ANTIFUNGAL DRUGS

&
ANTHELMINTHIC DRUGS

Dr Swathy A R
Dept of Pharmacology
SDMCMSH
• Fungal infection may be classified
Superficial mycosis

Clinically as :

Deep (systemic) mycosis

Superficial mycosis = infection of skin, hair, or mucous membrane

Deep (systemic) mycosis = infection affects deeper tissue & organs

 Polyenes (Disrupt membrane structure & function)

Azoles inhibit

Flucytosine inhibits DNA synthesis

 Classification based on mechanism of
action
1. Fungal cell wall synthesis inhibition: Caspofungin.
2. Bind to fungal cell membrane ergosterol: Amphotercin–B,
nystatin
3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine,.
4. Inhibition of ergosterol synthesis (Azoles) Miconazole,
clotrimazole, Ketoconazole, fluconazole, voriconazole.
5. Inhibition of nucleic acid synthesis: 5–Flucytosine.
6. Disruption of mitotic spindle and inhibition of fungal mitosis:
Griseofulvin.
7. Miscellaneous: Tolnaftate, Undecylenic acid, Benzoic acid
Polyene antibiotics
• Amphotericin B: (polyene group )
• Chemical structure is composed of large lactone
ring with conjugated double bonds

Hydrophilic part

Lactone ring

Lipophilic part
Mechanism of action
Pharmacokinetics
• Poorly absorbed orally
• Insoluble in water so given as iv
suspension prepared with sodium
deoxycholate(1:1 complex)
• 90% bound to plasma proteins
• Metabolized in liver slowly
excreted in urine
• t ½ = 15 days
• No dose adjustments in renal and
hepatic impairment
 Uses

• AMP –B still remain drug of choice in treatment

of invasive aspergillosis
• Mucormycosis
• Histoplasmosis
• Cancer patients with neutropenia who remain
febrile on broad spectrum antibiotics
Non AIDS cryptococcal meningitis
• Reserve drugs for resistant kala azar.
• Dose = 0.5-0.6 mg/kg day i.v infusion in 5% glucose for 4hrs.
• Treatment lasts till total dose of 1-2g is administered

• How ever because of toxicity once progression of fungal

infection is arrested maintenance therapy can be continued
with azoles
• Synergistic action with flucytosine
• Adverse events:
– Acute reaction: (infusion
reaction)
– Chills, fever, headache,
pain all over, nausea,
vomiting, dyspnoea
lasting 2-5 hrs
– can be treated with
hydrocortisone 0.6mg/kg
– Long term toxicity:
nephrotoxicity , anemia
– CNS toxicity : headache
 Disadvantages of AMB

Amphotericin B is toxic
SIDE EFFECTS OF AMB

Nephrotoxicity

Acute infusion related reactions

anemia
 Nystatin
 Similar to AMB in antifungal properties, high systemic
toxicity so used locally only
 Available as ointment ,cream , powder, tablet
 Uses: (primarly to treat candidial infection )
 vaginitis
 Prevention of oral candidiasis
 Can be used in oral, cutaneous candiasis
 Adverse events:
 Bitter taste on oral use`

 Nystatin = 5lac u.lac vagina tab, eye ointment.

Griseofulvin
• One of early antibiotics derived from penicillium
griseofulvum.
• Fungistatic, systemic drug for superficial fungal
infections.
• Active against most superficial fungal infection (tinea
infections of skin, hair & nail).
• Dermatophytes concentrate it actively hence selective
toxicity.
• Mechanism of action:
• Griseofulvin interacts with polymerized
microtubules and disrupts the mitotic
spindles thus arresting fungal mitosis
• Pharmacokinetics:
• irregular oral absorption, ↑ by fatty food
• Gets conc in keratinized tissue(stratum
corneum) of skin,
hair & nails
Interactions: (inducer of cyt p450
& ↓ effectiveness)
– Warfarin , OC Pills Disulfiram
like reaction with alcohol
Adverse events
• Headache most common
• GIT disturbances like nausea
• CNS symptoms: confusion, fatigue, vertigo
• Peripheral neuritis
• Rashes
Uses
• Treatment of tinea infection of skin, hair & nails
• Systemic azoles more effective and preferred .
• Treatment must be continued till infected tissue is completely
replaced by normal skin,hair, nail.
• Dose: 125 -250 mg QID with meals
Duration of treatment

• Body skin = 3 weeks

• Palm, soles = 4- 6 weeks
• Finger nails = 4- 6months
• Toe nails = 8 – 12 months

• Griseofulvin should be reserved for nail, hair or larger

body surface involvement
5 flucytosine
• Prodrug converted to active 5 FU
• Adverse events:
• Bone marrow toxicity , Alopecia, skin rashes, itching
• Uses:
• in combination with AMB in cryptococcal meningitis
• Advantages of combination:
• Entry of 5 FC
• Reduced toxicity
• Reduced duration of therapy
• Decreased resistance
Mechanism of action
• Azoles:
• Synthetic antifungals
• Broad spectrum
• Most commonly used
• Classified as imidazoles & triazoles

• Imidazoles:
• Topical: miconazole, clotrimazole
• Systemic : ketoconazole
• Newer : butaconazole, oxiconazole
• Triazoles :
• Systemic : Fluconazole, itraconazole,
voriconazole
• Terconazole: Topical for superficial infections

• Both these groups are

• Structurally related compounds
• Have same mechanism of action
• Have similar antifungal spectrum
Miconazole & clotrimazole(topical)
• Topical use(imidazoles)
• Uses:
• Dermatophyte infections (4 wks, BD)
• Candida: oral pharyngeal, vaginal, (2wks ,BD)
• Adverse events:
• Local irritation , itching or burning
• Miconazole shows higher incidence of vaginal irritation & pelvic
cramps
• No systemic side effects
Ketoconazole(Systemic )
–First orally effective broad spectrum antifungal
–Effective against
• Dermatophytosis, Deep mycosis , Candidiasis
Pharmacokinetics
• Effective orally
• acidic environment favours
absorption
• High protein binding
• Readily distributed,
not to BBB
• Metabolized in liver, excreted
in bile
• t1/2 = 8- 10 hrs
• Dose : 200 mg OD or BD
Adverse events
• Nausea , vomiting , anorexia
• Headache , paresthesia, alopecia
• ↓ steroid, testosterone & estrogen synthesis
• Gynaecomastia, oligospermia , loss of libido & impotence
in males
• Menstrual irregularities & amenorrhoea in females
• Elevation of liver enzymes
• Hypersensitivity reaction - skin rashes, itching
Uses(sup & deep )
• Dermatophytosis: conc in stratum corneum
• Monilial vaginitis : 5-7 days
• Systemic mycosis: blastomycosis, histoplasmosis,
coccidiodomycosis
• Less efficacy than AMB & slower response
• ↓Efficacy in immunocompromized and meningitis
• Lower toxicity than AMB higher than triazoles
• High dose used in cushings syndrome
• Topical: T.pedis, cruris, corporis, versicolor
Fluconazole
• Newer water soluble triazole
• Oral, IV as well as topical
• Broad spectrum antifungal activity
• Candida, cryptococcosis, coccidiodomycosis
• Dermatophytosis
• Blastomycosis
• Histoplasmosis
• Sporotrichosis
• Not effective against aspergillosis & mucormycosis contrast to
AMB
Pharmacokinetics

 94% oral bioavailability

 Not affected by food or gastric pH
 Primarily excreted unchanged in urine t1/2 = 25 -30
hrs (given as pulse therapy )
 Poor protein binding
 Widely distributed crosses, BBB

 Dose = 150- 400mg once daily

 Adverse events

 GIT upset
 Headache, alopecia, skin rashes
 Teratogenic effect
 CYP450 Enzyme inhibiting property less
 Effects hepatic drug metabolism to lesser extent than Ketoconazole
 H2 blockers & PPI do not effect its absorption
 No anti androgenic & other endocrine effects
Uses(superficial &deep)
 Candida:
 150 mg oral dose can cure vaginal candidiasis with few
relapse
 Oral candidiasis- 2 weeks treatment required
 Tinea infections & cutaneous candidiasis: 150 mg
weekly for 4 weeks, tinea unguim : 12 months
 systemic fungal infections: Disseminated candidiasis,
cryptococcal, coccidiodal meningitis 200-400 mg / day
4- 12 weeks or longer
 Meningitis: preferred drug
 Eye drops for fungal keratitis
 Triazoles

Itraconazole Fluconazole
- Varied absorption. - Completely absorbed and
Metabolized by cyt P450 better tolerated, Renal
excretion
- less endocrine effects but - Less endocrine effects
occur at high doses
- Penetrates well into CSF
- Less penetration in CSF
- Many drug interactions - Drug Interactions less
(due to inhibition of CYT
P450/ 3A4)
Voriconazole
 II generation triazole
 High oral bioavailability, low protein binding
 Good CSF penetration
 Doesn’t require gastric acidity for absorption
 T1/2= 6 hrs
 Uses:
 DOC for invasive aspergillosis
 Most useful for esophageal candidiasis
 Useful in resistant candida infections
 Dose and Adverse effects

• Dose : 200 mg BD
• Adverse events:
• Transient visual changes like blurred vision , altered color perception &
photophobia
• Rashes in 5 -6 %
• Elevated hepatic enzymes
• Prolongation of QT
Terbinafine
 Orally & topically effective drug against candida &
dermatophytes
 Fungicidal : shorter courses of therapy required & low
relapse rates
 Pharmacokinetics:
 Well absorbed orally 75%, Highly keratophilic & lipophilic
 High protein bound , poor BBB permeability
 Negligible effect on CYP450
 Mechanism of action:
Terbinafine
Squalene
Ѳ
squalene 2,3 epoxide

Lanosterol

Ѳ Azoles
14 α demethylase

Ergosterol
Adverse events and uses
 Adverse events:
 Taste disturbances
 Topical: erythema , itching , dryness , urticaria, rashes
 Uses: (superficial &deep fungal infection )
 Dermatophytosis: topically/ orally 2- 6 weeks
 Onychomycosis: first line drug 3- 12 months
 Candidiasis: less effective 2- 4 weeks therapy may be used
as alternative 250 mg OD
Caspofungin

 MOA: Inhibits B (1,3) D glucan an essential component

of fungal cell wall
 Uses: Treatment of invasive aspergillosis & candidiasis
(esophageal, intraperitoneal)
 Dose: IV 70 mg slowly then 50 mg daily infusion
 Adverse events:
 rashes , nausea, vomiting, phlebitis
Topical agents used in dermatophytosis

• Undecyclenic acid: 5% (Tineafax)

• Generally combined with zinc (20%)
• Requires prolonged treatment has high relapse rate
• Weaker antifungal action used in tinea cruris
• Topical azoles:
• Clotrimazole, oxiconazole, miconazole, econazole,
ketoconazole
• Used for tinea infections, oropharyngeal and vaginal
candidiasis
 Topical agents used in dermatophytosis

• Benzoic acid:
• Used in combination with salicylic acid
• Whitfields ointment: ( benzoic acid 6% + salicyclic acid 3 %)
• Salicyclic acid due to its keratolytic action helps to remove infected tissue &
promotes penetration of benzoic acid in fungal infected lesion
• Adverse events: irritation & burning sensation
Spectrum of action
AMB 5FC KTZ FLU ITR
Aspergillus -- -- -- Y
Blastomycosis -- Y Y Y
cryptococcus Y -- Y Y
Coccidiodo -- Y Y Y
candida Y Y Y Y
Histoplasma -- Y Y Y
mucor -- -- -- --
Sporotrichosis -- -- Y Y
Anthelminthic Drugs
Albendazole
• Subsequently introduced congener of mebendazole
• broad-spectrum activity
• excellent tolerability
• One dose treatment has produced cure rates in ascariasis, hookworm
(both species) and enterobiasis.
MOA
• The major site of action appears to be the microtubular protein ‘β-
tubulin’ of the parasite.
• Binds to β-tubulin of susceptible worms with high affinity and inhibits
its polymerization.
• Intracellular microtubules in the cells of the worm are gradually lost.
• Blocks glucose uptake in the parasite, inhibits some mitochondrial
enzymes and depletes its glycogen stores.
Adverse effects
• well tolerated;
• GI side effects have been noted.
• dizziness.
• Prolonged use, as in hydatid or in cysticercosis, has caused headache,
fever, alopecia, jaundice and neutropenia.
• Ascaris, hookworm, Enterobius and Trichuris: a single dose of 400 mg
(for adults and children above 2 yrs; 200 mg for 1–2 yr age) is
sufficient.

• Tapeworms and Strongyloides: 400 mg twice daily for 3 consecutive

days.

• Trichinosis: Three day treatment with 400 mg twice daily expels the
adult worm from intestine,
• Neurocysticercosis: Albendazole is the anthelmintic of choice for the
treatment of neurocysticercosis.

• Usually 8–15 days course of 400 mg BD (15 mg/kg/ day) is employed.

• Cutaneous larva migrans: Albendazole 400 mg daily for 3–5 days is
the drug of choice; kills larvae and relieves symptoms.

• Hydatid disease: 400 mg BD for 4 weeks, repeat after 2 weeks (if

required), up to 3 courses.
Pyrantel pamoate
• Pin worm, roundworm and hookworm as well.
• Pyrantel activates nicotinic cholinergic receptors in the worms
resulting in persistent depolarization, giving rise to slowly developing
contracture and spastic paralysis.
• Worms are then expelled.
• An anticholinesterase action has also been demonstrated.
• Only 10–15% of an oral dose of pyrantel pamoate is absorbed: this is
partly metabolized and excreted in urine.
• Adverse effects Pyrantel pamoate is remarkably free of side effects:
occasional g.i. symptoms, headache and dizziness are reported.

• Other advantages are—it is tasteless, non-irritant and does not

provoke abnormal migration of worms.

• Use and administration For Ascaris, Ancylostoma and Enterobius: a

single dose of 11 mg/kg is recommended.

• A 3 day course for Necator and for Strongyloides is needed.

Diethylcarbamazine citrate (DEC)
• first drug for filariasis
• t½ of usual clinical doses is 4–12 hours.
• microfilaricidal.
• A dose of 2 mg/kg TDS clears Mf of W. bancrofti and B. malayi from
peripheral blood in 7 days.
• The most important action of DEC appears to be alteration of
organelle membranes of the Mf promoting cell death.
• It is also suggested that muscular activity of Mf and adult worms is
affected so that they are dislodged. DEC is active against Mf of Loa loa
and Onchocerca volvulus as well.
• Filariasis: DEC 2 mg/kg TDS is the first line drug: produces rapid
symptomatic relief Mf disappear from blood and patient becomes
noninfective to mosquitoes in 7 days.

• Tropical pulmonary eosinophilia: DEC (2–4 mg/kg TDS) for 2–3 weeks
produces dramatic improvement in the signs and symptoms of
eosinophilic lung or tropical eosinophilia.
Adverse effects
• Nausea, loss of appetite, headache, weakness and dizziness are the
usual complaints.

• Fever , rash, pruritus, enlargement of lymph nodes, bronchospasm

and fall in BP may occur due to mass destruction of Mf and adult
worms.
Ivermectin
• drug of choice for single dose treatment of onchocerciasis and
strongyloidosis, and is comparable to DEC for bancroftian and brugian
filaria.
• It is microfilaricidal.
• Ivermectin (0.2 mg/kg single dose) is also highly effective in
cutaneous larva migrans and ascariasis.
• Certain insects, notably scabies and head lice are killed by ivermectin.
• Nematodes develop tonic paralysis when exposed to ivermectin.
• It acts through a special type of glutamate gated Cl¯ channel found
only in invertebrates.
• A single 10–15 mg (0.2 mg/kg) oral dose of ivermectin, preferably
with 400 mg albendazole, given annually for 5–6 years has been used
for filariasis.
• Single 0.15–0.2 mg/kg dose has yielded highest cure rate in
strongyloidosis, but repeat dose may be given if stool remains
positive.
• Ivermectin is the only drug effective orally in scabies and pediculosis.
Single 0.2 mg/kg dose cures most patients.

• Side effects have been mild—pruritus, giddiness, nausea, abdominal

pain, constipation, lethargy and transient ECG changes, but more
important are the reactions due to degeneration products of the Mf,
which are fever, urticaria, myalgia, edema and tender lymph nodes.
Niclosamide
• Regimen for tapeworm
• Niclosamide is available as 0.5 g tab (NICLOSAN). After a light
breakfast, 2 tablets are to be chewed and swallowed with water,
followed by another 2 tablets after 1 hr (total 2 g); total dose for
children 2–6 years is 1 g.
• A saline purge is given 2 hours after the later dose to wash off the
worm.
• The scolex should be searched in the stools to be sure that the worm
will not grow again.
• Cure rate of 85–95% has been obtained by one day treatment.
• MOA- interfering with anaerobic generation of ATP by the tapeworm
• tasteless and nonirritating
• Adverse effects
• well tolerated; minor abdominal symptoms are produced
occasionally.
• Malaise, pruritus and light headedness are rare.
Praziquantel
• act by causing leakage of intracellular calcium from the membranes
producing contracture and paralysis of the worms
• Tapeworms lose grip of the intestinal mucosa and are expelled
• no systemic toxicity.
• It tastes bitter: can produce nausea and abdominal pain.
• Other side effects are headache, dizziness and malaise.
• When used for schistosomes and visceral flukes, symptoms like
itching, urticaria, rashes, fever and bodyache occur as a reaction to
the destroyed parasites.

• Praziquantel administered as a single dose has achieved 90–100%

cure rate in all human tapeworms

• Praziquantel is the drug of choice for all schistosome and fluke

infestations except Fasciola hepatica.
Case report
• A 40-year-old male weighing 60 kg presented with history of 2
episodes of sudden onset fits over the past 3 days. There is no past
history of fits or any nervous disorder. The patient has been having
headache for the last one month or so which responds to
paracetamol. His wife who witnessed the fits gave a description which
fitted tonic-clonic seizures. The wife also informed of noticing some
behavioural changes for the last 2 months. The fits were followed by
confused behaviour and drowsiness for 2–3 hours. There is no family
history of fits or mental illness. MRI scan of the brain revealed 4
active cortical parenchymal cysticerci.
• What is your diagnosis ?
• What is the DOC for this condition?