M4

• Viruses are obligate intracellular parasites, and their replication depends on synthetic processes of the host cell
• Antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell to be effective
• Viral replication consists of several steps, including attachment of the virus to the host cell, entry of the virus through the host cell membrane, uncoating of viral nucleic acid, nucleic acid synthesis, late protein synthesis and processing, packaging and assembly, and viral release
• Agents to treat Herpes Simplex Virus (HSV) & Varicella-Zoster Virus (VZV) Infections:

  • Acyclovir: against HSV-1, HSV-2, and VZV
  • Valacyclovir: L-valyl ester of Acyclovir
  • Famciclovir: active against HSV-1, HSV-2, VZV, EBV, and HBV
  • Penciclovir: active metabolite of Famciclovir
  • Docosanol: for recurrent orolabial herpes
  • Trifluridine: for keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 and HSV-2
• Agents to treat Cytomegalovirus (CMV) Infections:

  • Ganciclovir: in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and KSHV
  • Valganciclovir: L-valyl ester prodrug of Ganciclovir
  • Foscarnet: in vitro activity against HSV, VZV, CMV, EBV, HHV-6, KSHV, and HIV-1
  • Cidofovir: in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, KSHV, adenovirus, poxviruses, polyomaviruses, and human papillomavirus
• Delavirdine (PO) is used for the treatment of HIV-1 infection in adults and adolescents over the age of 16 as part of a combination therapy
• Adverse effect of Delavirdine: rash accompanied by pruritus
• Antiretroviral Agents:

  • Highly active antiretroviral therapy (HAART) involves a combination of 3-4 antiretroviral agents
  • Combinations include nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and a fusion inhibitor
  • Single agents are seldom used to treat HIV infection due to the rapid mutation rate of HIV and to minimize drug toxicity
• Efavirenz (PO) is the only NNRTI approved for once-daily dosing
• Clinical uses of Efavirenz:

  • Therapy of HIV infection in adults and children
  • Postexposure prophylaxis
• Adverse effects of Efavirenz:

  • Rash
  • CNS effects (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria)
• Nevirapine (PO) is used for the treatment of HIV infection in adults and children as part of a combination therapy
• Adverse effects of Nevirapine:

  • During the first 12 weeks of treatment, patients must be closely monitored for the development of potentially fatal hepatic toxicity (i.e., hepatitis, hepatic necrosis, and hepatic failure) and skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions)
• Amprenavir (PO) adverse effects:

  • Nausea, diarrhea, vomiting, perioral paresthesias, depression, rash
• Saquinavir (PO) is a potent inhibitor of HIV-1 and HIV-2 proteases
• Contraindications and cautions for Amprenavir:

  • The oral solution, which contains propylene glycol, is contraindicated in young children, pregnant women, and patients with renal or hepatic failure
  • Not recommended for children under age 4 due to potential risks
  • Pregnant women should avoid Amprenavir oral solutions
  • Contraindicated in patients with a history of sulfa allergy
• Adverse effects of Saquinavir: GI discomfort and rhinitis
• Ritonavir (PO) is a potent inhibitor of HIV-1 and HIV-2 proteases and CYP3A4
• Adverse effects of Ritonavir:

  • GI disturbances
  • Paresthesias
  • Elevated serum aminotransferase levels
  • Altered taste
  • Hypertriglyceridemia
• Indinavir (PO) is a potent inhibitor of HIV reverse transcriptase
• Adverse effects of Indinavir:

  • Asymptomatic hyperbilirubinemia and nephrolithiasis due to crystallization of the drug
  • Important to consume at least 48 ounces of water daily to prevent nephrolithiasis
• Nelfinavir (PO) is probably the most commonly used protease inhibitor due to its low incidence of serious adverse effects
• Adverse effects of Nelfinavir: diarrhea and flatulence
• Lopinavir-Ritonavir (PO) is a licensed combination where subtherapeutic doses of Ritonavir inhibit the CYP3A-mediated metabolism of Lopinavir
• Adverse effects of Lopinavir-Ritonavir:

  • Diarrhea
  • Abdominal pain
  • Nausea
  • Vomiting
  • Asthenia (Lopinavir)
• Enfuvirtide (SC) is a fusion inhibitor, formerly called T-20, and the first representative of a new class of antiretroviral agents
• Adverse effects of Enfuvirtide: local injection site reactions
• Adrenergic Transmission:

  • Synthesis:
  • Tyrosine is converted to dihydroxyphenylalanine (DOPA), then to dopamine
  • The rate-limiting step is the hydroxylation of tyrosine
  • Inhibitors: metyrosine & carbidopa
  • Uptake into Vesicles:
  • Dopamine enters vesicles
  • Dopamine is converted to norepinephrine (NE)
  • Reserpine inhibits transport into vesicles
  • Release:
  • Calcium causes the release of NE
  • Guanethidine & bretylium block NE release
  • Amphetamine, methamphetamine, ephedrine, & tyramine cause NE release
  • Binding to Receptor
  • Removal:
  • Methylated by catechol O-methyltransferase (COMT)
  • Oxidized by monoamine oxidase (MAO)
  • Cocaine & TCA inhibit reuptake
  • Urine metabolites: vanillylmandelic acid (VMA), metanephrine, normetanephrine
• Cholinergic Drugs:

  • Cholinergic Agonists:
  • Direct-acting: bind and activate receptors
  • Indirect-acting: inhibit AChE leading to increased ACh
  • Direct-Acting Cholinergic Agonists:
  • Acetylcholine:
  • Prototype; most potent cholinergic agonist
  • Limited therapeutic use due to lack of selectivity and rapid degradation
  • Bethanechol:
  • Strong muscarinic activity
  • Specific for GIT & bladder
  • Used for increasing intestinal motility and acute nonobstructive urinary retention
  • Carbachol:
  • Has both muscarinic & nicotinic activity
  • Used for open-angle glaucoma resistant to pilocarpine
  • Methacholine (Provocholine):
  • Used for diagnosing asthma (methacholine challenge)
  • Alkaloids:
  • Pilocarpine:
  • Alkaloid from Pilocarpus sp.
  • Used for glaucoma treatment
  • Muscarine:
  • Alkaloid isolated from the mushroom Amanita muscaria
  • Causes various side effects
  • Indirect-Acting Cholinergic Agonists/Cholinesterase Inhibitors:
• • Irreversible: Organophosphates
  • Reversible: Edrophonium & Carbamates
• Organophosphates:

  • Highly lipid-soluble liquids
  • Form covalent phosphorous-enzyme bonds with AChE
  • Aging process strengthens the bond
  • Examples: Isofluorophate, Echothiophate, Malathion, Parathion, Tabun, Sarin, Soman
  • Toxicity leads to cholinergic crisis
  • Antidotes: Pralidoxime chloride (2-PAM) & Atropine
  • Carbamates:
  • Bind noncovalently to the anionic site of the enzyme
  • Examples: Physostigmine, Neostigmine, Pyridostigmine, Carbamate Insecticides
  • Quaternary Amine: Edrophonium
• Cholinergic Antagonists:

  • Muscarinic Blockers:
  • Atropine:
  • Central & peripheral muscarinic blocker
  • Blocks M1, M2, M3, M4, M5 receptors
  • Actions include mydriasis, cycloplegia, reduced GIT activity, urinary system effects, gland secretion reduction, and cardiovascular effects
  • Adverse effects include constipation, urinary retention, mydriasis, tachycardia, and more
  • Scopolamine:
  • M1, M2, M3 blocker
  • Used for motion sickness prevention and other indications
  • Adverse effects include CNS depression
  • Other Muscarinic Blockers: Homatropine, Cyclopentolate, Tropicamide, Ipratropium bromide, Pirenzepine
  • Nicotinic Receptors
• Cholinoceptors:

  • Muscarinic Receptors
  • Nicotinic Receptors
• Cholinergic Agonists:

  • Direct-acting: bind and activate receptors
  • Indirect-acting: inhibit AChE leading to increased ACh
• Direct-Acting Cholinergic Agonists:

  • Acetylcholine:
  • Prototype; most potent cholinergic agonist
  • Limited therapeutic use due to lack of selectivity and rapid degradation
  • Bethanechol:
  • Strong muscarinic activity
  • Specific for GIT & bladder
  • Used for increasing intestinal motility and acute nonobstructive urinary retention
  • Carbachol:
  • Has both muscarinic & nicotinic activity
  • Used for open-angle glaucoma resistant to pilocarpine
  • Methacholine (Provocholine):
  • Used for diagnosing asthma (methacholine challenge)
• Alkaloids:

  • Pilocarpine:
  • Alkaloid from Pilocarpus sp.
  • Used for glaucoma treatment
  • Muscarine:
  • Alkaloid isolated from the mushroom Amanita muscaria
  • Causes various side effects
• Indirect-Acting Cholinergic Agonists/Cholinesterase Inhibitors:

  • Irreversible: Organophosphates
  • Reversible: Edrophonium & Carbamates
• Pirenzepine:

  • M1 blocker
  • Selective for muscarinic receptor in the stomach
  • Poorly absorbed, leading to high concentration in the gut
  • Decreases secretion of acid & pepsin, useful for peptic ulcers
  • Adverse effects are few and relatively specific for gastric secretions
• Benztropine, Trihexyphenidyl, Oxybutynin:

  • M1, M2, M3 blockers
  • Used for Parkinson’s disease and extrapyramidal disorders
• Dicyclomine:

  • M1, M2, M3 blocker
  • Used for hypermotility of the bowel