ANXIOLYTICS & HYPNOTIC DRUGS Classification: 1. Benzodiazepines 2. Barbiturates 3. Non benzodiazepine and non barbiturates 4. Buspirone 5.β adrenoceptor antagonist 6. Diphenhydramine is an antihistamine used as sleeping pills particularly in wakeful children 1. Benzodiazepines: i) Midazolam: is ultra short acting , used as I.V. anaesthetic Ii)Alprazolam: has anxiolytic & anti depressant property iii)Diazepam: Used I.V for the treatment of status epilepticus iv) Clonazepam: is an anxiolytic drug especially in mania v)Flumazenil: Benzodiazepam antagonist vi) α1-selective Benzodiazepam: will be having anxiolytic property but no sedation vii) α2- selective Benzodiazepam: anxiolytic and muscle relaxant property Benzodiazepam doesnot effect random eye movement sleep(REM) Benzodiazepam doesnot effect growth hormone secretions Pharmacokinetics: Mostly they undergo metabolism by glucoronidation Hydroxy diazepam is called as Timazepam Hydroxy nor diazepam is called as Oxazepam Ioverdoses Benzodiazepam prolongs sllep without serious depression of respiratory (or) cardiovascular functions Short acting benzodiazepams cause severe withdrawal symptoms Severe psychological & physiological dependence occurs with Benzodiazepams Fumazenil can be used to reverse the effects of Benzodiazepines over doses Half life of Fumazenil 2hrs Fumazenil when given with Tricyclic anti depressants(TCA) precipates convulsions 2.Buspirone: Is a partial 5HT-1a agonist Ipsapirane & Jepirone are analogues to Buspirone 5HT receptors are anti inhibitory in nature Buspirone also shows activity of non- adrenergic in local cerulus region It takes several days to weeks to show action 1
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
ANXIOLYTICS & HYPNOTIC DRUGS
Classification:
1. Benzodiazepines
2. Barbiturates
3. Non benzodiazepine and non barbiturates
4. Buspirone
5.β adrenoceptor antagonist
6. Diphenhydramine is an antihistamine used as sleeping pills particularly in wakeful children
1. Benzodiazepines:
i) Midazolam: is ultra short acting , used as I.V. anaesthetic
Ii)Alprazolam: has anxiolytic & anti depressant property
iii)Diazepam: Used I.V for the treatment of status epilepticus
iv) Clonazepam: is an anxiolytic drug especially in mania
v)Flumazenil: Benzodiazepam antagonist
vi) α1-selective Benzodiazepam: will be having anxiolytic property but no sedation
vii) α2- selective Benzodiazepam: anxiolytic and muscle relaxant property
Benzodiazepam doesnot effect random eye movement sleep(REM)
Increases risk of anaemia related to vitB12 deficiency
Increases frequency of abortion & abnormal foetal abnormalities
Enflurane:
side effect of enflurane is convulsions(seizures)
produces malignant hyperthermia
Isoflurane:
most widely used volatile anaesthetic
causes hypotension due to coronary activity
exacerbate cardiac ischaemia in patients with coronary disease because of steal phenomena
Desflurane:
used for day case surgery
mainly causes respiratory tract irritation which leads to cough & bronchospasm
sevoflurane:
No respiratory irritation but produces malignant hyperthermia
Side effect: renal toxicity
I.V. anasthetics:
Thiopental:
Ultra short acting barbiturate can cause unconsciousness with in 20sec and lasts about for 5-10 min
Slowly metabolized because of high lipophilic character
Side effect:cardio vascular depression
It has no analgesic property
If injected into local tissues produce necrosis & ulceration,immediate injection of procaine through same needle is recommended if this accident occurs
Contraindicated in porphyria patients
Hang over effects are seen with thiopental 6
Etomidate:
Larger therapeutic index compared to thiopental
On prolonged therapy suppresses the production of adrenal steroids
It should not be used in patients with adrenal insufficiency
Induces involuntary movements during induction
Propofol:
Metabolized very rapidly hence given as continuous infusion
Particularly used in day case surgery
Ketamine:
analogue of phencyclidine( called as steet drug)
NMDA receptor antagonist
It takes 2-5 min for inducing anesthesia
Produces dissociative anesthetic action
Unwanted effects:
Produces cardiovascular or respiratory depression
Increases intracranial pressure
Produces cerebral ischaemia
The main drawback of ketamine is hallucinations delution & irritational behavior
Drug interaction:
Ketamine+benzodiazepam- used to induce anaesthetic activity in children
Midazolam:
Ultra short acting benzodiazepam
Doesnot cause respiratory or cardiac depression
It is often used as pre operative sedative & during endoscopy where complete anaesthesia is not required
GASTRO INTESTINAL TRACT
Classification:
i)Drugs used to inhibit or neutralize gastric acid secretion:
a)Antacids:
Magnesium hydroxide:
Insoluble powder that produces Mgcl in stomach
Doesnot produce systemic alkalosis
Magnesium trisilicate:
Prolonged anti acid effect
Inhibits absorption of pepsin
Side effect: Diarrhoea
Aluminium hydroxide gel:
Forms Aluminium chloride(Alcl3) in stomach
Increases gastric pH to 4
Inhibits absorption of pepsin
Colloidal AlOH combines with phosphate & increases the excretion of phosphate in feaces that results in decreased excretion of phosphate via kidneys (in treating patients with chronic renal failure)
NaHCO3:
Increases gastric pH to 7.4
7
Releases CO2 & inturn stimulates gastric secretions(releasing of CO2 is called as Bulching effect)
Side effect:Systemic alkalosis
Alginates are combined with antacids for relieving bloating & flatulence
H2 receptor antagonists:
Cimetidine inhibits cyp enzymes but its adverse effect is that it produces gynacomastia & inhibits sexual functions
Ex:ranitidine, nizatidine,famotidine
Cimetidine potentiates actions of oral anticoagulants & TCA
In general H2 antagonists produce alopecia & hyper gastrinaemia
MOA:They bind to the reverse transcriptase enzyme near the catalytic site and denature it.
Nevirapine: It can prevent mother to baby transmission of HIV if given to parturient mother & the neonate
Efavirenz: 99% protein bound drug and has the longest half life in nucleoside reverse transcriptase inhibiting activity around 50hrs.
Mefloquine: is the longest acting drug for 30 days
iii) Protease inhibitors:
1.Saquinavir
2.Nelfinavir
3.Indinavir
4.Ritonavir
5.Amprenavir
-Highest CSF concentrations can be seen with Indinavir
-Lowest CSF concentrations can be seen with
Saquinavir
Unwanted effects:
Diabetes(hyper glycaemic condition)
11
Rhabdomyolysis
Nevirapine & Ritonavir should be taken along with food
Saquinavir should be taken within 2hrs of meal
iii)DNA polymerase inhibitors:
Ex:Aciclovir:
It is a guanosine derivative
It is used in the treatment of Herpes simplex
It is also used for the treatment of Voricella zoster infections & Epstein-Barr virus infections
MOA:
Aciclovir is converted to monophosphate by thymidine kinase
Thymidine kinase is virus specific form of enzyme
The host cell kinases then convert the monophosphate to trisphosphate
It is the acyclovir trisphosphate that inhibits viral DNA polymerase terminating thenucleotide chain
Aciclovir acts as chain terminator
It can be given Orally, I.V. , & topically
Unwanted effects:
Contraindicated in renal dysfunction
Local inflammation with I.V. injection
Valaciclovir is the prodrug of Aciclovir
Famciclovir undergoes metabolism resulting in the formation of active metabolite compound called Penciclovir
Ganciclovir:
o It is an acyclic analogue of guanosine
o It is the drug of choice for cytomegalovirus promotes bladder cancer
o Mechanism of action is similar to acyclovir but unlike acyclovir it doesnot act as a chain terminator
o It is given by I.V. route
o It produces severe bone marrow depression
Tribavarin(ribavarin):
o It is a synthetic nucleoside , similar to structure to guanosine
o It acts by altering virus nucleoside pool or by interfering with the synthesis of mRNA.
o In aerosol form it is used in the treatment of influenza and infections with respiratory syncytial virus
o It is also used in the treatment of hepatitis C as well as lassa fever caused because of arenavirus infections
Foscarnet(Phosphonoformate):
o It is a synthetic non nucleoside analogue of pyrophosphate that inhibits the viral DNA polymerase by bindibg directly to the pyrophosphate-binding site
o It is a second line of drug in cytomegalo virus infections
o It causes severe nephrotoxicity
iv) Inhibitors of HIv fusion with host cells:
Ex: Enfurvirtide: It is given by sub cutaneous route
v)Neuraminidase inhibitors and inhibitors of viral coat assembly:
o Zanamivir and Oseltamivir are used in treating swine-flu infections
o These are active against both influenza A & influenza B virus
12
o Zanamivir is available as a powder for inhalation
o Oseltamivir is available as an oral preparation
Amantadine:
o It blocks M2 ion channels , thus inhibiting viral disassembly
o It is active against influenza A but not influenza B
o It is also used in the treatment of parkinsonism
Vi) Biologics and immunomodulators:
Immunoglobulin
Palivisumab:
o It is a monoclonal antibody used in respiratory and viral infection
o It is given by I.M. route
Interferons(α,β,γ):
Interferon γ : produced by T-lymphocytes they are called as immune interferon
Interferon (α,β): produced by B and T lymphocytes,macrophages and fibroblasts
MOA:
o Binds to specific ganglionic receptors on host cell membrane and also inhibits translaton of viral mRNA into viral proteins
o They donot cross BBB
Clinical uses:
o Interferon α 2a is used for the treatment of h$epatitis B infections and AIDS- related Kaposi sarcomas.
o Interferon α 2b is used in the treatment of hepatitis C
o Preparations of IFNs conjugated with polyethylene glycol(pegylated IFNs) have a longer lifetime
Ionosine pranobex: Immunomodulator interferes with viral nucleic acid synthesis & also promotes immune potentiation
HAART therapy:
-Highly active anti-retro viral therapy
-In this 2 nucleoside reverse transcriptase inhibitors+a non nucleoside transcriptase inhibitor(or) 2 protease inhibitors
ANTI-FUNGAL DRUGS
Amphotericin:
Source: cultures of streptomyces
o It is a polyene antibiotic
o It mainly interferes with permeability & transport functions of cell membrane
o They cause loss of intracellular potassium
o It is a good standard for treating Aspergillus & candida infections
Drug interaction:
Amphotericin+flucytosine= synergistic action
Pharmacokinetics:
It can be given orally, topically or by I.V route
For I.V. route it is complexed with liposomes or lipid containing preparations
Amphotericin+flucytosine is used in the treatment of cryptococcal meningitis
Unwanted effects:
13
Serious side effect is renal toxicity
Common side effects are hypokalaemia, hypomagnesinaemia,anaemia,anaphylactic reaction
If given by I.V. produces flebitis(inflammation)
If given by intrathecal infusion produces neurotoxicity
Nystatin(fungicidin):
No absorption on mucous membrane
Used for GIT infections
Griseofulvin:
It is a narrow spectrum antifungal agent
Source:pencillium griseofulvum
It is a fungistatic
MOA:
Interacts with fungal microtubules & interferes with mitosis
Potentially induces cytochrome p450 enzyme
Unwanted effects:
Photosensitivity reactions
Contraindicated in pregnanat woman
Echinocandins:
It comprises of a ring of 6 amino acids
Based on the structures of echinocandin B
MOA:
They inhibit the synthesis of 1,3 β glucan a glucose polymer necessary for the maintainence of fungal cell wall
Caspofungin:
It can be used for treatment of invasive aspergillosis that are refractory to amphotericin
It is given by I.V. once daily
Synthetic antifungal agents:
i)Azoles:
MOA:
Inhibits fungal cyt p 450,3a enzyme
i.e., lanosine 14-α-demethylase which converts lanosterol to ergosterol
Azoles also inhibits transformation of candidal yeast cells to hyphae
Drug interaction:
Azoles+Amphotericin= decreases the action of Amphotericin
1.Ketaconazole:used for systemic fungal infection
Unwanted effects:
Liver toxicity(valproate also shows liver toxicity)
-It also inhibits adrenocorticosteroids& testosterone synthesis when given in higher concentrations
Ciclosporin,terbinafine,astemizole increase plasma concentrations of ketaconazole Rifampicin:H2 receptor antagonist and antacids
Decreases absorption of ketaconazole
Flucanazole:
Drug of choice for fungal meningitis
Shows fungicidal action
Unwanted effects:
14
Stevens johnsons syndrome(skin infections)
Itraconazole:
Active against dermatophytes
Undergoes extensive hepatic first pass metabolism
Doesnot penetrate CSF
Unwanted effects:
Stevens johnsons syndrome(skin infections)
Inhibits cyp enzyme similar to that of ketaconazole
Miconazole: given for fungal infections in bone joints& lung tissues
Side effects:Blood dyscariasis(poisoning),Hyponatraemia
Clotrimazole,econazole,tioconazole,
Sulconazole are used only for topical applications
-Clotrimazole interferes with the aminoacid transport into the fungus
Flucytosine: given along with amphotericin for cryptococcal meningitis
MOA:Flucytosine is converted to the antimetabolite 5-fluorouracil in fungalbut not human cells.5-fluorouracil inhibits thymidylate synthase and thus DNA synthesis
MOA:Inhibits polymerization helminth β tubulin thus inhibits microtubule dependent functions such as glucose uptake
-Fatty meals increase the absorption of mebendazole
Unwanted effects:
Gastro intestinal disturbances
(common for all antihelminthics)
Albendazole:
Undergoes metabolism & results in the formation of sulfoxide & sulfone metabolites
Mebendazole is contraindicated in pregnancy & children below the age of two
Praziquantel:
Broad spectrum antihelminthic drug
Drug of choice for all forms of schistosomiasis
MOA: Disturbs Ca+ homeostasis by binding toprotein kinase C-binding sites in β-sub unit of voltage gated Ca+ channels
MOA2:15
Praziquantel also disturbs the tegument of the parasite unmasking novel antigen & increases susceptibility to the host normal immune responses
It is also effective in cysticercosis
It is considered to be a safe drug with minimal side effect
It is the drug of choice for tape worm infection
It can be given to pregnant & lactating woman
Side effect: Low grade fever
Piperazine:
Used for the treatment of round & thread worms
It reversibly inhibits neuromuscular transmission(NMT) by activating GABA-gated cl- channels
Polarized worms are expelled alive in condition
Unwanted effects:
Bronchospasms , It should not be given to pregnant patients or to those with renal or hepatic dysfunction
Niclosamide:
Widely used for the treatment of tape worm infections
MOA:
Scolex and the proximal segments are irreversibly damaged
For taenia solium infections the drug is given in single dose after a light meal followed by a purgative 2hrs later
Side effect: promote cysticercosis
Diethyl carbamazine citrate(DEC):
DEC is a piperazine derivative
Drug of choice for Bancrofti infections & lovalova infections
MOA:
It interfers with helminthic arachidonate acid metabolism
It makes the parasite susceptible for host immune responses
Unwanted effects:
Enlargement of lymph glands
Tachycardia
Respiratory disturbances
It should not be used in the treatment of onchocerciasis
Levamisole:
An antihelminthic drug showing immunostimulant activity
Increases IL2 expression
It shows nicotinic like action(stimulating & subsequent blocking of neuromuscular junction[NMJ])
Side effects: Encephalopathy
It can cross BBB
Ivermectin:
o Broad spectrum antiparasitic drug
o Drug of choice for filarial infections and also effective in the treatment of onchocerciasis which causes onchocercal blindness
o Can be used in the treatment of elephantiasis
MOA: It opens glutamate gated cl-channels which are present only in invertebrates
Unwanted effects:
o Enlargement of lymph glands
16
Verapamil can partially reverse Benzimidazole resistance in trypanosomes ANTICANCER DRUGS
i )Nitrogen mustards
Cyclophosphamide:
o Active form-phospharamide mustard
o Toxic metabolite: Acrolein
o It has an effect on lymphocytes and hence can be used as immunosuppressant
o Antidote for acrolein is MESNA or N-acetyl cysteine
o (MESNA-Sodium-2-mercapto ethane sulfone)
Estramustine:
Chlormethine(mustine)+estrogen= used for the treatment of prostate cancer
ii)Nitroso ureas:
lomustine and carmustine are highly lipophilic hence used for treatment of brain tumours
Busulfan:
Selectively suppresses bone marrow depressing the formation of granulocytes & platelets
Used in the treatment of chronic granulocytic leukamaeia(Blood cancer)
iii) Platinum compounds:
Cisplatin:
it causes intra strand cross linking between N7 & O6 of adjacent guanosine molecules resulting in local denaturation
mainly used in the treatment of solid tumours along with taxol
I.V. injection produces severe nephrotoxicity(foscarnet,amphotericin,&cisplatin also show nephrotoxicity)
In order to overcome nephrotoxicity of cisplatin more amount of water should be taken
Side effect: Vomiting can be treated with 5HT antagonists(ondansetron,gramisetron)
Carboplatin: produces less nephrotoxicity but more myelotoxic
Dacarbazine: prodrug activated in liver ,resulting compound is subsequently cleaved in the target cell to release an alkylating derivative
Temozolimide: Used for the treatment of malignant glioma
iv)Antimetabolites:
Methotrexate:
It contains pteridine ring(PABA & glutamic acid)
They donot cross BBB
Unwanted effects:
Folic acid deficiency it can be treated with folinic acid(active form of folic acid is poly glutamate form)
v)pyrimidine analogues:
Fluorouracil:
Inhibits thymidilate synthase enzyme
Given by parenteral route causes myelotoxicity & cerebral disturbances
Raltitrexed inhibits thymidilate synthase enzyme
Pemetrxed inhibits thymidilate transferase
Capecitabine: undergoes metabolism to form fluorouracil
Cytarabine(cytosine arabinoside):
is an analogue of nucleoside 2”-deoxycytidine
Inhibits DNA polymerase enzyme
17
Gemcitabine: analogue of citarabine
Given in combination with cisplatin
Side effect: Influenza like syndrome
vi)Purine analogues:
1.Pentostatin
2.mercaptopurine
3.thioguanine
4.fludarabine
Pentostatin inhibits adenosine deaminase enzyme important to convert adenosine to inosine.
vi)cytotoxic antibiotics:
They mainly contain anthracyclines
1.doxorubicin
2.Idarubicin
3.Epirubicin
4.Mitoxantrone
Side effect: cardiotoxicity
Inhibits DNA gyrase (or) Topoisomerase
Dactinomycin:
Doesnot produce cardiotoxicity
Mainly used for paediatric cancer
Bleomycin:
Metal chelating glycopeptides antibiotic
Degrades DNA causes chain fragmentation
Most effective in G2 phase of cell cycle, mitosis & also G0 phase
Side effect: pulmonary fibrosis, hyperpyrexia
Mitomycin:
Preferentially acts on O6 of guanosine nucleus
Produces nephro & pulmonary toxicity
Procarbazine:
Inhibits DNA & RNA synthesis and interferes with mitosis at interphase
Used for the treatment of Hodgkins disease
It causes disulfiram like actions
As it is a weak MAO inhibitor it produces hypertension when it is given with sympathomimetic agents
Produces blood cancer
Hydroxycarbamide(Hydroxy urea):
It is an urea analogue
Inhibits ribonucleotide reductase
Enzyme
Mainly used for the treatment of blood cancer
Plant derivatives:
Vinca alkaloids:
MOA: Binds to tubulin & inhibits its polymerization preventing spindle fobre formation during cell division & also inhibits leucocyte phagocytosis, chemotaxis and also axonal myelotoxicity
Taxanes:
18
Ex:Paclitaxel,Docetaxel
MOA:
They act on microtubules stabilizing them in polymerized state
Paclitaxel is given by I.V. infusion
Docetaxel is given Orally
Used in combination with carboplatin , paclitaxel is used in ovarian cancer
Corticosteroids & antihistamines pretreatment is necessary for Taxane therapy
Etoposides:
Inhibits mitochondrial function & nucleoside transport
Inhibits Topoisomerase II
Campothecins:
Ex:Irinotecan,topotecan
Inhibits Topoisomerase I
These alkaloids have fewer side effects compared with other anticancer drugs
Hormones:
i)Glucocorticoids:
Ex:Prednisolone, hexamethasone
Inhibits lymphocyte proliferation
Used in the treatment of leukaemias & lymphomas
Estogens:
Ex:Diethylstilbestrol,ethinyloestradiol
Used for the treatment of androgen dependent prostrate cancer
Prostrate cancer can also be treated with gonadotropin releasing hormone analogues
Progestrogens:
Ex:medroxy progesterone, megestrol
Used for the treatment of endometrial neoplasm and renal cancer
Gonadotrophin-releasing hormone analogues:
Ex:goserelin, buserelin
Used for the treatment of breast cancer in post menopausal women & prostrate cancer
Analogues of somatostatin:
Ex:Octreotide, lanreotide
Used for the treatment of neuro endocrine tumours
Hormone anatagonists:
Antioestrogens
Ex:Tamoxifen
Used for the treatment of breast cancer
It has cardioprotective activity by inhibiting LDL
Aromatase inhibitors:
Ex:Anastrozole, letrozole
Used for treatment of breast cancer
Aminoglutethimide blocks the generation of all steroids
Antiandrogens:
Ex:Flutamide, bicalutamide, ciproterone
Used in the treatment of prostrate cancer
19
Adrenal hormone synthesis inhibitors:
Ex:Trilostrane,Aminoglutethimide
Used to inhibit early stages of sex hormone synthesis
Radio active isotopes:
Ex: I131 used for treatment of thyroid cancer
Cisantaspase: It is the preparation of an enzyme asperginase
Adverse effect: Anaphylactic shock
Monoclonal antibodies:
Ex:trastuzumab,rituximab
Rituximab:
licensed for the treatment of lymphoma
It lyses B-lymphocytes by binding to Ca+ channel forming CD-20 protein & activating the complement.
Unwanted effects: Hypotension
Trastuzumab:
Is a humanized murine mab that binds to a protein termed HER2(Human epidermal growth factor receptor)
Imatinib mesylate:
Inhibitor of signaling pathway kinases
It inhibits not only platelet-derived growth factor but also a cytoplasmic kinase
Inhibits RAS pathway
Biological response modifiers:
Ex:Aldesleukin(recombinant interleukin 2)
The other drugs used are Tyrosine kinase inhibitors, angiogenesis & metalo proteinase inhibitors, cycloxigenase inhibitors, P53 in the another target, antigen oligo nucleotides & gene therapy ANTI PROTOZOALS:
Anti malarials:
P.falciparum -produces malignant tertian malaria
P.falciparum -no exo-erythrocytic cycle
P.malariae
P.vivax - benign tertian malaria
P.0vale
P.malariae- quartan malaria
Drugs used to treat acute attack/blood schizonticidal drugs:
They act on erythrocytic forms of the plasmodium
1.Quinoline-methanols Ex:Quinine,Mefloquine
2.4-aminoquinolines Ex:Chloroquine
3.phenanthrene deriv.: Halofantrine
4.Drugs inferring with folate synthesis: Sulfones
5. Drugs inferring with action of folate :
Ex:Pyrimethamine, Proguanil
6.Naphtoquinone derive.: Atovaquone
7.Antibiotics: Tetracyclines(Broad spectrum)
Used in losa losa fever
20
8.Compounds derived from qinghaosu:
Artemether, arteflene, artesunate
Drugs that effect a radical cure(root level):
Tissue schizonticidal drugs
Ex:8-amino quinolines : Primaquine and tafenoquine
They mainly act on liver parasites
Drugs used for chemophylaxis(causal prophylactic drugs):
They block the link between exoerythrocytic cycle and erythrocytic cycle
Ex:Chloroquine, mefloquine, proguanil, pyrimethamine, dapsone and doxycycline
Drugs used to prevent transmission:
They have gametocidal action
Ex: proguanil, pyrimethamine, priaquine
4-amino quinolines:
i)Chloroquine:
It is the most potent blood-schizonticidal agent
It is effective against all 4 forms of plasmodium sps.
At high concentrations it inhibits protein, DNA ,RNA synthesis(this is not related to antimalarial activity)
It inhibits haeme polymerase enzyme in parasite
Chloroquine is used as disease modifying antirheumatoid drug
Unwanted effects:
o In higher doses it causes retinopathy
o It has quinidine like action on heart
Note:Chloroquine can be considered as safe drug for pregnant women’
Quinoline –methanols:
Quinine:
o It is an alkaloid derived from cinchona bark
o It is effective against erythrocytic forms on 4 forms of plasmodium but has no effect on exo erythrocytic forms
o It inhibits haeme polymerase
o It is the main chemotherapeutic agent for p.falciparum
o It has a mild oxytocic effect on uterus
o It also has neuromuscular & antipyretic activity
Unwanted effects:
o Cinchonism
o It causes hypertension by increasing synthesis of insulin
o Rarely it causes black water fever a fatal condition associated with haemolytic anaemia and renal failure
Mefloquine:
o Blood schizonticidal quinoline-methanol compound active against p.falciparum and p.vivax
o It is used in combination with pyrimethamine
o It also inhibits haeme polymerase
o Its plasma halflife is 30days
Unwanted effects:
CNS toxicity-insomnia, psychosis, dizziness
21
Note:Contraindicated in pregnant women due to its long plasma half life
Phenanthrene-methanols:
Halofantrine:
o It is a blood-schizonticidal agent
o It is active against strains of p.falciparum that are resistant to chloroquine, pyrimethamine, quinine
o It is effective against P.vivax
Unwanted effects:
o It can cause severe cardiac dysrhythmia
o It prolongs QT interval
o Cough
o Haemolytic anaemia
Drugs affecting the synthesis or utilization of folate:
o Type I : Sulfonamides & sulfones
o They mainly act by competing with PABA
o TypeII : Pyrimethamine & Proguanil
o They inhibit dihydrofolate reductase
o Type I + Type II = Synergistic action
o Pyrimethamine is a 2,4-diaminopyrimidine and it is used only in combination with dapsone & sulfonamide
o Sulfodoxine is mainly used sulfonamide in malaria
o Pyrimethamine+sulfodoxine = used in chloroquine resistant malaria
o The active form of proguanil is cycloguanilproguanil has inhibitory blood schizonticidal activity
Unwanted effects:
o Pyrimethamine+dapsone: haemolytic anaemia, agranulocytosis, and eosinophilic alveolitis
o Pyrimethamine+sulfadoxine:blood dyscariasis, allergic alveolitis
o Pyrimethamine causes megaloblastic anaemia
8-aminoquinolines:
Ex:Primaquine, etaquine, tafenoquine
o Primaquine has little effect on erythrocytic state
o Tafenoquine is long acting
Unwanted effects:
o Methaemoglobinaemia with cyanosis
o Haemolysis in individuals with an x-chromosome-linked genetic metabolic condition-glucose 6 phosphate dehydrogenase deficiency
o Primaquine metabolites have greater haemolytic activity than parent drug
Antibiotics:
Tetracycline & doxycycline
Artemisinin:
o Drug of choice in cerebral malaria
o It has an endoperoxide linkage
o Artesunate is water soluble derivative of artemisinin
o Mechanism of action is mainly due to damage to DNA by generating free radicals
o The active form of artemisinin is dihydroartemisinin
Unwanted effects:22
o It causes decrease in neutrophil count
o Transient heart block
o It disturbs auditory functions
Artemisinin potentiates the effects of mefloquine, primaquine & tetracyclines
Artemisinin anatagonises the actionsw of the sulfonamides & the folate antagonists
Artemether and lumefantrine are used in combination
Hydroxy napthaquinine derivatives:
Atovaquone mimics the actions ofubiquinone possibly by inhibiting the mitochondrial electron transport chain in the parasite
Atovaquone + proguanil = SYNEGISM
New antimalarial drugs:
Pyonaridine is currently used in china
It is effective against xhloroquine resistant p.falciparum
DRUGS USED IN TOXOPLASMOSIS:
Causative organism: Toxoplasma conidia
Treatment:
o Pyrimethamine + sulfadiazine(to be avoided in pregnant patients)
o Trimethoprim + sulfamethaxazole
o Parenteral pentamidine
o Azithromycin is also used
CILIATE INFECTIONS:
Causative organism: pneumocystis carinii
Treatment:
o High doses of co-trimaxazole is the drug of choice
o Parenteral pentamidine
o Trimethoprim + Dapsone
o Atovaquone/Clindamycin + primaquine
TRICHOMONIASIS:
Causative organism:Trichomonas vaginalis
Treatment:
o Metranidazole
o High doses of Tinidazole
GIARDIASIS:
Causative organism: Giardia lamblia
Metronidazole is the drug of choice
AMOEBIASIS:
Causative organism:Entamoeba histolytica
Treatment:
o Metronidazole(or tinidazole) followed by diloxanide for acute invasive intestinal amoebiasis
o Diloxanide for chronic intestinal amoebiasis
o Metronidazole followed by diloxanide for hepatic amoebiasis
o Diloxanide for the carrier state
Metronidazole:
o It kills the trophozoites of E.histolytica but has no effect on cysts
23
o It acts by promoting apoptosis in the parasite
Unwanted effects:
o The drug has a metallic bitter taste
o It interferes with alcohol metabolism so concurrent use of it is strictly avoided
o This drug is contraindicated in pregnant women
Tinidazole also has the similar action but longer acting
Diloxamide:
o These drugs are used for the asymptomatic patients
o They show direct amoebicidal activity
TRYPANOSOMIASIS:
Causative organism:
Trypanosoma gambiense
Trypanosoma rhodesiense which causes sleeping sickness in Africa
Trypanosoma cruzi which causes chagas disease in South America
Treatment:
Drugs for sleeping sickness:
o Suramin, pentamidine(haemolymphatic stage)
o Arsenical melarsoprol for late stage with CNS involvement
o Other agents: nifurtimox(chagas disease), eflornithine
Suramin:
MOA:
It doesnot kill the parasite immediately but inhibits parasites enzyme inducing gradual destruction of organelles
Unwanted effects:
o Nephrotoxicity
o Should not be given to malnourished patients
o Optic atrophy
o Adrenal insufficiency
o Haemolytic anaemia
Pentamidine isethionate:
o It has a direct trypanocidal action
o It directly interacts with DNA
o It doesnot cross BBB
Unanted effects:
o Immediate hypotension followed by reflex tachycardia
o Breathlessnesss
o Kidney damage
LEISHMANIASIS:
Causative organism: Leishmania sps
Treatment:
The main drugs used are sodium stibogluconate, meglumine antimoniate, pentamidine isethionate, miltefosine
o Miltefosine(hexadecylphosphocholine) is effective in treating cutaneous and visceral leishmaniasis
o sodium stibogluconate its main unwanted effects are bradycardia, hypotension
24
MOA:
its main action is by increasing production of oxygen free radicals which are toxic to the parasite
DIURETICS
Classification:
i)Diuretics acting on proximal tubule:
loop diuretics
ii)Diuretics acting on distal tubule:
thiazide diuretics
Aldosterone antagonists
iii)Diuretics acting indirectly:
osmotic diuretics
Loop diuretics:
o Loop diuretics are the most powerful diuretics
o MOA:they inhibit the Na+/K+/2cl- carrier in the lumenal membrane
o These are also called as high ceiling diuretics
o They are sulfomoyl derivatives
o Ex:Furosimide, bumetanide,Toresamide, Ethacrynic acid, organomercurials(mersalyl)
o They increase excretion of calcium and magnesium and decrease excretion of uric acid(promotes gout)
o Thiazide diuretics: reduce excretion of calcium ions
o Loop diuretics are contraindicated in older woman
Unwanted effects:
o Hypotension
o Hypovolemika
o Hypokalemia
o Metabolic alkalosis
Note: Loop diuretics precipitates gout
Ethacrynic acid:when given with aminoglycosides it causes ototoxicity
Clinical uses:
o Drug of choice in CHF
o It is used for the treatment of hypertension complicated with renal impairment
o Hypokalemia increases toxicity of digoxin & type III antidysrhythmic drugs
Drugs acting on distal tubule:
o Ex:Bendroflumethazide, hydrochlorothiazide, chlortalidone, indapamide, metolazone
o Metolazone doesnot contain any thiazide nucleus
o MOA: it inhibits Na-cl transporter system
o Increases potassium & magnesium loss from the body
o Decrease uric acid secretion & also calcium excretion
o Thiazides are preferred over loop diuretics in term sof bone metabolism during long turn usage of older patients
o Loop diuretics +thiazide diuretics = synergism
o Thiazide diuretics cause hyperglycemia
o Diazoxide a non diuretic thiazide causes vasodilation by activating KATP channels
o They oppose the actions of oral sulfonyl ureas such as glibenclamide
25
o This diuretic can also be used in Diabetes insipidus
Pharmacokinetics:
Chlorpthalidone –longer acting thiazide diuretic acting on distal tubule
Uses:
o Used in nephrogenic insipidus
o Chlorpropamide used in neurogenic diabetes insipidus
o Metolazone especially used with loop diuretics
o It is used in recurrent stone formation in idiopathic hypercalciuria
Unwanted effects:
o Gitelmans syndrome due to inactivation of Na+/cl- cotransporter in the distal tubule
o Metabolic alkalosis
o Hypokalaemia
o Hypocalciuria may be beneficial as regards to bone metabolism and stone formation
o Erectile dysfunction seen with thiazide diuretics but reversible
o It precipitates gout & diabetes
Aldostreone antagonists:
Spiranolactone, Eplerenone
o MOA: it inhibits aldosterone activity
o Eplerenone differs from spiranolactone by replacement of 17α-thio acetyl group with a carbomethoxy group
o Plasma half life of spiranolactone is 10minutes
o Active metabolite of spiranolactone is canrenone
o (active) t1/2 = 16hrs
Unwanted effects:
o Hyperkalemia
o Metabolic acidosis
o Gynaecomastia
o Menstrual disorders
o Testicular dystrophy
Eplerenone has lower oestrogen like activities than spiranolactone
Uses:
o It is used along with digoxin for treatment of CHF
o Can inhibit cardiac remodeling
o Used in conns syndrome(hyper aldosteronism)
Triamterene and amiloride:
MOA: it blocks Na+ absorption in distal tubule
Unwanted effects: metabolic acidosis
Triamterine is guanidine containing diuretic it is seen in kidney stones
Diuretics that act indirectly:
o Osmotic diuretics: given by IV route Ex: mannitol
o They are not useful in treating conditions of heart failure associated with Na retention
o But can be used in emergencies for treating acutely raised intracranial & intraocular pressure
Unwanted effects:
o Expands extracellular fluid volume with a risk of causing left ventricular failure
26
o Hyponatraemia
Drugs that alter p H of urine:
o Citrate:inhibits carbonic anhydrase enzyme having antibacterial activity
o Barbiturate poisoning can alkalinize the urine by NaHCO3(used to treat salicylic acid overdose)
Drugs that decrease urinary p H : NH4cl
Diuretics that act indirectly:
Acetazolamide used in infantile epilepsy
Increases pH of urine and causes metabolic acidosis
Used in glaucoma
o Ethanol inhibits the secretion of ADH causing water dieresis and inhibition of transient diabetes insipidus
Drugs that inhibit action of ADH:
o Lithium –used in psychiatric disorder
o Demeclocycline- a tetracycline used not as an antibioticused in ling cancers with inappropriate ADH secretion
o Colchicines & vinca alkaloids cause nephrogenic dibetes insipidus
Nephrogenic diabetes insipidus: diabetes insipidus caused not by a failure to secrete ADH but by a failure of the renal collecting ducts to respond to its action
Hyperkalaemia:
o Treatment neede if plasma concentration exceeds ›6.5m mol/l
o Calcium gluconate is given by IV
o Salbutamol(albuterol) causes cellular K+ uptake
o Salbutamol + insulin = synergism
o Removal of excessive potassium from the body can be achieved by cation exchange resins such as sodium or calcium polystyrene sulfonate(sorbitol is given in combination to prevent constipation)
Drugs used in urinary tract infections:
Bed wetting(enuresis) is treated by v2 selective (ADH receptor)
Desmopressin (oral or nasal) restricting fluid intake
The use of alum as a water purifier led to dialysis dementia
Ca-containing phosphate binding agent(CaCO3) is used
An anion exchange resin sevelamer lowers plasma phosphate (contraindicated in bowel obstruction)
NOTES:wagners granulomatosis cause renal failure
o immunosuppressant drugs are used for this syndrome
o vit-D preparations(calcitrol & alphacalcidol) are used to treat osteodystrophy of chronic renal failure, 2) pagets disease of bone is treated by calcitonin