BETA LACTAM ANTIBIOTICS [4]: Penicillins, Cephalosporins, Monobactams, Carbapenems.

MOA- competitively inhibit transpeptidases of cell membrane thus preventing release of Dalanine of pentapeptide for formation of peptide linkages between NAM & NAG, resulting in cell wall deficient forms [giant protoplasts/ bizare, filamentous] whcich either lyse in hyperosmotic medium or do not multiply.

---

NATURAL PNENICILLIN [PnG or Benzyl Pn] : benzyl side chain with amide link to Pencillanic acid [betalactam ring + thiazolidine ring]  Single dose 0.5 – 5 MU (1MU = 0.6gm)

Narrow spectrum: Gm+ [pneumococcus, aerobic & anaerobic rods], Gm- [neisseria, E.coli, proteus], spirochetes, actinomycetes.

Bactericidal even in acidic pus & more active against Gm+[more proteoglycan] than Gm-[lipoprotein barrier]

Acid labile so no oral; poor CSF & synovium – penetrates only in inflammation; t1/2 is 30min, increased in renal disease/infants/elders/probenecid.

• CRYSTALLINE PnG  : Na+/K+ to thiazolidine; stable in dry form, aq sol freshly prepared for i.m/i.v; rapid plasma levels.
• REPOSITORY PnG: insoluble salt given only i.m (never i.v since microemboli, convulsions, hallucinations); sustained plasma levels.
  • PROCAINE PnG: sustained
  • FORTIFIED(Na+) Procaine PnG: rapid & sustained
  • BENZATHINE PnG: extremely slow release   [USES- early/latent syphilis 2.4MU/1-3wk; late syphilis 2.4MU/wk for 4wks; rh fever prophylaxis 1.2MU/4wk till 5yrs after/ 18yrs age; gonorrhoea/syphilis prophylaxis 2.4MU single dose within 12hrs]

USES OF PnG:

• strep pharyngitis, otitis media, scarlet fever, rh fever.
• [high dose + gentamycin] strep viridans/faecalis  SABE.
• drug of choice for syphilis.
• rare infs like anthrax, actinomycosis, trench mouth, rat bite fever, listeria, pasteurella.
• [hig dose] meningitis [rifampin for prophylaxis]
• ophthalmia neonaturum
• adjuvant in diphtheria, tetanus, gas gangrene.
• prohylaxis for endocarditis in valvular heart disease, rh fever, syphilis, gonorrhea, agranulocytosis, surgery/ invasive procedures.

Pn resistance:

1. inherant by location of transpeptidase deeper to lipoprotein barrier.
2. high resistance acquired primarily by production of Pn destroying penicillinase [used to destroy PnG in blood culture smaples]- Gm+[staph] produce large amounts which even diffuse into surroundings & also inducible by methicillin, unlike Gm-betalactamase [gonococci, E.coli, H.inf]
3. [low resistance] Pn tolerant by acquisition of low affinity transpeptidase [MRSA, Pneumococci], low penetrability [Gonococci, H.inf], altered porins [Gm-]

ADRs- [most non-toxic drug]

• pain on inj.
• thrombophlebitis.
• >20MU/renal disease causes convulsions & coma.
• intrathecal inj causes spinal cord degeneration.
• major problem: natural/semisynthetic Pn causes hypersensitivity rxn esp with parenteral procaine which unpredictably  can be mild rash/urticaria/wheeze/ exfoliative dermatitis or it can be life threatening (stop use)angioneurotic edema/anaphylaxis [intradermal test with BENZYL PENICILLINOYL POLYLYSINE/ hyposensitize IDinj/hr with increasing amounts].
• not used topically since contact sensitization except for gonococcal ophthalmia.
• JARISCH HERXHEIMER RXN in syphilitic due to sudden release of spirochetal lytic products after 12-72hrs causing exacerbation of lesions, myalgia, fever, shivering, vascular collapse.

SEMISYNTHETIC PENICILLINS – benzyl side chain substitutes on betalactam ring. aim-

1. acid stable/ oral use
2. pnicillinase resistant
3. broad spectrum
4. non-allergic

PnV – oral acid stable, used only for less serious strep pharyngitis,sinusitis, otitis media, prohylaxis for rh fever, trench mouth.

Pnase resistant: oral Cloxacillin, Oxacillin, Dicloxacillin, Flucloxacillin, [parenteral Methicillin,Nafcillin]- used only for Gm+ staph except MRSA.

Extended spectrum Pn – against Gm- also without any Pnase resistance.

AMINO Pns: acid stable; Gm+ [strep viridans, enterococci, pneumococci] Gm- [gonococci, meningococci, Hinf, E.coli, shige, salm, prot]

AMPICILLIN [ADRs- incomplete absorption causes diarrhoea, rashes with allopurinol/AIDS/EBV/LL. Interactions- failure of oral contraceptives] USES-

• resp infs – bronchitis, sinusitis, otitis media.
• one of the first line drug for NPPNG urethritis.
• alt to cipro for typhoid.
• shigella dysentry
• cholycystitis [high conc in bile]
• [with gentamycin] SABE
• [with gentamycin/3rd ceph] septicaemias, mixed infs
• [3rd ceph] meningitis.

AMOXICILLIN -ADV:complete absorption, higher plasma levels, no diarrhoea, preferred over ampicillin for typhoid, bronchitis, SBAE, gonorrhoea.

CARBOXY Pns: parenteral CARBENICILLIN < TICARCILLIN :

• against pseudomonas & indole+ proteus;
• USE -serious burns,UTI, septicaemia;
• ADRs- bleeding, fluid retention, CHF.

UREIDO Pns:

• parenteral PIPERACILLIN,MEZIOCILLIN : most potent anti-pseudomonal & serious Gm- Klebsiella inf in immunocompromised/burns with cocurrent gentamycin/tobramycin.
• parenteral MECILLINAM[AMDINOCILLIN]: Gm- kleb, salm, E.coli, enterobacter [not pseudomonas] – USE: typhoid, dysentry, UTI.

BETALACTAMase(except 2nd & 4th cephalosporinase) INHIBITORS: CLAVULINIC ACID>SULBACTAM/TAZOBACTAM

• MOA- progressive inhibitor [with time] :betalactam ring binds betalactamase of Gm+&-
• combined with amoxicillin/piperacillin respectively since t1/2 is similar.
• USE: empirical Rx of mixed nosocomial inf, PPNG.

---

CEPHALOSPORINS : 4 generations; bactericidal; MOA- bind to different traspeptidases so no cross resistance with Pn.
FIRST GEN : high activity against Gm+
CEPHALOTHIN i.v- primary indication for Pnase producing staph[not MRSA]
CEPHALEXIN, CEPHADROXIL>CEPHRADINE oral- commonly used ceph; less active on Pnase staph & Hinfl.
CEPHAZOLIN i.v- more active against kleb & E.coli; preferred parenteral first gen ceph esp for surgical prophylaxis.

SECOND GEN: more active against Gm- & anaerobes.
CEFOXITIN i.v- serratia, indole+ prot, bact.fr : anaerobic & mixed surgical/obstetric infs, lung abscess.
CEFUROXIME i.m- PPNG, meningitis form Hinf, meningococci, pneumococci.
CEFUROXIME AXETIL oral- incomplete absorption.
CEFACLOR oral- significant absorption.

THIRD GEN: higher activity against Gm-enterobacteriaceae & highly resistant to betalactamases.
CEFOTAXIME, CEFTIZOXIME i.m/i.v- aerobic Gm- infs: PPNG, meningitis[high CSF], nosocomial, septicaemias, in immunocompromised.
CEFTRIAXONE i.m/i.v- longer t1/2 but ADRs hypoporthromb & thrmbcytopenia; serious infs- meningitis in children, MDR typhoid, complicated UTI, septicaemias, PPNG, chancroid.
CEFTAZIDIME i.m/i.v- high activity against pseudomonas, used in burns, hematological malignancies in immunocompromised. ADR- hypoprothrmb.
CEFOPERAZONE i.m/i.v- high activity against pseudomonas, used in severe infs of urinary,resp, biliary, skin, soft tissue, meningitis, septicaemias. DAR- thrmcytopenia, disulfiram like rxn with alcohol.
CEFIXIME oral- highly active against enterobacteriaceae, Hinf, strep; used for rsp, urinary, biliary infs. ADR-diarrhoea.
CFEPODOXIME PROXETIL oral- highly active against entero,strep & also staph; used for resp, urinary, skin, soft tissue infs.
CEFDINIR oral- most resp Gm+ cocci are succeptible : pneumonia, chr bronchitis, ENT & skin infs.
CEFTIBUTEN oral- active against both Gm+&-; used in resp, urinary, GIT infs.

FOURTH GEN:
CEFEPIME i.v- 3rd ceph spectrum + highly resistant to betalactamases so pseudomonas & staph are also inhibited : serious nosocomial pneumonia, febrile neutropenia, bacteremia, septicaemia.
CEFPIROME i.m/i.v- zwitterion penetration thr Gm- porins, more potent than 3rd ceph against Gm+ & some Gm-, used for serious resistant nosocomial infs

ADRs- pain, thrombophlebitis, diarrhoea esp with cephradine & cefoperazone, hypersensitivty – mostly rash [cross reactivity with Pn, so CI in H/O immediate hypersensitivity rxn], nephrotoxicity with cephalothin/aminoglycoside/loop diuretics, bleed ing with cefoperazone & ceftriaxone due to hypoprothrmb, neutropenia & thromcytopenia with ceftazidime, disulfiram like with cefoperazone+alcohol.

USES-

• alt to PnG delayed hypersensitivity – 1st ceph
• Gm-[kleb,prot,serratia, enterobacter] resp, urinary, soft tissue infs – cefuroxime[2]/ceftaxime[3]/ceftriaxone[3]
• Pnase staph – cephalothin
• Gm- septicaemia – aminoglycoside+ceph
• surgical prophylaxis – cefazolin[1]
• Hinf & enterobacteriaceae meningitis – cefuroxime/cefotaxime/ceftriaxone.
• pseudomonas meningitis – ceftazidime+gentamycin
• PPNG, chancroid – ceftriaxone is first choice.
• alt to FQ for typhoid – ceftriaxone/cefoperazone
• mixed infs in cancer, colorectal surgery, obstetric complications – [3]cefotaxime,ceftizoxime,..
• prophylaxis in neutropenia – [3]ceftazidime,…

---

MONOBACTAMS:
AZTREONAM – use in Pn/Ceph allergy; spectrum: enterobacteriaceae, Hinf, Pseudomonas – used for nosocomial urinary/biliary/git/genito infs

---

CARBAPENEMS:
IMIPENEM [+cilastatin to inh renal hydrolysis]- spectrum: Gm+cocci, enterobacteriacea, Pseudomonas, anaerobes -used in seroius nosocomial infs & also in immunocompromised.
ADR- induce seizures.

---

MRSA [methicillin resistanat Staph.aureus]

[through acquisition of low affinity transpeptidase to drug]resistant to

1. betalactams
2. erythromycin
3. aminoglycosides
4. tetracyclines

sensitive to

1. ciprofloxacin
2. vancomycin
3. linezolid

QUINOLONES synthetic antimicrobials.

NALDIXIC ACID [low potency, limited spectrum, rapid resistance]

MOA- inhibit DNA gyrase.

Bactericidal to Gm- coliforms: E.coli, Kleb, Prot, shigella, enterobacter.

• second line drug in recurrent UTI [lethal urine conc >20 times plasma/tissues]
• diarrhoea by prot, E.coli, salmonella, ampicillin resistant shigella.

ADRs- infrequent git upset, rashes, neurological toxicity [headache, vertigo, drowsy, seizures esp in children] prolonged use causes parkinsonism like, leucopenia, biliary stasis.

CI- infants.

FLUOROQUINOLONES [high tissue penetrability except in CSF & eye]

First generation- 1Fsubstitution [Gm + & -]- pef,cipro,o,nor.

Second generation- >1F [resp Q active even against Gm+ cocci & anaerobes; long t1/2] – levo, lome, spar, gati, moxi.

Ciprofloxacin [oral drug]

Bactericidal -most potent First gen FQ [rapid acting = MBC~MIC], active against beta lactam & aminiglycoside resistant strains, low resistance.

Broad spectrum

highly succeptible – [aerobic Gm-]

• enterobacteriaceae [E.coli, Kleb, S.typhi, shigella, prot, enterobacter]
• Neisseria
• Hemophylus
• V.cholera

modrately succeptible – hiher MIC

• Gm+ :Staph. aureus & epidermidis, anthracis, listeria
• Gm- :pseudomonas, brucella
• brnhm/morax, legionella
• Mycob.t

variable succeptibility – strep, mycoplas, chlamydia, MAC

resistant – anaerobes [protective intestinal flora spared - no diahrroea ADR]

MOA- inhibit DNA gyrase(Gm-) & topoisomerase4(Gm+) which nick & introduce negative supercoils to prevent excess positive supercoiling that damage dsDNA during separation for transcription/replication.

ADRs- safe & better tolerability: mild nausea, impaired conc & dexterity[caution while driving], high dose/predisposition cause seizures mild hypersensitivity, tendonitis.

Interactions- inhibit metabolism of warfarin, NSAIDs enhance CNS toxicity, anatcids iron reduce absorption.

USES-

• UTI even in complicated/cath/prostatitis.
• Gonorrhoea [both]
• chancroid
• bacterial gastroenteritis – EPEC, shige, salm,camp, reduce stool vol in cholera.
• first choice in typhoid
• resist staph & Gm- :bone,soft tissue, gynec inf. [add clindamycin/metronidazole for anaerobes]
• resp inf [not primary drug] : Gm- & mycoplasma,legionella, Hinf, Brnhm
• MDR TB
• i.v for Gm- septicaemia
• [though poor CSF] bacterial meningitis esp in immunocompromised & CSF shunts
• prophylaxis in neutropenic
• topical for conjunctivitis

NORFLOXACIN - only urinary & genital inf.

PEFLOXACIN -derivative of norfloxacin; higher CSF conc – preferred for meningeal inf; longest t1/2 repeat doses accumulate & so effective in systemic infs also; reduce dose in liver disease.

OFLOXACIN - more potent for Gm+; dose reduc in renal disease; USES: Chr bronchitis & ENT inf, alt for cipro in systemic inf esp chlamydial urethritis & cervicitis, atypical[mycoplasma] pneumonia, MDR TB, leprosy alt regimen.

LEVOFLOXACIN - improved action against strep pneu; primary indication – community acquired pneumonia & exacerbations of chronic bronchitis, sinusitis, pyelonephritis.

LOMEFLOXACIN - more active against Gm- & chlamydia.

SPARFLOXACIN - more active against Gm+[strep,staph], anaerobes, mycobact; primary indication: pneumonias, exacerbations of chr bronchitis, sinusitis & ENTinf, TB,MAC,leprosy; no interaction with warfarin; ADR- phototoxic, QTc prolongation with cisapride/TCA/phenothiazines/1A & 3 antiarrhyth.

GATIFLOXACIN - excellent against many resp : strep,chlamydia,anerobes : community acq pneu, exacerbations of chr bronchitis, other upper/lower resp infs; CI- hypokalaemia/drugs that prolong QT.

MOXIFLOXACIN - topoisomerase4 of Gm+ is major target; high activity against strep,etc, including beta lactam/macrolide resistant & anaerobes: primary indication for pneumonias, bronchitis, sinusitis, otitis media. CI- seizure predisposition, with proarrhyth drugs.

SULFONAMIDES

[used against pyogens but now limited to malaria [trimethoprin+pyrimethamine] because of resistance & ADRs]

bacteriostatic – both Gm + & -; bactericidal conc in urine.

• sensitive organisms- Strep.pyo, H.infl, H.ducreyi, Calymm.granulomatis, V.cho, chlamydia, actinomyces, nocardia, tox.
• prominent resistant organisms- gonococci, pneumococci, meningococci, Staph.aureus, Strep.pyo, E.coli, shigella.

MOA- inhibits replication by competively inhibiting PABA incorporation in bacterial folic acid synthesis. [unlike bacteria, humans utilize preformed FA in diet]

• cross resistance among all sulfonamides
• pus & tissues are rich in purines,thymidine,PABA, & antagonize sulfonamide action
• wide distribution even into CSF & placenta.
• acetylated metabolite is inactive but contributes to ADRs since it is less soluble in acidic urine & ppt causes crytalluria. CI- renal failure.

ADRs [common]- nausea, crystauria [Rx- alk/ dillute urine], hypersensitivity – photosensitization/ exfoliative dermatitis/ stevens jonson syndrome, hepatitis, kernicterus by protein displacement, hemolysis in G-6PD deficiency, contact sensitization.

short acting [less lipid soluble, 6hrs]- SULFADIAZINE - preferred for meningitis & urinary cath with analgesic phenazopyridine.

intermediate acting [10hrs]-

SULFAMETHOXAZOLE - preferred combination[COTRIMOXAZOLE] with trimethoprim since similar t1/2 for

• UTI[acute, chronic, recurrent] [trimethoprime concentrates in prostratitis],
• resp inf by H.inf 7 Gm+ cocci, alt to FQ for typhoid,
• ampicillin resistant dysentry from cam/E.coli/ shigella,
• one of the drugs of choice for chancroid,
• alt to doxy/eryth for granuloma inguinale,
• Pneu.carinii

ADRs- stomatitis, nausea, trimeth is anti-folate causes teratogenic effects & megaloblastic anaemia in alcoholics & pregnancy, uremia in renal disease, marrow hypoplasia in AIDS & elders, thrombocytopenia with diuretics.

MOA- combination becomes bactericidal  by sequential block of folate metabolism & max synergism is at plasma conc 20sulf:1trim which is obtained by dose 5:1 since trim has larger distribution in tissues.

SPECTRUM – S.typhi, serratia, kleb, , P.carinii, sulf resistant staph,strep,shigella, E.coli, H.inf, gonococci, meningococci.

SULFAMOXOLE- sole sulfanamide therapy for chronic UTI, resp inf [strep pharyngitis & gum inf].

long acting [high protein bound,7days, low plasma conc so not used for acute pyogenic inf]]- SULFADOXINE, SULFAMETHOPYRAZINE - supra additive synergistic combination with pyrimethamine [sequential block] for single dose treatment of chloroquine resistant falciparum, Pneu.carinii, toxoplasmosis. ADR- prolonged use causes severe cutaneous rxns.

SPECIAL PURPOSE-

1. SULFACETAMIDE- topically for ocular chlamydial/bacterial inf. [eradication requires sytemic azith/tetracycline]
2. SULFASALAZINE -ulcer colitis, rh arthritis.
3. MEFENIDE [atypical sulfonamide with action in pus & against pseudomonas, clostridia] – topical prophylaxis for <20% burns to prevent septicaemia. ADRs- severe pain, systemic absorption causes carbonic anhydrase inhibition – acidosis & hyperventilation.
4. SILVER SULFADIAZINE [antimicrobial action from slow release of silver ions]- topical prophylaxis in burns & nosocomial bacterial/fungal inf resistant to other sulfonamides.

TETRACYCLINE ANTIBIOTICS

oral broad spectrum except fungi& viruses [now many Gm+ cocci are resistant, Mycobacteria are naturally resistant but most Gm+ bacilli are sensitive, enterobact(pseudo,prot,kleb,s.typhi, b.frag) are resistant but some Gm- bacilli like Calymm.granulomatis, V.cholerae, yersinia, brucella, F.tularensis are sensitive, anaerobes & entamoeba,plasmodia  require higher MIC other misc sensitive ones are spirochetes, borrelia, ricketsiae, chlamydia]

MOA - bacteriostatic; inhibit bacterial protein synthesis by binding to 30s ribosomal subunit & preventing binding of aminoacyl tRNA to A site.

high intracellular penetration hence accumulate & penetrate even non-inflamed meninges & secreted in milk.

only doxycycline is metabolised so enzyme inducers reduce its t1/2.

most potent is minocycline.

ADRs-

• irritant [esophageal ulceration esp wiht doxy],
• liver damage [tetra & oxyt are safer],
• reversible faconi like syndrome [since all except doxy accumulate] in preexisting renal disease,
• phototoxicity on exposed parts [esp with demeclo & doxy so CI in malaria prophylaxis],
• brown discolaration & tooth caries & temporary bone growth suppression if given during late pregnancy & children<6yrs,
• inhibit protein synthesis & increased urea so CI with diuretics,
• demeclo causes Dinsipidus, mino causes vestibular toxicity,
• high doses [except completely absorbed mino & doxy] cause Cl.dificile pseudomembranous enterocolitis superinf,
• contact sensitization so not to be used topically except for ocular.

USES- only when more selective & less toxic antibiotic is not available [for empirical treatment of mixed infs combination of penicillin + aminoglycoside/3rd cephalosporin/FQ is preferred]

first choice in venereal diseases[lymphogranuloma, granuloma inguinale], atypical[mycoplasma] pneumonia, reduce stool vol in cholera, brucellocis, suspected cases in epidemic plague, borrelia relapsing fever, riskettsia – typhus/rocky mt spotted/Q fever.

second choice to

• ampicillin for tetanus, anthrax, actinomycetes, listeria.
• Pn allergy/cipro/ceftr for gonorrhoea/syphilis
• azithr for chlamydial[urethritis, trachoma, pneumonia]
• cotimox for chancroid & E.coli.
• strptomycin for tularemia.

misc uses- chr intestinal amoeb, adj in falciparum resistant malaria, severe acne, prophylaxis of  meningitis epidemic.

AMINOGLYCOSIDE ANTIBIOTICS

[produced from soil actinomycetes, not absorbed orally- given i.v, extracellular distribution -crosses placenta but  not BBB, excreted unchanged in urine, bactericidal to (coliforms)aerobic Gm- bacilli esp in alkaline pH, narrow safety margin]

MOA-[cidal unlike other inhibitors of protein synthesis since additional mechanism]- inhibit bacterial protein synthesis by binding to 30s-50s interface & causing mRNA codon misreading, / freezing initiation & polysome fromation.  +  altering cell membrane permeability.

single inj of the total daily dose is more effective & less toxic.

ADRs-

• ototoxicity [cochlear -initial tinnitus & later permanent frequency loss starting with high freq, vestibular -initial headache & later vomiting, vertigo, nystagmus, ataxia],
• nephrotoxicity- reversible tubular damage causing low urine concentration & enhancing ototoxicity,
• apnoe from NM block after appling to peritoneal/pleural cavities.
• [CI- pregnant, ototoxic drugs (high ceiling diuretics, minocycline), nephrotoxic drugs (amphotericinB, vancomycin, cephalothin, cyclosporin, cisplatin), caution - old age & muscle relaxants]

STREPTOMYCIN- low potency & narrow spectrum but lowest nephrotoxicity.

• tuberculosis with Ethambutol when hepatitis develops from H/R/Z [acts only on rapidly multiplying extracellular] [rapid resistance & streptomycin dependence if used alone]
• confirmed cases of plague [tetracycline for epidemics]
• drug of choice for tularemia [tetracycline for mild cases]

GENTAMYCIN- cheapest, more potent, broad spectrum but more nephrotoxic.

• First line amynoglycoside  for serious acute Gm- bacillary infections – [combined with pencillin/cephalosporin]
• resp infs in immunocompromised & implants.
• pseudomonas/proteus/klebsiella inf in burns,UTI, pneumonia/abscess, otitis media, osteomylitis(acrylic beads), septicaemia. [topical use is permissible in burns & conjunctivitis]
• meningitis
• SABE

KANYAMYCIN - more toxic, similar to S – second line drug in resistant TB.

TOBRAMYCIN - more potent & less toxic, reserve alternative to gentamycin.

AMIKACIN - widest spectrum since resistant to bacterial inactivation, higher dose required, reserve drug in nosocomial genta/tobra resistant Gm- bacillary infs.

NETILMICIN - widest spectrum since resistant to bacterial inactivation, possibly less toxic so preferable in immunocompromised & nosocomial genta resistant infs.

NEOMYCIN & FRAMYCETIN – only topical use since high systemic toxicity. [combined with polymyxin,bacitracin], wide spectrum including some Gm+ cocci.

• topically for wounds, ulcers,burn, ext ear, conjunctivitis.
• orally for bowel surgery preparation, hepatic coma(lactulose preferred) for inhibiting intestinal flora NH3.
• ADRs- prolonged oral use causes malabsortion by damaging villi & candida superinf by suppressing flora, small amounts are sytemically absorbed so CI in renal impairment.

MACROLIDE ANTIBIOTICS- erythromycin, spiramycin, roxithromycin, clarithromycin, azithromycin

MOA-  [bacteriostatic at low conc] inhibits bacterial protein synthesis by binding to 50s subunit of ribosome & preventing translocation of aminoacyl tRNA from acceptor to peptidyl site, thus terminating peptide chain elongation. [link to animation]

Bactericidal at high conc, depends even on organism & its multiplication rate.

[SPIRAMYCIN - toxoplasmosis & recurrent abortion in pregnant]

ERYTHROMYCIN-

Spectrum – narrow overlaping with PnG [most Gm+, few Gm-]  Str.pyo, Str.pneu, N.gono, C.diphth, Clostridia, Listeria, B.pertussis; in addition campylobacter, legionella, branhamella/moraxella, gardenella, mycoplasma are highly sensitive.

cocci develop rapid resistance & cross resistance with other macrolides.

widely distributed except BBB.

ADRs- safe drug -abdominal cramps, very high dose reversibly impairs hearing, hypersensitivity to estolate[enteric coat] causes hepatitis esp in pregnant, inhibits CYP3A4 causing arrhythmias from terfenadine/astemizole/cisapride.

USES-

1. alternative to penicillin for strep pharyngitis/Rh fever/SABE, resp inf by pneumococci & H.infl, carrier & acute stage of diphtheria, adjuvant in tetanus.
2. first choice in atypical[mycoplasma] pneumonia, whooping cough [effect depends on stage], chancroid [~ cotrimox/ceftria].

limitations of erythromycin – narrow spectrum, acid labile, short t1/2, interactions.

ROXITHROMYCIN - long t1/2 & acid stable – alt to erythro for resp inf.

CLARITHROMYCIN -  better gastric tolerability & more active on sensitive Gm+ cocci & also MAC & other atypical Mycobact & M.leprae – used in first line regimen for MAC, second line in other atypical mycobact & leprosy, H.pylori triple regimen, Strep resp/ear/skin inf.

AZITHROMYCIN - acid stable, better gastric tolerability, no interaction with CYP3A4, intracellular penetration, long t1/2, more potent than other macrolides on resp pathogens & chlamydia. first choice in legionnaires & chlamydial pneumonia, Ch.trachomatis [urethritis,trachoma], MAC, strep resp/ear/skin inf, gonorrhoea.

Anthelmintics

GIT is the abode of many helminths, but some also live in tissues or their larvae migrate into tissues.They harm the host by depriving him of food, blood loss, organ injury, itestinal or lymphatic obstruction, secreting toxins.But rarely fatal.

MEBENDAZOLE -preferred drug for multiple infestations & trichuriasis.

• Broad spectrum – ascaris, ancylostoma, necator, enterobius, trichuris.
• MOA- Slow action [2-3days] by blocking glucose uptake, depleting glycogen stores, loss of microtubules.
• ADRs- nausea, abbnormal expulsion of ascaris due to slow death, high doses -allergic rxns, hair loss, granulocytopenia.
• CI-pregnancy.

ALBENDAZOLE - single dose. superior over mebendazole in hydatid disease, ancylostoma, necator. drug of choice for neurocysticercosis.

• Broad spectrum – ascaris, ancylostoma, necator, enterobius, strongyloidis & taenia & trichinosis [3day course],  hydatid [4wk, repeat after 2ks if needed], neurocysticercosis & other tissue except occular[1mos], filariasis [adjuvant].
• MOA- similar to mebendazole + absorbed fraction is alos converted to active metabolite so effective in tissues as well.
• ADRs- nausea, prolonged use causes fever, hair loss, neutropenia, jaundice.
• CI- pregnancy, hepaic & reanl disease.

PYRANTEL PAMOATE – remarkably free of ADRs [nonirritant]

• Efficacy comparable to mebendazole against  ascaris, ancylostoma, enterobius [singloe dose] but lower in necator & strongyloides [3day].
• MOA- activates N[Ach] receptors causing depolarization & spastic paralysis. [antagonist - piperazine]
• PIPERAZINE – safe in pregnancy.
• MOA- GABA agonist causing hyperpolarization & flaccid paralysis [so preferred in ascaris intestinal obstruction].  Worms get expelled but recover in piperazine free medium, so purgative is given.
• ADRs -occasional nausea.
• CI- renal disease, epileptics.

LEVAMISOLE -restricted[second choice] to ascaris[1dose] & ancylostoma[2doses].

• MOA- stimulates ganglia causing tonic paralysis.
• ADRs -low & well tolerated with 1or2 doses.

DIETHYL CARBAMAZINE CITRATE- highly selective action on Mf in peripheral blood [7days] – Filariasis & tropical eosinophilia.

• MOA- alteration of Mf membranes so that they are readily phagocytosed by tissue monocytes + hyperpolarization by piperazine moiety.
• ADRs- common. starting with a low dose minimises allergic rxns to mass destruction of Mf / for already occured rxns[fever,rash,puritus, lymphadenopathy, fall inBP] temporarily hold DEC & antiH/steroids given then subsequently DEC is administrated.

IVERMECTIN - drug of choice for onchocerciasis & strongyloidosis – single dose.

• MOA- acts on glutamate gated Cl- channels causing tonic paralysis.
• Filariasis – single dose along with albendezole
• Scabies & Pediculosis – only oral drug.
• ADRs- mild so preferred for loa loa & onchocerciasis

NICLOSAMIDE- higly effective against cestodes [Tsaginata, D.latum, H.nana]

• MOA- inhibits oxidative phosphorylation & anaerobic resp.
• REGIMEN- 1g after breakfast, then 1g after 1hr, then saline purge after 2hrs. H.nana -repeat fro 5days since cysticerci develop by 4days. [T.solium -ova released from digested segments develop into larvae in  intestine, so thorough purge required]
• ADRs- nonirritant, no sytemic absorption, safe in pregnancy.

PRAZIQUANTEL - Broad spectrum : drug of choice for schistosomes & other  trematodes[except Fasciola hepatica], cestodes & their larvae [hence T.solium]. [Single dose even in H.nana]

• MOA- leakage of intracellular calcium causing paralysis.
• ADRs- nausea, sedation. visceral flukes destruction causes urticaria, fever.
• Interactions- therapeutic failure from induction by phenytoin, carbamazepine use in neurocysticercosis.

Anti-amoebic drugs

Endemic in developing countries due to poor sanitation & low socio-economic status [faecal contamination of food & water]

TISSUE AMOEBICIDES-

1. for both intestinal & extraintestinal – metronidazole, secni-,  satrani-, emetine, dehydroemetine.
2. for extraintestinal – chloroquine.

LUMINAL AMOEBICIDES-

• diloxamide furoate
• 8-hydroxyquinolines [QUINIODOCHLOR, IODOQUINOL-least absorbed so safer]
• tetracyclines

METRONIDAZOLE -[tinidazole- once daily,higher cure rates, low ADRs;  secnidazole -single dose;  satranidazole -no metallic taste/ CNS/ disulfiram like rxns/carcinogen]

• broad spectrum cidal activity – protozoa [entamoeba, trichomon, giardia], anaerobic bacteria [bacteroides, fusobact, clostridium, Cl.difficle, H.pylori, streptopepto].
• MOA- anerobes’ redox proteins reduce nitro group to reactive nitro radical which damages DNA.
• ADRs- metallic taste, anorexia, glossitis, rash, neutropenia, chronic use causes neuropathy.
• CI- CNS disorders, blood disorders, pregnancy[carcinogen], intolerance in some alcoholics.
• USES-

1. Amoebiasis – first line drug for all froms : invasive dysentry, liver abscess, mild intestinal [almost complete absorption so less effective on luminal cysts]
2. other protozoal – giardiasis, trichomonas vaginitis.
3. anaerobic bacterial infections – colorectal & pelvic surgery, brain abscesss, endocardiits, pseudomembranous enterocolitis, ulcerative gingivitis, trench mouth, H.pylori(triple regimen).

EMETINE -potent, direct amoebicide, reserve drug for severe intestinal/extraintestinal amoebiasis or intolerance/resistance to metronidazole.

• kills only trophozoites, not cysts by inhibiting protein synthesis.
• rapid symptomatic relief in 1-3 days, but not curative.
• s.c/i.m inj till acute dysentry subsides/not more than 10 days & since it accumulates, second dose given after 6wks.
• ADRs – pain, vomiting, diarrhoea, stiff muscles, tachycardia & hypotension[ strict bed rest for 2mos] DIHYDROEMETINE is less toxic to heart.

CHLOROQUINE – only in hepatic/extraintestinal amoebiasis.

• complete absorption [so luminal amoebicide always given to abolish luminal cycle]-highly concentrated in liver & kills only trophozoites.
• as effective as emetine & less ADRs but long[2-3wks] treatment & more relapses.

DILOXANIDE FUROATE- directly kills luminal trophozoites, drug of choice given after tissue amoebicide to cure asymtomatic cyst carriers [chronic intestinal amoebiasis], ADRs- flatulence, nausea, itch.

8-HYDROXYQUINOLINES- kills cyst forming luminal trophozoites [also girdia, trichomonas, dermatophytes, candia, some bacteria], ADRs- nausea, green stools, itch, chronic use causes goitre, iodism[furunculosis, inflamed mm, angioedema, cutaneous hmrrhg], myelo-optic neuropathy. CI- children [blindness] & not more than 14days.

high doses of OLDER TETRACYCLINES- by incomplete absorption inhibit flora with which entamoebae live symbiotically, used as adjuvant in chronic amoebiasis.

Rx:

1. Dysentry/ invasive intestinal amoebiasis – tinidazole [severe cases -dihydroemetine till acute symptoms get controlled in 3 days]
2. chronic/ asymptomatic cyst carriers – diloxanide furoate(2 or more courses are needed) second choice is tinidazole esp for latent hepatic inf; thrid choice hydroxyquinoline for not >2wks; adjuvant is older tetracycline.
3. hepatic amoebiasis – tinidazole [alt dihydroemetine if intolerant]; after that chloroquine to ensure eradication of motile forms; then a luminal amoebicide to eradicate intestinal reservoir of infection.

Anti-Malarial drugs.

Causal prophylaxis - targets the liver preerythrocytic phase.

1. PROGUANIL for P.falciparum. [not used since daily dose]
2. PRIMAQUINE for all species. [not used since toxic]

Suppressive prophylaxis – targets erythrocytic phase. limited to short term use in special risk groups like nonimmune travellers to endemic areas for fixed periods & pregnant women.. .

1. CHLOROQUINE is the drug of choice, but not given for >3yrs since cumulative toxicity.
2. PROGUANIL with CHLOROQUINE for low ressistant falciparum.
3. MEFLOQUINE for resistant falciparum.
4. DOXYCYCLINE for mefloquine intolerance [CI in pregnant & <8yr]

Clinical cure - target erythrocytic phase. radical cure for falciparum, but ralpses of vivax/ovale continue.  fast acting  high efficacy drugs [chloroquine,quinine,artemisinin] articularly for deadly falciparum. slow acting low efficacy drugs [proguanil,pyrimethamine,sulfonamide,doxycycline] are used only in combination.

1. CHLOROQUINE is drug of choice.
2. PYRIMETHAMINE+SULFONAMIDE for chloroquine intolerant /resistant.

Clinical cure for chloroquine/multi-resistant falciparum – mefloquine,quinine,pyremethamine+sulfonamide,artemisinin.

Clinical cure for severe/complicated falciparum – parenteral  quinine, artemisinin.

Antirelapse/Radical cure – target exoerythrocytic phase in relapsing vivax/ovale, used only in very low transmission nonendemic areas, during epidemics after effective vector control measures. .

1. PRIMAQUINE given immediately after erythrocytic schizontocide.

Gametocidal – to reduce disease transmission to mosquito.

1. PRIMAQUINE for all species, a single dose immediately after clinical cure of falciparum.
2. CHLOROQUINE,QUININE for vivax.
3. PROGUANIL,PYRIMETHAMINE make gametes sterile.

CHLOROQUINE - faster high efficay erythrocytic schizontocide for all species.

• MOA- weak base, accumulates in intraerthrocytic plasmodia acidic vesicles, no nontoxic hemozoin, heme-chloroquine complex damages membrane. [analogous MOA- mefloquine,quinine]
• ADRs -cumulative toxicity since high tissue affinity so not >3yrs, low frequent sideeffects -anorexia,itching,headache; chronic use causes loss of hearing, rash, photoallergy, myopathy, gray hair, neuropsychiatirc rxns;  rapid i.v causes arrhythmia & convulsions in children; chronic high dose for RA&DLE causes retinal damage.
• USES- drug of choice for suppressive prophylaxis[1wk before -10wks after] & clinical cure[not antirelapse] of all types of sensitive malaria [safe in pregnancy]. [oral for uncomplicated, i.v in adults only for sever/complicated] ; extraintestinal amoebiais, RhArthritis, DLE, lepra rxn.
• clinical cure for chloroquine resistance in falciparum – sulfa-pyrimethamine, in vivax – mefloquinine/quinine+primaquine.

AMODIAQUINE - faster, more palatable than chloroquine for clinical cure of uncomplicated falciparum.

MEFLOQUINE - intermediate acting erythrocytic schizontocide.

• ADRs – vomiting, diarrhoea, sinus bradycardia, neuropsychiatric rxns.
• limitations – long t1/2 [enterohepatic circulation & high tissue affinity] increases the chances of resistant strains selection & restricts wider use, cannot be given parenterally in complicated cases.
• USES- reserve drug for uncomplicated multiresistant falciparum [suppressive prophylaxis & clinical cure].

QUININE - fast acting erythrocytic schizontocide for all species, gametocide for vivax.

• ADRs – occasional hemolysis,HBuria,kidney damage; cinchonism [tinnitus, vertigo, perspiration,hypotension, respiratory depression, arrhyhtmia]] with higher doses, idiosyncratic -rash,itch,purpura, angioedema, bronchoconstriction.
• USES-  oral for uncomplicated chloroquine resistant, i.v for complicated falciparum[hypoglycemia sideeffect -5%dextrose]; noctornal muscle cramps, myotonia congenita, varicose veins, spermicidal.

PROGUANIL - slow acting erythrocytic schizontocide, sterilize gametes.

• MOA- active metabolite inhibits plasmodial DHFRase.
• limitations- no conversion to active metabolite in some, slow acting disadvantage in nonimmune, cannot be used in pregnancy, rapid resistance.
• USE- suppressive prophylaxis of low chloroquine resistance falciparum.

PYRIMETHAMINE - more potent than proguanil[slow acting erythrocytic schizontocide for falciparum & secondary tissue phase of vivax], directly inhibits DHFRase.

• limitaiotn – slow action so not used for clinical cure, rapid ressitance if used alone.
• USE- suppressive prophylaxis for vivax, given for 10wks after.

PYRIMETHAMINE-SULFONAMIDE/DAPSONE - faster acting due to supra additive synergistic sequential block.

• ADRs- more than sigle dose causes severe cutaneous rxns. CI- infants &hypersensitivity to sulf.
• USE- single dose for clinical cure of chloroquine resistant/intolerant falciparum; first choice for toxoplasmosis.

PRIMAQUINE - targets primary & secondary tissue phases, hypnozoites & gametocytes.

• ADRs- oxidant porperty causes hemolysis, tachypnoea..esp in G-6PD deficiency & RhArthritis,SLE, acutely ill.  CI- pregnancy since foetus is G6PD deficient.
• USE- single dose as gametocide in low trasmission areas after effective vector control measures.

BULAQUINE - better tolerated than primaquine esp in G6PD deficient.

DOXYCYCLINE -

• Clinical cure -always used in combination for chloroquine resistant falciparum [with quinine/pyrimeth-sulf/artimisinin]
• 2nd prophylatic for chloroquine resistant falciparum.

ARTEMISININ- potent & fastest blood schizontocide. some are gametocidic.

• MOA- heme cleaved endoperoxide releases free radicals cause parasite lysis.
• ADRs- safe but close monitoring required for ECG changes.
• USE- reseve drug for acute severe multiressitant falciparum. Recrudescence from short action can be prevented by extending the 3-5day artemisinin monotherapy with long acting mefloquine.

Anti-Viral drugs

Viral chemotherapy is difficult since viruses use host metabolic machinery to synthesize new virus particles & targetting it reuqires interference with host cellular metabolism.

Drugs target :

• virus dirested enzymes [some have few enzymes of their own]
• cell penetration
• uncoating
• reverse transcription
• progeny assembly

Therapy has to be prohylactic [in incubation period itself], since in majority of acute infections replication is already at its peak when symptoms appear.

Anti-Herpes

IDOXURIDINE

• MOA- competes with thymidine forming faulty DNA & wrong viral protein synthesis.
• limitations- only DNAviruses, low selectivity causing high toxicity on i.v.inj.
• USE- 0.1%drops for  initial attacks & superficial H.simplex Keratoconjunctivitis.
• ADRs- edema lids, irritation, photophobia.

ACYCLOVIR

• MOA- selectively converted in infected cells to an active metabolite that inhibits DNA lenthening.
• advantage- low toxicity.
• USE-
  • GenitalH.simplex – Primary disease – oint when early & mild, oral when late & severe. Recurrent disease – i.v for severe cases, oral is slow & incomplete so prophylaxis if >8 [does'nt prevent transmission].
  • Mucocutaneous[lips,gums] H.simplex – immunodeficient only require oral/i.v.
  • H.simplex Encephalitis – early stages respond  well to i.v.
  • H.simplex Keratitis – oint[slow action, good corneal penetration] for late deep infection.
  • Herpes Zoster – immunodeficient/severe cases can only use i.v. [prosthetic neuralgia not prevented].
  • Chickenpox – immunodeficient & neonates require i.v to reduce symtoms & viscereal complications.
• ADRs- most imp is decrease in g.f.r.

FAMCICLOVIR :USE- good bioavilability – alternative to acyclovir in genital herpes & herpes zoster.

GNACICLOVIR :USE- high toxicity -restricted to severe CMV infections in immunodeficient.

FOSCARNET :USE- high renal damage -acyclovir resistant infections in AIDS [also reduces HIV titre].

Anti-Retrovirus

NRTIs

ZIDOVUDINE

• MOA- after activation selectivel inhibits viral reverse transcriptase, prevents new synthesis from the integrated viral DNA.
• ADRs- anaemia,neutropenia from partial inhibition of cellular DNA polymerase. toxicity increases with paracetomol,anti-fungals.

DIDANOSINE :ADRs- pancreatitis & peripheral neuropathy.

STAVUDINE :ADRs- peripheral neuropathy.

LAMIVUDINE :USE-anti-HIV, chronic hepatitis B.  [diadvantage- rapid resistance & cross rsistance].

NNRTIs

NEVIRAPINE,EFAVIRENZ

• more potant on HIV-1 than NRTIs.succeed when earlier regimen has failed.
• MOA- direct inhibition of reverse transcriptase. [induce CYP450 enzymes.
• ADRs- headache, rashes.

PIs

SAQUINAVIR,INDINAVIR,NELFINAVIR,RITONAVIR

• MOA- at the last step of  viral repliction interferes with the cleaving of polyprotein into functional components[immature progeny], in both newly & chronically infected cells. [inhibited CYP3A4.
• ADRs- git,headache,rash. [indinavir- crystaluria].

HAART -3drugs to aggressively reduce HIV-RNA<50/ml. [monitor interactions & toxicities]

2NRTI + 1PI

2NRTI + 1NNRTI

3NRTI [less advanced cases]

NRTI+NNRTI+PI [reserved for advanced idsease/ repeated failures/short life expectancy].

INITIATE IN WHOM?

suboptimal response- CD4<200 [high risk for oppurtunistic infection]

all cases of symtomatic HIV.

asymptomatic with CD4<200

asymtomatic CD4>200 <350 with yearly decreae rate >100, HIV-RNA >20000.

Change Regimen?

<10 decline rate.

not decreased to<50/ml in 6mos.

recurrent rise to >400/ml after initial suppression.

Clinical detoriation.

Prophylaxis-

ZIDOVUDINE +/- another drug  :healthcare workers, HIV+ pregnant, neonate.

Anti-Influenza virus

AMANTADINE [RIMANTADINE -more potent, long action, high oral bioavailability]

• MOA- targets M2 ion channel & acts at early & late stages of viral replication.
• ADRs- anorexia, insomnia, hallucinations, ankle edema, postural hypotension.
• CIs- epilepsy, gastric ulcer, pregnancy.
• USE- InfluenzaA2 prophylaxis & early treatment, Parkinsonism.

NON-SELECTIVE ANTI-VIRAL DRUGS

RIBAVIIRN

• MOA- active metabolites inhibit viral RNA synthesis.
• Broad spectrum – InfluenzaA&B, RSV, many DNA & dsRNA viruses[measles, herpes, acute hepatitis, chronic hepatitisC, AIDS, .
• ADRs- hemolysis, git,cns, teratogenic.

INTERFERON [s.c/i.m inj]

• MOA- bind cell surface receptors  affect viral replication at multiple steps.
• Broad specturm- chronic hepatitis B&C, Kaposi sarcoma, Hairy cell leukaemia, podphyllin refractory condyloma acuminata, Hsim Hz CMV in immunodeficient, prophylaxsis for Rhinoviral cold.
• substantialADRs- flu-like, neurotoxicity, liver, thyroid dysfunction, transient arrhythmias, alopecia.

Patient COMPLIANCE & MOTIVATION.

MOTIVATION  means  teaching one to long for the long boundless sea.

• to achieve a change in the behaviour of the patient, discussion is the predominant instrument for motivation.
• the success of a doctor’s involvement is closely related to his own conviction about the advice & recommendations for therapy.the example of the doctor is itself a motivating & demotivating factor of major importance.
• it is persuasion by logic,psychology & rhetoric.
• it is going into conviction & the objective must be recognizable, attainable, realistic & desired by the patient.
• particular grounds for motivation aggregate from the range of reasons for action such as hopes, ideals, needs.
• it is not manipulation by consciously using prohibited techniques/ doubtful tricks & suggestions or creating anxiety/guilt/shame or attacking deeply established habits/articles of faith lead to demotivation.
• cognitive/intellectual impairment or differrent cultural values block motivation from the very onset.

The art of attaining the most optimal compliance possible finally rests on exhausting all of the measures which encourage motivation  and on clearing away as many factors which lead to non-compliance as possible.

COMPLIANCE  is willingness to follow a recommendation, cooperation as a result of partnership-like-relationship between doctor & patient, not training/instant obedience/patronizing the patients.

• one must  convince about a thing, mere proof is not enough.
• it is less the result of ethics but much more of the art of successful speech.

Non-compliance:

• cannot be taken for granted as natural weakness out of old habits or forgetfulness.
• it arises due to descrepency in subjective estimation & objective findings, & undeveloped trusting relation between doctor & patient.
• its the way one resolves the internal pressure arising out of cognitive dissociation between one’s beliefs & acceptance of truth.

Compliance depends on factors pertaining to the instructions, both the doctor & patient perspectives, the particular therapy & disease.

Instructional factors hindering compliance:

success depends on well-founded recommendations given in a comprehensible content, reasonable extent & empathizing delivery.

• unspecific objective without a quantified value.
• unilaterally exaggerating the objective or overestimation of a certain type of therapy.
• usage of specialized jargon instead of conveying in simple understandable statements.
• cognitive overloading without consideration to the patient’s attention span.
• unprioritized recommendations instead of approaching one step at a time & presenting positive consequences.
• insufficient involvement of patient’s responsibility & independence.
• uncompromising & authoritative pressure on objectives without taking risks & failures into account.
• dealing in differing realities, not fulfilling the expectation of the patient & the opportunity to present his own view & experience.
• impersonal/universal statement instead of focusing on the patient’s situation.
• hypothetical statements instead of presenting a standard & present positive consequences.
• threats/shock/anxiety provoking statements  instead of giving strenght at the point where the patient could not continue any longer & awakening  hope that the therapy will be effective.
• self-worth/ self-respect attacks instead of driving performance through self-assurance & assertion.

Doctor factors:

Doctor should be a trusted confident, helper, psychologist with a motto ‘victory is possible’  & willingness to compromise for aiding sustenance towards objective.

• credibility/competence which the patient ascribes to his doctor.
• extent to which doctor established a trusting relation with the patient.
• not being a respected example.
• cool distant routine approach, not accentuating the importance of prescription.
• unanswered questions hinders the patient’s self-initiative.
• although risks to health are accepted generally, they are not applied to the patient himself.
• lecturing/preaching instead of recommending actions on appropriate facts.
• authoritative behaviour instead of partnership.
• unmotivation from the doctor himself.
• not probing the patient’s personality.

Patient factors for unsuccessful motivation:

These need persistent long-term intervention for successful compliance.

• negative attitude towards health or medicine.
• playing down of the risks to health (often from defence mechanisms).
• passive attitude favorized by excess health insurance, puts off responsibility/ self-initiative.
• habits, prejudices, fixed ideas or psuedo arguments [can balance with sport, till now nothing happened so, one cant live for health alone].
• hypochondria, limited cognition or concentration.
• fear of addiction, high anticipation of side-effects usually from the type of medication or extent of explanation or those around the patient.

Treatment factors causing non-compliance:

• impractical/stressful/incovenient & limits life quality or individual situation.
• taste,shape,size,smell of medication.
• type/extent of side-effects or detailed list of all possible side-effects provokes uncertainity/suspicion.

Disease factors causing non-compliance:

• image of disease in soceity or from media reports/critical approach on behalf of patient.
• extent of suffering.
• objective severity of disease.

Optimal measures :

1. tangible objective -standard, attainable & worthwhile, focusing on situation of patient, one step at a time.
2. present positive consequences – motto ‘victory is possible’
3. take risks & failures into account -show willingness to compromise & agreeing appointments for checking progress. [ not only does this support the patient in the belief that the doctor is really concerned about him and interested in his progress, but it also affords the doctor the chance to check compliance]

Supportive measures:

1. written info as memory aids.
2. involve a key person – concerned & acceptable, introduce a helpful person.
3. encourage self-checking, independence & self-responsibility.

Checking compliance:

1. signs of the major pharmacological response.
2. specific side-effects.
3. direct questioning of the patient.Questions such as: “Many people find it difficult to remember to take their tablets regularly. Do you find that you sometimes forget to take your tablets?” are usually answered.

Anti-Fungals

[iatrogenic causes of decrease in host immunity :broad spectrum antibiotics, corticosteroids, cytotoxic drugs, catheters, implants, AIDS.]

polyenes: amphotericinB, nystatin, natamycin

1. amphotericinB-
   • MOA: higher affinity for ergosterol in fungal cell membrane, forms a micropore causing exodus of cell contents.
   • enhances immunity.
   • fungicidal at high concentrations.
   • broad spectrum.
   • administration : i.v suspension with deoxycholate [new liposomal preparation delivers it to RES in liver&spleen, valuable in kalaazar & immunocompromised].
   • most effective for acute systemic mycosis [candida, histoplasma, blastomyces, coccidiodes, aspergillus] , resistant kalaazar & mucocutaneous leishmaniasis.
   • orally unabsorbed : use in intestinal candidiasis.
   • ADRs: ACUTE RXN [5HRS: chills, fever, nausea, aches, dyspnoea ;Rx: hydrocortisone], NEPHROTOXIC, ANAEMIA.
2. nystatin- higher systemic toxicity, use only – oral corneal conjunctival cutaneous candidiasis.
3. natamysin- non-irritating, use -fusarium solani keratitis.

heterocyclic benzofuran: griseofulvin

• MOA: interferes wuth mitosis -distorts microtubules causing abnormal metaphase  resulting in multinucleated & stunted hyphae.
• fungistatic - fungus persits in infected skin only & treatment duration depends on turnover rate of keratin [body 3-6wks, nails 4-12mos].
• narrow spectrum – [large surface/ nail/ hair involvement only]dermatophytes only concentrate it.
• systemic use only – oral absorbtion improved by microfining.
• ADRs: headache, GIT, neuritis, allergy.

antimetabolite; flucytosine

• narrow spectrum fungistaic.
• synergistic with low dose toxic amphotericin  -cryptococcus menigeal & nonmeningeal.
• sole therapy in chromoblastomycosis.
• ADRs: pancytopenia, not used to in deep mycosis due to rapid resistance.

azoles: imidazoles [clotrimazole, econazole, miconazole, ketoconazole], triazoles [fluconazole, itraconazole]

• MOA: inhibit cytP450 enzyme impairing cell membrane ergosterol synthesis.
• broad spectrum
• topical -
  • clotrimazole [tinea, candidosis -oral, cutaneous, vaginal(residual effect favors)],
  • miconazole [higher efficacy, ADR- vaginal irritation].
• oral – ketoconazole
  • recurrent monilial vaginitis, less serious systemic mycosis since slow response
  • gastric acidity facilitates absorption
  • ADRs- nausea, headache, parasthesia, rash, decrease androgen/estrdiol synthesis -gynaecomastia, hair loss, oligospermia / menstrual irregularities, elevation of liver enzymes, CI-pregnancy, ventricular arryhthmias with cisapride.
• oral & i.v -fluconozole -
  • wider spectrum [cryptococcus, candida, histoplasmosis].
  • unaffected by gastric acidity & no ventricular arryhthmias with cisapride.
  • ADRs -nausea, headache, rash, elevation of liver enzymes, CI-pregnancy.
  • tinea, keratitis,  cutaneous & systemic candidosis, cryptococcus & coccidial meningitis preferred drug.
• oral -itraconozole-
  • fungistatic but effective in immunocompromised,
  • spectrum [including molds],
  • nonmeningeal systemic mycosis, preferred drug in paracoccidiomycosis,
  • gastric acidity facilitates absorption,
  • ADRs >400mg/day -GIT, headache, pruritus, elevation of liver enzymes, ventricular arryhthmias with cisapride

allylamine : terbinafine - MOA: inhibits ergosterol synthesis resulting in squalene accumulation in fungal cells -fungicidal -short course, topical & oral [first line for dermatophytosis (higher efficacy than griseofulvin & itraconozole)], ADRs- GIT, rash, liver dysfunction, blood disorder.

other topical [dermatophytes]:

• tolnaftate[less irritating],
• benzoic acid [whitfield's ointment with salicylic acid in hyperkeratotic lesions],
• quiniodochlor[also for luminal amoebiasis, furonculosis, seborrhoeic dermatitis],
• sodium thiosulfate [malassezia furfur].

Pediatrics vedios

BALLARD SCORE: newborn assessment -neuromuscular  done immediately after birth & physical  done within 24hrs of birth. [download pdf]

1. Methods of determine gestational age, Discussion of active and passive muscle tone]
   
2. Assessing Flexor tone, Appropriate for 20-44 weeks gestation, Neuromuscular Assessment, Posture, Square Window, Arm Recoil
3. Neuromuscular Assessment (continued) [Popliteal Angle, Scarf Sign, Heel to Ear]
   Physical Assessment [Skin, Lanugo]
4. Physical Assessment (continued) [Lanugo (continued), Plantar Surface, Breast, Eye/Ear]
5. Physical Assessment (continued)[Male,Female], Summary of Gestational Assessment and the New Ballard Score

INFANT REFLEXES:

1. Galant’s reflex [Hold the baby horizontally and prone in one of your hands. Stimulate one side of the baby’s back approximately 1 cm from the midline along a paravertebral line extending from shoulder to the buttocks. This produces a curving of the trunk toward the stimulated side, with shoulders and pelvis moving in that direction. Pelvic response to stimulation of the back and flanks should be symmetrical. This reflex is absent in transverse spinal cord lesions or injuries]
2. Grasp reflex [Stimulate the palm of the baby's hands and observe the reflex grasping of your finger. Stroke the sole of the foot, and the toes will flex and curl around your examining finger. Make sure that the response is not inhibited by unintended stimulation of the dorsal aspect of feet and hands.
   Persistence of the palmar grasp reflex beyond 6 months suggests cerebral dysfunction. It should be noted that babies normally hold their hands clenched during the first month of life. Persistence of the fisted hand beyond 2 months also suggests central nervous system damage]
3. Pull to sit [Starting in the supine position, the baby is pulled by the arms to the sitting position. The head and the arms are observed during the maneuver. The arms should remain partially flexed at the elbow and the head may lag behind the trunk. When the baby is in the sitting position, the head should be able to come to the upright position for at least a few seconds before dropping forward or backward.Watch the sternocleidomastoid muscles which should bilaterally anticipate the pull to sit; the head flexes for a moment before head lag occurs]
4. Moro reflex/Startle response [In response to loss of balance (the infant's head suddenly shifts position), the baby arches his back, flings his arms outwards, extends his legs, and opens his hands, after which he slowly returns to a flexed position, often resembling an embrace. The infant cries loudly (0-3 months)]
5. Magnet reflex [If light pressure with e.g. the thumb is applied to the sole of the foot of a newborn lying in a supine position, the baby pushes back against the pressure. And when the parent withdraws his thumb, he has the sensation that his thumb is drawing the limb out as by a magnet]
6. Crawling reflex [it can be stimulated by placing the neonate prone on a flat surface. The neonate will attempt to crawl forward when the sole of his feet are touched. Voluntary crawling begins around 7 months]
7. Rooting reflex [With the baby’s head positioned in the midline and hands held against the anterior chest, stroke with your finger the perioral skin at the corners of the baby’s mouth and the midline of the upper and lower lip. In response, the mouth will open and turn to the stimulated side. This response will also occur with stimulation of the infant’s cheek at some distance from the corners of the mouth. Absence of this reflex indicates severe generalized or central nervous system disease]
8. Sucking reflex [The sucking reflex is common to all mammals and is linked with the rooting reflex and breastfeeding. It causes the child to instinctively suck at anything that touches the roof of their mouth. You can test this reflex with a pacifier, baby's finger or your finger]
9. Stepping/Walking reflex [Keep the baby upright and allow the soles of the feet to touch the surface of the table. Move the baby forward to accompany any stepping. Alternating stepping movements with both legs will occur. This response depends on arousal of the baby but it’s continuous absence can indicate paresis or be present in babies born by breech delivery]
10. Tonic neck reflex [With the baby in the supine position, turn the head to one side, holding the jaw over the shoulder. The arm and leg on the side to which the head is turned extend, while the opposite arm and leg flex. This response does not normally occur each time this maneuver is performed, and when it is elicted each time it is evoked it should be considered abnormal, at any age. It will persist beyond the time of expected disappearance in major cerebral damage]
11. Glabellar tap [when the glabella is tapped, the eyelids of neonate blink]
    
12. Head lifting reflex [lifts his head when placed on his stomach. Five days after birth 50 % of the neonates can lift their head by bending their back for at least 2 sec. Absence of this reaction might reveal brain damage]
13. Reverberatory reflex [In supine position the arms of healthy babys are partly or totally flexed. When both forearms are extended and then suddenly released, they reverberate (spring) immediately to their original, flexed position]
14. Babinski’s reflex [When a newborn's foot is stroked on the outside of the sole, the baby will flex the big toe upward while the other toes fan out.The reflex is caused by a lack of myelination in the corticospinal tract in young children]
15. Landau’s reflex [With the examiner's hand supporting the trunk - face down, the baby raises his head, arch his back and extends his arms and legs and thus showing muscle tone. When the head is gently pushed into flexion, the legs drop into flexion like a clasp-nife. The reaction is elicitable from the 3rd to 9th month]
16. Diving reflex
    

PHYSICAL EXAMINATION VEDIOS OF THORAX, ABDOMEN, LOWER LIMBS

• Medical Video lecture series- FREE at Learnerstv.com thorax surface anatomy- trachea,intercoastal,spinous processes, lung lobes. [later part has brief resp lung exp,tactile fremitus- refer resp vedio.]

• Medical Video lecture series- FREE at Learnerstv.com breath sounds consolidation- bronchial sound- bronchophony, prectiloq, egophony crackles,wheeze,rhonchi end part has review of key points.

• Medical Video lecture series- FREE at Learnerstv.com lung expansion tactile fremitus percussion

• Medical Video lecture series- FREE at Learnerstv.com

  percussion analogy procedure [later part has heart- surface anatomy- refer cardio vedio]

• Medical Video lecture series- FREE at Learnerstv.com heart- surface anatomy, inspection, palpate [great] , perc, ausc. [good - compensate with virginia's cvs heart sounds description]
• Medical Video lecture series- FREE at Learnerstv.com initial part has BP later part of the vedio has JVP

• Physical Examination-Abdomen-Part1 clear surface anatomy

• Physical Examination-Abdomen-Part2 surface anatomy

• Medical Video lecture series- FREE at Learnerstv.com clear & regular than virginia, though less details for lower limb examination.
• Physical examination of knee
• Upper extremities examination-1
  
• 2-Upper limb & Spine examination
  

Physical Examination -Neurological examination

Complete examination module -quick with great details: from Uni of Toronto

Some other souces: [given in reverse order]

• Physical Examination-Detailed Neurological examination-Part7

  weber & rhinne test for hearing reinforcing reflexes- jadr manuever/ clench+fist pronator drift discrimination spinal cord lesion- blunt/pin touch – over severeal dermatomes

• Physical Examination-Detailed Neurological examination-Part6

  clear procedure- smell, taste, visual acuity, visual fields, corneal reflex, mastication ms

• Physical Examination-Detailed Neurological examination-Part5

  prone elicitation of reflexes [initial part in previous part with supine elicitation] grading of reflexes good proprioception procedure tips vibration ex procedure

• Physical Examination-Detailed Neurological examination-Part4

  femoral & peroneal nerve ex, muscle strength grading details reflexes

• Physical Examination-Detailed Neurological examination-Part3

  good tips- cranial nerves except optic , passive range of movts of limbs.

• Physical Examination-Detailed Neurological examination-Part2

  optic nerve ex – good tips & pt advice on procedures & ophthalmoscope use tips.

• The Neurologic Examination

  check out the sections: testing cranial nerves, reflexes, gaits, coordination

local anaesthetics

others capable of LA: ice, CO2 snow,ethylchloride spray [systemic ADRs: propranolol, chlorpromazine, H1antagonists, quinine]

LA safe,preferred in minor/restricted area surgery in cooperative[even though ill] pt retaining consciousness,vital functions.
MOA: state dependent blocking [rapidly firing neurons/high freq stimulus but not resting nerve with closed Na ch/ propagating AP with high Ca+2] of peripheral nerve impulse in both sensory[analgesia] & motor[paralysis] fibres [ionised form in low ICFpH]by binding to ICF part of activated[open] Na+ channel —> no Na+ influx/deplz/AP —> stabilizing the ch in inactivated state.
ADRs:
high doses cause CNS initial stimulation(from inh of inh neurones) [esp COCAINE :euphoria, allays fatigue, tremor, twitch, convulsions] later stimulation [unconscious, resp depr]. Rx:DZP.
N dose of LIDOCAINE causes drowsiness also.
N dose -CVSdepr [decr HR & BP] except COCAINE /w sympthmimetic -incr HR & BP.
high dose incr QTc –>arrhyth [BUPIVOCAINE most cardiotoxic]
antiarrhyth -PROCAINAMIDE, LIDOCAINE.

link between hydrophilic & lipophilic parts of LA:

1. ester –> : PROCAINE, COCAINE, TETRACAINE[toxic], BENZOCAINE.
   • rapid plasma hydrolysis so short acting.
   • PABA release causes hypersensitivity [angioedema, brspasm, dermatitis, rash], cross reactivity with sulfanamide & other LAs.
   • unstable so ionizes in high ECFpH –> lipid insoluble[low potency, ion trap in gastric mm].
2. amide –> : LODOCAINE, BUPIVOCAINE[cardiotoxic], ROPIVOCAINE, DIBUCAINE.
   • slow liver metabolism so long acting.
   • no allergic rxn so used for nerve block & infiltration.
   • stable unionised in high ECFpH –> lipid soluble[high potency].

• low potency =only inj –> PROCAINE
• mod inj potency & duration [low potent SA] –> [COCAINE only SA], LIDOCAINE.
• high potent inj & long duration [mod SA] –> TETRACAINE, BUPIVOCAINE, ROPIVOCAINE, DIBUCAINE.
• high potent SA only [no absorp -no systemic toxicity]–> BENOXINATE, BENZOCAINE, BUTAMBEN, OXETHAZAINE.

COCAINE-

• use only as ocular SA
• not inj –> necrosis sloughing of cornea, conjunctival bv constr.
• high abuse since no tolerance dev for CNS stimulation[euphoria, endurance]
• sympth & vagal centre stimulation -incr HR, BP, temp, mydriasis, vomiting.

LIDOCAINE -most widely used & versatile

• low pKa[=low ICFpH] causes shift of equilibrium to unionised form so rapid onset=3min & mod potency 1-2hr duration.
• both SA[ear, nose, respT, anorectal] & inj[all]
• only LA on intact skin[graft, iv canulation] –> eutctic cream w/ PRILOCAINE emulsified at 25degC
• antiarrhyth

TETRACAINE -[toxic]

• high potent inj spinal.
• mod SA [eye ear, respT]

BUPIVACAINE -[cardiotoxic -no iv regional, so prefer ROPIVACAINE]

• high potent inj [infiltrate, nerve block, spinal, epidural]
• continuous epidural [no motor block, only analgesia & blood levels< tissues] –>vaginal delivery, postoperative pain relief.

DIBUCAINE -[most systemic toxicity]

• most potent, longest action –.SA delicate mm: anorectal [piles,fissures]

only as SA-[no absorption -no irritant/systemic ADRs]

1. BENOXINATE -eye for IOP topometry.
2. BENZOCAINE,BUTAMBEN -wounds/ulcer ointment, sore throat/ stomatitis lozeng, anoractal suppository.
3. OXETHAZINE -lipid soluble even at acidic pH [gastritis,GERD, IBS gastrocolic reflex & pyogenic abscess]

LIDOCAINE	iv REGIONAL [elevate & bandage limb, then tourniquet]
LIDOCAINE BUPIVOCAINE	INFILTRATION -incision, excision, hydrocele, herniorhaphy FIELD[diff N]/ NERVE[trunk/plexus] BLOCK -intercoastalN-rib, ulnar brachial femoral -fracture setting, trigem & sciatic -neuralgia last resort, lingual-tooth extract, phrenic-hiccup. EPIDURAL -[difficult but ADRs less] -T[thoracic, Uabd], L[Labd,pelvis, L], CAUDAL[pelvis, perinium]
TETRACAINE LIDOCAINE,BUPIVOCAINE,DIBUCAINE	spinal [L234] – low abd, pelvis (obstetric,prostrate), LL. ADRs: resp centre depr, decr sympth[decr BP & HR -Rx:ephidrine, mephentermine], skms paralysis decr Vreturn, caudaequina syndrome[incontinences], headache, meningitis inf.

skeletal muscle relaxants -decr ms tone

1. peripherally acting on NMJ Nm receptors (i.v. for short procedures) (quaternary -no BBB/oral/placenta) – nondeplz[dTB], deplz[SCh] –> paralysis(voluntary movts lost)
2. directly acting on ms by decr Ca+2 release – dantrolene –> drug of choice in malignant hypothermia(from flourinated anaesthetics/SCh in succeptibles), decr UMNDspacticity in hemi/paraplegia,Cpalsy,MS,ALS,spinal inj.incr RP & decr excitation quinine -use in myotonia congenita, nocturnal leg cramps [ADR-decr ms strength,sedation,diarrhoea,liver toxicity]
3. spamolytics acting centrally by decr spinal supraspinal reflexes of ms tone without affecting stretch reflex [ADR-sedation]–>
   • pain<–>spasm: acute (overstretch,sprain,tear, dislocation,bursitis, rheumatoid disorders), torticollis,lumabago,backacke,neuralgias -mephenesin like/DZP +analgesics.
   • deseased desc pathways(UPMND)–>spasticity: decerebrate rigidity, hemi/paraplegia, MS,ALS, Cpalsy, parkinsonism, spinal inj, stroke -DZP,baclofen,tizanidine.
   • hyperreflexia of anxiety -DZP,chlormezanone.
   • ECT, ortho manipulations,tetanus -DZP [w/ SCh]

nondeplz/competitive Nm blocker	deplz/noncompetitive Nm blockers
bulky molecule – metabolized by AChE.	slender long flexible -cant be disossiated.
affinity to alfa subunits  + physically block preventing subunits conformational changes.	affinity to alfa subunits + intrinsic partial deplz of Na+ ch.
no Na+ ch opening -decr end plate pot -no AP –> initial weakness, flaccid paralysis first of small/fast response ms[eye,limbs] & last on head trunk[diaphragm] –> use in ocular,abd,thoracic surgery to produce adequate ms relxn & decr reflex contr during light anaesthesia [among more potent long acting drugs -pancuranium is inexpensive so used in developing countries] severe tetanus & status epilepticus uncontrolled by DZP. rocuranium intermediate acting use in intubation w/out SCh ADRs. [ADR- prolonged apnoea w/ long acting drugs: dTB,pan,dox,pipe -neostigmine reversal required]	Na+ ch in open inactivated state –> initial fasciculatiins [soreness in man]. decr EPP -no AP –> flaccid paralysis [phase1]  rapid onset & recovery w/out the ms sequence appreciation & only transient apnoea –> use intubation, endoscopy, ortho manipulations, ECT. [ADR- prolonged/high dose SCh/deficient pseudoChE/florinated anaesth --> phase2 slow onset & recovery of desensitization to ACh --> prolonged apnoea]
dTB,pancuronium,vecocuranium -block autonomic ganglia[Nn] –>vagal tachycardia. decr BP by ganglion block+limb ms paralysis+histamine (CI- hypovolemia, hepatic/renal insufficiency – so CISATRACURIUM can be used /w does not release histamine & undergoes hoffman elimination spontaneously in plasma)	SCh stimulates autonomic ganglia –> vagal brdycardia initially, later sympth tachycardia. sympth HTN, incr postoperative Paralyticileus.
dTB causes high histamine release -flushing, decr BP, brspasm & incr secretions(ppt asthma) [not w/ cisatracurium, rocurarium]	low histamine release -flushing
	burns/tetanus + prolonged SCh deplz –> hyperkalaemia -arrhyth [CI- digitalized Pt]

diuretics

plasma proteins,lipids –> filtrate –> 99% reabsorbed [diuretics block by 1% -->twice incr filtrate] –>urine N=1.5l/day.

ICF rich in [K+] & reabsobed proximally,secreted distally.

PCT -max [Na+] reabsorption  –> but diuretic action is weak & ADRs: compensatory mech incr salt reabsorption distally, CAi disturb acid base balance.

medullaryAscLH –>FUROSEMIDE high efficacy since less compensation distally.

corticalAscLH –>THIAZIDE medium efficacy.

DT,CD –>K+ SPARING mild diuresis.

PCT -reabsorption of

• Na+, Na+Glu by elecchgrad
• K+, Glu, AA, PO4-3, OrgAn- by symporter
• NaHCO3 by NaH+antiporter, CA, Na+HCO3-symporter
• Cl- by paracellular passively w/ other anion
• Na+ H2O to maintain isotonicity balance.

thickAscLH – reabsorb maxNa+Cl- by Na+K+2Cl- cotransporter & elecchgrad  [high at papilla tip from passive countercurrentmech(hairpin loop) & vasarecti shunts decr blood flow]  –> luminal hypotomic but hypertonic hypertonic /w absorbs H2O form descLH making that lumen hypertonic.

corticalDT – reabsorb some more NaCl by a symporter.

terminalDT,CD - reabsorb of

• Na+ by aldosterone w/ passsive Cl- reabsorption & secretion of K+,H+.
• H2O by ADH & medulla elecchgrad causing luminal hypertonicity.

free water clearance [vol/unit time to excrete solute isoosmotically] -

• 0 if urine isotonic
• + if hypertonic
• - if hypotonic

GFR depends on:

• co
• renal blood flow
• aff  & eff arterioles diff
• elecchgrad in juxtamed nephrons(20%) altered by redistr of blood
• RAS
• Adr, PG, ANP

high ceiling  -loop diuretics -FUROSEMIDE, BUMETANIDE (more potent lowADR:myopathy),  mercurials,EA

• med oral absorp, rapid short action, max diuresis [10l], dose dependent response, chr use nephron hypertrophy resistance.
• inh  AscLH Na+K+2Cl-cotransporter [incr distal K+excr -hypokalaemia (low since short action allows compensatory repletion)] & abolish medulla high elecchgrad [urine stays isotonic]  –> both strong diuresis –> initial Rx for all edema [cardiac,renal,liver,lung], alt to mannitol in intracranial edema & poison forced diuresis, complicated HTN [renal failure, cirrhosis, CHF, vasodil complication, thiazide resistance, emergency HTN w/ vol overload, blood transfusion overload].
• GFR unaltered [compensatory mech to the incr renal flow & medulla redistribution] –> use in renal insufficiency & resistant nephrotic edema.
• iv inj incr venodil –> decr preload –> quick relief to LVF & pulm edema before natriuretic effect.
• incr Ca+2, Mg+2 excr –> use in hypercalcaemia & renal stones.
• decr urea,Glu excr –> ppt gout,DM.

mod efficacy -thiazides & thiazide like -

• good oral , 1hr onset, long action, flat dose response.
• only inh cortical DT Na+Cl-symporter [but prominent hypokalaemia since long acting] [hypertonic urine +free water clearance] –> maintenance therapy of mild mod edema esp cardiac, 1st choice in uncomplicated mild(10mm)HTN esp elders, diabetes insipidus.
• decr renal blood flow & GFR  [causing resistance] –> CI: renal failure, cirrohsis.
• incr Mg+2, Glu excr.
• decr Ca+2 [use in hypercalcaemia of recurrent renal stones], urea excr –> ppt gout.

chronic use of high dose loop & thiakide diuretics complications -

• hypokalaemia (fatigue, ms cramps, arrhyth, alkalosis).  Rx -high K+ diet/supplements, K+ sparing diuretics in cirrohsis, post MI, digitalis, quinidine, sulfonylurea, TCA, elders.

• dehydration, low BP from isotonic natriuresis esp furosemide.  Rx-saline.
• dilutional hyponatremia, edema -incr thirst. Rx-glucocorticoids, stop water intake & diuretic use.
• ototoxicity from incr Na+ in endolymph.
• CI- PIH, gout, Dnephropathy, dyslipedemia, DM.
• allergy, git, cns symptoms.

interactions-

• potentiate antiHTNsives
• hypokalaemia w/ digitalis, quinidine, sulfnylurea, TCA
• rise Li+ levels
• nephrotoxicity w/ aminoglcosides, 1st cephalosporins, amphotericinB.
• inh by NSAIDs, probenecid.

CAi -acetazolamide -

• decr NaHCO3 reabsorp in PCT & incr K+ excr distally[hypokalaemia] –>mild alk diuresis [but self limiting & decr NH3 absorp(cirrhosis -->hepatic coma)]- use in UTI, incr acidic drug excr
• decr IOP by inh aqh form -use adj in glaucoma
• incr CO2(sedation) –>decr siezure threshold in brain – use adj in abscence siezures.
• ADR- BMdepr, allergy, git, cns symptoms.

K+sparing diuretics acting on CD —> mild natriuresis w/out K+loss –> use to prevent hypokalaemia w/ other diuretics, break thiazide resistance from hyperaldostr esp in cirrhosis & nephrotic syndrome

SPIRANOLACTONE – steroid antagonizing aldosterone by binding its ICF receptor –> decr AIP[NaKATPase,Nachannel].  [ADR- hirusitism, gynaecomastia, impotence, menstrual irregularities]

TRIAMPTERENE, AMILORIDE -nonsteroids directly inh Na+channel.  [ADR- git] add uses- prevents Dinsepidus ADR from Li+reabsorp, incr fluidity of cystic fibrosis secretions.

CI- renal insufficiency[-->hyperkalaemia], cirrhosis[-->acidosis], PUD, ACEi/AT1antagonists.

interactions- incr digoxin, inh by aspirin.

osmotic diuresis- iv MANNITOL

• inert low molwt nonelectrolyte –> decr ICP in head inj stroke, decr IOP in glaucoma, low plasma osmolarity of rapid dialysis.
• incr blood vol , GFR, ion excr, urine vol –> use in impending renal failure , poison forced diuresis.

DESMOPRESSIN -selective V2 agonist in CD incr ADH action –> neurogenic Dinsepidus [pituitary ADHdef], nocuria.  ADR-fluid retention, hyponatrimea.

antiparkinsonian drugs

extrapyramidal motor disorder

• rigidity, tremor, hypokinesia
• secondary -defective posture gait, mask face, sialorrhoea
• progression to immovable, inbreathable – chest inf, embolism.

DOPAMINERGIC PRECURSOR -LEVODOPA

• high first pass metabolism in git liver. 95% decarboxylated in perihery. DA acts on heart, bv, CTZ -tachycardia, postural hypoTN, vomiting. Tolerance dev. [Rx- antidopaminergic domperidone bocks only  CTZ]
• 1-2% crosses BBB into DAneurones, stored & released- alerting response on behavior. rigidity, hypokinesia resolve first. other symptoms gradually.
• initial ADRs [tolerance dev]- arrhyth, postural hypoTN, vomiting, altered taste.
• late ADRs [no tolerance]- involuntary movts [tics,grimacing, choreoathetoid], abn behavior [anxiety, mania, depr, hallucinations, psychosis, incr sex activity], ON-OFF effect [disease progression -inability store relese, synthesis moment basis -rapid unpredictable fluctuations in motor control].  Rx- divided dose & frequent administration.

PERIPHERAL DECARBOXYLASE INH -CARBIDOPA, BENSERAZIDE

• administered along with ldopa -prolongs peripheral t1/2 [less DA form -less vomiting, tachycardia, hypoTN], incr & sustained availability to brain, so less dose is needed & on-off effect is minimised. increased response is noted.
• ADRs: early & intense involuntary, behavior abn, postural hypoTN.

DA agonists -bromocriptine, ropinirole, pramipixole.

MAO-B[brain] inh of DA -selegiline

DA facilitator -amantadine

anticholinergics -benzhexol, procyclidine, biperiden, cycrimine, ethopropazine.

opiods

MOA: opiod receptors[3- in git & limbic reinforcing] are prejunctional inhibitory to excitatory NT in CNS & MYENTERIC PLEXUS.

AGONIST [morphine, dynorphin, encephalins]  cause intracellular decr cAMP, opens K channels & suppress Ca channels —> decr intracellular levels of Ca –> decr excitatory NTs release.

MORPHINE -

• natural alkaloid acting on all 3 receptors. has both CNS depr & stimulant action. poor oral bioavailability.  its effects are potentiated by CPZ,TCA,MAOi, Amphetamine, Neostigmine.
• specific strong analgesic – visceral>somatic, nociceptive receptor> neuritic damage pain. decr sympth autonomic effects of excess pain- sinking, nausea, apprehension, sweat,  palpitation, incr/decr BP, incr resp.  Rx- MIischemic pain,  cancer, neurogenic shock [tauma, burn], postoperative.
• in apprehensive subjects – decr central sympth stimulation –> calming mood, decr concentration & initiative. Rx- MI, Internal bleeding [hematemesis, threatening abortion], preanaesthetic.
• Sedation without motor incoordination. use: anaesthetic.
• high sensitivity to antitussive action [dry cough]
  
• dose dependent decr resp[decr drives,rate, tidal vol -apparant decr O2 need- accumulatedCO2] & vasomotor centre [greater sys vasodil (shifts pulmn edema),incr ICP, postural hypoTN, decr Presis & preload CO, reflex tachycardia. use-acuteLVF.  CI: LABOR -foetal apnoea [quicker- poor BBB], resp insufficiency [emphysema], head inj [incr ICP from vasodil + overriding signs -resp decr, miosis, sedation, vomiting].
• relaxes smms [git,ut,uterus,bronchi] & incr sphincter spasm – chronic constipation, urinary hesitency, prolonged labor, ppt asthma. CI: biliary colic,diverticulitis, pancreatitis, BPH eldermales.
• pokilothermic.
• decr hypothalamus-pituitary action: decr FSH,LH,ACTH -steroids, sex hormones. incr ADH, GH, Prolactin.

tolerance dev to all except constipation & miosis

• stimulates: CTZ -vomiting, EWnucleus -miosis, incrIOP, vagal tone -bradycardia, cortex-hippocampus -rigidity, convulsions, rapid iv euphoria; sympth stimulation -mild hyperglycemia.
• H release -itch, lip swelling, urticaria, brconstr.
• high abuse -phy&psy dependence.
• withdrawl symtoms- mydriasis, lacry, sweat, goose flesh,  diarrhoea, abd colic, anxiety, insomnia, rapid wt loss. Rx-METHADONE.
• POISONING- CNSdepr: coma, decr resp BP, pin point pupils, pulm edema. Rx- KMnO4 lavage, opiod antagonist.

CODEINE-

• less potent & eficacious
• sub-analgesic doses: higher affinity to antitussive receptors [dry cough]
• analgesic doses: decr diarrhoea & improve concistency in colostomy.

PHOLCODEINE- less constipating.

contrast with PETHIDINE-

• synthetic
• good oral but accumulates os no repeat doses.
• only receptor
• more potent analgesic & preanaesthetic
• few CVeffects
• decr only tidal vol resp
• less smms spasm -miosis constipation urinary retention use- preferred in biliary colic
• less foetal apnoea use- preferred opiod analgesic during labor
• miosis+ no corneal reflex since corneal anaesthesia
• less H -safer in asthma
• anticholinergic- dry mouth, blurring
• withdrawl symptoms less severe.
• no abuse since slow tolerance, dependence
• poisoning - CNSexcitation tremor, mydriasis, delirium, convulsions, hyperreflexia.

FENTANYL- high lipid solubility

• BBB -short acting anaesthetic
• transdermal -chr cancer pain

METHADONE- long acting

• less kick abuse
• late mild withdrawl symtoms
• Rx- wean from opiod dependence

PURE OPIOD ANTAGONISTS: act on all receptors, morphine dependence diagnosis -ppt withdrawl symptoms

NALOXONE -iv short acting, Rx- alchohol & morphine poisoning, reverse apnoea [foetal/intraoperative]

more potent NALTREXONE -oral long acting, Rx- opiod & alcohol deaddiction.

alcohol

alcohol has low safety margin to anaesthesia & death.

[conc: 30-100 euphoria lack caution & self criticism, 100-150 thought clouding decr memory, 150-200 ataxia, 200-300 stupor]

disulfiram

• irreversible[7-14days] inhibitor of aldehyde dehydrogenase causing acetaldehyde accumulation.
• aldehyde syndrome: flush, burning, sweating, headache, vertigo, risk of severe rxns.
• use: alcohol deaddiction in phy not dependent addicts.

methanol poisoning-

• slowly  metabolised to formic acid –> retinal damage, acidosis.
• CNSdepr –> decr HR,BP,resp.
• vomiting, headache.

Rx:

• 10%ethanol to saturate enz & decr metabolism [disadv- unstable conc, no iv preparation, long treatment, risk intoxication & hypoglcemia]
• alcohol dehydrogenase inh -FOMEPIZOLE
• folate to hasten formic acid removal.

antipsychotics

MOA: block D2 receptors in limbic & mesocortical regions.

• initial adaptive incr in DA turnover [antiemetic(drug/disease induced)  but no extrapyramidal effects]
• later tolerance to enhancing effect of DA turnover in basal ganglia [dev of extrapyramidal effects], but not in limbic area [continued antipsychotic action]

high potency drugs: ADR-extrapyramidal motor disturbances [parkinsonian rigidity tremor mask facies shuffling gait rabbit syndrome-after yrs; ms dystonia grimacing torticollis; akathesia restlessness Rx-propranolol; malignant neuroleptic synd fever BP HR tremor rigidity Rx-dantrolene, bromocriptine; late tardive dyskinesia lick chew pout puff] -reduce dose, add antich antipark-benzhexol, cycrimine, ethopropazine…

• haloperidol [no incr wt], trifluperidol – acute schizo
• piperazine: fluphenazine
• penfluridol – chronic schizo
• flupenthixol – negative schizo
• pimodine [arrhyth] – schizo maintenanace

atypical/ second generation drugs: less extrapyramidal effects [uncommon tardive dyskinesia]

• respiridone -[less extrapyrmdl & seizures] [incr prolactin, postural hypoTN, agitation]
• olanzepine -schizo,bipolar,mania [less extrapyrmdl & prolactin] [dry mouth, constipation,incr wt, seizures, agranulocytosis]
• clozapine -resistant schizo [less extrapyrmdl & prolactin] [incr wt,HR,BP, sedation,seizures, agranulocytosis, urinary incontinence,salivation, myocarditis]

low potency drugs [antipsychotic effect dev after wks]: ADRs- sedation, ppt seizures, poikilothermia[decr temp], jaundice, rash, urticaria.

• chlorpromazine
• triflupromazine
• thioridazine [blue exposed skin, opaque cornea]

TOLERANCE dev to Sedation & HypoTN.
no dependence.

pharmacological actions: uses & ADRs.

• decr irrational behavior, aggressiveness, hallucinations, delusions. Rx- functional pschoses [schizo(+>-),paranoia,acute mania], resistant anxiety, initially in organic diseases. [NEUREOLEPTIC syndrome in normal people:decr initiative, psycomotor slowing, indifferent, emotional quietening, sleep (different from CNSdepr)] potentiate all CNSdepressants so used in anesthesia.
• low potent drugs have blocking[postural hypoTN,hypoTN by vasodil/water retention/no presyn & central vaso tone inh, palpitation, impotence] & anticholinergic [dry mouth, blurring vision, constipation, urinary hesitancy]  [atypical clozapine causes myocarditis,salivation by central action, pimodine is arrhyth]
• high potency drugs are antiH.
• decr skms spasm by central action. Rx- intractable hiccups, tetanus, Gilles de la Tourette, huntingtons chorea.
• incr blood glucose & lipids –>wt gain.
• incr prolactin by pituitary Dblock.
• decr gonadotropin –> amenorrhoea, infertility, gynecomastia, galactorrhoea.
• decr ACTH –> no incr steroid during stress.
• decr ADH –>polyuria.

lithium carbonate

• prolonged administration stabilises mood in bipolar & acute mania, recurrent depression, cluster headaches [by displacing Na & modifying membrane property in brain cells & decreasing NA,DA,inositol]
• Li2CO3 is converted to LiCl in stomach /w ic hygroscopic & irritant. decr ADH,thyroxine,blood glucose. tolerable ADRs:vomiting,diarrhoea,polyuria[Dinsepidus],polydipsia, incr wt by edema, goitre, hypoglycemia. CI: DM,Sick sinus.
• excreted in saliva,sweat,milk,crosses placenta. CI:pregnancy,brestfeeding [foetal goitre, cardiac defects].
• low TI & individual variation, hence divide dose to avoid high peaks & monitor serun levels after 12hrs [toxic>1.5mEq].  toxicity: tremors,ataxia,nystagmus,slur,incoordination,hyper-reflexia, drowsy,delirium,coma,convulsions, hypoTN, albuminuria, arrhythmias.  Rx: amiloride[not vasopressin], osmotic diuresis, [HCO3]- infusion, >4 toxicity requires hemodialysis.
• most reabsorbed in renal PCT. so blood levels rise in renal insufficiency, diuretic drugs, Na restriction.
• incr WBC –>use in leucopenia, agranulocytosis.

antiepileptics

Epilepsy-

• focal origin –>spread –>postictal depr.
• unconscious + convulsions/sensory/psychiatric effects.
• primary -genetic
• secondary -head trauma/surgery/ischemia/tumor/cyst –>early responds w/ all drugs, late [8mos-2yr] Rx w/ PB,P.

40% GENERALISED- both hemispheres.

• GTC/grand mal- 1-2min commonest, aura-cry-unconscious-tonicspasm-clonic jerking-froth incontinence -sleep CNSdepr confusion, febrile convulsions.
• Abscence/petitmal- children, thalmcort T Ca++ 3cycles/sec spike wave, stare 0.5min
• atonic- ms relax
• myoclonic- momentary contr of limb/body [phy while passing thr deep sleep]

60% PARTIAL- one part of hemisphere.

• simple/cortical/somatosensory- conscious+convulsions/sensory perception
• complex/temporal/psychomotor- unconscious+bizarre behavior/emotio/puposeless movts.

Tcurrent Ca++ Ch inh	VA, Ethosuccimide.
Na+ Ch inh	VA, Phenytoin,CBZ.
GABA potentiation	VA,Clonazpm, Phenytoin,CBZ, Phenobarbitone,
Glutamate inh	Phenytoin,CBZ, Phenobarbitone
Ca++ influx inh	Phenytoin,CBZ, Phenobarbitone

GTC/Grandmal	Phenytoin,CBZ,VA, PB. New drugs: Lamotrigine [monotherapy] adjuvants- Gabapentine, Topiramate.
Abscence	VA,Ethosuc, Clonazpm,
Atonic, Myoclinic	VA,Clonazpm,
Infantile spasm	CORTICOSTEROIDS, [adjuvant:VA,Clonazpm]
Simple partial	Phenytoin,CBZ,VA,PB New drugs: adjuvants- Gabapentine, Topiramate.
Complex partial	CBZ, Phenytoin,VA, PB New drugs: Tigabine, Vigabatrin.
Secondarily GTC	Phenytoin,CBZ, VA

	oral, PPB, t1/2	metblsm,urine excr, enzinduc.
PB	slow, yes, long	yes,yes,yes
P	slow,yes -displaced by VA,progressive incr.	metab inh by AMA & Warfarin, 5% excr unchanged, inducer.
CBZ	slow, yes, decr by autoinduc	metab inh by AMA, active metabolite, auto+others induc[P,VA,PB,steroids]
E	slow, NO, 48hrs	25% exc unchanged.
VA	good, yes, long action.	complete, active metabolite, inducer.
C	good, yes, 24hrs.	complete

	ALLERGY [rash, lupus]	CNS [drowsy, vertigo, ataxia]	GIT [epigastric pain, vomiting]	TERATOGEN	MISC
PB	in some similar to P	sedation, decr memory & IQ, behaviour abn.
P	neutropenia, megalo[folate] anaemia.	+excitement	+	fetal hydantoin syndrome [cleft, microcephaly]	gum hyper, hirsutism, osteomalasia, hyperglycemia.
CBZ	agranulocytosis, aplastic anaemia, hepatitis.	+neurotoxic, coma, covulsions, CVcollapse.	+	minor malformtn [incr W/ VA]	incr ADH -water retention, hyponatremia.
E	dyscrasia, fatal BM depr		+++		headache, tiredness
VA	thrombocytopenia, pancreatitis, fulminant hepatitis in children.	+tremor	+anorexia	neural tube defects [incr W/ CBZ]	alopecia, curling of hair, incr blood NH3.
C		little sedation, behavior abn, ataxia

	SEIZURE TYPE	OTHER USES
PB [cheapest, least toxic]	4th choice- GTC,SP,CP.
P [CI in females]	1st choice- GTC,SP. 2nd choice- CP.	iv FOXPHENONIUM in status epilepticus, arryth by digitalis, 2nd chice in trigeminal neuralgia.
CBZ	1st choice in CP. 2nd choice in GTC,SP.	1st choice in trigeminal neuralgia, alt to Li in bipolar
E [exclusive action on thalamocortex]	2nd choice in Abscence.
VA [prevents kindling & secondGTC] [CI in children] [w/ Clonazpm ppt abscence seizure]	1st choice in Abscence,atonic, myoclonic. adj in GTC,SP,CP.	alt to Li in bipolar.
C	absence

treatment of epilepsies: cause should be searched & removed, initiate Rx early to decr the propensity to further attacks, if monotherapy fails combine drugs w/ diff MOAs,atleast 3yrs or lifelong, withdrawl should be gradual [since ppt status epilepticus, abrupt only if toxicity] if no family history, recent onset, chilhood, primaryGTC, no cerebral disorder/EEG.

febrile convulsions[GTC]- <5yr age , some become chr. prevention: temp rise should be dampened w/ paracetmol/cooling, intermittent prophylaxis w/ diazepam at onset of fever.

status epilepticus- sudden severe continous

• diazepam/clonazepm ivbolus then slow to control fits
• phenobarbitone/phenytoin after convulsions
• general anaesth, crurarization, positive pressure resp for refractory fits.

NEWER DRUGS:

• LAMOTRIGINE -Rx both mania,depressive phases of bipolar disorder.
• GABAPENTINE, PREGABALIN -Rx for nerve pain associated with diabetes/herpes zoster.