acid(not marketed)

flunixin

ketoralac

ketoprofen

phenylbutazone

carprofen

meloxicam

meloxicam

tepoxalin

carprofen

etodolac

dercoxib

firocoxib

most common NSAIDS used in small animal?

large animal?

meloxicam

carprofen

large animal=flunixin

potent analgesia

produce euphoric and sedative effect

high therapeutic index

few drug interactions

few contraindications

may be administered locally

reversible (nalonone)

analgesia

sedation

euphoria

dysphoria/excitment

• What are some of the disadvantages of opioids?

short half life

poor oral absoption

tolerance with chronic use

abuse by humans

celiling effect with partial agonists

side effects: constipation, excitement, nausea, vomiting

mu

analgesia, supraspinal, spinal

kappa

analgesia, spinal

delta

analgesia, supraspinal, spinal

sigma

unknown significance

strong to mu

weak to kappa

moderate to mu

moderate to delta

strong to mu

strong to delta

bradycardia

vasodilation

smooth muscle spasm

constipation

nausea

vomiting

respiratory depression

panting

these drugs affect:

thermoregulatory centers

vomiting center

intestinal receptors

vagal effects

histamine release

morphine

oxymorphone

hydromorphone

meperidine

fentanyl

IV

IM

SQ

rectal

epidural

local infusion

morphine-6-Glucouronide

(20%-200% activity of morphine)

fentanyl

alfentanil

sufentanil

carfentanil

IV formulation (Submimazine)

transdermal patch (Duragesic)

buccal tablet (Fentora)

oral delivery (Actiq)

to compare Fentanyl and Morphine:

50ug/hr Fentanyl patch with equivalent to how much morphine per day?

Transdermal Fentanyl in cats:

lag time?

rate of delivery?

% absorbed

steady state concentration?

lag time= 12 hours

rate of delivery= 8.5 mcg/hr

% absorbored= 36%

steady state concentration = 2.0ng/mL

Pentazocine

Butorphanol

Buprenorphine

Buprenorphine has a high affinity for mu-receptor

this may prolong the duration of activity

Buprenorphine has  a high affinity for mu-receptors but less intrinsic activity

may compete with other mu-agonists

the drug is a weak base

therefore the absorption of the drug if favored by the high pH of the cat saliva

drug is nearly 100% absorbed because the pH is the environment (cat's mouth) is higher than the pKa of the drug

administer pre-operative for maximum benefit

administer on regular schedule

compare a pure opioid agonist vs. opioid agonis/antagonist and partial agonists

continue drug administration for 24-48 hours post-operatively

Tramadol

Gabapentin

Transdermal fentanyl

Amantadine

Bisphosphonates

injection

immediate release tablets

slow release tablets

combined immediate and extended release

1.tolerance

with chronic administration, equivalent doses become less effective for analgesia, with fewer adverse effects

2. dependence

psychological dependence, euphoria, addiction

weak mu-receptor agonist

decreases reuptake of norepinephrine and seratonin

mild analgesic

not a controlled substance

inhibits re-uptake of serotonin

alpha 2 agonist

opiate effects

inhibits N-metyl-D-aspartate receptors

(NMDA produces central sensitization of pain)

this drug is an anticonvulsant that inhibits the a2sigma subunit of the voltage dependent Ca channel of neurons?

it is also a structural analog of gamma-aminobutyric acid (GABA)

This drug inhibits bone resorption

decreases bone turnover by inhibiting osteoclastic activity

reduces the pain associated with bone cancer or cancer that has metastisized to the bone

accurate diagnosis

knowledge of the life cycles

environment and management practices

reduce parasite burdens

wide therapeutic index

does not require multiple dose regimen

easily administered

no residues in food animal

paralysis of the parasite by stimulating or inhibiting the neurotransmitters

alteration of metabolic processes

alters parasite reproduction

macrolide endectocides

benzimidazoles

Clorsulon

Piperazine

inherent toxicity to the parasite

ability to reach the parasite or infection site

dosing rate

route of administration

SQ

IM

SQ

IM

oral

drench

in a sample deworming schedule for horses, when should you use each drug:

ivermectin?

Fenbendazole?

Mexidectin?

Double dose strogid P or Praziquantel?

ivermectin

March/April

September/October

Fenbendazole

Janurary/February

Moxidectin

May/June

November/December

Double dose Strongid P or Praziquantel

July/August

Which are more susceptible to the actions of Piperazine?

(mature worms or larval stages)

animals with liver or kidney disease

animals with high ascarid load (ascarid impaction colic or perforation of the small intestine)

Piperazine in swine:

how is it administered?

Why is it administered?

put in feed/water for 1-2 days

treats ascarids or nodular worms

this antiparasitic drug is rapidly absorbed from the GI tract and rapidly eliminated.

What can we infer about the drug based on this?

DEC

can infer that it has low toxicity

DEC

(Filbariabits)

DEC is mostly larvacidal and effective against microfilaria

if you give DEC and the animal has adult worms, it may result in hypovolemic shock

binds nematode dimeric tubulin (prevents polymerization of tubulin during microtubule assembly)

large strongyles

small strongyles

Ostertagia

lung worms

kidney worms

nodular worms

lung worms

whip worms

Trichinella

hookworms

ascarids

whipworms

tapeworms

prodrugs that don't have any anthelminthic activity until metabolized

example is Febantel which is converted in the GI tract to Fenbendazole and Oxfendazole

adult strongyles

ascarids

pinworms

Fenbantel is formulated with Praziquantel or Praziquantel + pyrantel (Drontal Plus)

effective against hookworms, ascarids, whipworms, tapeworms

ganglion stimulant (cholinomimetic)

paralysis of worms (depolarizing neuromuscular blockade or sustained muscle contraction)

abomasal worms

intestinal worms

lung worms

ascarids

lungworms

nodular worms

kidney worms

(should administer with food and water)

in the form of pellets or powder

fed daily to horses

prevents migration of large strongyles

acts as nicotinic agonist

causing muscular contraction and tonic paralysis

Which is more potent?

(Morantel or Pyrantel)

S. vulgaris

Parascaris

Pinworms

ascarids

nodular worms

stomach worms

hookworms

ascarids

stomach worms

intestinal worms

most often used in cattle and goats

swine

horses

dogs

coumaphos

because milk residues are a concern with other organophosphates

worms

insects

rapidly absorbed in the GI tract

then rapidly detoxified

hookworms

ascarids

whipworms

ascarids

nodular worms

whipworms

cholinesterase inhibitors

tranquilizers

muscle relaxants

dogs with heartworm infections

which method of coumaphos administration has a wider margin of safety?

(feed supplement or drench)

immature and mature ascarids

adult pinworms

bots

ascarids

strongyles

ascarids

large strongyles

pin worms

ascarids

hookworms

whipworms

mange

fleas

agonist of GABA receptors

(therefore causes paralysis of the parasite)

What are these:

Ivermectin, Doramectin, Selamectin, Eprinomectin

which route of administration of Ivermectin has a greater rate of absorption?

(SQ/dermal or oral)

all GI worms (including Ostertagi)

lung worms

bots

stomach worms

small and large strongyles (including migrating larvae)

pinworms

ascarids

GI worms

lung worms

kidney worms

ascarids

hookworms

whipworms

heartworm preventative

(extra-label) microfilaricide

heartworm preventative

hookworms

CNS depression

ataxia

tremors

mydriasis

possible death

Which has a greater half life?

(Doramectin or Ivermectin)

major GI worms

lung worms

kidney worms

lice

mange mites

heartworms

ectoparasites

(hookworms and roundworms in cats only*)

hearworms

hookworms

ascarids

whipworms

amitra-resistant Demodex canis

injectable moxidectin

provides 6 months of heartworm protection

pulled in 2004 and reintroduced in 2008

vets must complete training before purchase

must require signed "informed consent" from pet owner before the product can be administered

hepatotoxicity

nephrotoxicity

Melarsomine

because it is less toxic

has a longer retention time and slower clearance

the toxicity can be reversed

Praziquantel

Epipraziquantel

Taenicide=causes death of the tape worm in situ

Taeniafuge=facilitates tapeworm expulsion

rapidly absorbed in the GI tract

then readily distributes throughout the host

Dipylidium caninum

Taenia pisiformis

What are these drugs:

Mebendazole, Fenbendazole, Oxfendazole, Albendazole?

Anticestodal drugs

(class Benzimidazole)

we don't know much

hasn't been throughly assessed

most susceptible

10-12 weeks after infection (in the bile duct)

least susceptible

when they become adult flukes and become progressively walled off by connective tissue

Clorsulon

but not approved for use in dairy cattle

Resorantel

Bithionol

Praziquantel

Albendazole

fenbendazole

What are these drugs:

Metronidazole, Tinidazole, Dimetridazol, Ronidazole, Iprmidazole?

Metronidazole lipid solubility?

(high or low)

lethargy

weakness

teratogenic effects

Nitrofurans

Arsenicals

Paromomycin

Benzimidazoles

amoeba

coccidia

piroplasms

ciliates

sulfonamide

polyether ionophores

inhibit folic acid synthesis

most effective against asexual stages