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Antifungal medication
Dr Ilham SayedClinical pharmacist
Introduction
• An antifungal medication is a pharmaceutical fungicide used to treat mycoses such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others.
• Such drugs are usually obtained by a doctor's prescription or purchased over-the-counter.
Classes• Polyene antifungals• The polyene antimycotics bind with sterols in the fungal
cell membrane, principally ergosterol. • This changes the transition temperature (Tg) of the cell
membrane, thereby placing the membrane in a less fluid, more crystalline state. (In ordinary circumstances membrane sterols increase the packing of the phospholipid bilayer making the plasma membrane more dense.)
• As a result, the cell's contents including monovalent ions (K+, Na+, H+, and Cl-), small organic molecules leak and this is regarded one of the primary ways cell dies.
• Amphotericin B• Candicidin• Natamycin • Nystatin• Rimocidin
Imidazole, triazole, and thiazole antifungals
• Azole antifungal drugs inhibit the enzyme lanosterol 14 α-demethylase; the enzyme necessary to convert lanosterol to ergosterol.
• Depletion of ergosterol in fungal membrane disrupts the structure and many functions of fungal membrane leading to inhibition of fungal growth.
Imidazoles
• Clotrimazole• Econazole• Ketoconazole• Miconazole.• Triazoles• Albaconazole• Fluconazole• Itraconazole
Thiazoles
• Abafungin.• Allylamines• Allylamines inhibit squalene epoxidase, another
enzyme required for ergosterol synthesis:• Amorolfin• Butenafine• Naftifine• Terbinafine
Echinocandins• Echinocandins may be used for systemic fungal
infections in immunocompromised patients, they inhibit the synthesis of glucan in the cell wall via the enzyme 1,3-β glucan synthase:
• Anidulafungin• Caspofungin• Micafungin• Echinocandins are poorly absorbed when administered
orally. • When administered by injection they will reach most
tissues and organs with concentrations sufficient to treat localized and systemic fungal infections.
Others• Benzoic acid – has antifugal properties, but must be combined with a
keratolytic agent such as in Whitfield's ointment• Ciclopirox – (ciclopirox olamine) – is a hydroxypyridone antifungal which
interferes with active membrane transport, cell membrane integrity, and fungal respiratory processes. It is most useful against tinea versicolour.
• Flucytosine or 5-fluorocytosine – an antimetabolite pyrimidine analog• Griseofulvin – binds to polymerized microtubules and inhibits fungal
mitosis• Polygodial – strong and fast-acting in-vitroantifungal activity against
Candida albicans.• Tolnaftate – a thiocarbamate antifungal, which inhibits fungal squalene
epoxidase (similar mechanism to allylamines like terbinafine)• Undecylenic acid – an unsaturated fatty acid derived from natural castor
oil; fungistatic, antibacterial, antiviral, and inhibits Candida morphogenesis
• Crystal violet – a triarylmethane dye, it has antibacterial, antifungal, and anthelmintic properties and was formerly important as a topical antiseptic.
Adverse effects
Apart from side effects like liver damage or affecting estrogen levels, many antifungal medicines can cause allergic reactions in people.
For example, the azole group of drugs is known to have caused anaphylaxis.
Drug interactions• There are also many drug interactions. • For example, the azole antifungals such as ketoconazole or
itraconazole can be both substrates and inhibitors of the P-glycoprotein, which (among other functions) excretes toxins and drugs into the intestines.
• Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4, causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.
Antiviral drug
• Antiviral drugs are a class of medication used specifically for treating viral infections.
• Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
• Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses (best known for causing cold sores and genital herpes, but actually the cause of a wide range of other diseases, such as chicken pox), the hepatitis B and C viruses, which can cause liver cancer, and influenza A and B viruses.
• Virus is a nucleic acid, either DNA or RNA which is infectious in nature.
• Virus can infect all kind of organisms including plants, animals and bacteria.
• This nucleic strand of the DNA is called genome. Outside genome there is covering of proteinaceous coat called capsid.
• Outside the capsid there presents a fatty envelope. Capsid and genome together is known as nucleocapsid and all the three capsid, genome and envelope together is known as virion.
• Virus is an obligate parasite i.e. active only inside the host cells.
• Viruses are parasites that cannot reproduce on their own.
• They recognize specific molecules on the surface of target cells and bind to them.
• After entering the cells, viruses take off their protein coat'a process called un-coating'to release the genome (DNA or RNA).
• They use the host cell's tools to reproduce themselves.• Released viruses find new host cells to infect. • Antiviral medications prevent viral entry, un-coating,
replication of viral genome (DNA or RNA), re-coating and spread of viruses to new host cells.
Classes
• Antiviral drugs are classified into following classes:-• a) Anti-herpes virus- Acyclovir, Gancyclovir,
Idoxuridine& Foscarnent.• b) Anti-influenza virus- Amantadine & Rimantadine• c) Broad spectrum antivral drugs- Vidabarine &
Ribavarine• d) Anti-HIV virus- Stavudine, Zidovudine, Carbovir &
Didanosine• e) Anti-small pox virus- Methisazone & Anildone
Actions• Nucleoside-Analog Reverse Transcriptase
Inhibitors (NRTI). These drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and are incorporated into viral DNA (they are chain-terminating drugs). – Zidovudine (AZT = ZDV, Retrovir) first approved in
1987 – Didanosine – Zalcitabine – Stavudine
_ Lamivudine
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• In contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV replication directly by binding non-competitively to reverse transcriptase. – Nevirapine – Delavirdine
• Protease Inhibitors. These drugs are specific for the HIV-1 protease and competitively inhibit the enzyme, preventing the maturation of virions capable of infecting other cells. – Saquinavir - first approved in 1995 – Ritonavir – Indinavir – Nelfinavir
Side effects
• Anemia• ii) Granulocytopenia• iii) Thrombocytopenia• Bronchospasm• GI upset and headache• Renal dysfunction
Limitations of vaccines • Vaccines bolster the body's immune system to better attack viruses
in the "complete particle" stage, outside of the organism's cells.• They traditionally consist of an attenuated (a live weakened) or
inactivated (killed) version of the virus. • These vaccines can, in rare cases, harm the host by inadvertently
infecting the host with a full-blown viral occupancy. • Recently "subunit" vaccines have been devised that consist strictly
of protein targets from the pathogen. They stimulate the immune system without doing serious harm to the host. In either case, when the real pathogen attacks the subject, the immune system responds to it quickly and blocks it.
• Vaccines are very effective on stable viruses, but are of limited use in treating a patient who has already been infected. They are also difficult to successfully deploy against rapidly mutating viruses, such as influenza (the vaccine for which is updated every year) and HIV. Antiviral drugs are particularly useful in these cases.
• Entry inhibitor• A very early stage of viral infection is viral entry,
when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV.
• HIV most heavily targets the immune system's white blood cells known as "helper T cells", and identifies these target cells through T-cell surface receptors designated "CD4" and "CCR5". Attempts to interfere with the binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.
• Reverse transcription• One way of doing this is to develop nucleotide or nucleoside
analogues that look like the building blocks of RNA or DNA, but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of reverse transcriptase (RNA to DNA) than with "normal" transcriptase (DNA to RNA).
• The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analogue.
• An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections.
• Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase.
• Another target being considered for HIV antivirals include RNase H – which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA .
Analgesics, Anti-inflammatory- Antipyretics
Analgesia • An analgesic, or painkiller, is any member of the
group of drugs used to achieve analgesia — relief from pain.
• Analgesic drugs act in various ways on the peripheral and central nervous systems.
• They are distinct from anesthetics, which reversibly eliminate sensation.
• Classes: 1_ paracetamol (known in the US as acetaminophen).
2_ The non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, and
3_ Opioid drugs such as morphine and opium.
Major classes • Paracetamol and NSAIDs:• The exact mechanism of action of
paracetamol/acetaminophen is uncertain but appears to act centrally in the brain rather than peripherally in nerve endings.
• Aspirin and the other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases, leading to a decrease in prostaglandin production.
• In contrast to paracetamol and the opioids, this not only reduces pain but inflammation as well.
Side effects
• Paracetamol has few side effects and is regarded as generally safe, although excess or sustained use can lead to potentially life-threatening liver damage and occasionally kidney damage.
• While paracetamol is usually taken orally or rectally, an intravenous preparation introduced in 2002 has been shown to improve pain relief and reduce opioid consumption in the postoperative setting.
• NSAIDs predispose to peptic ulcers, renal failure, allergic reactions, and
• Occasionally hearing loss, and they can increase the risk of hemorrhage by affecting platelet function.
• The use of aspirin in children under 16 suffering from viral illness has been linked to Reye's syndrome, a rare but severe liver disorder.
COX-2 inhibitors
• These drugs have been derived from NSAIDs. • The cyclooxygenase enzyme inhibited by
NSAIDs was discovered to have at least 2 different versions: COX1 and COX2.
• Research suggested that most of the adverse effects of NSAIDs were mediated by blocking the COX1 enzyme, with the analgesic effects being mediated by the COX2 enzyme.
• The COX2 inhibitors were thus developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general).
• These drugs (such as rofecoxib, celecoxib and etoricoxib) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular.
• After widespread adoption of the COX-2 inhibitors, it was discovered that most of the drugs in this class increased the risk of cardiovascular events by 40% on average.
• This led to the withdrawal of rofecoxib and valdecoxib, and warnings on others.
• Etoricoxib seems relatively safe, with the risk of thrombotic events similar to that of non-coxib NSAID diclofenac.
Opioids and Opiates
• Morphine, and various other substances (e.g. codeine, oxycodone, hydrocodone, dihydromorphine, pethidine) all exert a similar influence on the cerebral opioid receptor system.
• Buprenorphine is thought to be a partial agonist of the opioid receptor, and tramadol is an opiate agonist.
• Tramadol is delivers analgesia by not only delivering "opiate-like" effects (through mild agonism of the mu receptor) but also by acting as a weak but fast-acting serotonin releasing agent and norepinephrine reuptake inhibitor.
• Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), seizures (tramadol), but there is no dose ceiling in patients who accumulate tolerance.
Side effects• Opioids, while very effective analgesics, may
have some unpleasant side-effects. • Patients starting morphine may experience
nausea and vomiting (generally relieved by a short course of antiemetics such as phenergan).
• Pruritus (itching) may require switching to a different opioid.
• Constipation occurs in almost all patients on opioids, and laxatives co-prescribed.
• When used appropriately, opioids and similar narcotic analgesics are otherwise safe and effective, however risks such as addiction and the body becoming used to the drug (tolerance) can occur.
• The effect of tolerance means that frequent use of the drug may result in its diminished effect so, when safe to do so, the dosage may need to be increased to maintain effectiveness.
• This may be of particular concern regarding patients suffering with chronic pain.
Specific agents • In patients with chronic or neuropathic pain, various
other substances may have analgesic properties.• Tricyclic antidepressants, especially amitriptyline,
have been shown to improve pain in what appears to be a central manner.
• Nefopam is used in Europe for pain relief with concurrent opioids.
• The exact mechanism of carbamazepine, gabapentin and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with differing degrees of success.
• Anticonvulsants are most commonly used for neuropathic pain as their mechanism of action tends to inhibit pain sensation.
Anti-inflammatory
• Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation.
• Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system.
Classes
• Steroids Many steroids, to be specific glucocorticoids, reduce inflammation or swelling by binding to glucocorticoid receptors.
• These drugs are often referred to as corticosteroids.
Non-steroidal anti-inflammatory drugs
• Non-steroidal anti-inflammatory drugs (NSAIDs), alleviate pain by counteracting the cyclooxygenase (COX) enzyme.
• On its own, COX enzyme synthesizes prostaglandins, creating inflammation. In whole, the NSAIDs prevent the prostaglandins from ever being synthesized, reducing or eliminating the pain.
• Some common examples of NSAIDs are: aspirin, ibuprofen, and naproxen.
• The newer specific COX-inhibitors - it is presumed, sharing a similar mode of action - are not classified together with the traditional NSAIDs.
• On the other hand, there are analgesics that are commonly associated with anti-inflammatory drugs but that have no anti-inflammatory effects.
• An example is paracetamol, As opposed to NSAIDs, which reduce pain and inflammation by inhibiting COX enzymes, paracetamol has recently been shown to block the reuptake of endocannabinoids, which only reduces pain, likely explaining why it has minimal effect on inflammation
Antipyretic
• Antipyretics are drugs or herbs that reduce fever.• Antipyretics cause the hypothalamus to override an
interleukin-induced increase in temperature. • The body then works to lower the temperature,
resulting in a reduction in fever.• Most antipyretic medications have other purposes. • The most common antipyretics are ibuprofen and
aspirin, which are used primarily as pain relievers. • Non-steroidal anti-inflammatory drugs (NSAIDs) are
antipyretic, anti-inflammatory, and pain relievers.
