anti TB and othes.pptx

Mycobacterial infections
Treating mycobacterial infection present problems:
– They are slow growing microbes.
– Can also be dormant; resistant to many drugs.
– Lipid rich cell wall is impermeable to many agents.
– A substantial portion is intracellular;
Needs prolonged treatment.
Drug toxicity & poor patient compliance.
High risk of emergency of resistant bacteria.

Mycobacterial infections
• Combinations of two or more drugs are required to overcome and
prevent emergence of resistance during the course of therapy.
• The response of mycobacterial infections to chemotherapy is slow, and
treatment must be administered for months to years, depending on
which drugs are used.

The objective of therapy
 To eliminate symptoms & prevent relapse.
 To accomplish this goal treatment must kill actively dividing & resting
mycobacteria.
 Since the response of mycobacterial infections to chemotherapy is
slow, treatment is prolonged.
 Combination of drugs are required to prevent the emergence of
resistance.

TUBERCULOSIS
• Tuberculosis is a kind of communicable chronic disease caused by M.tuberculosis,
which can invade various tissues and organs of the whole body.
• The mycobacteria are slow-growing intracellular bacilli that cause tuberculosis.
• In the past decade, tuberculosis cases have significantly increased, chiefly among
HIV/AIDS patients

Worldwide condition
• A total of 1.5 million people died from TB in 2020 (including 214 000
people with HIV).
• In 2020, an estimated 10 million people fell ill with tuberculosis (TB)
worldwide. 5.6 million men, 3.3 million women and 1.1 million
children.
• TB is present in all countries and age groups. But TB is curable and
preventable

DRUGS USED IN TUBERCULOSIS
• Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide,
ethambutol, and streptomycin are the five first-line agents for
treatment of tuberculosis

TB resistance can be:
Mono drug resistance
Multi drug resistance (MDR-TB)
Extensively drug resistance (XDR-TB)
Total drug resistance (TDR-TB )

Individual Antituberculous Agents
First-line agents (in order of preference):
 Superior efficacy & acceptable toxicity.
Isoniazid: 300 mg/day
Rifampin: 600 mg/d
Pyrazinamide: 25 mg/kg/d
Ethambutol: 15–25 mg/kg/d
Streptomycin: 15 mg/kg/d
Dosage: adult dose in normal renal function

Second-line agents:
Adult dose in normal renal function:
Amikacin: 15 mg/kg/d
Aminosalicylic acid (PAS): 8–12 g/d
Capreomycin: 15 mg/kg/d
Ciprofloxacin: 1500 mg/d, divided
Clofazimine: 200 mg/d
Cycloserine: 500–1000 mg/d, divided
Ethionamide: 500–750 mg/d
Levofloxacin: 500 mg/d
Rifabutin: 300 mg/d OR
150 mg/d if used concurrently with a protease inhibitor
Rifapentine: 600 mg once or twice weekly

ISONIAZID (INH)
MOA:
H inhibits synthesis of mycolic acid, which is an essential component of
mycobacterial cell wall.
H is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.
The activated form of H forms a covalent complex with an acyl carrier protein
(AcpM) & KasA, a beta-ketoacyl carrier protein synthetase, which blocks
mycolic acid synthesis & kills the cell  cidal

Pharmacokinetics
 Well absorbed PO or IM.
 Distributed widely: CSF  20% of plasma conc. Increased in meningeal inflammation.
 Metabolized by acetylation; N- acetyltransferase
– Fast acetylation: hepatotoxicity
– Slow acetylation: peripheral neuropathy
 Acetylation status does not generally affect the outcome with daily therapy.
Therapeutic Uses
1. Component of all TB chemotherapeutic regimens.
2. Alone is used to prevent TB (The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice
weekly for 9 months)

Adverse effects
 Allergic reactions (fever, skin rashes)
 Direct toxicities
1. Drug induced hepatitis: high risk age, rifampin, alcohol.
2. Peripheral neuropathy;
– Due to relative pyridoxine deficiency
 Promotes excretion of pyridoxine
– Likely to occur in slow acetylators & pts with predisposing factor [malnutrition,
alcoholism, diabetes, AIDS & Uremia].
Reversed by administration of vitamin B6.

1. Other adverse effect  reversed by vitamin B6.
– Convulsion, optic neuritis, psychosis.
Drug interaction
– Reduces metabolism of phenytoin.
– Absorption of INH is impaired by Al(OH)3

RIFAMPICIN(R)
MOA: binds to the -subunit of bacterial DNA dependent RNA polymerase 
inhibits RNA synthesis (transcription)  cidal
Pharmacokinetics
– Well absorbed; distributed throughout the body.
– Excreted mainly through liver into bile.

Therapeutic uses
 Mycobacterial infection;
TB: cidal for intra & extracellular bacteria.
In TB prevention as an alternative to H.
Leprosy
 Prophylaxis in contacts of children with H.influenzae type b disease(meningitis).

 In combination with other agents;
• For Rx of serious staphylococcal infections;
Osteomyelitis
Prosthetic valve endocarditis.

Adverse effects
– Hepatitis
– Hypersensitivity reactions
Fever
Flushing
Thrombocytopenia
Interstitial nephritis
– Miscellaneous adverse reaction
Harmless orange color appearing in urine, saliva, tears, sweat & soft
contact lenses.

ETHAMBUTOL(E)
MOA:
 Inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB
operon.
 Arabinosyl transferases are involved in the polymerization reaction of
arabinoglycan, an essential component of the mycobacterial cell wall
  bacteriostatic.

ETHAMBUTOL(E)
• Ethambutol is well absorbed from the gut.
• About 20% of the drug is excreted in feces and 50% in urine in unchanged form.
• Ethambutol accumulates in renal failure, and the dose should be reduced by half if
creatinine clearance is less than 10 mL/min.

Therapeutic use: TB.
Adverse effects
– Retrobulbar neuritis (optic neuritis)
Loss of visual acuity & red-green color blindness.
– GI intolerance.
– Hyperuricemia due to deceased uric acid excretion.

PYRAZINAMIDE(Z)
Synthetic pyrazine analogue of nicotinamide.
• Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by
mycobacterial pyrazinamidase, which is encoded by pncA .
Largely Bacteriostatic, but can be cidal on actively replicating mycobacteria.
• The specific drug target is unknown, but pyrazinoic acid disrupts mycobacterial cell
membrane metabolism and transport functions.
• Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that
impair conversion of pyrazinamide to its active form.

PYRAZINAMIDE(Z)
MOA: The specific drug target is unknown
Disrupts cell membrane metabolism & transport functions  static
Inhibit fatty acid synthase(FAS) I, which is required to synthesise fatty
acids.
In acidic media pyrazinoic acid accumulated -> disrupts membrane
potential & interferes with energy production necessary for survival of
M.tuberculosis at acidic site of infection.

Therapeutic use: for RX of TB only.
 Allows total duration of therapy to be shortened to 6 months
Adverse effects
 GI intolerance,
 Joint pains (arthralgia),
 The most hepatotoxic agent
 Hyperuricemia.

PYRAZINAMIDE(Z)
• Pyrazinamide is well absorbed from the gastrointestinal tract and
widely distributed in body tissues, including inflamed meninges.
• The half-life is 8–11 hours. The parent compound is metabolized by
the liver, but metabolites are renally cleared

STREPTOMYCIN
• Streptomycin penetrates into cells poorly and is active mainly against extracellular
tubercle bacilli.
• Streptomycin crosses the blood-brain barrier and achieves therapeutic
concentrations with inflamed meninges.
• Streptomycin sulfate is used when an injectable drug is needed or desirable and in
the treatment of infections resistant to other drugs.

Adverse effects
• Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are
the most common adverse effects and may be permanent.
• Toxicity is dose-related, and the risk is increased in the elderly. As
with all aminoglycosides, the dose must be adjusted according to renal
function

ANTI-TB DRUGS
 Drugs available in Ethiopia:
ERHZ – 275/150/75/400 mg
RHZ – 150/75/400 mg
RH – 150/75 mg
EH – 400/150 mg
 TB medicines available as loose form are:
– Ethambutol 400mg,
– Isoniazid 300mg,
– Streptomycin sulphate vials 1gm

PHASES OF CHEMOTHERAPY
There are two phases:
1. Intensive (initial) phase(IP)
 Consists of 4 or more drugs.
 Duration;
8 wks for new cases, and
12 wks for re-treatment cases.
 The drugs must be swallowed daily under DOT.
Rapid killing of actively growing & semi dormant bacilli.
It renders the patient non infectious ( 2wks).
 Protects against the development of resistance.

2. Continuation phase
 Immediately follows the intensive phase.
 Consists of 2 or 3 drugs.
 Duration is 4 – 6 months.
 Except for re-treatment cases drugs must be collected every month.
 Eliminates bacilli that are still multiplying.
 Reduces failures and relapses.

1. New Patients
 New patients presumed or known to have drug-susceptible TB, pulmonary TB:
2HRZE/4HR.
2. Previously Treated Patients
 Specimens for culture and drug susceptibility testing (DST) should be obtained
from all previously treated TB patients at or before the start of treatment.
 DST should be performed for at least Isoniazid and Rifampicin.
 Recommendation: 2HRZE(S)/1HRZE/5HRE.

MDR-TB
• Isoniazid is the most powerful mycobactericidal drug available to treat
tuberculosis
• rifampicin is crucial to the prevention of relapse because of its mycobactericidal
and sterilizing activities.
• Single Isoniazid or Rifampicin resistance is not MDR - TB
• Resistance to either drug may be managed with other first-line drugs but resistance
to both isoniazid and rifampic results in the development of what is known as
multidrug-resistant tuberculosis (MDR-TB).

Extensively drug resistant tuberculosis (XDR TB)?
• Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB.
• XDR TB is defined as TB which is resistant to isoniazid and rifampin, plus
resistant to any fluoroquinolone and at least one of three injectable second-line
drugs (i.e. amikacin, kanamycin or capreomycin)

MDR TB and HIV
 MDR TB occurs with the same frequency in HIV patients as in TB patients who
are smear negative
 Transmission of drug-resistant strains among HIV-infected patients in congregate
settings occurs leading to ‘outbreaks’ of MDR TB in such settings
 Infection control measures absolutely essential in settings where large number of
HIV TB patients stay together

SECOND-LINE DRUGS FOR TUBERCULOSIS
• The alternative drugs are usually considered only:
 In case of resistance to first-line agents;
In case of failure of clinical response to conventional therapy; and
 In case of serious treatment-limiting adverse drug reactions.

2nd line agents
Ethionamide
 Chemically related to H & similarly blocks the synthesis of mycolic acid.
 Poorly water soluble & available only in oral form.
 Metabolized by the liver.
Capreomycin
 Is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces
capreolus.

2nd line agents
Aminosalicylic Acid (PAS)
 A folate synthesis antagonist that is active almost exclusively against
M tuberculosis .
 It is structurally similar to PABA & sulfonamides

Drugs active against atypical Mycobacterium
 M.avium: cause disseminated TB in late stages of AIDS.
 Azithromycin or Clarithromycin plus Ethambutol: well tolerated
regimen.
 Rifabutin and Clarithromycin: prevent M.avium complex bacterimia in
AIDS patients

MTB: Considerations in Pregnancy
• Treatment considerations
• INH: hepatotoxicity more frequent; monitor
• RIF: higher risk of hemorrhagic disease in neonates born to women on RIF;
give prophylactic vitamin K
(10 mg) to neonate
• PZA: limited experience in human pregnancy (not teratogenic in animals);
WHO recommends routine use; if PZA not used in initial treatment, minimum
duration of therapy is 9 months
• EMB: teratogenic in animals at high dosages; no evidence of teratogenicity in
humans; no evidence of ocular toxicity in exposed infants

ANTILEPROTIC DRUGS
 Leprosy is caused by Mycobacterium leprae.
There are two types of leprosy;
1. Lepromatous Leprosy
– Severe
– Rapidly progress
– Marked ulceration
– Tissue destruction & nerve damage
– TXt lasts at least 2yrs with Dapsone + Rifampicin+ Clofazimine.

ANTILEPROTIC DRUGS
2. Tuberculoid Leprosy
- Mild infection.
- Slow in progress & loss of sensation.
- TXt lasts 6months(Dapsone + Rifampicin).

DAPSONE/SULFONES
 The primary drug (effective, low in toxicity & inexpensive).
MOA: inhibition of folate synthesis.
 Pharmacokinetics: given orally, well absorbed.
– Widely distributed.
– Enterohepatic recycling.
– Excreted as metabolites renally.
 Adverse effects
– Rashes
– GI disturbance
– Show erythema nodusom ( Inflammatory rxn).

CLOFAZIMINE
 Weakly bactericidal.
MOA: not known, may involve DNA binding
 Has anti-inflammatory action.
 Used together with or as an alternative to Dapsone in sulfone-resistant leprosy or
when patients are intolerant to sulfones.
Adverse effects
– Red brown to nearly black discoloration of the skin & conjunctiva.
– GI intolerance (occasionally)

ANTIFUNGALAGENTS
 Fungal infection termed as mycosis.
– Superficial infection (affecting skin, nails, scalp or mucous membranes).
– Systemic infection (affecting deeper tissue & organ).
Superficial fungal: dermatomycosis & candidiasis.
– Dermatomycosis: skin, hair, & nail caused by Trichophyton, Microsporum &
Epidermophyton spp.,these causes various types of ring worms & tinea.
Tinea capitis: scalp; Tinea pedis: foot
Tinea cruris: groin, thigh; Tinea barbae: beard
Tinea corporis: body.
– Superficial candidiasis: mucous membrane of mouth (thrush), vagina or skin.

Systemic fungal disease:
– Systemic candidiasis; other more serious cryptococcal meningitis or
endocarditis, pulmonary aspergillosis,& rhino cerebral mucormycosis.

ANTIFUNGALAGENTS
• The antifungal drugs presently available fall into several categories:
Systemic drugs (oral or parenteral) for systemic infections
• Amphotericin B, Flucytosine, Azoles
Oral drugs for mucocutaneous infections
• Griseofulvin, Terbinafine
Topical drugs for mucocutaneous infections
• Nystatin, Topical Azoles (clotrimazole and miconazole)

AMPHOTERICIN
 Amphotericin A & B are antifungal antibiotics produced by Streptomyces
nodosus.
 Amphotericin A is not in clinical use.
Amphotericin-B
MOA: binds to sterols in the fungal cell membrane  alters the permeability by
forming amphotericin B-associated pores  Loss of intracellular K+.
– Greater avidly to ergosterol.
– Enhances antifungal effect of flucytosine

Pharmacokinetics
It is nearly insoluble in water & is therefore prepared as a colloidal suspension of
amphotericin B & sodium desoxycholate for intravenous injection.
Absorption from GIT is negligible: effective on fungal in lumen.
 Antifungal activity;
– Systemic fungal infections.

Therapeutic uses
 Intrathecal infusion in meningitis caused by coccidioides.
 IV administration of amphotericin B treatment choice for mucormycosis,
aspergillosis, extracutaneous sporotrichosis, cryptococcosis, trichosporonosis &
penicilliosis morneffei.
 Bladder irrigation: in candida cystitis.
 Topical amphotericin B in cutaneous candidiasis.
 Oral tablet to decrease colonization of intestine by candida.

Adverse effects
Infusion related toxicity (immediate reactions)
 Nearly universal & consist of fever, chills, muscle spasms, vomiting, headache,
and hypotension.
They can be ameliorated by slowing the infusion rate or decreasing the daily dose.
Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can
be helpful.

Cumulative Toxicity
 Renal damageis the most significant toxic reaction.
 Anemia due to reduced erythropoietin production by damaged renal tubular cells.
 Seizures & chemical arachnoiditis after intrathecal therapy
 Abnormalities of liver function tests (occasionally)

FLUCYTOSINE
MOA:
 Is taken up by fungal cells via the enzyme cytosine permease.
 It is converted intracellularly first to 5-FU & then to 5-FdUMP & FUTP, which
inhibit DNA and RNA synthesis, respectively. (inhibit thymidylate synthetase)
 Human cells are unable to convert the parent drug to its active metabolites,
resulting in selective toxicity
• Its spectrum of action is much narrower than that of amphotericin B.

Pharmacokinetics
 Given by IV infusion, also be given orally.
 90% excreted renally unchanged.
 Combined with amphotericin for severe infections such as cryptococcal
meningitis.
 Side effects are infrequent: anaemia, neutropenia, thrombocytopenia & alopecia;
reversed when therapy ceases.

AZOLES
• Synthetic fungistatic agents with a braod spectrum of activity.
• MOA: Azoles inhibit the synthesis of ergosterole, the main component of fungal
cell membrane.

AZOLES
According to the number of nitrogen atoms in the five-membered azole ring they
can be;
Triazole(3-N) Imidazole(2-N)
– Fluconazole - Clotrimazole
– Itraconazole - Miconazole
– Terconazole - ketoconazole
– Voriconazole - Oxiconazol
– Posaconazole - Sulconazole
- Econazole

AZOLES
MOA: reduction of ergosterol synthesis by inhibition of fungal cytocrome P450
enzymes.
 Greater affinity for fungal than for human CYP450 enzymes.
 Imidazoles exhibit a lesser degree of selectivity than the triazoles, accounting for
their higher incidence of drug interactions and adverse effects.
Therapeutic uses
– Systemic fungal infections;
• Cryptococcal meningitis (fluconazole).
– Vaginal candidiasis.
– Severe recalcitrant cutaneous dermatophyte infections.

KETOCONAZOLE
• broad spectrum antifungal drug
• useful in both superficial and systemic mycoses.
genital candidiasis.
resistant or disseminated candidiasis.
 Drug interactions
– Inhibit CYP450: inhibit metabolism of protease inhibitors, TCAs,
benzodiazepines, warfarin.
 Adverse effects
– Primarily GI effects, hepatotoxicity

ITRACONAZOLE (PO)
Pharmacodynamics
 Absorption reduces in fasting, reduced gastric acidity
 Itraconazole concentration are decreased by concomitant therapy with rifampin,
phenytoin & carbamazepine, as well as by drugs that reduce gastric acidity- H2
antagonist & proton pump inhibitor.
Therapeutic use:
 Preferred over ketoconazole for txt of nonmeningeal hystoplasmosis.
 Cryptococcus may respond better with amphotericinB or fluconazole.
Untoward effect: occasionally, hepatotoxicity & rash.

FLUCONAZOLE
 Completely absorbed, not affected by food, gastric acidity.
 Diffuses readily into body fluids.
Drug interaction:
Increase plasma levels of phenytoin, zidovudine, Rifabutin, cyclosporine,
sulfonylureas & warfarin

Therapeutic use
 Candidiasis: oropharyngeal, esophageal, vaginal candidiasis, deep candidiasis.
 Cryptococcosis: to prevent relapse cryptococcal meningitis in AIDS patient
whose infection has been controlled by amphotericin B.
 Treatment choice for coccidioidal meningitis because of much lesser morbidity
than with amphotericin B.
Untoward effect:
 Nausea & Vomiting: antiemetic drug may be used.

Pharmacologic properties of five systemic azole drugs

Nystatin
• Nystatin is a polyene macrolide much like amphotericin B.
• toxic for parenteral administration and is only used topically.
• not absorbed to a significant degree from skin, mucous membranes, or the
gastrointestinal tract.
• As a result, nystatin has little toxicity, although oral use is often limited by the
unpleasant taste.

Nystatin
Therapeutic use- local candidal infections.
• oropharyngeal thrush
• vaginal candidiasis
• intertriginous candidal infections.

GRISEOFULVIN
 Active against the dermatophytes: Microsporum, Epidermophyton &
Trichophyton.
MOA: Fungistatic by interacting with microtubule & interfering with mitosis.
 To treat dermatophyte infections of skin & nail.
 Treatment need very prolonged.
 Given orally.
 Deposited in keratin precursor cells.

Therapeutic uses
Mycotic disease of skin, hair & nails.
Infection of hair (tinea capitis).
Ringworm of the glabrous skin.
Tinea cruris & tinea corporis.
Tinea of hand & bread.
Athlete’s foot.
Not effective in subcutaneous or deep mycosis.

RX of Superficial Fungal Infections
 Diseases include;
Dermatophytosis(ring worm),
Candidiasis,
Tinea versicolor,
Tinea nigra &
Fungal keratitis

A. Clotrimazole
 Available as: 1% cream (body, vaginal), lotion & solution
 Skin apply BID.
B. Miconazole
 Therapeutic use: 2% vaginal cream, 100mg suppository at bed time for 7days
(vulvovaginal candidiasis).
 In txt of tinea pedis, tinea cruris & tinea versicolor.
 ADR: vaginal application  burning, itching or irritation.

C. Nystatin
MOA: binds to fungal sterols.
Therapeutic uses
– Candidiasis of intestine, mouth, skin, etc.
Adverse effects
– Nausea
– Bitter taste

Introduction
 Protozoal infections are;
Common among people in underdeveloped tropical & subtropical countries,
where;
Sanitary conditions,
Hygienic practices, &
Control of the vectors of transmission are inadequate.
However, with increased world travel, protozoal diseases are no longer
confined to specific geographic locales.

Introduction
 Protozoas are unicellular eukaryotes
 Have metabolic processes closer to those of the human host than to prokaryotic
bacterial pathogens.
 Less easily treated than bacterial infections,
 Serious toxic effects in the host, particularly on cells showing high metabolic activity.
 Most antiprotozoal agents have not proven to be safe for pregnant patients.

MALARIA
 Caused by protozoa of the genus plasmodium.
 Affects > 5million people; killing > 2 million each year.
 Life cycle of malaria parasite: takes place in two hosts.
In human (asexual reproduction) &
Female anopheles (sexual reproduction)
Types of malaria
Caused by five different species of plasmodium (P.Vivax, P.Falciparum, P.Ovale,
P.Malariae, P.Knowlesi).

Chemotherapy of Malaria
Considered in relation to the biology of infection.
1. Drugs active against Sporozoites:
– True causal prophylaxis.
No drug is yet available.
2. Drugs active against Pre or Primary Exo-erythrocytic Stage;
– Causal prophylaxis [primary tissue schizonticides]
Proguanil & Pyrimethamine
 Kill the parasites before RBCs are invaded.
Primaquine has causal prophylaxis activity especially against P.falciparum but its use is
unsafe.

Chemotherapy of Malaria
3. Drugs active against the secondary exo-erythrocytic stage (persistent liver
cycle, hypnozoite).
 Secondary tissue schizonticides.
 Primaquine acts on hypnotic of P.Vivax.
4. Drugs active against the erythrocytic stage (blood schizonticides)
 Suppression or clinical prophylaxis.
 Chloroquine, Proguanil, Mefloquine.
 Used for temporary prevention of clinical symptoms.
 Kill blood schizonts, but the tissue schizonts are not destroyed.
 Falciparum promptly cured.

Clinical cure:
A. 4-aminoquinolines: Chloroquine, Amodiaquine
B. Quinoline methanol: Quinine, Quinidine, Mefloquine
C. Arthmisinine compounds:
Dihyddroartemisinin, Artemether, Artesunate
 Interrupt the erythrocytic cycle of the malaria parasite.
5. Drugs active against the sexual stage
A. Gametocidal: Primaquine
B. Sporontocides: Proguanil & Pyrimethamine
 Gamates become incapable of forming sporozoite.

CHLOROQUINE
MOA:
 Acts by concentrating in parasite food vacuoles, preventing the bio-crystallization
of the haemoglobin breakdown product, heme, into hemozoin, and thus eliciting
parasite toxicity due to the build up of free heme.
 Inhibition of heme polymerase

Therapeutic uses
 Malaria:
A highly effective blood schizonticide for all forms
Moderately gametocidal for P vivax, P ovale, and P malariae but not against those
of P falciparum.
Chloroquine is not active against liver stage parasites (hypnozoites)
Chloroquine reaches high liver concentrations and may be used for amebic
abscesses that fail initial therapy with metronidazole

Therapeutic uses
• Chloroquine is the preferred chemoprophylactic agent in malarious regions
without resistant falciparum malaria.
• Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic
stages.

Adverse effects
 CVS (parenteral dose): vasodilation, hypotension, decrease myocardial
infarction, ECG changes.
 Oral route can cause (high dose)
– Visual disturbance
– Urticaria
– Head ache
– GI upset
 Rare reaction include hemolysis in pts with G6PD deficient.
 High daily doses of chloroquine: irreversible ototoxicity & retinopathy.
Contraindication: psoriasis, porphyria cutanea tarda it may precipitate
acute attacks of these diseases.

QUININE & QUINIDINE
 Derived from the bark of cinchona.
MOA: unknown;
Pharmacological effects
– Quinine acts primarily as blood schizonticidal.
• Gametocidal for P.Vivax, P.Ovale, P.Malariae
• Not effective liver stage parasite.
– Quinine is the drug of choice for severe illness due to chloroquine resistant &
MDR strains of P.falciparum.
– Potentiation of neuromuscular blocking drugs.

Therapeutic use
 Rx malaria
– Cure of chloroquine resistant & MDR P.falciparum.
– Rx nocturnal leg cramps.
Toxicities & side effects
– Commonly causes:
Tinnitus
Nausea
Head ache Cinchonism
Dizziness
Flushing

Toxicities & side effects
 Hyperinsulinema- severe hypoglycemia.
 Stimulate uterine contraction.
 Black water fever:
Marked hemolysis & hemoglobinuria.
Due to hypersensitivity reaction to the drug.
Contraindications
 Hypersensitivity reaction to quinine.
 Severe Cinchonism.
Drug interactions
 Absorption blocked by aluminum containing antacids.
 Should not be given concurrently with Mefloquine (cardiac arrest).

MEFLOQUINE
MOA:
– Effective blood schizonticidal.
Therapeutic use
 Chemoprophylaxis: nonimmune travelers
 Treatment: for malaria caused by chloroquine resistant & MDR P.falciparum.
For severe or complicated malaria: Quinine or Quinidine are selected.

Adverse effects
– NVD; Abdominal pain, dizziness, dysphoria
– Higher doses cause
• Neuropsychiatric toxicity [disorientation, seizure, encephalopathy].
• Alter cardiac conduction, arrhythmias & bradycardia.
Contraindications
– History of seizure & neuropsychiatry.
– Combination with quinine & Quinidine  Arrhythmia

PRIMAQUINE
Chemistry: synthetic 8-aminoquinoline.
MOA: not completely understood
 Metabolites of primaquine are believed to act as oxidants that are responsible for the
schizonticidal action as well as for the hemolysis & methemoglobinemia encountered as
toxicities.
 Active against hepatic stages of all human malarial parasite.
 Gametocidal.

Therapeutic uses:
Reserved primarily for radical cure of vivax & ovale malarias.
Occasionally to interrupt malarial transmission by rendering plasmodial
gametocytes noninfectious to mosquitoes.
Primaquine +Clindamycin: an alternative regimen for PCP.

PRIMAQUINE
Adverse effects: generally tolerated
 Infrequently causes: nausea, epigastric pain, abdominal cramp, head ache.
 Hemolysis & methehemoglobinemia especially in persons with G6PD deficiency.
Contraindication
 Granulocytopenia.
 Methemoglobinemia.
 Pregnancy as the fetus is deficient in G6PD.

ARTEMISININ & ITS DERIVATIVES
 Artemisinin or Qinghaosu was isolated in 1972 from Artemisia annua L.
 Has been used in traditional Chinese medicine.
 Derivatives: Artemether, Arteether, Artesunate, Artlinic acid.
MOA:
Production of free radicals that follows the iron-catalyzed cleavage of the
artemisinin endoperoxide bridge in the parasite food vacuole or from inhibition of
a parasite calcium ATPase.
In contrast to other antimalarials:
 Artemisinins have very fast action.
 Parasite clearance times are short.
 Unlike most of the antimalarials work at the late trophozoite & schizont stage;
Artemisinin & its derivatives also acts at the early trophozoite.

Therapeutic uses
 Active against all plasmodium species.
 Should be administered in combination in order to:
– Reduce recrudescence.
– Prevent or slow development of resistance.
 Uncomplicated malaria.
 Due to short t1/2, they are not useful for chemoprophylaxis.
Adverse effect: safe & well tolerated.
NVD.
Avoided in pregnancy if possible.

INHIBITORS OF FOLATE SYNTHESIS
(PYRIMETHAMINE, PROGUANIL)
MOA: Inhibit dihydrofolate reductase of plasmodia.
Therapeutic uses
 With sulphonamide.
 Not 1st line because it is slow to act.
Suppressive Rx of chloroquine resistant P.falciparum.
Given concurrently with sulfadiazine for Rx of toxoplasmosis.
Adverse effect
 Erythema multiform
 Toxic epidermal necrosis

PROGUANIL
 Prodrug metabolized to an active metabolite, cycloguanil.
MOA: inhibits DHFR
– Inhibition of DNA synthesis.
– Depletion of folate co-factors.
 Slow antimalarial action.
Therapeutic uses:
– With chloroquine used as alternative to Mefloquine for prophylaxis.
– Not suitable for acute attack.
– Considered safe for use during pregnancy.

HALOFANTRINE & LUMEFANTRINE
HALOFANTRINE:
 Effective against erythrocytic stages of all for human malaria species.
 Oral absorption is variable & is enhanced with food.
 Plasma t 1/2  4 days.
ADRs:
Generally well tolerated.
Abdominal pain, Diarrhea, Vomiting, Cough, rash & head ache, Altered cardiac
conduction.

LUMEFANTRINE
Available in fixed dose combination with artemether as Coartem.
T 1/2  4.5 hrs
COARTEM®: very effective for Rx of P.falciparum.

Drugs for Amebiasis
Amebiasis: infestation with E.hystolytica.
 Usually asymptomatic, when symptoms are present the most characteristics are:
– Diarrhea & abdominal pain.

Classification of Antiamebic agents
Luminal Amebicides
–Diloxanide
–Idoquinol
–TTCs
–Paramomycin(an aminoglycoside)
Tissue Amebicides
–Both intestinal & extraintestinal
Metronidazole
Tinidazole
Emetine & Dihydroemetine
–For extraintestinal only
Chloroquine

METRONIDAZOLE
MOA:
 Amebas possess ferredoxin-like, low-redox-potential, electron
transport proteins that participate in metabolic electron removal
reactions.
 The nitro group of metronidazole is able to serve as an electron
acceptor, forming reduced cytotoxic compounds that bind to proteins
and DNA  death of the E. histolytica trophozoites

Pharmacokinetics
 Absorption: complete & rapid after PO
 Distribution: well throughout the body.
Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast
milk & CSF.
 Metabolism: depends on hepatic oxidation of its side chain by mixed-function
oxidase, followed by glucuronidation. Therefore, concomitant treatment with
inducers of the cytochrome P450 enhances the rate of metabolism & inhibitors
prolong the plasma half-life of metronidazole.
The drug accumulates in patients with severe hepatic disease.
 Excretion: via urine (parent drug & its metabolites)

Therapeutic uses
1. Amebiasis
For all symptomatic tissue infections: used with luminal amebicide.
Combination provides cure rates of > 90%
2. Gardiasis: highly effective, lower dosage than for amebiasis
3. Trichomoniasis: highly effective, can be given topically
4. Anaerobic(G-/+ve) bacterial infection;
– Bacteriodes, Clostridium (pseudomembranous colitis), Fusobacterium.
5. H. pylori (PUD): with other ABX
6. To facilitate extraction of guinea worm in drancunculiasis.

Adverse effects
 Common: head ache, nausea, dryness of mouth, metallic taste, dizziness.
 Has a disulfiram like effect copious vomiting, flushing, palpitation, head ache.
Used with caution in pts with active disease of CNS.
Its use during 1st trimester is not recommended.
Drug Interaction
With alcohol: disulfiram like effect.
Inhibits inactivation of oral anticoagulant.
Phenobarbitone: enhaced metabolism of metronidazole.
Cimetidine: reduces metabolism of metronidazole.

TINIDAZOLE
 2nd generation nitroimidazole.
 Similar to Metronidazole.
 Differ in: better toxicity profile & higher t½.

DILOXANIDE FUROATE
Useful in the Rx of:
 In conjugation with metronidazole in the Rx of intestinal & systemic amebiasis.
 90% absorbed & the nonabsorbed is effective.
Adverse effect
– Flatulence
– Dryness of mouth

EMETINE & DEHYDROEMETINE
MOA: inhibits protein synthesis by blocking chain elongation.
IM is the preferred route, since it is an irritant when taken orally.
Due to its toxicity, it has largely been replaced by metronidazole.
Use: as alternative agent
Adverse effects
– Pain at the site of injection
– Transient nausea & vomiting
– Cardio toxicity [arrhythmia, CHF]
– Neuromuscular weakness
– Dizziness & rash.

Drugs For Pneumocystis Jiroveci Pneumonia (PCP)
– Cotrimoxazole
– Pentamidine
– Trimethoprim + Dapsone
– Primaquine + Clindamycin
DRUGS FOR TRICHOMONIASIS
– Metronidazole
– Tinidazole
DRUGS FOR TOXOPLASMOSIS
– Pyrimethamine + Sulfadoxine = (FANSIDAR®)
– Pyrimethamine + Sulfadiazine

DRUGS FOR LEISHMANIASIS
 Has three different forms:
Cutaneous leishmaniasis
Mucocutaneous leishmaniasis
Visceral leishmaniasis [kalazar]
 Drugs include:
– Pentavalent antimony(Sb)
• Sodium Stibogluconate (SSG): 1st line agent
• Meglumine antimonite(MA)
– Allopurinol + SSG
– Miltefosine: visceral
– Amphotericin-B
– Ketoconazole

DRUGS FOR TRYPANOSOMIASIS
(AFRICAN SLEEPING SICKNESS)
Caused by:
A. Trypanosomia brucei gambiense
- Slow to enter CNS
- Causes sleeping sickness
Suramine & Pentamidine are used in early stage of the disease
[hemolymphatic stage]
Pentamidine interferes with parasite synthesis of RNA, DNA,
phospholipids & proteins.
Enflornithine: used in early stage or CNS involvement.

B. Trypanosomia brucei rhodesiense
- Early invasion of the CNS
- Usually fatal if not treated
Melarsoprol:
A trivalent arsenical compound
MOA: reacts with sulfhydryl groups of various substances, including enzymes in
both the organism and host
Use: involvement of CNS in both ‘a’ & ‘b’

CHAGA’S DISEASE [AMERICAN TRYPANOSOMIAS]
- Caused by Trypanosoma cruzi.
- Parasites invade cardiac cells & neurons of myenteric cause
cardiomyopathy & mega colon  death.
Rx options:
- Nifurtimox &
- Benznidazole22:

Benznidazole22
Nitroimidazole derivative
MOA: similar to nifurtimox.
Better tolerated than nifurtimox
An alternative for the treatment of Chagas disease

Helminthic Infestation
And
Drugs of Choice

ANTHELMINTICS
Helminthes: Parasitic worms.
Classification of parasitic worms;

NEMATODE INFESTATION [INTESTINAL]
1. ASCARIASIS (Giant round worm infestation)
Most prevalent helminthic infestation.
Adult worm inhabit the intestine
heavy infestation  intestinal blockade.
Drug of choice: Albendazole
Mebendazole
Pyrantel pamoate
Alternative drug: Piperazine citrate 4g stat

ALBENDAZOLE
MOA: produce many biochemical changes.
Inhibition of mitochondrial fumarate reductase.
Uncoupling of oxidative phosphorylation.
Inhibits microtubule polymerization  irreversibly impairing glucose
uptake  immobilized & slowly die.
Pharmacokinetics:
– Erratically absorbed PO.
– Rapidly undergoes 1st pass metabolism in liver to albendazole sulfoxide.
–  absorption when taken with fatty meal.

Albendazole
…
Adverse effects
– Fewer ADR when used for short term therapy
abdominal pain
Diarrhea
Nausea & dizziness
Head ache
– With protracted therapy
GI pain
Severe head ache
Fever
Fatigue
Loss of hair
Leucopenia & thrombocytopenia

MEBENDAZOLE
MOA: prevents uptake of glucose  Immobilization & death.
Therapeutic use: drug of choice for most intestinal round worms [pin worm,
hookworm, whipworm, Giant worm].
Pharmacokinetics: Only 5-10% is absorbed & rapidly metabolized.
Adverse effect:
– Transient abdominal pain & diarrhea[massive infestation].
– Embryocytotoxic & teratogenic in rats.

PYRANTAL PAMOATE
MOA: depolarizing neuromuscular blocker.
Therapeutic uses:
– Alternative to mebendazole for infestation with: hookworm, pinworm,
Giant worms.
PIPERAZINE CITRATE
MOA: paralysis of ascaris by blocking Ach
Therapeutic uses:
– Alternative to albendazole or mebendazole in the Rx of ascariasis.
Adverse effect: NVD, Dizziness & headache

2. ENTEROBIASIS (Pinworm infestation)
Most common helminthic.
Serious infections are rare but may cause intense perineal itching.
It is readily transmissible; family members should be treated.
Drugs of choice: Albendzole
Mebendazole
Pyrantel pamoate

3. ANCYLOSTOMIASIS & NECATORIASIS (Hookworm infection)
Common in rural area (barefoot)
Adult worm attach to intestine chronic blood loss anemia.
Nausea, vomiting & abdominal pain
– Albendazole, Mebendazole, Pyrantel pamoate.
4. TRICHURIASIS (Whipworm infestation)
 Mebendazole[drug of choice].
 Albendazole
5. STRONGLOIDIASIS (Threadworm infestation)
– Larva & adult inhabit small intestine
Drug of choice: Ivermectin
Albendazole
Thiabendazole

THIABENDAZOLE
MOA: inhibit helminth specific fumarate reductase.
Therapeutic use: alternative drug against
– Strongloidiasis
– Trichinosis
Adverse effect: incidence is high, most common includes:
 GIT: Anorexia, nausea & vomiting
 Neurological: dizziness & drowsines

NEMATODE INFESTATION (Extra intestinal)
1. TRICHINOSIS (Pork roundworm infestation)
Acquired by eating uncooked pork infested with encycted larva of
T.spiralis.
Adult worm reside in intestine; Lareva migrate to skeletal muscle &
become encysted.
Symptoms include:
– Muscle pain
– Sore throat
Potential lethal complications:
Heart failure, meningitis, & neuritis.
Drugs of choice: Mebendazole
Albendazole
Prednisolone is included to reduce inflammation during larva movement.

2. WUCHERERIASIS & BRUGLASIS (Lymphatic filarial
infestation)
W.bancrofti & B.malayi invade the lymphatic system.
Heavy infestation  lymphatic destruction  Elephantiasis.
Drug of choice: Diethylcarbamazine.

DIETHYLCARBAMAZINE
Pharmacokinetics:
– Readily absorbed & extensively metabolized.
Therapeutic uses:
 Drug of choice for filarial infestations;
– Destroys microfilariae of W.bancrofti, B.malayi
– Onchocerciasis: but it does not kill the adult worm.

Adverse effects
 Reactions caused directly by DEC are minor:
Headache, Dizziness, Nausea, Vomiting.
 Occurring secondary to death of the parasite are more
serious:
These can be decreased by pretreatment with glucocorticoids.

ONCHOCERCIASIS (River blindness)
 O.volvulus is found in stream & rivers.
 Heavy infestation causes:
– Dermatologic
• Nodules
• Pruritic dermatitis
– Opthalmic
• Occular lesions,
– The drug of choice is Ivermectin.

IVERMECTIN
MOA: disrupts nerve traffic & muscle function in target parasite.
Pharmacokinetics:
– Administered p.o.
– Distribution to CNS is poor
Therapeutic uses: onchocerciasis, intestinal strongloidiasis.
 Used extensively in veterinary medicine.
Adverse effects:
 Mazotti reaction (fever, urticarial, swollen &tender lymph nodes,
tachycardia, hypotension ,edema, athralgias) when used for
onchocerciasis.
 Due to allergic & inflammatory response to death of microfilariae.
 No data on pregnant women; teratogenic in mice, rats, rabbits[ cleft
palate].

CESTODE INFESTATIONS
1. TAENIASIS [beef & pork tape worm]
 Treated by: praziquantel
Niclosamide
2. DIPHYLLOBOTHRIASIS [Fish tapeworm infestation]
Worms are killed by: praziquantel
Niclosamide

NICLOSAMIDE
MOA: inhibits mitochondrial oxidative phosphorylation in
tapeworm  cessation of ATP production  death.
Therapeutic uses:
–Alternative to praziquantel in Rx of Cestode infestation.
Adverse effects:
–Absorption is poor  systemic ADR is minimal.
–GIT: ANV.

PRAZIQUANTEL
MOA: absorbed by helminthes.
At low concentration  spastic paralysis  detachment of worms.
At high concentration  disruption of the tegument of the worm 
rendered vulnerable to lethal effect of host defenses.
Therapeutic uses:
– Active against cestodes and trematodes.
Adverse effects:
Transient headache
Abdominal discomfort
Drowsiness

TREMATODE INFESTATION
1. Schistosomiasis (blood fluke infestation)
– For both acute & chronic phase, praziquantel is the drug of choice.
2. FACILIASIS (Liver fluke infestation)
– Praziquantel is the drug of choice
– Bithionol is the alternative
3. FASCIOLOPSIASIS (Intestinal fluke infestation)
– Praziquantel is Rx of choice

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