2. Baxdrostat for Treatment-Resistant
Hypertension
Mechanism of Action - Aldosterone synthase controls the synthesis of
aldosterone and has been a pharmacologic target for the treatment of
hypertension for several decades. Baxdrostat acts by inhibiting Aldosterone
Synthase. Baxdrostat significantly decreases aldosterone in plasma and urine,
while increasing plasma renin as a physiological compensatory change. These
changes in aldosterone and renin following treatment with baxdrostat reflect less
salt exposure to the kidney and reduced blood pressure over time.
Advantages - Selective inhibition of aldosterone synthase is essential but difficult
to achieve because cortisol synthesis is catalyzed by another enzyme that shares
93% sequence similarity with aldosterone synthase. In preclinical and phase 1
studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at
several dose levels reduced plasma aldosterone levels but not cortisol levels.
3. Dosing- Dose-dependent changes in systolic blood pressure of −20.3 mm Hg,
−17.5 mm Hg, −12.1 mm Hg, and −9.4 mm Hg were observed in the 2-mg, 1-mg,
0.5-mg, and placebo groups, respectively.
Adverse Effects - Baxdrostat was well tolerated with no serious adverse events
deemed related to treatment, Freeman reported. A total of 18 serious adverse
events occurred in 10 patients, 6 of which were in a patient with urosepsis.
Adverse events of special interest occurred in eight patients, including
hyponatremia, and hyperkalemia.
4. Finerenone in patients with diabetic kidney
disease
Mechanism of Action - Finerenone , a first-in-class, orally administered,
selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), is
being for the treatment of diabetic kidney disease (DKD) and heart failure
(HF), including chronic HF (CHF).
Finerenone has been approved in the USA to reduce the risk of sustained
estimated glomerular filtration rate (eGFR) decline, end stage renal disease
(ESRD), cardiovascular death, nonfatal myocardial infarction (MI), and
hospitalization for HF in adults with chronic kidney disease (CKD)
associated with type 2 diabetes (T2D).
5. Advantages -Patients with kidney disease, would originally be given
spironolactone or epleronone to antagonize the mineraclocorticoid
receptor. spironolactone has low selectivity and affinity for the receptor; it
dissociates quickly and can also have effects at the androgen, progesterone, and
glucocorticoid receptors. Epleronone is more selective and has longer lasting
effects. More selective nonsteroidal mineralocorticoid antagonists such as
finerenone were later developed. Finerenone was at least as effective as
spironolactone 25 or 50 mg/d in decreasing biomarkers of hemodynamic stress,
but it was associated with significantly smaller mean increases in serum
potassium concentration than spironolactone (0.04–0.30 and 0.45 mmol/L,
respectively; P<0.001 to P=0.01) and lower incidences of hyperkalemia
Adverse effects-
>10% Hyperkalemia (18.3%)
1-10%Hypotension (4.8%),Hyponatremia (1.4%)
6. Dosing –
Starting dose
Determine starting dose by eGFR (mL/min/1.73m2)
eGFR ≥60: 20 mg PO qDay
eGFR 25-60: 10 mg PO qDay
eGFR <25: Not recommended
Increase dosage after 4 weeks to the target dose of 20 mg qDay based on
eGFR and serum potassium thresholds
7. Zavegepant for acute treatment of
migraine in adults
Mechanism of Action - Several calcitonin gene-related peptide (CGRP)
receptor antagonists are available by oral formulation for acute migraine
treatment. Zavegepant is the first CGRP-receptor antagonist to be
approved for intranasal administration .
In a trial of 1405 adult patients with migraine, those assigned to
zavegepant 10 mg were more likely to be pain free at two hours than
patients assigned to placebo ; resolution of the most bothersome acute
symptom (eg, photophobia, nausea) was also more common with
zavegepant.
Nasal administration of a CGRP-receptor antagonist provides rapid
absorption and may be preferred for patients with nausea/vomiting who
are unable to tolerate oral options.
8. Adverse Reactions: Most common adverse reactions were taste disorders
including dysgeusia and ageusia, nausea , nasal discomfort , and vomiting.
Warnings and Precautions: Hypersensitivity reactions, including facial
swelling and urticaria, have occurred. If a hypersensitivity reaction occurs,
discontinue and initiate appropriate therapy.
9. ACG Releases New Gastroparesis
Guidelines for Diagnosis, Management
The chronic symptoms associated with gastroparesis include postprandial
fullness, nausea, vomiting, and upper abdominal pain.
After exclusion of mechanical obstruction, several tests are available to
objectively document the presence of delayed gastric emptying. The gold
standard is scintigraphic assessment, which includes appraising the
emptying of a solid meal over a duration of 3 hours or more.
In patients with idiopathic and diabetic gastroparesis, pharmacologic
treatment should be considered to improve symptoms, based on the
benefits and risks of treatment.
10. The guidelines suggest treatment with metoclopramide over no treatment for
management of refractory symptoms. Metoclopramide is the only US Food and
Drug Administration (FDA)–approved medication for the treatment of
gastroparesis. The FDA has warned about the risk for side effects, including
tardive dyskinesia, particularly among high-risk groups such as older women,
patients with diabetes, patients with liver or kidney failure, and patients receiving
antipsychotic drug therapy. Newer trials with the intranasal formulation show
that the most common adverse effects are dysgeusia, headache, and fatigue.
Domperidone is available for gastroparesis treatment under a special FDA
program. In clinical trials, domperidone has been associated with symptom
improvement, as well as a reduction in the frequency and intensity of symptoms.
Prokinetic agents, such as 5-HT4, have shown symptomatic benefit in clinical
trials, though the data were inconsistent. Generally, the guidelines recommend
treatment over no treatment to improve gastric emptying.
Motilin agonists, which include erythromycin, clarithromycin, and azithromycin,
are generally used for short-term treatment (1-4 weeks) owing to development
of tachyphylaxis.
11. Updates in Clinical Practice Guidelines for
Lyme Disease
Lyme disease is caused by the bacterium Borrelia burgdorferi and rarely,
Borrelia mayonii. It is transmitted to humans through the bite of infected
blacklegged ticks.
Flulike illness - Fever, chills, malaise, myalgias, arthralgia, headache Tender
local adenopathy (local, not diffuse),Erythema migrans (EM) - Rash
We all know that the best way to treat any disease is by preventing it. The
following measures are recommended as tools to prevent infection:
personal protective wear, repellents, and removal of the attached tick.
Recommended repellents include DEET, picaridin, IR3535, oil of lemon,
eucalyptus, para-Menthane-3,8-diol (PMD), and permethrin. If a tick is
found, it should be removed promptly by mechanical measures, such as
with tweezers.
12. Following a high-risk tick bite, adults and children can be given prophylactic
antibiotics within 72 hours. It is not helpful for low-risk bites.
If the risk level is uncertain, it is better to observe before giving antibiotics.
For adults, a single 200-mg dose of doxycycline can be given. In children, 4.4 mg per
kg of body weight, up to 200 mg max, can be used for those under 45 kg.
For patients with a tick exposure and erythema migrans, a clinical diagnosis of Lyme
disease can be made without further testing. If the clinical presentation is not typical,
it is recommended to do an antibody test on an acute phase serum sample followed
by a convalescent serum sample in 2-3 weeks if the initial test is negative.
Recommended antibiotics for treatment include doxycycline for 10 days or
amoxicillin or cefuroxime for 14 days. If a patient is unable to take these,
azithromycin may be used for 7 days.
