6302 - Tran / Chung Portion

Mean pulmonary artery pressure (mPAP) >20 at rest, measured by RIGHT heart catheterization

Definition of Pulmonary Hypertension (PH)

-Elevated Pulm. Artery Pressure

-INC'd Pulm. Vascular Resistance (PVR) - PVR > 2 wood units

-Pulmonary Artery Wedge Pressure (PAWP) ≤15 mmHg

PAH Group 1 characterization

-INC Vasoconstrictiors (like ET-1)

-DEC Vasodilators (like Nitric oxide)

Imbalance during PAH

-Aminorex

-Benfluorex

-Dasatinib

-Dexfenfluramine

-Fenfluramine

-Methamphetamines

DEFINITE Drug-Induced Causes of PAH

-Cyclophosphamide

-Mitomycin C

-Amphetamines

-Cocaine

-Phenylpropranolamine

-St. John's wort

-Bosutinib

-Leflunomide

-Bevacizumab

-Sofosbuvir

-Carfilzomib

POSSIBLE Drug-Induced Causes of PAH

What is required for DEFINITIVE Diagnosis of PAH?

Right Heart Catheterization

When catheter is in heart still, they'll administer one of these and see what happens in the measuring device while the drugs are in the system:

-Inhaled Nitric Oxide

-IV Epoprostenol

Vasoreactivity Testing

-Drop in mPAP ≥10 mmHg to absolute value ≤40 mmHg w/o a decrease in Cardiac Output

"Positive" Response to Vasoreactivity Test (rare)

→ High dose CCB

(Nifedipine)

(Amlodipine)

(Diltiazem)

**AVOID VERAPAMIL !!*** 😡

(Add PAH-targeted therapy if lack of long-term response)

Tx in ppts w/ Positive Vasoreactivity Test

→ Use targeted PAH therapies depending on risk strat

Tx in ppts w/ Negative Vasoreactivity Test

-Sildenafil (Revatio) PO/IV

-Tadalafil (Adcirca) PO

PDE-5 Inhibitors

(safe in pregnancy)

**do NOT use w/ Riociguat or Nitrates

-Riociguat (Adempas) PO

sGC Stimulators [REMS]

**also not recc'd in CrCl

-Bosentan (Tracleer) PO *binds to A and B [REMS]

-Ambrisentan (Letairis) PO *binds to A only (less liver toxic)

-Macitentan (Opsumit) PO *binds to A and B

Endothelin Receptor Antagonists (ERAs)

**do NOT use in pregnancy**

-REMS → monthly pregnancy test

-Dual contraception methods advised d/t DEC'd effectiveness of oral contraceptives

-INC LFTs/Hepatotoxicity **

-DO NOT use w/ Cyclosporine A or Glyburide

Bosentan (Tracleer), an ERA

-Riociguat

-Bosentan

PAH Drugs that are REMS

-This class of PAH agent requires monitoring of Liver enzymes and Hemoglobin prior to initiation, at 1 month, and PRN

-This class requires Dual Contraception methods

ERAs

-Epoprostenol (Veletri) *continuous IV

-Trepostinil (Remodulin IV/SC) (Tyvaso inh sol.) (Orenitram PO ER) (Yutrepia inh powd) **oral → take w/ food

-Selexipag (Uptravi) PO

**ALL AGENTS HERE HAVE JAW PAIN and GI ADRs**

Prostacyclin Pathway Agents

-This is the only PAH drug to show improved survival in RCT 😊

-Must be protected from light

-Continuous IV

-DO NOT use in HFrEF

-Avoid abrupt discontinuation or dose reductions → rebound Pulm HTN

Epoprostenol (Veletri)

These 2 agents are PARENTERAL Prostacyclins and we must avoid abrupt D/C or dose reductions b/c it can lead to rebound Pulm HTN !!! → Need backup pump and med

Trepostinil (Remodulin IV/SC) and Epoprostenol (Veletri)

This prostacyclin AGONIST (selective for IP receptor) (non-prostanoid) is contraindicated if using Gemfibrozil

Selexipag (Uptravi)

These are the INHALED Prostacyclin agents

Tyvaso (Trepostinil inh sol), Yutrepia (Trepostinil inh powder)

-Sotatercept (Winrevair) SC

Activin Signaling Inhibitors (DEC PVR)

**has bleeding risk**

**AVOID use in Pregnancy**

-Prostacyclin Pathway Agents (Epoprostenol, Trepostinil, Selexipag)

-PDE-5 inhibitors

Safe PAH agents to use in Pregnancy

MHC Presents to T cell receptor

Signal 1

Co-stimualtion signal by CD80/86 to CD28

(required for full T-cell activation)

Signal 2

Proliferation Signal, activation by IL-2

Signal 3

This class of organ transplant med Blocks Signal 1

Calcineurin Inhibitors (Tacrolimus, Cyclosporine)

This class of organ transplant med Blocks Signal 2

Costimulation Blocker (Belatacept)

This class of organ transplant med Blocks Signal 3

IL-2 receptor antagonist (Basiliximab)

These class of organ transplant meds work Downstream of Signal 3

-Antimetabolites (Mycophenolate, Azathioprine)

-mTOR Inhibitors (Sirolimus, Everolimus)

-CNIs

-Costimulation blocker (Belatacept)

-Antimetabolites/Antiproliferative agents (Azathioprine, Mycophenolate)

-Corticosteroids

Combine 2-3 of these for Immunosupp. MAINTENANCE

-Corticosteroids + Antibody Therapy:

IV Methylprednisolone AND+

Thymoglobulin (rATG, for high risk ppt) OR Basiliximab (if low risk)

Induction of Immunosupp. (Organ Transplant)

(1) Cyclosporine OR Tacrolimus

PLUS +

(2) Prednisone

[for a 2-drug combo]

----------

PLUS+

(3) Mycophenolate OR Azathioprine OR Everolimus / Sirolimus

[for 3-drug combo]

Maintenance of Immunosupp. (Organ Transplant)

CNIs (Tacrolimus, Cyclosporine) and mTOR inhibitors (Sirolimus, Everolimus)

Requires TDM

-Biopsy for Diagnosis

-Often asymptomatic (INC SCr +/- Proteinuria)

Acute T-cell Mediated Rejection (TCMR)

-DSA (donor-specific antibodies)-driven attack

-C4D deposition may be in Biopsy

-INC SCr +/- Proteinuria

-May have new/worsening HTN

Antibody-Mediated Rejection (AMR)

Methylprednisolone Pulse dose (IV, daily, x3-5d)

Tx of T-cell Mediated Transplant Rejection (MILD-MOD)

Thymoglobulin IV (1.5 mg/kg daily, x5-14d)

Tx of T-cell Mediated Transplant Rejection (MOD-SEVERE)

Plasmapheresis + IVIG +/- Corticosteroids

**Adjunct: Rituximab

Tx of Antibody-Mediated Transplant Rejection

This is used for Prophylaxis only and ONLYYY for EBV-Seropositive, Kidney transplant ppts

Belatacept

This class has POOR WOUND HEALING ADR 🩹

-Also Proteinuria, Leukopenia, Thrombocytopenia, Mouth ulceration, etc.

-HYPERLIPIDEMIA too

-Adjust based on whole-blood TROUGH

mTOR (Sirolimus, Everolimus) ADRs/about

-PTLD, PML (leukoencephalopathy)**

-Monitor for Neuro/Cognitive/Behavioral sx

Belatacept ADRs

-You must administer this 4 hours after Cyclosporine :(

-BOXED: DO NOT RECC for Liver/Lung transplant

Sirolimus (Rapamune)

Risk of renal/hepatic artery THROMBOSIS*** within 30 days post-transplant

Everolimus (Zorstress) ADR

-ATG / Thymoglobulin

-Alemtuzumab

T-cell depleting antibodies, used for Induction

-CYTOPENIAS: Leukopenia, Neutropenia, Thrombocytopenia, Anemia

ADR of T-cell depleting antibodies (ATG, Alemtuzumab)

-Destroys all T-cell types (depletion)

-Polyclonal

-WBC 2-3k or Platelets 50-70k → DEC dose by 50%

-WBC

Thymoglobulin (ATG)

-Nephrotoxic

-HTN

-Dyslipidemia

-Gingivial Hyperplasia

-Hirsutism

ADRs of Cyclosporine

Cyclosporine inhibits Enterohepatic Recirulation which DEC what drug level exposure?

Mycophenolate (MPA)

-Nephrotoxic

-Neurotoxic → TREMORS*

-ALopecia

-Hyperglycemia

ADRs of Tacrolimus

-Bone marrow suppression (esp in NUDT15 def / TPMT def)** → MONITOR CBC, hold if significant

**DEC dose if using Ganciclovir/Valganciclovir, Bactrim, Febuxostat, or Allopurinol (b/c BMS)

-Hepatotoxic

-Pancreatitis, Alopecia

ADRs of Azathioprine

(also DEC dose if CrCl

-Diarrhea

-Myelosuppression, Leukopenia, Neutropenia → Monitor CBC

-INC risk for CMV

-Teratogenic ⚠️

-DEC'd exposure if taking w/ Cyclosporine

Mycophenolate (Cellcept, Myhibbin)

*take on empty stomach

-Erythromycin

-Grapefruit Juice

These INC absorption of Cyclosporine/Tacrolimus → INC toxicity

-Diltiazem

-Erythromycin

-Ketoconazole/Voriconazole

-Nicardipine

-Verapamil

DENKVV

These DEC metabolism of Cyclosporine/Tacrolimus → INC toxicity

-INH

-Phenobarbital

-Phenytoin

-Rifampin

-St Johns Wort

IPPRS

These INC Metabolism of Cyclosporine/Tacrolimus → INC Rejection risk...

These organ transplant meds have ADR of HTN

-Cyclosporine

-Tacrolimus

-Steroids

These organ transplant meds have ADR of Hyperlipidemia

Cyclosporine, Steroids, Sirolimus/Everolimus

These organ transplant meds have ADR of Bone Marrow Suppression

-Azathioprine

-Mycophenolate

-Sirolimus/Everolimus

-Steroids

This MAY slow down progression of Cardiac Allograft Vasculopathy

MTOR inhibitors

Culture growth, Pathogen Detection

Definitive Test for "Infection" as opposed to "Rejection

Biopsy of Graft

Definitive Test for "Rejection" as opposed to "Infection

This is for CMV Prophylaxis in HIGH RISK (D+/R-) Kidney transplant recipients

Letermovir

-Mild-Mod: Valganciclovir (Valcyte) PO 900 mg daily

-Severe: Ganciclovir (Cytovene) IV 5 mg/kg/d

**both require renal dose adj

CMV Prevention, drugs (generally 3-6 months long)

CMV Serostatus: (D+/R-)

High risk → DEF requires Prophylaxis

CMV Serostatus: (D+/R+) or (D-/R+)

Intermediate risk → most require Prophylaxis

CMV Serostatus: (D-/R-)

Low risk → No ppx needed

-Ppx: Bactrim 1SS or DS Tab QD

-Tx: Bactrim 15-20 mg/kg/d in 3-4 divided doses IV

Pneumocystitis Tx (common in lung/heart transplant)

→ Reduce immunosuppression when feasible (e.g. hold antimetabolite / lower CNI target by 25-50% / keep low-dose steroids to protect graft, etc)

→ If persistent/progressive/advanced disease: Use Rituximab **monitor for HBV reactivation

Tx Strategies for PTLD

→ Converting to mTOR inhibitors from a CNI

How to Approach Kaposi Sarcoma (cutaneous lesions); or tbh, reduction of immunosupression

-Tacrolimus/Cyclosporine

-Azathioprine

-Corticosteroids

Safe Organ Transplant meds in Pregnancy