IMCP Deiab

Finasteride Details and MOA

• Indicated for BPH and male pattern baldness.
• Off-label, it is used for acne in females.
• Finasteride inhibits the conversion of testosterone to DHT.
• It functions as a 5a-reductase inhibitor.

Non-Steroidal Androgen Receptor Antagonists

• Apalutamide
• Bicalutamide
• Flutamide
• Nilutamide

Hormonal Contraceptives and Their Adverse Effects

• Estrogen levels: very low to low doses are most common to reduce estrogen-related adverse effects.
• High doses can cause breakthrough bleeding and reduce the efficacy of certain drug interactions.
• Mild adverse effects (ADEs) associated with hormone levels include:
  • Estrogen too low: breakthrough bleeding (early), light menses, vaginal dryness.
  • Estrogen too high: bloating, breast tenderness, nausea, weight gain, and fibroid growth.
  • Progestin too low: breakthrough bleeding (late), heavy menses, and no withdrawal bleeding.
  • Progestin too high: decreased libido, depression, low energy, noncyclical weight gain, androgenic effects (acne, hirsutism, cholestatic jaundice), and increased libido.

Tamoxifen Details: MOA, Adverse Effects (AE), and Structure-Activity Relationship (SAR)

• Indicated for breast cancer treatment.
• MOA: acts differently in various tissues as a selective estrogen receptor modulator (SERM).
• Functions as a selective agonist/antagonist at the estrogen receptor.
• Acts as an agonist at ERβ in bone, increasing bone density.
• Acts as an antagonist at ERα in the breast, inhibiting breast cancer growth.
• SAR: the aminoethyl ester is essential for activity.
• AEs include increased proliferation of endometrial tissue, potentially leading to endometriosis, and cataracts.

Enzymes for Tyrosine to Norepinephrine Conversion and NT synthesis from amino acids.

• NE is synthesized from tyrosine via dopa/dopamine.
• Dopamine is synthesized from tyrosine.
• Acetylcholine requires a specific precursor that was omitted.
• Glutamate is synthesized from glutamine.
• GABA is synthesized from glutamate.
• Serotonin is synthesized from tryptophan.

Drug-Drug Interactions (DDIs)

• Zaleplon's notable DDI: Cimetidine.
• Buspirone's notable DDIs: MAO-I, serotonergic agents, and CYP3A4 inhibitors/inducers like citalopram, duloxetine, and sertraline.

Flumazenil: Mechanism of Action and Indications

• MOA: Competitive BDZ antagonist at the GABA-A receptor.
• Indications: Used as a rescue agent for benzodiazepine (BZD) overdoses.

Levetiracetam

• The antiepileptic drug stimulates GABAergic transmission.
• Blocks calcium channels.

General Anesthetics Administered via Inhalation

• Typically administered as gases or volatile liquids.
• Class effect: Affect nerve transmission in the brain.
  • Low doses act on the substantia gelatinosa in the spinal cord.
  • Higher doses distribute to other brain regions.
  • General MOA: Allosteric modulator of the GABAA receptor.
• Soluble in blood, tissue fluids, and tissues.
• Usually lipophilic.
• Requires continuous administration.
• Halogenation affects potency, flammability, metabolism, and arrhythmic properties.
• Potency increases with the size or heaviness of the halogen. There is a direct correlation between lipophilicity and potency.
• Chemical stability is improved with halogen substitution of H atoms.
• CNS effects lead to unconsciousness, analgesia, amnesia, muscle relaxation, increased cerebral blood flow (CBF), increased intracranial pressure (ICP), and decreased cerebral metabolic oxygen use.
• Cardiovascular effects: Dose-dependent decreases in mean arterial pressure (MAP), coronary vasodilation, increased heart rate (HR), decreased left ventricular (LV) stroke volume, and QT prolongation.
• Respiratory effects include increased rate, decreased tidal volume, decreased airway resistance, and decreased ventilatory response to CO2.

Specific Inhalational Anesthetics

• Nitrous Oxide: Non-irritating, non-toxic gas, but an incomplete anesthetic agent alone; it does not cause respiratory depression. Possible NMDA receptor inhibition. Low solubility and potency; increases CBF but does not change ICP.
• Halothane: The most potent inhalant causes increases in CBF and ICP, and triggers malignant hyperthermia. Metabolization by CYP2E1 results in trifluoroacetic acid (TFA) which can cause liver toxicity. High potency for hypnosis, but slow induction and recovery.
• Isoflurane: Used for maintenance, not induction. It has slow-intermediate induction and recovery. It is primarily eliminated through the lungs, making it less hepatotoxic than halothane. Maintains cardiac output.
• Enflurane: is of medium potency, allows medium induction and recovery, increases CBF and ICP, has muscular relaxant effects, but can increase convulsions and cardiosuppression in high doses.
• Sevoflurane: Medium-high potency, fast onset of action and recovery. Increased CBF and ICP. Non-irritating to the airway.
• Desflurane: Low potency, fast onset and recovery, increased CBF and ICP and muscle relaxation. Due to pungency, it can cause broncho-tracheal irritation, it should be avoided in patients with known QT prolongation.

Organ Effects

• Inhaled anesthetics enhance the effect of depolarizing/non-depolarizing muscle relaxants.
• They can cause dose-dependent decreased respiratory depression like Isoflurane & Enflurane.
• Halothane causes hepatotoxicity (likely immune response; trifluoroacetylates) and Enflurane/Isoflurane (less common).
• Nephrotoxicity: metabolism to fluoride ions leads to renal tubular damage, which is equal for enflurane and sevoflurane and more than isoflurane.

IV Anesthetic Drugs

• General MOA: (+) allosteric modulator of GABAA receptors.
• Barbiturates:
  • Methohexital is ultra-short acting.
  • AE: May cause myoclonus activity (dose-dependent).
• Benzodiazepines: Have a slower onset and recovery.
  • Midazolam (Versed): Lidocaine co-administered, used for sedation, benefit of amnesia. Half-life is 2 hours.
  • Diazepam (Valium): Lidocaine co-administered, long half-life (30-50 hours), highly lipophilic.
• Propofol: MOST COMMON IV parental anesthetic
  • Use: For induction and maintenance for in/out-patient surgery and agitation treatment in ICU patients.
  • Onset of action: Less than one minute.
  • Half-life: 2 hours.
  • AE: Pain at injection site.
• Etomidate:
  • Uses: induction and maintenance of general anesthesia.
  • AE: painful at injection site, which is treated by lidocaine co-administration
  • No known DDIs
• Ketamine:
  • MOA: (-) allosteric modulator of NMDA receptor and an agonist at the mu opioid receptor.
  • PD: No muscle relaxant effects
  • Rapid onset (1 min)

Anesthetic pharmacokinetics

• Renal elimination.
• AE: Increased BP, HR, or bradycardia, increased CBF, ICP
• DDIs: strong inhibitors/inducers CYP314/2C9
• Equilibrium between ionized and non-ionized forms at physiological pH determines of the % of drug that crosses the cell membrane.
• The non-ionized form crosses cell membrane and intracellular pH ionizes the drug.
• Ionized drugs bind to the active Na channel to block flux of Na into cell and depolarize the membrane.
• This process inhibits of Na channels and blocks nerve conduction

Intravenous General Anesthetics

• Half-life increases modestly with continuous infusion for ketamine, propofol, and etomidate.
• Diazepam, thiopental/methohexital, and midazolam have increased half-life with continuous infusion.

Key factors influencing a drug's function

• Rate of distribution.
• Amount of drug accumulated in fat tissue.
• Drug's metabolic rate.
• Benzocaine cannot be given IV because it is fatal.
• Benzocaine can only be given topically (gels, creams, lozenges).
• It is an amino ester with a metabolism to PABA, where sulfonamide antibiotics antagonizes antibacterial activity.

Propofol

• MOST COMMON IV parental anesthetic
• Use: induction and maintenance for in-/out- patient surgery & treatment of agitation in mechanically-ventilated ICU patients
• IV onset of action: < one minute
• t 1/ 2 = 2 hours
• Adverse Effect: pain at injection site; no analgesic effects.

Inhibitors of Thyroidal Peroxidase

• Propylthiouracil (PTU) can be used for hyperthyroidism and thyroid storm.
• By blocking the biosynthesis of T4 and T3 which inhibits thyroidal peroxidase (TPO), means T4 cannot be converted to T3
• Short t 1/ 2 = ~75 minutes, required frequent dosing
• AE: Hepatitis/acute liver failure (black box warning), and leukopenia and nephritis/glomerulonephritis,
• Methimazole can be used for hyperthyroidism, with frequent thyroid levels monitored
• Bocks the biosynthesis of T4 and T3 and inhibits TPO, but LACKS 5'-de-iodinase inhibitory activity.
• Longer duration of action and less toxic than PTU with minor skin rash, urticaria, N/A is slightly more severe agranulocytosis, thrombocytopenia, anemia and liver impairment is possible but less than PTU.
• Radioactive iodine; is a D/c drug 1 week in advance and inhibits vit. K which will increase anticoagulant activity where caution about pregnancy is increased to the 1st trimester due to fetal abnormalities.
• Adjunct therapy is advised in Thyroid Storm (Thyrotoxicosis) for symptomatic control due top elevated thyroid hormone levels.
• Beta-blockers can be taken to antagonize sympathetic stimulation at B-1/ B-2 receptors with Propranolol or Esmolol.
• Verapamil/diltiazem can be alternatives for those intolerants to B-blockers.

Growth hormone synthesis

• Growth Hormone receptors are cytokine type that stimulates synthesis via JAK/STAT pathway, where GH is a peptide hormone with Anabolic and catabolic effects that reduces insulin sensitivity in tissues.
• Entacapone is advantageous over tolcapone in Parkinson's disease, where REVERSIBLE inhibition of COMT is only PERIPHERIAL meaning it DOES NOT CROSS BBB. The AE is nausea, dyskinesia but NO hepatotoxicity and can combined with selegiline, but not general MAO-I.
• Talcapone contains REVERSIBLE inhibition of COMT meaning it CROSSES BBB, AE is HEPATOTOXICITY, CNS issues along with diarrhea and dyskinesia that requires readjustment of L-dope levels.

Neuromuscular Paralysis

• Succinylcholine is short-acting and depolarizing, metabolized by esterase with very rapid onset that is ideal for induction, however shorter duration of action meaning it is not good for maintenance. This then binds to the receptor and keeps ion channel open and blocked causing bradycardia, muscle pain with increase release of potassium with trauma conditions. Hydrolysis is by plasma butyryl-cholinesterase and Succinylcholine can be associated with higher incidence of malignant hyperthermia
• Carbidopa inhibits aromatic amino acid decarboxylase, decreasing peripheral metabolism of L-DOPA to dopamine and increasing central dopamine in the BBB. Thus, carbidopa relieves nausea and vomiting side effects. DDI includes MAO-Inhibitors and COMT-I
• Can be reversed by non-polarizing reversal agents that Increases Ach levels at NM-junction, by Cholinesterase inhibitors (AChE-I) such as neostigmine or pyridostigmine along with Chelates steroid type non-depolarizing agent like sugammadex
• Edaravone reduces progression of disability in ALS; it is a free radical and peroxynitrite scavenger
• Tetrabenazine is used to treat HD and is a reversible inhibitor of VMAT2. It depletes NT by decreasing vesicular accumulation of dopamine. AE is with sedation/somnolence and Parkinson like symptoms that is increased when taken with a strong CYP2D6 and CNS depressant agents
• Asthma & COPD may cause in cholinergic activity and cause bronchoconstriciton. The paralytic Isoquinoline derivatives are Atracurium, Cisatracurium, Mivacurium, Tubocurarine
• Advantage of levothyroxine or liothyronine can be helpful in treatment of anti-coagulant problems and effectiveness to treat insulin with diabetics, but should not combined with drug containing Digoxin

Thyroid drugs

• Levothyroxine is synthetic, 100% T4, and has longer half life meaning t 1/ 2 = 6-8 days. Should not be given with Digoxin, or if the patient has food/supplements reduce absorption
• Liothyronine is synthetic, 100% T3 and has agonist affinity. Shorter half life of 2 days and increase chances anti-coagulant response.
• Menotropins contain both LH and FSH pituitary hormones.