Exam 4 Flashcards
Drugs affecting Blood and Blood Elements
Platelet Aggregato Inhibitors
Aspirin
-Acetylsalicyclic acid
-Irreversible inhibition of Cox-1
-Does not affect Cox-2
-PGI2 synthesis not affected
-No new Cox-1 can be made, platelets do not have nucleus where protein is synthesized, 4-6 day lifespan, conjugated into salicylate by liver and excreted in urine.
30% of dogs do not respond
-Feline: too wide of dose range, inconsistent responses
Indications
-Feline arterial thromboembolism (clopidogrel better)
-Proteinuric renal disease (glomerulonephropathy)
Clopidogrel
Often used with aspirin
-Cytochrome P450 in liver
-Active metabolite in serum
-P2Y12 receptor on platelet binding
Prevents ADP binding
-Irreversible
-50:50 fecal/urine
-Canine, feline, equine (endotoxemia, laminitis?)
Clinical Indications
-K9 dilatory cardiomyopathy
-Immune mediated hemolytic anemia
-Thromboembolic disorders
-Glomerulonephropathy
-Heartworm infestation
-Feline hypertrophic cardiomyopathy
Anticoagulants
Warfarin (Coumadin, Jantoven)
-Inhibitor of Vitamin K dependent factor production
-Factors 2, 7, 9, and 10
Factor VII has the shortest half life, so use the OSPT test
-Quinone Reductase enzyme inhibition
-Prevents recycling of Vit K
-Variability cytochrome P450 and metabolism
Clinical Indications
Contraindicated with many other drugs due to P450
-Requires careful monitoring
-Highly variable dosing in cats
-Dose adjust based on OSPT or INR
-Reversible: Vitamin K Phytonadione, Phytomenadione
**Do not use Vitamin K3, K4 **
Anaphylactic if IV
Factor Xa inhibitors: (Rivaroxaban, Apixaban)
-Factor Xa structurally similar across species
-Inhibits at the beginning of common pathway
-Prevents production of Thrombin, and downstream
Advantages over Warfarin
-Fixed dosing schemes
-Pharmacokinetics are predictable
-No need for monitoring
-Not affected by dietary factors
-Less drug interactions
-Feline,canine, equine
Clinical Use
-IMHA
-Thrombosis in cats: no adverse bleeding noted
Reversal Agent
-Andexanet alfa
-Binds Factor Xa inhibitors to free up factor Xa
-Emergency surgery
-Expensive
Thrombin inhibitors
(Dabigatran etexilate)
-Direct, irreversible, competitive binding to active site
-Bound and unbound fibrin
-Inhibits circulation and clot-bound THROMBIN
-Prevents feedback to factors V, VIII.
Reversal Agent
-Idarucizumab: monoclonal antibody that binds dabigatran and metabolites
Heparin
-Potentiates Antithrombin III
-Enhances ATIII by 1000x
-Feedback inhibition: factor IXa, Xa, Thrombin
Low molecular weight Heparin
-Enoxaparin
-Dalteparin
-5000 weight
Less side effects
-No OSPT or ACT test
-Low dose protocol
Clinical Uses
-Hypercoagulability disorders
-Thromboembolism
-Venous thrombosis
-Disseminated Intravascular coagulopathy (DIC)
-IMHA
-Pulmonary thromboembolism
-99% of time: heparinized saline for flushes
Pro-coagulants
-Post op care for bleeding
-Limb amputation
-Greyhounds
-vonWillebrand patients
-Trauma
-Diseases that promote hemorrhage (e.g., hemangiosarcoma)
Antifibrinolytics
-Aminocaproic acid: Lysine analog
-Competitive binding to plasminogen
-Complex can not bind to fibrin
-Prevents fibrinolysis
Pro-palets aggregators
-Yunnan Baiyao: Chinese herbal blend
-Increases expression of platelet surface glycoproteins
-ADP and arachidonic acid 3-5x response
-Enhances recruitment and activation of platelets
-Improves TEG and clot formation
No side effects
Fibrinolytics
What breaks down a clot?
-Plasminogen to plasmin
-Plasmin fragments fibrin
-Fibrin degradation products (FDPs)
- Streptokinase
- Urokinase
Rh-Tissue Plasminogen Activator
Indications: None, never, lose your license
Erythropoetic drugs
EPO
-Epogen
-Epoetin-alfa
-Stimulates stem cell in bone marrow to differentiate
-Problem: recombinant human products
Monitor HCT weekly until you reach goal then reduce
Molidustat drug
-Hypoxia inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PH)
-Inhibits PHD to increase relative to levels of HIF-alpha
-Facilitates iron bioavailability in bone marrow
-Increases production of endogenous EPO
Hemostasis
Primary Hemostasis
-Platelet Activation
-Collagen
-vWF, fibrinogen
-Platelet adhesion, release and aggregation
-Platelet plug
Coagulation Cascade
-Tissue Factor
-Thrombin
-Fibrinogen —Fibrin
-Blood clot
=Plasmin, Fibrinolysis.
Mediators of Primary Hemostasis
ADP
Cox-1 leading to Thromboxane A2
-Post activation: self activation until stopped by PGI2 and NO
Thrombotic Disease
Thrombosis in the arterial system
-Arterial (high flow)
-Platelet activation
-White thrombi
-Platelets»_space; Fibrin
Thrombosis in the venous system
-Decreased flow with RBCs trapped into fibrin network
-Activation of coagulation cascade
-Red thrombi
-Fibrin»_space; platelets
What are the mediators of platelet activation in primary hemostasis? What stops it?
Where does each drug work?
Antiviral Medications
All drugs are virustatic NOT virucidal
Most antivirals works during replication
Limited clinical trials to show efficacy
Treatment of viral disease if problematic
What are we treating?
Cats
-FIV
-FIP
-FeLV
-Herpes virus-1
Dogs
-Parvovirus
-Canine influenza
Where do they work?
Replication cycle
-Receptor homologues/antagonistis
-Receptor and co-receptor proteins
Receptor Homologues/Antagonist
Plerixafor
CXC chemokine receptor 4 antagonist
-Decreases proviral load
-FIV-infected cats
-CXR4 Receptor binding prevented by blocking Ca influx
-Minimal side effects: decrease in serum Mg
Reverse Transcriptase Inhibitors
Retroviruses: rapid replication of nucleic acid, reverse transcriptase used.
Zidovudine
(Azidothymidine, Retrovir)
Oral liquid
-Nucleotide analog
-Herpesvirus
-Lentivirus
-FIV cats
-Reduces stomatitis, improves immunologic response
Side effects: anemia, resistance due to point mutation
Integrase Inhibitors
Raltegravir
-Inhibitor of integration of proviral DNA
-FeLV
-Hepesvirus-1
Side effects: glucoronidation into water soluble substance, but minimal side effects
Rebound viremia and recurrence when drug is stopped
Nucleotide Synthesis Inhibitors
Inhibit nucleotide synthesis by blocking normal cellular mechanisms non-selectively
Foscarnet
-IV infusion only
-Major side effects
Ribavirin
-FIV use
-Side effects: anemia, hemorrhage, thrombocytopenia, liver, etc.
Interferons
Interfere with viral replication by inducing release of cytokines of host cells and lymphocytes
-Trigger apoptosis and T-cells to attack
Types
Type I: INF-alpha
Type II: INF-gamma
Type II: INF-28A
Human INF-alpha
-USA
-High dose 1000-10000 U/kg SQ qd
-FeLV
-FIV
Feline IFN-w
-Europe and Japan
-No longterm reactions
DNA/RNA Nucleoside Analogue
Acyclovir
-Herpes mistakenly uses it for DNA
-Requires initial viral phosphorylation
-Creates terminal segment and virus can not be completed
-No effects on latency, only actively replicating virus
-FHV-1
-HSV
-ACV + INF-alpha: synergistic
Famciclovir
-Penciclovir becomes an analogue of GUANINE
-Better than Acyclovir higher serum concentration
Drug of choice for FHV
-Side effects: vomiting, diarrhea, pu/pd, inappetence
-Rapid improvement after 2 weeks
Herpesvirus
Tx Options
-Raltegravir
-Nucleoside analogues: Acyclovir, Famciclovir, Idoxuridine
Nucleotide synthesis inhibitors = toxic
L-Lysine
-Not an antiviral but needs to be discussed
Ophthalmics
Idoxuridine
-Highly toxic systematically, but great topically
-Short half life, dose q4hr
-Halogenized thymidine analogue
Trifluridine
-2x more potent and 10x more soluble
-Fluorinated thymidine analogue
-Highly effective, similar q4hr dose
Peptide
l-Lysine
-ARGININE antagonism
-Reduces viral replication
-Excess lysine competes with arginine and virus can’t replicate
-Not effective against Feline Herpesvirus-1
Immunomodulators and Biologic Response Modifiers
Glucocorticoids
- Prednisone
- Prednisolone
Backups
-Methylprednisolone (oral)
-Dexamethasone SP
-Dexamethasone
-Triamcinolone
MOA: bind intracellular receptors, translocate to the nuclei, bind receptor sites on genes. Modulate transcription of CG responsive genes, alter protein synthesis
The signal caller
-Neutrophils: inhibited apoptosis
-Macrophages: inhibited phagocytosis
-Lymphocytes: T-cells more affected than B-cells at lower GC levels. Reduced Ig level at high GC doses
-Other: Inhibit release of cytokines IL-1, TNF-alpha, prostaglandins, IL-2
-Anti-inflammatory
-Immunosuppressive
The Three Ds
Drug
Dose
Duration
Patient
-Comorbidities
-Species differences
-Cost
-Monitoring
-Owner’s (in) tolerance of side effects
-Withdrawal times
Potential Side effects
-PU/PD
-Diabetes mellitus
-Polyphagia
-Behavioral changes
-Opportunistic infections
-Adrenal suppression
-Delayed wound healing
-Catabolic effects on muscle, connective tissue
-Gastric ulceration
-Panting
-Hypertension/CHF
-Proteinuria
-Calcinosis cutis
When to Modify the Plan
-When GC aren’t being effective
-Intolerance of side effects
-Illness life-threatening
Calcineurin Inhibitors
- Cyclosporine
(Tolycladium inflates soil fungus)
-Atopica
-Cyclavance
-Neoral
-Equoral
MOA: suppresses IL-2 gene
-Decreases production of TNF-alpha, IL-3, IL-4, INF-y
-Inhibits IgE
-Reduces eosinophil recruitment and lymphocyte activating functions of antigen-presenting cells
-More specific for T cell than B cells
-Not typically myelosuppressive
-Cytochrome P450 enzyme in the liver. Systemic absorption 20-30%
Caution with MDR-1 deficient dogs
-Biliary excretion predominates
-Renal excretion is minor
Synergistic with Ketoconazole
Side effects
-GI signs +/- maropitant
-Gingival hyperplasia
-Opportunistic infections, papillomavirus lesions
-Elevated liver enzymes +/- glucose
-Hirsutism
-Rarely: anaphylaxis, Pruritus
-Assess peak 2 hours after dosing, trough immediately before next dose
-Adjust dosage based on patient’s clinical performance
-Taper to qod or twice weekly
- Tacrolimus
-aka FK506
-Ointment ONLY, orally terrible side effects
-Tx: Atopy, perianal fistula
-10-100x cyclosporine
Omega 3 FA, DHA/EPA
Canine and Feline Osteoarthritis
Omega 3 FA
-Evidence for efficacy
Chondroitin and glucosamines
-(worse than negative control-placebo)
DHA/EPA MOA
-Specialized pro-resolving mediators (SPMs)
-Inflammation: generation of eicosanoids (PGs, leukotrienes) from arachidonic acid (omega-6) in conjunction with cytokines, chemokine, complement
-SPMs are enzymatically derived from essential FA to serve as immunoresolvents that limit acute responses and promote the resolution of non-infectious inflammation and tissue injury such as OA pain
-SPMs: composed of lipoxins, E-series and D-series resolvins, protecting, and margins (activate regulatory T cells)
RESOLVINS
Glucosamine
-Collagen synthesis in cartilage
-Contributes to glycosaminoglycans and proteoglycan synthesis
Chondroitin
-Contributes to extracellular matrix of cartilage
-Adds to resistance and elasticity of cartilage
-Inhibition of destructive enzymes in joints
-Contributes to synthesis of glycosaminoglycans and proteoglycan
Medicinal herbal supplements MOA
Green-Lipped Mussel Extract
-New Zealand (Perna Canaliculas)
-Chondro-modulatory and anti-inflammatory properties
MOA
-Contains glycosaminoglycans (chondroitin sulfate)
-Amino acid (glutamine)
-Omega-3 FA (including DHA, EPA)
-Prebiotic activity in the intestines
-Proteins and peptides: anti-microbial, anti-inflammatory, anti-oxidant, bio-adhesive and anti-hypertensive properties
-Inhibit COX-1, COX-2, Prostaglandisn, Lipogenase, leukotrienes
Biota orientalis plant (Epiitalis)
-Antioxidant, anti-inflammatory
-Hight NMIFA
-Reduces: PGE2, COX2, replace AA
-Reduces synovial PGEs and GAG
-Reduces IL-1
-Inhibition of MAPKs
-Increases chondrocyte numbers
-Inhibition of osteophytes growth
Avocado soybean unsaponifiable
-Inhibition of inducible NO synthase and MMP-13
-Tx canine OA
-Increases TGF-B1 and 2, chondrocyte production of collagen and proteoglycans
UC-II
MOA: alleviates inflammatory T cell response and activates T-regulatory cells via its oral tolerance ( immune process to distinguish harmful from non harmful compounds) mechanism, which reduces cartilage damage
Cannabinoids and their MOA
Endocannabinoid System
-ECS plays key roles in control of various systems
-Nervous, metabolic, digestive, reproductive, immune function
-Cannabinoid receptor 1 (CB1R)
-Cannabinoid receptor 2 (CB2R)
-Endogenous cannabinoid ligands (endocannabinoids, eCB)
-Anandamide (AEA)
-2-AG
Metabolizing enzymes
-Fatty acid amide hydrolase (FAAH): hydrolyzes AEA
-Monoacyglycerol lipase (MGL): hydrolyzes 2-AG
Cats with chronic gingivostomatitis: reduces pain, increases healing
ECS
-Parallels and interacts with other major endogenous pain systems
-Ecosanoid pathways
-Vanilloid/transient receptor potential
-Endorphin/enkephalin
-Endocannabinoidome (eCBome)
Cannabinoids and Phytocannabinoids
