Category: 2. Chemotherapy

Vinca Alkaloids

Mitotic spindle poisons.

Vincristine is obtained from Vinca rosea

Mechanism of Action

– dimeric form, bind tubulin to form tubulin complex

– inhibit polymerization required for formation of microtubules

– mitotic arrest in metaphase, cell are not able to divide

Uses

1. Hematological – ALL / lymphoma / Multiple myloma

2. Pediatric – Wilm’s tumor, Ewing’s sarcoma, neuroblastoma

Toxicity

1. Neurotoxicity – per. sens neuropathy, CN palsies, ataxia,  seizures, coma

2. ANS dysfunction

3. SIADH

Image courtesy of CDC/Amanda Mills

Vinblastine

Source & Mechanism of Action – as vincristine

Toxicity

• Nausea
• Vomiting
• Alopecia
• Myelosuppression
• Potent vesicant, thrombophlebitis at site of administration

Uses

1.      Breast,
2.      Germ cell,
3.      Lymphomas

Vinorelabine

Semisynthetic compound

Mechanism of Action – as vincristine

Toxicity 

a.      Nausea
b.      Vomiting
c.       Myelosuppression
d.      Neurotoxicity
e.       SIADH
f.        Elevated LFTs

Uses

• Non Small Cell Lung cancer,
• Breast cancer

Taxanes

Paclitaxel

Obtained from Taxus brevifolia & T. baccata

Mechanism of Action

• Enhances tubulin polymerization
• Mitotic spindle poison

Microtubules formed are not stable structurally, in absence of tubulin associated proteins, CTP leads to disruption, so known as mitotic spindle poisons.

Uses

Solid tumors ( breast, lung, ovarian, prostate, head/neck, esophagus, bladder, Kaposi’s sarcoma )

Toxicity – hypersensitivity – treated by premedication (H2 blockers, dextramethasone)

– albumin-bound (abraxane) is having no hypersensitivity

Docetaxel

It is a semisynthetic derivative of Paclitaxel

Epipodophyllotoxins

Etoposide & Teniposide

Podophyllotoxin – semisynthetic derivative.

Mechanism of Action

• Inhibit topoisomerase II, uncoiling is inhibited, leading to DNA brakes
• DNA-drug-enzyme – complex is formed, drug acts by binding both DNA and enymes

Uses

• lymphoma
• gastric
• lung
• germ cell

Camptothecins

Topotecan & Irinotecan (prodrug)

• Obtained from Camptotheca acuminata
• Topotecan is prodrug, active metabolite is 1000 times active than parent compound.

Mechanism of Action – inhibit topoisomerase I, interfering with DNA replication

Uses – metastatic colorectal Carcinoma

Adverse Drug Reactions –Myelosuppression / Diarrhea (acute & chronic)

Giving atropine effectively treats diarrhea. Chronic diarrhea appears 2-10 days after treatment.

Hormones & Anti-hormones

• Glucocorticoids
• Estrogen
• Progestins
• Androgens

Antihormones

a. Anti-estrogen – Tamoxifen
–used in breast Cancer
b. Anti-androgen – Flutamide
–used in prostate Cancer
GnRH agonist – Goserelin / Leuprolide
– transient release of FSH / LH, pulsatile nature is suppressed, effective in releasing sex hormones, estrogen and progesterone

– used in prostate Cancer

d. GnRH antagonist   – Abarelix

e. Aromatase inhibitor  – Anastrozole

                                               – Aminoglutethimide

– inhibit conversion of androgen to estrogen in fatty tissues of body

– used in prostate / breast Cancer

Asparaginase

Enzyme – produced by bacterial culture e.g. E. coli

Mechanism of Action

Normally L-asparagine present in blood is taken up by malignant cells and used to synthesize proteins, as have no asparagine synthase so rely on external source.

On other hand, normal cells have enzyme for own protein synthesis, when asparaginase enzyme is given, it degrades it into aspartic acid and ammonia, thus malignant cells are unable to produce it.

– Lack of asparagine synthetase – inhibits protein synthesis

Toxicity

– Hypersensitivity

–  Neurotoxicity

–  Pancreatitis

–  Altered clotting factors

Uses –  ALL (childhood)

Retinoic acid derivatives

Tretinoin

Used in APL

Mechanism of Action-Induction of terminal differentiation of promyelocytes.

Toxicity

Very typical toxicity profile.

Vit A toxicity
a.      Dry skin, mucous membranes
b.      Pruritis
c.       Conjunctivitis
d.      fever

Retinoic acid syndrome

Manifests as:

a.      Fever
b.      Leukocytosis
c.       Weight gain
d.      Pleural and pericardial effusion
e.       Pulmonary infiltrate
f.        Dyspnea

Hyperlipidemias

a.      Increased cholesterol
b.      Increased TGs
CNS 
a.      Dizziness
b.      Anxiety
c.       Agitation
d.      Depression
e.       Confusion

GIT / Hepatic
a.      Abdominal pain
b.      Diarrhea

c.       Transient increase in LFTs

Monoclonal antibodies

Monoclonal antibodies are the molecules formed against antigen. They are produced by single B-cell line, so called so. They are highly specific towards single type of antigen, so toxic effects are limited because of high specificity.

Production

Antigen of interest is injected into animal e.g. mice, whose immunity is stimulated. B cells against antigen start forming antibodies, which are quantitively very less thus cannot be used clinically. These stimulated B cells are removed and are fused with myeloma tumor cells. Myeloma is a B cell cancer having lost the capacity to form antibodies but having rapid replication or growth rate.

• Hybridoma – B-cell + Myeloma tumor cell

Once fused, B cells also replicate, thus lots of antibodies are produced. Either germ tissue culture is obtained or injected back into animal where grow and give rise to lots of antibodies. Not used because of ethical issues.               

Chimeric antibodies may produce hypersensitivity reactions where administered to humans. Humanized by removing major portion of animal origin and replacing it with antibody portion:

1. Constant portion human origin
2. Antigenic variable portion of animal source.

There are many examples:

• Rituximab – anti CD20 on B lymphocytes

  –used in Non Hodgkin’s lymphoma

• Trastuzumab – anti EGFR receptor (epidermal growth factor receptor) – HER-2/neu

–used in metastatic breast Cancer

• Bevacizumab – anti-VEGF-A

–used in metastatic colorectal Cancer

Cytokines

Small protein molecules/peptides normally present in body.

Interferons

• Three forms: Alpha / beta / gamma
• Alpha form is in clinical use.

Mechanism of Action – mainly immunomodulatory

• When immunity is depressed, they enhance it.
• When overexpressed, suppress it.
• Act as Antiproliferative

Uses – IFN-α  –

1.      CML
2.      hairy cell leukemia
3.      malignant melanoma
4.      kaposi’s sarcoma
5.      hepatitis B & C

Toxicity 

1.      fever
2.      chills
3.      myalgias
4.      headache
5.      depression
6.      myelosuppression

IL-2

1. Malignant melanoma
2. metastatic renal cell Carcinoma

Anti-Metabolites

Anti metabolites are used to inhibit different metabolic pathways, as rate of metabolism and required metabolites are much higher for malignant cells.

3 groups are present:

Methotrexate

Mechanism of Action

• Inhibits dihydrofolate reductase – blocks conversion to tetrahydrofolate for synthesis of many cellular components.        
• Interferes with synthesis of thymidylate, purine, serine, methionine, proteins, RNA, DNA

Pharmacokinetics

• Given orally, I/V or by intrathecal route
• In cells, it is converted to methotrexate polyglutamate by addition of glutamate residues required for therapeutic effects.

Resistance

1. decrease in permeability into cells
2. decrease in formation of polyglutamate in cells
3. alteration in target enzyme dihydrofolate reductase (decreased affinity or increased production)
4. formation of P170 glycoprotein –efflux pumps pump out drug from cells

Uses

       1.  anticancer (head & neck, breast, CNS, bladder osteogenic sarcoma, NH lymphoma)

2. rheumatoid arthritis
3. psoriasis (autoimmune)

Toxicity

– General / mucositis

– Lucovorin rescue (increased levels of methotrexate lead to leucovorin reduced formation so folates are given, called leucovorin rescue)

5-Fluorouracil

Purine analog

Pharmacokinetics

• Given I/V, it is a prodrug, inside body converted into active metabolites, fluorouridine monophosphate
• Metabolized and dihydropyridine dehydrogenase in some is completely or partially deficient, thus toxicity may be seen.

Uses

– colorectal ( FOLFOX)

– solid tumors (breast, stomach, pancreas, esophagus, liver, head & neck, anus)

Toxicity

1.  Bone marrow suppression
2. GIT toxicity
3. Head foot syndrome of skin
4. Neurotoxicity

Mechanism of Action & Pharmacological effects

Converted into

Different metabolites affect DNA, RNA, protein synthesis and function.

1. One is 5 FdUMP having affinity for thymidylate synthase and reduced folate. It inhibits synthesis of thymidylate which is in turn responsible for DNA synthesis and function.
2. FUTP interferes with RNA processing and translation.
3. FdUTP directly incorporates into DNA inhibiting DNA function.

Purine Antagonists

6-Thiopurines

2 agents are commonly used:

1.      6-Mercaptopurine

• Prodrug –different metabolites  6-thioinosinic acid.
• Both monophosphate and triphosphate forms produce effect, interfere with purine synthesis, ultimately DNA, RNA synthesis is affected.
• Inactivated by xanthine oxidase into 6-thiouric acid–
• Use –ALL

When used in blood cancers (leukemia) in which rapid cell turn over occurs, leading to increased uric acid and allopurinol is given, which is xanthine oxidase inhibitor, toxicity may be seen. 50-70% dose reduction is done.

2.      6-Thioguanine

• Has no drug interaction with allopurinol, is metabolized by TPMT (thiopurine methyltransferase). Some patients are genetically deficient in this enzyme, so toxicity may be seen.

Antibiotics

Anthracyclines:

• Produced by Streptomyces peucetius var caesius

Mechanism of Action

1. Cause Cross linking of DNA strands
2. Cause DNA breaks
3. Inhibit Topoisomerase II, when DNA has to undergo replication it exists in supercoiled form, for the purpose of uncoiling certain breaks in DNA strand are made, which are then resealed. Topoisomerase II is responsible for breaks in double stranded DNA, thus no brakes are produced
4. Change in membrane fluidity & ion transport, disrupting cellular functions
5. Produce oxygen free radicals – cardiotoxicity

Pharmacokinetics – I/V

Toxicity

– Myelosuppression

– Mucositis

– Cardiotoxicity

I. acute –first 2,3 days in form of arrhythmias, changes in ECG, myocarditis, pericarditis

II. chronic ­–occurs late as dilated cardiomyopathy, cardiac failure

For prevention, patient is administered iron chelating agents. Dexrazoxane used because formation of free radicals is iron dependent, thus no iron is available.

Radiation recall reaction

If patient is already undergoing radiotherapy leads to redness, erythema, acne.

Uses

1. Cancer – breast, endometrium, ovary, testicle, thyroid, stomach, liver,lung, bladder, head & neck, soft tissue sarcoma

2. Pediatric cancers – neuroblastoma, Ewing’s sarcoma

3. Hematological cancers – ALL / AML / CML / M. myeloma /  lymphoma

Mitomycin

• Antitumor antibiotic, when given, in cells converted into compounds which acts like alkylating agents.
• Hypoxic tumor stem cells –favourable areas for reduction of mitomycin
• Drug of choice with radiation therapy to kill hypoxic stem cells

Uses

1. Squamous cell Carcinoma – cervix / anus
2. Breast / Gastric / Pancreatic
3. Administered intravasically for superficial bladder Cancer

Bleomycin

Antitumor antibiotic, small peptide having 2 binding sites:

1. DNA
2. Iron

Mechanism of Action – DNA-bleomycin-Fe complex is formed which is responsible for breaks

Uses – skin, cervix, vulva, head/neck, germ cell, Lymphomas

Toxicity – Pulmonary, cough, dyspnea.

On examination, inspiratory crackles are heard.

On X ray chest, infiltrates are seen. 

Alkylating agents are the broad spectrum agennts.

Chemistry

• Different reactive moiety: Bis (chloroethyl) amine / ethyleneimine / nitrosourea, responsible for different actions
• Either two or more of these are present known as Bi-  / Poly-functional

Mechanism of action

1. These molecules undergo intracellular circulization forming Etyleneimonium ion reacting with cellular components, further change into carbonium ion, alkylating cellular components
2. In cell, different groups are present to which alkylating agents bind mainly Imidazole / amino / OH / COOH / SH / PO₄  groups
3. Nitrosourea – carbamoylation of lysine
4. DNA – N7 G / N1,N3 A / N3 C / O6 G
5. Interfere DNA synthesis, replication, transcription, alkylate one base causing joining of two bases.
6. DNA cross-linking, breaks
7. Interfere RNA, protein synthesis

Pharmacokinetics

• Given Oral / IV, metabolized by microsomal enzymes, mainly conjugated and excreted out.

Resistance

Different mechanisms:

1.      Decreased permeation into cells
2.      Increased DNA repair by cells
3.      Increased production of glutathione (GL- S transferase) leading to glutathione conjugation, making alkylating agent ineffective.

Toxicity

Same as in general toxicity with some additional effects

Uses

1. Blood,
2. Bone marrow
3. Lymphomas,
4. Breast,
5. Ovarian,
6. Gastero-esophageal,
7. Colorectal,
8. Lung,
9. Bladder,
10. Head & neck,
11. Melanoma,
12. Soft tissue sarcoma,
13. Neuroblastoma

Cyclophosphamide

Prodrug, commonly used

Pharmacokinetics – given orally or I/V

                                    – metabolism occurs inliver

Metabolism Of Cyclophosphamide

Acrolien has side effect of hemorrhagic cystitis. Liver is protected by inactivation into 4 ketocyclophosphamide and carboxyphosphamide.

Resistance

Same as other alkylating agents

Toxicity – general

Hemorrhagic cystitis –specific effect

Provide sufficient hydration.

Mesna given –organosulphur compound which detoxifies metabolites in bladder and prevents.

Uses 

1. Breast,
2. Ovarian,
3. CLL,
4. Non-hodgkin’s lymphoma,
5. Wilms’tumor

Busulphan

• Used in CML

Nitrosoureas

• Carmustine,
• Lomustine,
• Streptozocin

Mechanism of Action

Alkylation (same as other alkylating agents)

–  Carbamoylation of lysine

–  No cross-resistance

Pharmacokinetics

–given orally or I/V

-non-enzymatic decomposition

-highly lipid soluble

Toxicity

STREPTOZOCIN has minimal bone marrow toxicity

Uses

• Insulinoma,
• Brain,
• Lymphomas

Platinum Analogs

Cisplatin – Inorganic metal complex

Mechanism of Action – same as alkylating agents

Toxicity – general

–  Nephrotoxicity – hydration by oral I/V fluids

–  Neuropathy

–  Ototoxicity

Uses

a.      Solid tumors
b.      lung / esophageal / gastric / head & neck / testicular / ovarian / bladder

Carboplatin -Second generation

–Less toxic

-May cause myelosuppession

Oxaliplatin   -Third generation

-for those resistant to 1^st and 2^nd generation

-Used in colorectal cancer (FOLFOX)

-Neurotoxicity (acute triggered by exposure to cold)

Chronic adverse effects–dose dependent)

FOLFOX – 5-FU + Oxaliplatin + Leucovorin

Cancer chemotherapy includes the drugs used to treat neoplasms, tumors or cancers. These include:

• Antineoplastic agents
• Anticancer drugs
• Cytotoxic drugs

Cancer, neoplasm or tumor is defined as:

“Disease characterized by loss of normal control over cell division and proliferation or differentiation.”

Tumor stem cells are subpopulation of malignant cells which have the capability of further dividing, proliferating or differentiating. There are two types of cells:

1. Those differentiated fully –can’t proliferate
2. Those which can proliferate further, the stem cells, also have the capability to travel to distant organs, colonize and produce new growth known as metastasis.

Cancer Chemotherapy is different because:

1. In others, organisms are foreign to the body structure, thus anti-microbial agents can be given having less side effects to human cells
2. Body itself starts immune response against bacteria, viruses but in cancer cells, because these are human cells, body does not feel need of defense mechanism.
3. Drugs used affect normal cell machinery and lots of toxic effects are produced.

The Cell Cycle

Causes Of Cancer

1. Age / sex / race
2. Unknown
3. Genetic association
   • Oncogenes (bcl-2) : genes which predispose a person to developing cancer, found to be overexpressed in certain cancers.
   • Tumor suppressor genes (p53) : seen mutated in many types of cancers
4. Environmental / occupational

• Tobacco smoke
• Exposure to chemicals, benzene, asbestos
• Exposure to ionizing radiations

5. Biological agents –viruses, e.g. hepatitis B and C with hepatocellular carcinoma
6. Diet –excessive use of BBQ food, less intake of fiber à colorectal cancer
7. Iatrogenic –certain drugs, anticancer drugs like alkylating agents cause blood cancers

Management

Prevention

• Primary

1. Lifestyle modificatin
2. Risk factors avoidance

• Secondary

1. Screening
2. Early detection & diagnosis

Treatment modalities

1. Surgery
2. Radiotherapy
3. Chemotherapy
4. Stem cells transplantation
5. Psychotherapy

Antineoplastic Agents

Approaches

• Primary induction –no other modality other than anti cancer drugs, (palliative )
• Neoadjuvant (curative) –cancers where antineoplastic treatment is given but other modalities are used like surgery, radiotherapy for complete cure.
• Adjuvant –in this alone surgery or radiotherapy is not effective, antineoplastics are added to increase survival and decrease recurrence.

Evaluation of response

• Sign / symptoms
• Size
• Lab diagnostics / markers

Cell cycle kinetics – gompertzian growth

When progression to cancer occurs, malignant cells keep on increasing in number,  one way is exponential growth like in leukemias. But in solid tumors or neoplasms, maximum growth fraction is seen when size of neoplasm is about 37% of its overall size. After that availability of blood supply and metabolites goes on decreasing.

Although size increases but fraction of cells is less, called Gompertzian growth.

Combinations*

1. Efficacy of therapy is enhanced
2. If resistance develops to one agent other may act
3. All act by different mechanisms
4. Adverse effects are decreased

Aim of combination therapy

Efficacy  / /  toxicity  

Principals For Effective Combinations

1. Efficacy
2. Toxicity
3. Optimal Scheduling
4. Mechanism of Interaction
5. Avoidance of Arbitrary Dose Changes

Drug Resistance

1. Primary –inherited, most cases p53 gene mutations
2. Acquired –in most cases MDR 1 gene is responsible for expression of p-glycoprotein 170, efflux pumps are overexpressed and drug enters cells but is not effluxed out.

General Toxicity

1. Bone marrow

Action is more on rapidly multiplying cells, thus cells of bone marrow are affected more which may lead to granulocytopenia, thrombocytopenia, etc.

2. Lymphoreticular tissue

Decrease in WBCs, increased chances of infection, increased risk of bleeding

3. GIT

Nausea, vomiting, due tooth mechanisms:

• Local irritation of GIT
• Stimulation of vomiting center contrally

4. Gonads

• Oligospermia,
• anovulation,
• amenorrhea

5. Skin
6. Nephrotoxicity
7. Neuropathy
8. Cardiotoxicity
9. Pulmonary toxicity
10. Hyperurecemia –when rapid turn over
11. Carcinogenicity
12. Pregnancy –fetal toxicity and abortion

Management

1. Pulses / courses– 3to 4 weeks interval to recover
2. Combinations –less doses are given
3. Local administration –intra arterial, intra peritoneal, intra pleural route
4. Antiemetics added
5. Biological response modifiers (erythropoietin, colony stimulating factors)
6. Specific treatment:

1. Mesna with cyclophosphamide
2. folic acid with methotrexate
3. allopurinol in blood cancers

Classification Of Antineoplastic Drugs

Chemical Classification

I. Alkylating Agents –most commonly used

a. Classical

• Cyclophosphamide
• Melphalan
• Chlorambucil
• Busulfan
• Carmustine
• Lomustine
• Thiotepa     

b. Non-classical

• Procarbazine
• Dacarbazine

c. Platinum Analogs

• Cisplatin
• Carboplatin
• Oxaliplatin

II. Anti-Metabolites               

a.  Folic Acid Analog

• Methotrexate

b.  Purine derivatives

• 6 Mercaptopurine
• 6 Thioguanine
• Azathioprine
• Fludarabine

c.  Pyrimidine derivatives

• 5- Flourouracil
• Cytarabine

I. Antitumor Antibiotics 

a.  Anthracyclines

• Daunorubicin
• Doxorubicin
• Epirubicin
• Idarubicin
• Mitoxantrone

b. Miscellaneous

• Bleomycin
• Dactinomycin
• Mitomycin

IV.   Vinca Alkaloids

• Vincristine
• Vinblastine
•  Vinorelabine

V.    Epipodophyllotoxins

• Etoposide
• Teniposide

VI.   Taxanes

• Docetaxel
•  Paclitaxel

VII.  Camptothecins

• Irinotecan
• Topotecan

VIII. Hormones & Anti-hormones

a. Hormones

• Estrogen
• Glucocoticoids
• Progestins
•  Androgens

b. Anti-hormones

• Anti-estrogen   – Tamoxifen
• Anti-androgen  – Flutamide
• GnRH agonist  – Goserelin / Leuprolide
• GnRH antagonist       – Abarelix
• Aromatase inhibitor  – Anastrozole

                                      – Aminoglutethimide

IX.  Miscellaneous

a. Asparaginase
b. Retinoic acid derivatives
c. Monoclonal antibodies

•   Trastuzumab
•   Imatinib
•   Rituximab

d.    Cytokines

• Interferon
• Interleukins-2 (IL-2)

On Basis of Cell Cycle Specificity

A. Cell Cycle Specific (CCS)

I. Anti-Metabolites    

a.  Folic Acid Analog

• Methotrexate

b.  Purine derivatives

• 6 Mercaptopurine
• 6 Thioguanine
• Azathioprine
• Fludarabine

c.  Pyrimidine derivatives

• 5- Flourouracil
• Cytarabine

II.    Vinca Alkaloids

• Vincristine
• Vinblastine
• Vinorelabine

III.    Epipodophyllotoxins

• Etoposide
• Teniposide

IV.    Taxanes

• Docetaxel
• Paclitaxel

V.    Antitumor Antibiotic

• Bleomycin

B.         Cell Cycle Non-Specific Drugs (CCNS)

I.  Alkylating Agents

a. Classical

• Cyclophosphamide
• Melphalan
• Chlorambucil
• Busulfan
• Carmustine
• Lomustine
• Thiotepa

b. Non-classical

• Procarbazine
• Dacarbazine

c. Platinum Analogs

• Cisplatin
• Carboplatin
• Oxaliplatin

II.   Anthracyclines

• Daunorubicin
• Doxorubicin
• Epirubicin
• Idarubicin
•  Mitoxantrone

III.  Antitumor antibiotics

• Dactinomycin
• Mitomycin

IV.  Camptothecins

• Irinotecan
• Topotecan

V. Hormones & Anti-hormones

a. Hormones

• Estrogen
• Glucocoticoids
• Progestins
• Androgens

b. Anti-hormones

• Anti-estrogen   – Tamoxifen
• Anti-androgen  – Flutamide
• GnRH agonist  – Goserelin / Leuprolide
• GnRH antagonist       – Abarelix
• Aromatase inhibitor  – Anastrozole

                                     – Aminoglutethimide

Sites Of Action Of Cytotoxic Agents

Cell cycle level

Cellular level

General Adverse Drugs Reactions  of Antihelminthics

1. Intestinal Actions

Intestinal actions include nausea, vomiting, diarrhea, anorexia and abdominal pain

2. Allergic Reactions

When worms die in the intestine, proteins are released that are foreign to the body, leading to antigen antibody reaction. This results in allergic response including skin rash, itching, pruritis, enlargement of lymph nodes, arthralgia, fever and blood dyscrasias (eosinophilia, leukopenia, agranulocytopenia) etc.

3. CNS

CNS symptoms include headache, dizziness, drowsiness and vertigo.

Image courtesy of CDC

Piperazine Citrate

Piperazine citrate is the oldest drug used for worm infestation. Chemically it is a piperazine derivative available in the form of hexahydrate.

Mechanism of Action

1. It decreases the response to acetylcholine by muscles of worm, leading to decreased action of acetylcholine on neuromuscular junction. This leads to decreased contraction and flaccid paralysis. Thus the worm is unable to maintain its position in the gut and is expelled by normal peristalsis.
2. It causes hyperpolarization by acting like GABA, leading to paralysis of muscles of worm.

Adverse Effects

1. General toxicity (already explained)
2. Specific toxicity:
   • Convulsions
   • Respiratory depression
   • Lymphadenopathy

Contraindications

1. Epilepsy
2. Kidney failure (increased chances of neurotoxic effects)

It is safer in pregnancy.

Uses

1. Ascariasis (75 mg/kg TD for 2 days)
2. Oxyuriasis (65 mg/kg for 7 days)

Dose

1. Tablets (250 mg)
2. Suspension (100 mg/ml)

Diethylcarbamazine

It is a piperazine derivative.

Mechanism of Action

The mechanism of action is same as that of piperazine citrate. Additional actions include:

1. Changes in skin (tegument) of parasites, making them more vulnerable to host defense mechanism.
2. Interferes with macromolecules transport across membranes of parasites.

Pharmacokinetics

1. Rapid oral absorption
2. Half life is 2-3 hours in acidic urine. It is 10 hours in alkaline urine
3. Unchanged drug and N-oxide metabolites are excreted in urine
4. The dose has to be decreased in patients of urinary alkalosis and renal impairment

Adverse Effects

1. General (already explained)
2. Specific
   • Ocular changes including keratitis, uveitis and changes in retinal pigments
   • Lymphadenopathy; localized swelling in W. bancrofti and W. malayi, small wheals in skin in L. loa and flat papules in M. streptocerca infection
   • Proteinuria (due to release of proteins from dying microfilarae)
   • Encephalitis
   • Leukocytosis
   • Allergic reaction to dying microfilarae, which is mild in W. bancrofti, intense in W. malayi and severe in L. loa

Contraindications

Children under 2 years of age. It is safe in pregnancy

Uses

1. Effect against microfilarae (developmental forms of parasites in blood) leading to disappearance of microfilarae)
2. Used against W. bancrofti, Brugia malayi, Loa loa, for which it is the drug of choice. It is also effective against Onchocercus volvulus, but now has been replaced by Ivermectin.
3. Used prophylactically for loa loa, Bancrofti and Malayan filariasis
4. Tropical eosinophilia, for which it is given orally
5. Mansonella streptocerca; effective against adults and microfilarae

Dose

1. For W. bancrofti 2 mg/kg for 5-7 days
2. For Loa loa 2 mg/kg for 2-3 weeks

Helminthies are commonly known as worms, which infect humans and animals. They are common in villages and areas of poor sanitary conditions. Children are mainly affected, as they have the habit of taking everything into mouth.

Those infecting humans are known as metazoa, which are of two groups:

1. Round worm -nematodes
2. Flat worm –cystodes, tramatodes

Worms are motile. Motility is essential for developmental cycle, which is a complicated process, involving one or more intermediate hosts.

Clinically worms are divided into two groups:

1. Those infecting intestines –intestinal helminthes
2. Those infecting tissue/viscera –visceral helminthes

Nematodes

• Ascaris lumbricoides
• Ancylostoma duodenale
• Enterobius vermicularis
• Dracunculus medinensis
• Strongyloides stercoralis
• Trichuris trichura
• Wuchereria bancrofti

Cestodes (Tape worms)

• Taenia saginata
• Taenia solium
• Diphyllobothrium latum
• Hymenolepis nana

Echinococcus granulosus

Trematodes (Flukes)

• Blood fluke
• Intestinal fluke
• Lung fluke
• Liver fluke

Intestinal Helminths

• Ascaris lumbricoids
• Ancylostoma duodenale
• Enterobius vermicularis
• Strongyloides stercoralis
• Trichuris trichura
• Taenia saginata
• Taenia solium

Tissue/visceral Helminths

• Echinococcus granulosus
• Wuchereria bancrofti
• Blood fluke

HELMINTH NEMATODESAscaris lumbricoidesAncylostoma  duodenaleEnterobius  vermicularisStrongyloides  stercoralis	OTHER NAME Round wormHook wormPin wormThread worm	DISEASE AscariasisAncylostomiasisEnterobiasis (pin worm infection)Strongyloidiasis
Trichuris  trichuraDracunculus medinensisWuchereria bancrofti	Whip wormGuinea worm             —-	TrichuriasisDracunculiasisFlariasis
CESTODESTaenia saginataTaenia soliumDiphyllobothri-um latumHymenolepis nanaEchinococcus granulosus	TAPE WORMSBeef tapewormPork tapewormFish tapeworm     Dwarf tapeworm           —-	TaeniasisCysticercosisDiphylobothri-asisHymenolepiasisHydatid disease
TREMATODESSchistosomaHeterophyes heterophyesParagonimus westermaniClonorchis sinensis	FLUKESBlood flukeIntestinal flukeLung flukeLiver fluke	Schistosomiasis             —-ParagonimiasisClonorchiasis

Classification

Drugs Acting Against Nematodes

Ascariasis (round worm infection)

Albendazole

Mebendazole

Pyrantel pamoate

Ivermectin

Ancylostomiasis (Hook worm infection)

Albendazole

Mebendazole

Pyrantel pamoate

Dracunculiasis (Guinea worm infection)

Metronidazole

Enterobiasis (Pin worm infection)

Albendazole

Mebendazole

Pyrantel pamoate

Ivermectin

Filariasis (Wuchereria bancrofti)

Diethylcarbamazine

Stongyloidosis (thread worm)

Ivermectin

Thiabendazole

Drugs Acting Against Cestodes

Taeniasis

Niclosamide

Praziquantel

Albendazole

Mebendazole

Hymenolepiasis

Niclosamide

Praziquantel

Diphylobothriasis (Diphyllobothrium Latum)

Niclosamide

Praziquantel

Hydatid disease (Echinococcus) –surgery is required for ultimate treatment

Albendazole

Mebendazole

Niclosamide

Drugs Acting Against Trematodes

Schistosomiasis (blood flukes)

Praziquantel

Metrifonate

oxamniquine

Intestinal Flukes

Praziquantel

Liver flukes

Praziquantel

Lung flukes

Praziquantel

Mebendazole

• Synthetic benzimidazole
• Wide spectrum antihelminthic  activity
• Low incidence of side effects

Pharmacokinetics

• Poorly  absorbed (< 10%)

• Absorption increased with fatty meal
• Highly protein bound -PPB >90%
• Half life 2-6 hrs.
• Rapidly metabolized in liver & mostly renaly  excreted

Mechanism of action

Primary Action

Binds with β tubulin of microtubules  & inhibit its synthesis à worm becomes immobile & dies slowly

Other Actions

• Blocks glucose uptake
• Uncoupling of oxidative phosphorylation

Results in loss of ATPs

Resistance

Point mutation in β tubulin results in decreased binding affinity to Mabendazole

Therapeutic Uses

Tablet should be chewed before swallowing.

Drug of choice for:

1. Pinworm Infections (enterobiasis) (single dose of 100 mg once, repeated after 2 weeks)
2. Round worm infection (Ascariasis)
3. Whip worm infection(Trichuriasis)
4. Hookworm infections
5. Intestinal capillariasis -200 mg twice daily for 21 days

Also used as alternative drug for:

1. Hydatid disease –surgery ultimate treatment
2. Taeniasis
3. Trichinosis

Adverse Effects

On short term therapy like intestinal nematodes

1. Mild nausea,
2. vomiting,
3. diarrhea, and
4. abdominal pain

On prolong duration therapy like hydatid cyst

1. hypersensitivity reactions (rash, urticaria),
2. agranulocytosis,
3. alopecia, and
4. elevation of liver enzymes

Drug Interactions

Enzyme inhibitors (Cimetidine) increase drug levels

Enzyme inducers (phenytoin) decrease drug levels

Contraindications

1. Pregnancy
2. children < 2 yrs age

Albendazole

•   Benzimidazole
•   Broad spectrum

Pharmacokinetics

•   Erratically absorbed, rapidly metabolized in liver
•   Absorption increases with fatty meal
•   Active metabolite is albendazole sulfoxide
•   Half life 8-12 hrs. (longer than mebendazole)
•   Mostly protein-bound

•   Distributes well to tissues, enters bile, cerebrospinal fluid, and hydatid cysts.
• Metabolites are excreted in the urine.

Mechanism of Action

  Same as mabendazole (binds beta tubulin, resulting in immobility)

Larvicidal effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection

Ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis

Because of these two effects, albendazole is superior than mebendazole.

Uses

Taken on empty stomach when used for intestinal infections (ascariasis, enterobiasis)

Taken with fatty meal when used for tissue infections for increased absorption.

1. Drug of choice for Hydatid Disease (surgery)

Dose is 400 mg twice daily for one month.

2. Drug of choice for Ascariasis
3. Hookworm infection
4. Pinworm infections
5. Trichuriasis -400 mg OD for 3 days
6. Neurocysticercosis (pretreatment with glucocorticoid because dying worms produce inflammation, leading to allergic reaction)

Alternative drug for:

1. Gnathostomiasis

2. Cutaneous & visceral larva migrans
3. Intestinal capillariasis
4. Clonorchiasis

Adverse Effects

1.      On short term therapy like intestinal nematodes

1. Mild nausea,
2. vomiting,
3. diarrhea, and
4. abdominal pain

2.      On prolong duration therapy like hydated cyst

1. hypersensitivity reactions (rash, urticaria),
2. agranulocytosis,
3. alopecia, and
4. elevation of liver enzymes

Contraindications

• Pregnancy
• Children < 2 yrs age

Thiabendazole

• Benzimidazole compound
• Chelating agent forming stable complexes with a number of metals including iron, but does not combined with calcium.

Pharmacokinetics

• Rapidly absorbed when given orally
• half-life is 1.2 hours
• Metabolized in liver
• Excreted in urine
• Also absorbed from skin

Mechanism of Action

Same as other benzimidazoles

1. Binds beta tubulin inhibiting motility, worms die slowly
2. Decrease uptake of glucose
3. Uncoupling of oxidative phosphorylation

Uses: both oral and tropical

Thiabendazole is an alternative to Ivermectin for the treatment of:

1. strongyloidiasis and
2. cutaneous larva migrans.

Adverse effects

Much more toxic than other benzimidazoles, thus not preferred.

1. Common adverse effects include:

• dizziness,
• anorexia,
• nausea, and
• vomiting.

2. Less frequent problems are:

• epigastric pain,
• abdominal cramps,
• diarrhea,
• pruritus,
• headache,
• drowsiness, and
• neuropsychiatric symptoms.

3. Irreversible liver failure and fatal Stevens-Johnson syndrome
4. Crystaluria and hematuria
5. Urine has characteristic odor  due to metabolite

Contraindications

• Pregnancy
• Children < 2 yrs age
• Renal and hepatic disease

Pyrantel Pamoate

• Tetrahydropyrimidine derivative having broad spectrum
• Poorly  absorbed and excreted in feces
• First introduced in veterinary medicine, but due to effectiveness and lack of ADRs, tests were conducted for human trials.

Pharmacokinetics

1. Poorly absorbed from GIT
2. Highly active against luminal helminthic infection
3. Over half of administered dose is removed from body by feces.

Mechanism of Action

• Depolarizing neuromuscular blocking agent. It blocks NM transmission.
• Increases Acetyl choline release and inhibits Acetyl choline esterase
• Both effects result in increased acetylcholine at NMJ.
• Spastic paralysis
• Worm becomes immobile & expelled out

Uses

a.      Pinworm,
b.      Ascariasis,
c.       Hookworm,
d.      Trichostrongylus orientalis

Dose: 11 mg/kg. For Ascaris and hookworm, single dose is effective, while for pinworm infection, dose is repeated after 2 weeks.

Not effective against trichoriasis but one analog, oxantal palmoate has been successively used for this condition.

Adverse effects

Adverse effects are infrequent, mild, and transient.

1. nausea,
2. vomiting,
3. diarrhea,
4. abdominal cramps,
5. dizziness,
6. drowsiness,
7. headache,
8. insomnia,
9. rash,
10. fever, and
11. weakness

Contraindications

• Pregnancy
• Children < 2 yrs age

Ivermectin

Semisynthetic macrocyclic lactone, mixture of avermectin B_1a and avermectin B_1b

Mechanism of action

Potentiate release and binding of GABA, resulting in increased influx of calcium chloride and hyperpolarization, leading to flaccid paralysis. Worm becomes immobile and is expelled out.

Pharmacokinetics

•   Rapidly absorbed from GIT
• wide tissue distribution and a volume of distribution of about 50 L
•   half-life is about 16 hours
•   Excreted in the feces.

Uses

Drug of choice for:

1. Onchocerciasis –does not kill adult worm, only microfilariae. 150 mcg/kg taken on empty stomach, singly dose, rapidly reduces count of microfilariae which remains low for many months, then starts growing again. Dose is repeated every year, complete removal may take 10 years or longer.
2. Strongyloidiasis –200 mcg/kg for two days

Alternative for:

1. Ascariasis
2. Cutanous larva migrans

3. Trichuriasis
4. Brugia malayi
5. Lice
6. Loasis
7. Scabies

Adverse effects

In treatment of Strongyloidiasis, side effects are infrequent and mild:

1. fatigue,
2. dizziness,
3. nausea,
4. vomiting,
5. abdominal pain, and
6. rashes

In Onchocerciasis principally because of dying microfilariae:

Mazotti reaction occurs due to killing of microfilariae

Includes:

1. fever,
2. headache,
3. dizziness,
4. somnolence,
5. weakness,
6. rash,
7. increased pruritis,
8. diarrhea,
9. joint and muscle pains,
10. hypotension,
11. tachycardia,
12. lymphadenitis,
13. lymphangitis, and
14. peripheral edema

This reaction starts on the first day and peaks on the second day after treatment

In 5-30% cases mild reaction occurs, in 1-3% of cases moderate to severe reaction occurs and in 0.1% cases very severe reaction with very high fever, hypotension, bronchospasm occurs.

To avoid, pretreatment with glucocorticoids is recommended.

Contraindications

• Pregnancy
•  < 5 yrs age

Niclosamide

• Salicylamide derivative
•   Minimally absorbed when taken orally
•   Rapidly kills adult worms (but not ova)

Mechanism of Action

• Inhibition of oxidative phosphorylation or stimulation of ATPase activity.
• Both result in decreased ATP, leading to death of worm.

Uses

2^nd line drug for tape worm infection, chewed properly before swallowing.

•   T. Saginata                  
•   T. Solium
•   Diphylobothrium latum
•   Hymenolepis nana – 2g for 7 days
•   Hymenolepis diminuta
•   Dipylidium caninum
•   Intestinal fluke infections –alternate drugs, dose 2g on alternate days for 3 days

Adverse effects

Infrequent, mild, and transitory adverse events include:

1. nausea,
2. vomiting,
3. diarrhea, and
4. abdominal discomfort.

Contraindications

•   Pregnancy
•   Children > 2 years

Praziquantel

Chemistry-isoquinoline pyrazine

Pharmacokinetics

•   Rapidly absorbed
•   Absorption increase with a high carbohydrate meal
•   Bioavailability of about 80%
•   PPB 80%
•   Rapidly metabolized to inactive mono- and polyhydroxylated products
•   Half-life is 0.8–1.5 hours
•   Excretion via kidneys (60–80%) and bile (15–35%).

Mechanism of Action

Increase the permeability of calciumà spastic  paralysis àdislodgement  à death

Uses

Should be taken with liquid after a meal & should be swallowed without chewing because its bitter taste can induce retching and vomiting.

Drug of choice in:

1. Tape worm infections –single dose, 2-10 mg/kg sufficient
2. Trematodes or flukes -200 mg/kg, 2doses after 4-6 hours

Alternative drug for:

1. Neurocysticercosis
2. Hydatid disease

Adverse effects

Mild and transient, begin within several hours after treatment, may persist for one day. Include:

1. Headache,
2. dizziness,
3. drowsiness, and
4. lassitude;
5. nausea,
6. vomiting,
7. abdominal pain,
8. loose stools,
9. pruritus,
10. urticaria,
11. arthralgia,
12. myalgia, and
13. low-grade fever

Contraindications

• Pregnancy
•  < 4 yrs age

Drug Interactions

• Enzyme inhibitors (Cimetidine) increase drug levels
• Enzyme inducers (phenytoin) decrease drug levels

Metronidazole is a prodrug itself, activated by reduction of nitro group.

Structure

Mechanism Of Action

Protozoa get energy by ketoacids e.g. pyruvates. This mechanism is described as:

The active form:

1. affects DNA structure
2. react with other proteins and molecules in protozoa and some anaerobic bacteria.

In DNA:

1. loss of helical structure
2. strand breakage may occur
3. intercalation when molecules fits between base pairs.

Mechanism of resistance

1. These protozoa are anaerobic, thus have mechanisms for scavenging oxygen or ROS. If mechanisms which scavenge oxygen are effected, decreased clearance of ROS occur leading to excess and decreased reduction of nitro group of metronidazole due to competitive inhibition with reduction reaction.
2. In ETC,
i. PFOR

ii. Ferridoxin are important

Now in some there is decreased PFOR and ferridoxin probably due to chromosomal mutations, leading to decreased action of drug.

This can occur by:

1. Increasing the dose
2. Prolonging therapy

This resistance is seen in:

1. Giardiasis
2. Trichomonas infection
3. Microaerophilic bacteria i.e.
   • H. pylori
   • Campylobacter species

Resistance is not seen in E. histolytica.

Spectrum of activity

A)     Anaerobic protozoa

1. E. histolytica
2. T. viginalis
3. B. coli
4. Giardia lamblia and G. intestinalis

B)      Anaerobic bacteria

Both gram positive and negative.

1. Bacteroides species esp. B. fragilis
2. Clostridial spp
3. Peptococcus
4. Peptostreptococcus in oral cavity, so used by dentisits
5. Fusobacterium
6. eubacterium

C)     Microaerophilic bacteria

1. H. pylori
2. Campylobacter spp

D)     Adult dracunculis medinensis (Guinae worm)–

1. Especially metronidazole aids extraction of worm
2. Does not kill the worm

Therapeutic Uses

Spectrum	Therapeutic uses
E. Histolytica	Acute intestinal amoebiasisHepatic amoebiasisAmoebomaTissue amoebiasisOral tabletsI/V infusion in severe cases 3 times per day7-10 day course -400 mg tablets thrice daily
T. Vaginalis	Vaginal & urethral TrichornoniasisTreat both male and femal patients2g/day in OD dose
Giardia lamblia	Giardiasis250 mg thrice daily for 7-10 days.
Ballantidium coli	Ballantidiasis
AnaerobesBacteroides fragilisHelicobacter pylori	Pelvic and other below the diaphragm anaerobic infections(appendicitis, combined with penicillin or aminoglycosides)Triple regime is used.Indolent ulcersPeptic ulcerAlso used in NSAIDS induced ulcers. Used in combination with:AmoxicillinClarithromycinProton pump inhibitors e.g. omeprazole
Gardenella vaginalis	Gardenella vaginalis infectionNon specific vaginitis
PeptococcusPeptostreptococcusFusobacterium	Acute ulcerative gingivitisCancrum oris causing gangrene and scarsOther dental infectionsUsed with penicillins

Other Uses

1. Crohn’s disease
2. Guinea worm infestation (extraction)
3. Pseudomembranous enterocolitis due to prolonged use of ampicillin or clindamycin, etc. Metronidazole is drug of choice. Vancomycin can be used (its only oral indication).

Pharmacokinetics

1. Oral, I/V, vaginal creams or even topical preparations
2. Very well absorbed, very little reaches colon, so usually combined with luminal anti-amoebics e.g. Diloxinide etc.
3. Distribution is equal to total body water
4. PPB is <20%
5. Distributed to saliva, milk and CSF, pleural cavity, vaginal secretions, urethra and even in bones.
6. Metabolism occurs in liver by oxidation and glucuronidation. It can be increased by phenobarbitone, phenytoin sodium and rifampicin. It can be inhibited by cimetidine.
7. Excretion of metabolites occurs through kidneys.

Side-effects

Toxic and Irritative actions

1. nausea
2. headache
3. dry mouth
4. metallic taste (as secreted in saliva like clarithromycin, very unpleasant taste)
5. dark coloured urine (reddish brown in color due to excretion of pigments like furazolidine and rifampicin)

One needs to educate patients about these effects.

CNS

1. diziness,
2. vertigo,
3. insomnia,
4. parasthesias

Others

1. leukopenia,
2. phlebitis (i/v),
3. mutagenic in bacteria and carcinogenic in rodents –not seen in humans AIMS test is done to check it.

Teratogenic

1. not significant effect
2. avoided in 1^st trimester

Allergic reactions

1. Pruritis,
2. Urticaria,
3. Flushing,
4. Stevens johnson’s syndrome (erythema, multiformis major oral mucosa and conjunctiva)

In severe cases –myocarditis, pleuritis, may be fatal.

Super-infections

1. Oral candidiasis
2. Stomatitis

Disulfiram like reactions

When combined with alcohol. Symptoms include:

1. nausea
2. vomiting
3. abdominal pain
4. dizziness
5. vertigo
6. even seizures

Used in alcohol aversion therapy. Other drugs causing it include:

1. Cephalosporins (having MTT ring)
2. Sulfonyl ureas

These drugs are not only effective against amoebia but also against some others:

Common diseases treated by these drugs

A) Amoebiasis

In 10% of population (50 million people) causing around 100,000 deaths/year.

Causative organisms

1. Entamoeba histolytica –causes active disease
2. E. despar –cause 90% of infection but no symptoms occur, no treatment is required

These cannot be differentiated on light microscopy, but by PCR or ELISA.

Mode of transmission

• Feco-oral route via contaminated food, drinks, water, etc. man is the only host.
• Cysts of E. histolytica resist stomach acidity, they develop into trophozoites in gut, causing invasive disease.
• In distal GIT, trophozoites again convert into cysts, probably due to decreased water content. They are excreted in feces.
• Trophozoites cannot survive in the adverse conditions, but cysts are able to tolerate.

1.  Asymptomatic carriers

Can cause totally asymptomatic carrier state. They require treatment as are source of infection to others.

2.  Intestinal colitis

Mild to moderate –diarrhea like condition, stool with mucus or blood occasionally

Severe –flask shaped mucosal ulcers, which bleed, leading to dysentery

3. Perforation
4. Peritonitis
5. Appendicitis even
6. Hepatic abscess

In gut trophozoites enter circulation by reaching liver. They can cause amoebic liver abscess with high grade fever.

7.   Amoeboma

Appear like tumor, may form as constricting circulation ring in GIT.

8.  Other extraintestinal manifestations

e.g.

a. pneumonia

b. lung infection

c. brain abscess

Rampant in poor hygienic conditions, overcrowding, etc. even in hostels, mental hospitals.

B)    Giardiasis

Caused by

1. Giardia intestinalis
2. Giardia lamblia

May be asymptomatic.

May take the form of:

1. GIT irritation e.g. diarrhea (self limiting in 5 days)
2. Foul smelling stools
3. May be chronic:

i. Malabsorption due to steatorrhea

ii. Weight loss

C) Trichomoniasis

An sexually transmitted disease, causing:

a. in males causing urethritis

b. in females causing vaginitis

If one partner is affected, others is treated as well, as it can be transmitted.

D) Balantidiasis

• By B. coli
• Produces diarrhea similar to amoebiasis.

Chemical Classification

Nitroimidazole derivatives

• Metronidazole,
• Tinidazole, (fasigen)
• Secnidazole
• Benznidazole,
• Ornidazole,
• Nimorazole

Dichloroacetamide derivatives

• Diloxanide furoate (also used with metronidazole called entomazale)
• Clefamide,
• Teclozan,
• Etofamide

4- aminoquinoline derivatives

• Chloroquine

Alkaloids of Ipecacuanha

• Emetine, (very toxic)
• Dehydroemetine (less toxic)

Antibiotics

• Tetracycline
• Paromomycin
• Erythromycin

8-hydroxyquinoline derivatives

• Diiodohydroxyquin (iodoquinol) (comes with metronidazole called metodine)
• Clioquinol  (not used due to optic toxicity)

Misc.

• Nitazoxanide ( used against i. giardiasis ii. Amoebiasis)

Therapeutic classification

Drugs effective in luminal infection only

(some also have actions against cysts, so helpful in elimination of carrier state)

• Diloxanide furoate
• Diiodohydroxyquin
• Tetracyclines,
• Paromomycin

Drugs effective in hepatic and tissue amoebiasis only

• Chloroquine,
• Emetine,
• Dehydroemetine

Drugs effective in luminal & tissue amoebiasis (though less in lumen)

Not effective against cysts

• Metronidazole,
• Tinidazole,
• Secnidazole,
• Ornidazole

Usually combined with luminal agents.

Tinidazole, Secnidazole and Ornidazole

Mechanism of Action

Similar to metronidazole. Can be used in single dose instead of 7-10 days.

Therapeutic uses

Tinidazole –against microaerophilic bacteria

Usually against anaerobic bacteria but not bacteriodes species.

Emetine and Dehydroemetine

Source

Natural, obtained from Ipecac root (Brazil root), used in older days for inducing vomiting when gastric lavage was not available.

Acts by:

1. direct irritation
2. effects CTZ

Dehydroemetine is synthetic and has less toxic profile than emetine.

Pharmacokinetics

Always parentally (I/M or S/C but never I/V or orally).

Cumulative action especially deposit in liver, kidneys, spleen and lungs.

Half life is 5 days.

Excretion is by urine –even after 1-2 months of therapy it is excreted.

Mechanism of Action

Inhibit protein synthesis as prevent movement of ribosomes on mRNA.

Also effective against E. histolytica.

Have:

1. alpha blocking property
2. anti-cholinergic property

Indications

1. Tissue amoebiasis –when metronidazole not available or C/I
2. Ballentidiasis

Adverse effects

Local:

1. pain at site of injection
2. sterile abscess may form
3. weakness of muscles when injected

GIT

1. stimulate CTZ
2. nausea
3. vomiting
4. diarrhea
5. abdominal discomfort

CVS

1. severe hypotension (alpha blocking activity)
2. reflex tachycardia
3. arrhythmias (atrial, ventricular)
4. precipitation of CCF
5. ECG abnormalities, e.g.
   1. T wave flattening or inversion
   2. Prolongation of QT interval

So should be used only when:

1. patient is hospitalized
2. being monitored

Misc

1. dizziness
2. headache
3. rash

toxicity is decreased when used for 3-5 days. It occurs when used for more than five days.

Contraindications

1. children
2. renal disease
3. cardiac problems
4. pregnancy

Chloroquine (Anti-amoebic use mentioned only)

Reserved for hepatic amoebic abscess disease because it gets concentrated in liver. May be more than 100 times than in plasma. It has special affinity for hepatocytes.

Mechanism of Action

Direct amoebicidal to E. histolytica

Well absorbed from GIT, very little reaches colon. So less effects on GIT amoeba. Thus used with luminal agents.

Dose

1 g for 2 days.

Then 500 mg for 2- 3 days.

Adverse Drug Reactions

1. nausea
2. vomiting
3. dizziness
4. no danger of retinopathy or neuropathy (only occurs when used for long time in rheumatoid arthritis)

Diloxanide Furuate

Mechanism of Action

In intestine splits to

1. diloxanide
2. furaic acid

Diloxanide is 90% absorbed,

10% is unabsorbed-which is therapeutically active.

Exact mechanism is not known.

Adverse Drug Reactions

1. flatulence –common
2. abdominal discomfort
3. skin rashes

Used alone only I/M for asymptomatic carriers.

Otherwise combined with metronidazole.

Iodoquinol

Has iodine in structure.

Usually well tolerated if not used for more than 20 days.

Mechanism of Action

Luminal agent.

Exact mechanism is not known.

Dose

650 mg thice daily.

Also used in combination with metronidazole called metodine.

Adverse Drug Reactions

1. Neuropathy
2. Optic neuritis in children
3. GIT
   • nausea
   • vomiting
   • diarrhea
   4. Signs of iodine toxicity e.g.
   • pruritis
   • urticaria
   • fever

Paromomycin

An aminoglycoside.

Luminal agent

Also acts indirectly.

Mechanism of Action
binds 30S subunit, resulting in misreading and inhibition of formation of initiation complex.

Pharmacokinetics

No absorbed orally.

Destroys bacteria on which amoeba feeds, so indirect killing.

Not used I/V, otherwise toxicity occurs, as with other aminoglycosides.

Therapeutic uses

1. amoebiasis
2. Giardiasis
3. Cutaneous leishmaniasis –topically

Tetracyclines

Mechanism of Action

Same as previously described.

Destroy bacteria on which amoeba feed.

Indirect killing like aminoglycosides.

Contraindications

Not used in children less than 8 years of age.

Can be combined with metronidazole.

Qinghaosu (Artemisinin)

• Derivatives are the most novel and recently introduced. Now highly recommended.
• These drugs are artemisinin derivatives, discovered by Chinese scientisits.

Source:        

Plant source:      

a.      Qinghao,
b.      Artemisia annua

Chemistry: 

Sesquiterpene lactone endoperoxide

History:

Use dates back 2000 years, when plant was used in herbal tea for febrile illness. It was also known as “sweet swarm wood”. Chinese used its derivatives against tertian febrile illness particularly by mosquito plasmodium. In 1971 military institute started exploring alkaloids in this plant and in 1972 work was started on discovering a new antimalarial drug. In 1979, they were finally able to discover and synthesize derivatives.

Semisynthetic derivatives:

1.      Dihydroartemisinin –reduced form
2.      Artemether –oil soluble, given orally                         
3.      Artesunate –hemisuccinate salt of dihydroartemisinin, water soluble given oral, I/V, I/M or even rectally
4.      Arteether                            
5.      Artilonic

• Used in developed countries and WHO recommended for multidrug resistant falciparum malaria, chloroquine resistant and severe malarial infections.
• Chinese herbal medicines which were used as antipyretic.
• Blood schizonticides against all types of malaria including chloroquine-resistant p. falciparum.
• Unknown mechanism of action.

Mechanism of action

Consist of endoperoxide group

1. Cleavage of endoperoxide group takes place, facilitated by heme component of human cells, plasmodium species itself liberates it from human species
2. Next step is intramolecular rearrangement, radicals are produced,
3. covalently inhibit protein synthesis within parasite
4. hence metabolic processes are inhibited, further growth of plasmodium does not take place.

Pharmacokinetics

1. Different compounds are given differently. Can be given orally, I/V, rectally or in suppositories.
2. Artemether is mainly given orally as highly unstable and oil soluble
3. When administered quickly absorbed, peak plasma levels occur within 30 minutes to 1 hour.
4. Half life is in range of 1-3 hours
5. Metabolized by liver CYP3A4 and CYP2C9
6. Are converted into active metabolites
7. Dihydroartemesinin is proven to have more potent antimalarial activity than parent compound
8. Excreted by kidney.

Uses:

1. P. falciparum cerebral malaria (oral & parenteral).

Rapidly acting, active against all species of plasmodium, target is trophozoite stage of asexual replication. Effects appear within 12 hours, improvement in febrile conditions occur. Rapidly acting blood schizonticidal agent. No activity on hepatic stage or tissue schizonticidal activity.

2. Not used prophylactically as short half life.
3. Use is recommended in children and pregnancy as easily tolerated, effects within pregnancy are not established, it is emberytoxic in rats.
4. Also used effectively in severe cerebral malaria (artesunate is highly effective) although chloroquine is used as well
5. Chloroquine resistant falciparum malaria
6. Multidrug resistant falciparum malaria

Nowadays therapy is not initiated as resistance might occur, therefore combination therapy is given. One of most effective combination is CoArtem (artemether and lumefantrine) which is most promising combination therapy in endemic areas.

Adverse Effects

Highly safe drug, which is the reason why it is highly recommended in children. Adverse effects include:

1. Nausea
2. Vomiting
3. Diarrhea
4. Few studies indicate cardiac problems, still not alarming situation
5. Some CNS manifestations including seizures, psychosis –data is little in humans, seen only in animal studies

Safely given to G6PD deficient patients as hemolytic anemia seen with conventional antimalarials is not seen with this.

Lumefantrine

Lumefantrine is not an effective antimalarial itself but in combination synergistic effects occur against falciparum malaria and resistant cases. Only disadvantage is that it is not cost effective.

Mefloquine 

Discovered during the Vietnam war to protect American soldiers from the multidrug resistant falciparum malaria, against which conventional antimalarials are not effective.

Restricted for use against multi-drug resistant P. falciparum only.

Chemistry

Resembles quinine, it is 4-amino quiniline.

Mechanism of action

Similar to quinine and quinidine. Inhibits heme polymerase enzyme, toxic heme is retained which is fatal to plasmodium.

Unlike quinine, it does not intercalate with DNA strand.

Pharmacokinetics:

–          Can only be given orally

–          Well absorbed , peak plasma conc. in 18 hrs.

–          Highly protein-bound, extensively distributed in tissues

–          Slow elimination – allow for single doses

–          Terminal half-life – 20 days – this is reason for weekly chemoprophylaxis dosing

–          Undergoes enterohepatic circulation

–          Mefloquine & acid metabolites excreted in feces

Uses

1. Effective against multidrug resistant malaria
2. Chloroquine resistant malaria
3. Chemoprophylaxis –weekly dose

Safe in G6PD deficient state. More activity against P. falciparum and P. vivax. Cannot be given to treat severe falciparum malaria condition.

Adverse Effects

More common with high doses

1. nausea,
2. vomiting,
3. dizziness,
4. sleep/behavioral disturbances,
5. epigastric & abdominal pain,
6. diarrhea,
7. headache,
8. rash
9. Neuropsychiatric toxicities
10. Leukocytosis,
11. thrombocytopenia &
12. increases in aminotransferase

Most troublesome is neurotoxicity, more prone to cause:

1. convulsions
2. seizures
3. psychosis
4. confusion

Some cardiovascular manifestations:

1. delayed cardiac conduction
2. arrhythmias
3. QT prolongation

Contraindications

Not used in:

1. Patients with CNS disorders, psychosis
2. CVS abnormality
3. Not used with quinine and quinidine as both potentiate each others’ effect.

Tissue Schizonticide

Primaquine (8- aminoquinoline derivative)

It is a tissue schizonticide, effective against hepatic stages of plasmodium life cycle (P. vivax and ovale).

Mechanism of action

Exact mechanism is not known.

1. May effect at cellular level. It inhibits electron transport mechanism within mitochondria.
2. It has a cellular oxidant activity and possibly interferes with mitochondria function,
3. Gametocide, so inhibits infection transmission by mosquito.

Uses:

1.  Eradication of liver stages (hypnozoites) of P.vivax & P. ovale, after standard chloroquine therapy to prevent relapse

In most cases blood schizonticide (chloroquine) is used, when erythrocytic stage is eliminated then primaquine is administered for about 14 days to eliminate liver stage as well.

Care is taken that primaquine is only administered if G6PD state of patient is evaluated as it is contraindicated in G6PD deficiency.

2.      If plasmodium has lodged into hepatocytes, capable of causing relapsis, it can be given to effectively inhibit relapsis chances.

It should not be given if there is risk of reinfection.

3.      Inhibits transmission by mosquito.
4.      Along with Clindamycin effective against Pneumocystis Jeroveci

Adverse effects:

1. GIT upset,
2. pruritis,
3. headache,
4. arrhythmias
5. methemoglobinemia,
6. hemolysis especially in G-6-PD deficient

Atovaquone

• Component of Malarone (Atovaquone 250 mg + Proguanil 100 mg), recommended for prophylaxis & Treatment of P. falciparum, resistant cases as well.
• Advantage with combination is that:

1. duration of therapy is decreased
2. well tolerated
3. easily administered

But not cost effective

Mechanism of Action

At cellular level, appears to disrupt mitochondrial electron transport, as a result of which cellular metabolic processes are inhibited.

Pharmacokinetics

Only oral administration, bioavailability is low but increased by fatty food (absorption is increased)

• Heavily protein-bound; half-life of 2-3 days
• Eliminated unchanged in feces

Uses:

1. Besides malaria, alternative treatment for Pneumocystis jiroveci pneumonia
2. May be effective in immunocompromised with toxoplasmosis

Must be taken with food

Adverse Effects:

1. Fever,
2. rash,
3. nausea,
4. vomiting,
5. diarrhea,
6. headache,
7. insomnia

Chlorguanide (Popular as Proguanil) and Pyrimethamine

Antimetablites, proguanil is biguanide. Pyrimethamine is antimetabolite within protozoa.

Mechanism

Same as trimethoprim, inhibit dihydrofolate reductase, sequential steps in which PABA is coverted into dihydrofolic acid and tetrahydrofolic acid in synthesis of purines and DNA.

Proguanil is a prodrug, mainly converted to an active metabolite called Cycloguanil pamoate, an active antimalarial agent.

It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. This enzyme is not effective in humans, very high concentration of drug is required for such effects, thus selective.

Both are given orally and excreted in urine.

	Pyrimethamine	Proguanil
Peak plasma levels	2-6 hours	5 hours
Elimination half life	3-5 days (85-90 hours)	16 hours

Uses

Pyrimethamine is given for prophylaxis, as once weekly dose is required due to long elimination half life.

Proguanil is given on daily basis

Proguanil has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection.

It is also effective in suppressing the clinical attacks of P. vivax malaria.

Adverse Drug Reactions

• Produces occasional nausea and diarrhea, skin allergies
• Safe drug and can be used in pregnancy.

Mainly given in combination for treating different infections, such as:

1. Chloroguanide along with Chloroquine is used as prophylaxis effective against P. falciparum malaria.
2. Sulfadoxine + Pyrimethamine (Fansidar) –highly convenient, cost effective, easily administered, effective, better compliance, less ADRs but resistance has limited its use.
3. Chlorproguanil + Dapsone (LapDap) –effective where Fansidar is ineffective
4. Pyrimethamine + sulfadiazine for toxoplasmosis (folic acid is administered on daily basis 6-10 mg daily)

Halofantrine

• Previously used antimalarial, no longer recommended as having cardiovascular effects.
• Unknown mechanism of action.
• Used only by oral route in P. falciparum cerebral malaria.
• No parenteral preparation.
• Not used for prophylaxis.
• Not used during pregnancy unless benefit outweighs the risk.

Drugs obtained from Alkaloids 

Quinine Alkaloids from Cinchona

Two drugs are obtained:

1. Quinine
2. Quinidine

Source & History

Chief alkaloid of cinchona bark (known as ‘Fever Bark’), a tree found in South America (Peru).

a. Jesuit’s Bark

b. Cardinal’s Bark

It was discovered as a cure for malaria in 1633 and has a colourful history of more than 350 years. In 1667 it was established that it was effective in tertian malaria. In 1820, two scientists extracted quinine and quinidine from cinchona bark.

Even today, Quinine is obtained entirely from the natural sources due the difficulties in synthesizing the complex molecule.

Quinine and Quinidine

Quinidine is as potent as quinine but due to high toxicity, quinidine is not recommended.

Mechanism of action

Mechanism is somewhat similar as chloroquine, which involves:

i.      Getting incorporated in DNA strand

ii.      Inhibiting replication

iii.      Hence RNA transcription is inhibited

Chloroquine	Quinine
Has to be trapped inside food vacuole	not required

Pharmacological Actions

1. Anti malarial action

Intercalation into DNA, inhibiting metabolic process, producing anti-malarial effects.

2. CVS

1. depression of cardiac conduction,
2. hypotension (severe),
3. QRS lengthening

3. Insulin – releasing action

Therefore, in severe hypoglycemia administration of glucose is recommended along with quinine.

4. GIT

Anti muscarinic effect is produced (anti-cholinergic) causing:

1. Severe dryness of mouth
2. Constipation
3. Blurring of vision

5. Oxytocic Effect

Uterine contractions with use. Gravid uterus is much sensitive to effects in which excessive uterine contractions occur. Chances of abortion esp. during last trimester of pregnancy.

6. Curare – like action

Muscle relaxation (NMJ blockage)

Therapeutic Uses

1.      Effective anti malarials

• Used as blood schizonticides.
• Also used in regions where chloroquine resistance is seen
• Gametocidal against P. vivax and ovale but not for P. falciparum
• Also used in severe cerebral malarial condition

2.      Babesiosis

Tick like parasite is involved, may have some role when used in combination with Clindamycin

3.      Previously used for nocturnal leg cramps relief, now FDA has withdrawn it.

Pharmacokinetics

• Readily/rapidly absorbed when given orally or I/M
• Peak plasma concentrations are achieved within 1 – 3 hours after oral dose
• Most absorption occurs from upper part of small intestine
• Plasma half-life is about 11 hours.
• High PPB
• Widely distributed & metabolised
• Excretion in urine, alkaline so acidic medium facilitates elimination
• In acute malaria, the volume of distribution of Quinine contracts and clearance is reduced, and the elimination half-life increases (up to 18 hours) in proportion to the severity of the illness. Still adverse effects are not seen in acute malaria as quinine binding to plasma proteins is increased and clearance is reduced.

Quinine – Adverse Effects

1.      Cinchonism

In form of specific triad called Cinchonism.

• Rhinitis
• Angioedema
• Tinnitus
• Vertigo
• Dizziness
• Fatigue
• Hot sweaty skin
• Fever
• Rash
• Blurring of vision
• Dizziness
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Impaired hearing

Excessive toxicity occurs by massive doses, thus dose adjustments are done, characterized by:

• Confusion
• Seizures
• Blindness
• Deafness

2. CNS

• Dizziness
• Headache

3. CVS

• Depressed cardiac conduction
• Severe hypotension
• QRS widening

4. GIT

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain

5. Antimuscarinic action

• Blurring of vision
• Constipation
• Dryness of mouth

6. Hypoglycemia
7. Abortion
8. Hypersensitivity reactions
9. Blood dyscrasias

Hemolytic anemia and thrombocytopenia (G6PD deficiency) 

10. Black-water fever

In severe cases on I/V administration hemolysis occurs, resulting in:

• Hemoglobinurea.
• Urine and feces turn dark
• Anuria
• Excessive coagulation
• Renal failure
• Uremia occur
• Damage to 8^th nerve also occurs
• Retinal artery stenosis
• Ischemia
• Diplopia
• Blurring of vision
• Night blindness
• Visual field impairment
• Mydriasis
• Even blindness can occur on excessive doses