Past, Present & Future of Pharmacotherapy of Affective Disorder

Introduction

Disorder of mood (affective disorder) are common in GP as well as in psychiatry.

Two main types of depression

Major Depression :- A depressed mood on daily basis for minimum peroid of 2 wk.

Incidence :- App 15 % of general population (major depression) 6 – 8 % are correctly diagnosed out of which only ½ - 1/3^rd are adequately t/ted.

10 – 15 % pt of (MD) are prone – suicide.

Manice (M) :- Opposite of depression – euphoria, HM, etc.

Unipolur depression :- Depression / mania with wa x s waning nature.

Bipolar depression :- Cyclically alternating manic & depressive phases.

Bipolar I – Mania predominates

Bipolur II – Depression predominaly

Biochemical changes in Depression

Post :- Older Humoral theories of (AD) affective D. Ancients belived that temprament and mood depended on (4) humours :- likely

1. Blood
2. Black bole
3. Choler
4. Phelgm

Transmitter Hypothesis :- 1960 have attracted supported by mood of action attension 1^st genration (AD) which NA S-H and less ofent (DA) in synapses. Conversly – Reserpic – deplition (MA) – depression

Hypothesis :- (NA) major (NT) in aff. Dis.

1^st coined by schildkraut 1965.

Schildkraut et al showed that meta of (NA) 3 – methoxy – 4 hydexyphengl gycol (MHPG) ed in urine D CSF samples in depression ed in munia and normal during remission in bipolur depression.

History of Antidepressent drug discovery

1. Lithium 1948 John Cade
2. ICAs :- In 1940 Hafliger and Schildler made > 40 comp. Dibenzazepine (imipramine)

In 1958 khun – imipramine effective in mood of depressed pt

1951 (INH) it's iscprepyl derivative iproniazid

3. MAOI :- 1952 Zeller and Co-workers found that iproniazid had a mood elevating effect in pt of TB and later condueled it was MAOL.

1^st MAOI used :- Hydrazine derivatives phenelzine and isocurboxuzide its less hepototixc congerers and nonhydrazine

MAOI – Tranglcypromine became popular in 1960's but their toxicity and interaction placed them to a minor role in psychiatry

Present Trends of affective disorder pharmachotherapy

Most important development of (AD) in 1990s are

1. Selective 5 – HT rut inhubitors SSRIs
2. Reversible and selective of MAO RIMAs
3. Selective serotonergic and (NA) nergic rut NASSRI
4. Selective (NA) nergic rut (SNRI)
5. Almost 40 years ago 1^st (An were introduced

These were

Both classes of drugs are effective in t/t of depression but both posses considerable disadvantage B/o. (AE) profile.

With drawn B/o. (AE) (a) clinical efficucy uncertain classified as (NA) and specific 5 – HT tnergic (AD)

1. (TCAs) rute of (NA) and 5 – HT potentiate their action they differ markedly in their potency

(NA) > 5.HT

1. Nortryptyline
2. Desipramine
3. Protryptegline
4. Amosapine

Mech of action + post synaptic recpt (AR) – ed responsineness – (AD)

Gaba ® - Unclear

P₂ presynaptic autorecptor – desensitization

(DA) in forebrain – (AD)

AE :- Anticholinergic action, post hypotension

• Sinus tachy cardia.
• Arrhythmics

(SSRIs) are free from this (AE)

Current status :- TCAs like

Are now "2^nd drug of choice" in (MD)

2. SSRIs. At present there are 5 marketed SSRIs

• Fluoxitine
• Fluvoxamine
• Paroxetine
• Sertraline
• Citalopram nes

1. Same mech of action, 2. Only differ in their ½ life (SSRIs)

SSRIs have same efficay

(AE)

1. Naused, vomitting are common (AE) of all SSRIs ranfoing (20 – 37 %)
2. Headache
3. Saxual dysfuntion

In comparision to (TCAs) all SSRIs have fuvorable (AE) profile ie : they lack

Anticholinengic of properties as sedating tree from HR arryth as in TCAs lesstoxic in suicidal overdose ed incid :- of suicide as to TCAs interaction

Plasma TCAs l;evel when used in combination – ppt. TCAs poisoning

TCAs are superior in efficacy to SSRIs used in resist depression.

Current status :- From 1960 – 1990 TCAs were more commoly used to t/t depression.

SSRIs posses a preferable (AE) profile.

Ie :- Free of sedation freedom from congnative and psychomotor SSRIs

Frequently used on (OPD) basis.

D.O.C also 1^st D.O.C.

1 – in medically ill pt

2 – Potentially saicidal pt.

(AE) reported during compurative controlled clinical trul of (Citalopram and {TCA}

(AE) interaction

Combination of SSR/s along with 5-H-T agonist should be aavoided

B / o may cause

B / o Serotonin sgndrome"

5-H-T_1A (R) Hyperwtimullllutⁿ

MAO / S

Substrate for type 'A' and type 'B'

Monoamine oxidase

MAO (A) MAO (B)

Preferred substrate : (NA)

5-H-T

Phenylethylamine

Benzylamines

Non specific subst :

Dopamine

Tyramine

Subs. For both MAO 'A'

MAO (B)

Irreversible

Specific inhibitors

Clorygyline (AD) action (A)

Selegiline used parkinsons dise (B)

Nonspecific inhibitors :

MAO 'A' and 'B'

Hypertensine crisis when tyramine rich food ingested chees reaction

Minor role as (AD)

Used only when other drugs fail

Pargyline Tranyl cypromine phenclzine

Specific inhibitors of MAOCA :-

In 1968 2 functional isoforms of MAO discovered development of new MAOI for t/t of depression focused on

1. With selective of MAO 'A' keeping MAO 'B' active to leaminate potentially hazardous tyramine.
2. Reversible and competitive property of this inhibition allowing other subs (Tyraramine) to displuce the inhibitor or (drug) from binding site k/as (RIMAs). Druggare

• MoClo Bemide
• Brofaromine
• Cimoxatone (only in france with weak MAOCA) action.

Moclobemide :- RIMAs isoengyme MAO'A' – only safer than older MSOIs.

• Recent clinical trials and meta analysis have confirmed the efficacy of moclobemide of good (AD) agent
• Moclobemide is of efficacy to – TCAs
• SSRI
• Older MAIL
• Some studies shows that

Moclobemide was less effective than clomipramine in t/t of severly depressed pt where clomipramine was also more effective than SSRIS like – citalopram and parotetine comparative studies show moclobemide better tolerated than.

1 – TCA

2 – nomselective MAOIs

Mochlobemide lacks follow (AE) like

• Anticholinegic effects
• Sedative
• CUS (AE)

Molocbemide vs SSRIs

• Efficaccy almost to SSRIs
• Tendency to cause fewer 91 T AE

91T (AE) SSRI > moclobemide.

• No sexual dysfuntion reported with modobemial of are common in SSRIs sexual dyfu SSRIs > moclo.

Current status

Moclo causes no cognative and psychomotor impairn used in elderly pt.

Or

400 – 600 mg

pt with curdiovascular disease

cost effective – cheeper than older (AD).

Venlafaxine :- Selective 5 – H tnergic (NA) rut pharmacodynamically venlafaxine is to TCAs venlafaxin posses both (5HT) and (NA) rut ing action

It has 5 times more (5 – HT) nergic rut tion action

It is only drug avialable from the group (SNRI)

Pharmucokinetic :-

Venlufaxine recemic mixture

Both enantiomers are active

Venlafaxin demethylatn

Metabolite

0, demethglvenlafaxin

(ODV)

elimination t/2

It also posses (AD) action

Venlufaxin – 5 hr and (ODV) = t/2 = 11 hr.

Plasmu protien binding is – 27% venlafaxin

(PPB) Fluoxetine – PPB – 94%

SSRLS like Paroxetine – PPB – 95%

PPB vcnlagaxin < PPB SSRIS

Compppured to (TCAS) / venlufaxin has less / no

• No anticholinery acit
• No anti histaminergic
• No x1 AK bloxking

Current status

1. Pt with suicidal temdancy

Clinical trials show

• Venlafaxin superior to placebo in (MD) for 6 wk.
• In comparative (OPD) trial (VS) imipramine

Efficacy of venlufaxin imipramine

Eff. Venlafaxin > Fluoxetine

• Venlufaxin has comparitiuely faster onset of action with 4-7 day of t/t (?)

Dose yes ponse velationship exist with BP.

75 mg OD (VLF) BP was / mm Hg; 225 mg of BP 2 mmg Hg 375 mg OD BP by 7.5 mm Hg.

Nefazodone : Congener of trazadone 5-H-T x. (Selective) 5HT rut X of fluoxetive with 5-H-T (R) blaking action very less x1 (AR) binding as comp to trazadone risk of priaapism less than trazadone efficacy of nefazodone imipramine for sever depression

Depression with anxity

Recurrent depression

(AE) Dry mouth

Weakness Rause

Consstipation

Blurredvision

(AE) likr that of SSRIs are absent may be B/o (5-H-T₂) antagonism onset.

Nefazodone REM sleep stage 3 and 4 sleep

Current status

Used in t/t of depression with insomnia recurrent depression.

Mianserin : Presynaptic x2 AR bloxk

(NA) release (AD) effect.

Not inhibiting (NA) and (5HT) rut.

H1 block by mainserin sedution releves anxity with depression

(AE) blood dyscrasis – Hepatotoxic

Use restricted

Currently not popular AD.

New drug

Noradrenaline

Serotonin

Mirtazapine

Mirtazapine enchaces NA nergic and 5 – 1 + T, mediate (NT)

Mirtazapine is a (NA) nergic and specific (5 tnergic (AD) (NaSSA) used in (MD).

A newer (AD) drug with unique mode of action efficacy of mirtazapine + to that of TCAs

= to Trazadone in modrate – sever depression and with Anxity and insomnia

evidence for faster onset of action tht (SSRIs) but tolerability profile of (Mtz) = (SSRIs)

(AE) seen of in (TCSa)

Apetite and wtgain common with (mtz) > to other (AD)

Mirtuzapine (mtz) low affinity for cholinergic (R)

• (DA)
• Muscarine (R)

High affinity for (H1R) sedation

(mtz) more cost effective than Fluoxetine or amitryptgline

For t/t of (MD)

Conclusion :- nely developed (AD) seem to posses certain advantage (TCAS).

2 major medical need – for t/t of depressedpt have not been met.

1. Superior officacy to (TCAs)
2. Faster on set of action.

Newer (AD) have some advantages over (TCA)s are

1. No sedation (expt. Mirtazapine)
2. No anticholinergic and cardiotoxic effect
3. Headache and insomnia with RIMA (Moclo).

Bipolar ddisorder

Morden t/t of (BP) disorder was revolutionized with Li⁺ in 1949. Lt⁺ was gradullay accepted world wide 1960 – 705.

At present Li⁺ is use prophylactically for t/t of (BP) disorder. But requires serum levels assesment frequently for (AE)

• Antiepileptics lide carbazmazepine

Valproate

Also have mood stabilizing property

And they are used as alternatives to Li⁺

In acute manice :- as Li⁺ has slow onset of action

Pts are 1^st controlled by

Low compliance in pt on Li⁺ - 10 razepam

Or

• Clonazepan.

Than gradually Li⁺ is introduced for long term mood stabilization.

Clinical trial show.

Carbamazipine = Li⁺ for protection rates efficacy. Combination of Li+ earbazi has in short term trials better efficacy.

• Valproate is better toleruted clinically.

Future :- GABA nergic agents like – Clobazam

Gabapentin

Lamotrigine

Vigabatrin

• Ca²⁺ channel Blocker need further evaluation as moodstabilizing agents

Atgpical Antiphychotics like – "Clozapine" should be considerd (Doc) for (BPD)

Future in )VD) t/t

• New pharmacological mech should be found to overcome the efficacy disadvartage of exsisting (AD).

1. Modulatⁿ of Neuropeptides :- As (NP) play key role in regulatocy CNS function.
2. Direct influence on 2^nd messenger system Via :- IC AMP

Or

Zphosphatidly inositol system

1^st step in this direction was Rolipram

3. Another intresting approch would be to dwelop CNS selective MAADDI with no effect on peripheral and hepatic MAO.

Drig is – MDL – 72394 (prodruy)

Irreversible central MAO – A Inhibitor

4. Very diff. Approch to (AD) t/t which might fullfil some of stated fzatuas of AN I deal AD is S – adenosy L – L – Methionine k/of (Same, ademetionine)

Same – Causes ed conversion phosphatidyl ethunolamine SAMe

Phosphutiiasl choline (ptc)

This – (ptc) Fluidity of (CM)

(NT) sion by No receptors

efficacy of receptor – effector coupliny

Uptill now no major progress has be made dixovery of imipramine – 1950s.

References

1. Goodman Gillman
2. Harrison's priciples of Internal medicine
3. Lewis's phormacology.
4. Principles of clinical psychiatry
5. Drugs :- 1996, 51 No. 3
6. Drugs :- 1992 43 supp. 2
7. Drugs :- 1999 57 (4)
8. Drugs :- 1996 52 (5)
9. Rang and Dale pharmacology

Summary

Major limitation of efforts to develop new (AD) is lack of exact pathophsiological mech of major depression and bipolr disorder despite decades of research work.

Most important development of (AD) in 1990s

Were – SSRI

• RIMAs
• (NA) ut
• SNRI

These compounds have very low binding capacities at other receptors not linked to their (AD) action – Tolerability improved.

But still no one of them fullfil critearum

• Superior efficacy to TCAs.
• Faster on set of action.
• Effectiveness in t/t of Resistant dep.

Multi Drug Resistant Mycobacterium Tuber Culosis "Molecular – Perspective"

Tuberculosis

Is an infectious disease caused by bacteria belonging to the mycobacterium tuberculosis complex

It affect the lung

In 1/3^rd cases :- Other organs involved

Etid - pathogenesis :-

1. M. tuberculosis is a rod shaped, AFB
2. Transmission : Droplet nuclei
3. Crowding and poor ventilation
4. Endogenous factor

Transmission through respiratory route

Bacilli enter into the lung

Bacilli ingested by macrophage and transported to regional lymph node

Bacilli reaches to the blood steam

Dissemination ocuure

(primary infection)

Tuberculosis develops within wks after primary infection.

Problem of tuberculosis

TB has reemerged as one of leading cause of death

Global incidence of TB

• Estimated 8.8 million new cases every yrs. In world
• Nearly 3 million deaths annualy
• 52,000 death / wk
• > 7000 death each day

Factors :-

1. Productive age 15 – 49 yr.
2. HIV infection

Incidence and mortality is high in developing country (India)

Clinical presentation :- Patient presents with

• Fever
• Bight sweats, wt. Loss
• Anorexia, weakness

Majority of Cases

• Cough with expectoration
• hemoptysis

Clinical manifestation :-

Classifies as :-

• Pulmonary TB
• Extra – pulmonary TB

Pulmonary TB :-

• Primary disease
• Secondary (Post primary)

Primary pulmonary TB :- it result from initial infection with tubercle baulci.

• localized to middle and lower lung zones.
• Seen in children

Secondary TB :- Result from endogenous reactivation of latent infection

• Localized to upper lobe
• Occur in adult

Extra pulmonary TB :- Common sites are lymph node, pleura, U.T. bones, ioint

Pharmacotherapy

I^st Line Drugs :-

1. INH
2. Streptomycin
3. Rifamicin
4. Pyrazinamide
5. Ethambutol
6. Thiacetazone

II^nd Line Drugs :-

1. Ethionamide
2. Cycloserine
3. Kanamycin
4. Amikacin
5. Caprecmycin

Short course chemotherapy :- For 6 – 9 month duration

Goals :- Who regimens for tuberculosis

It consists of following category

Category I :-

1. New SP. + VE pulmonary TB
2. SP. – VE + extensive parenchymal involvement
3. New cases of extra pul TB

Category II :- SP. + VE failure, relapse

Category III :- New SP. – VE + parenchymal + less extra pul.

Category IV :- Chronic cases MDR

Category – wise treatment regimens

R + H – ZE + S + Cipro

INH :- Primary drug for chemotherapy

Bacteriostatic and bacteriocidal

Mech :- Inhibit the biosynthesis of mycolic acid

Kinetic :- orally absorb

• Peak plasma conc^N 3 – 5 ug / ml – 1 – 2 hrs.
• INH acetylation shows genetic variation fast and slow acetylators

AD effect :- Skin Rashes

• Iaundice peripheral neuritis

Interaction :- Phenytion – Hepatic biotransfor mation by INH

Dose :- 300 mgs daily

Rifampioin :- Semisynthitic derivative of rifamycin B

• It is bacteriostatic.

Mech :- Inhibit DNA dependent RNA polymerase of mycobacteria forming stable drug enzyme complex leading to suppression of chain formation in RNA synthesis.

Kinetics :- Absorb orally

• Peak plasm concⁿ :- 2 + hrs about 7 g / ml
• T½ - 1.5 – 5 Hrs.
• 80 % bound to plasma protein
• Desacetyl rifampicin – active metabolite

AD effect :- Nausea, Hepatitis, Flu – like syndrom

Interaction :- Drug is inducer of hepatic microsonal enzymes t½ fo many compound

1. Yarapamil, OC
2. Propranolol, sleroids

Streptomycin :- Bctericidal durg

Toxic in nature least used

Pyrazinamide :- Synthetic pyrazine analog of nicotinamide bactericidal in nature.

Kinetic :-

• Absorb from G.I.T.
• PPC – 45 mg / ml at 2 hrs. – after dose of 2 gms.

AD effect :- Hepatotoncity

Hyperuricemia

Dose :- 2 gms daily

Ethambutol :- Bacteriostatic drug

• Inhibit protein synthesis in cell
• It prevent from development of resistance

Dose – 250 mgs OD

S.E. :- Postural hypotension

Olfactory disturbance, blurred vision

Thiaceazone :- Static drug low efficacy

• hepatotoxic

II^nd Line drugs

1. Ethionamide – Structurally similar to INH

• Has short duration of action

S.E. – hepatitis intolerence

Dose – 1 gm / day.

1. Cycloserin :- Antibiotic, analouge of D. alanine

• It inhibit bacterial cell wall synthesis
• CNS toxicity is high

Dose – 100 mg / day

1. Other aminoglycoside :- More toxic

• Kanamycin
• Amikacin
• Capreomycin

Increased death rate is due to emergence of new strains of M. Tuberculosis resistant to some or all current anti – TB drugs.

50 – 80 death raies associated with MDR – TB.

"MDR State" in mycobactesiology refers to simultaneous resistance to at least rif and INH with or without resistance to other drugs.

Etiopathogenesis of MDR

1. Improper prescriptiions
2. Improper Dosage
3. Non compliance of patient
4. Associated HIV infection
5. The drug fail to reach the target site
6. Inactivation of drug.

The discovery of drug resistant was made by middle book and yegian 1947

1. Streptomycine resistance – Prolonged exposure
2. Pas – Bacteriostatic agent.

Less resistant then streptomycine

3. INH resistant demonstrated in trials
4. Rostogi reported a case of MDR at institute pasteur serial isolates of myco. TB were coltured from patient who fail to responds chemo therapy.

1^st Isolates – INH, RIF

2^nd Isolates – ENB

3^rd Isolates – PZA

Last Isolates – Cipro, sparfloxacin.

5. – Genetic and molecular analysis – Resistance is acquired by the bacilli

• Alteration of drug target through mutation

Resistance is high for less effective drugs

• Thibacetazone
• Etbiconamide
• Capreomycine, cycloserin

Intermedate :- INH, SM, EMB

• PAS, Kanamycin

Lowest :- Rifampicin

Tupes of drug resistants :-

Primary drug Resistant :- Is that encountered in patient who have never HID any chemotherapy arising either from mixed population of both sensitive and resistant organisms.

Secondary :- Result from inadequate drug therapy

Acquired :- patient who were previously infected with sensitive organsisms but later developed resistance due to faulty treatment.

Initial :- Patient reporting for the first time with drug resistance strain.

Epidemiology :-

1. Prevelence rate of MDR :- 48 % in developing countries.
2. In Nagpur – Study was done 1997 shows that – 22.11 % MDR TB

Chart showing resistant and sensitive strain

Mechanism of Resistance :-

In the past, few years, genetic and molecular insight have unravelled the mech. of drug reststance.

But now with the development of various molecular strategies to rapidly detect MDR – TB.

Resistance to INH

Resistance of – INH ethionamide :-

Inha locus is responsible for co-resistance to INH and ethionamide

• Inha locus composed of two open reading frames (ORFs) disignated as orf1 and inha seperated by 21 – bp noncoding region Inha an – ACP reductase
• Mutation in the putative prometer region hyper-expression of inha, result in INH resistance.
• Inha mutation occure along with katg mutation in relation to lipid metabglism of INH resistant isqlates which play the tole of the respective loci in the mechanisms of action of INH and acquisition of drug resistance.

Resistance to rif

Mechanisms of action

RNA Polymerase Composed of and different subint

• Rpr gene in E-coli demonstrated that rif interacted with the B subunit of RNA polymerase so mutation occure in rpob locus, leading to defective binding of the drug and resistance occure.

Mutation – rpob lacus acts as surrogate market for KDR – TB

• Shows single A.A. substitution in bp core region of rpob gens.
• Change in codon se – 531 and his 52 account for more than 70 % mutation with rif. Resistance
• RIF pemeability and mutation in alternate subunits of RNA polymerase – resistance.

Mutation can be detected by following techniges

• PCR
• Finger printing
• Line probe hubidization

Resistance to EMB :-

1. Indentificaition of arabinosm transferasc as the primary traget for EMB resistance.
2. Locus consists of 3 complete ORF's EMB EmbA, EmB

• EMB interects with Emb CAB proteins coded by Embs, Emba, Embb leads to inactivation of arabino – galaction synteesis.
• EmbB lacks A potenential ribosomes binding site so it coupled to Emb A – Leads to resistance.
• Lyperexpression of the EMB – CAB protein.

Resistance to FQ's

Mechanisms of action :- AQ's binds with greater affinity to single stranded DNA. Leads to inhibit DNA regulation leads to effective transcription block and cellular death.

• Mutation in 9 yr A and 9yrB genes leads to resistance
• Amind acids substitution at position 88, 94
• Mutation in 9yrA – Change in permeibicity (cell wall)

Resistance to SM :-

Mechanisms of Action :_ SM disarupts the decoding of amino – acyl RNA and thus inhibit mRNA translation.

1. Resistance :- Due to acetylation of the drug by dmino glycoside modifyni enzymes.
2. Mutation –

1. S12 ribosonal protein – rpsl gene
2. 12S rRNA encoded by rrs.

1. There occure two distinct classes of mutation

1. Point mutation in S12 ribasomal protein encoded by rpsl gene
2. Mutation in the rrs encoding the 16S rRNA.

Point mutation in the rpsl gene result in single amino – acid substitution that affect the higher under structure of 16S rRNA and resistance occure

• Mution affect lysing residues of position 43, 88 leads to substitution with either arginine at 88 or arginine and theonine at 43.

2. Mutation in the rrs lacus have been mapped to two region

1. 530 loop and 915 region of amino acid.

3. Role of cell wall permeability.

Resistance to PZA :-

1. Point mutation in the pncA gene of PZA – resistant MTB strains – leads to resistance
2. Substitution of Cys 138 – Ser.

Asp 63 – His.

Deletion of G. nucleotide at position 162, 288 resulted in defective pzoase.

Gene loci involved in conferring drug resistance in mycobacterium tuberculosis.

Treatment of Nor

Basic principles to treat MDR – TB as follows

1. Drugs to be given in adequate doses and for adequate duration.
2. Drugs used must not have been given in past.
3. First line drugs are preferred. As they are more effective and less toxic.
4. INH must be used in all regimens.

Potential regimens for patients with MDR – TB

b :- If resistance to amikacin, kanamycin, SM, then capreomycin is good alternative. Given daily new anti – TB drugs.

c :- Drugs like clofazimine, amoxicillin – clavulanate, clarithro xycin, azithromycin, rifabutin are useful but unproved utility.

2. Dot programene (Directly observed treatment)

• The NTCP helps patient getting best medicine available.

Under DOT, A patient is required to ingest the medicine in presence of physician or trained person.

• SSC is used under DOT programme.

MDR infection inHIV + VE patient

Initial reposts shows that MDR TB and Aids has high and rapid mortality.

Mortality – 85 % after diagnosis.

• DOT
• ANTI – HIV therapy
• Life time fallow up

Prevention of MDR – TB

Two main approahes

1. Indentification and treatment of MDR
2. Indentification of person with tubercular infection and their prophylatic treatment – the aim is to prevent 5- 10 % risk of diseases development.

Chemoprophyaxi of MDR

INH is the acsepted drug

If resistance to INH, RIF then – PZA + EMB PZA with or without ciprofloxin

Summary :-

• MDR strains of mycobacterium tuberculosis seriously threaten tuberculosis control and prevention efforts.
• Molecular studies of the mechnism of action of anti – tubercular drus have elucidated the genetic basis of drug resistance in myco – TB.
• Drug resistance of M. Tuberculosis is attributed primarly to the accumulation of mutation in the drug target genes, these mutation leads to an altered target or to change in titration of drug.
• Development of specific mechanism – Based inhibitors and techniques to rapidly detect multi – drug resistance will require further studies addressing the drug target interaction.

References :-

1. Satoskar
2. Thripathi
3. Good – man – gilman's
4. The Indian iournal of tuberculosis

Jan 99, 46, 1

5. Livette S. Johnson, Kent A. Sepkawitz
6. Published paper of Dr. V. A. Rajadnya

N. J. medical College, Pune.

7. Drugs 94, 48 (5)
8. Harrissons
9. Unpublished paper from dept. of TB and chest diseases, GMC, Nagpur.

Advances In control of Ischemic Heart Disease

Definition

Impairment of heart function due to decrease in blood flow caused by obstructive changes in coronary circulation to heart (WHC)

Epidemiology

• Modern epidemic worldwide
• Cause of 25 – 30 % deaths in MCST industrilised countries
• Proportional mortality ratio

30 % male

25 % female

• Loss of expectation of life by 3.4 – 9.4 yrs. In male more female
• Despite advances in MGT,

Mortality – 10 % in 1^st yr.

Age standerdised death rates / 1 lac

IHD in India

On screening persons 730 yrs. By 12 left prevalence in Urban – 65.4 / 1000 male

47.8 / 1000 F

In Rural – 22.8 / 1000 M

17.3 / 1000 F

Pattern in India :-

IHD appears 10 yrs. Earlier than in developed.

Ischemic Heart dislast

Clinically, IHD gives rise to

1. Angine Dectoris (A.D.)
2. Myocardial Infacction (M.I.)

Clinical Features

1. Angina Pectoris : 3 forms

1. Chronic Stable (Classic Stable)

Retrosternal Chest pain Episndic, Typically Calsed by exertin and Reletived by rest lasts for 1-5 min.

2. Unnstable (Classic Unstable)

New onset angyny (< 2 months). That is severe &/or frequent (<3 / D). Accelerating angina usually ass with accelerating stenosis in 1 / more eppicard A.

3. Variant (Prinzmetal) A.P.

Chest pain AT rest.

May last for > 10 Min.

Due to focal vaso spasm.

1. Myocardial Ischemia

Retrosternal pain usually radiatim.

Severe / Intolerable. Than A.P.

Lasts longer (>.30 Min).

Not Releived by Rest or N.P.

Nausia, vomittima, Diarrhora.

Excessive Perspiration.

Management of IHD

Main Pharmacotherappeutic Goals

Releif of pain.

Reduction of Myocard Ischemia during attack.

Rediction of silent myocardis.

Improvement in

Pathophyslology

Haemodynamic profile

Neuroendocring activity.

Striated Muscle metabolism

Prevention of Progression

Redution of coronary Atheroma.

Improvement in Risk profile.

Limitation of infarct size

Extension of life span.

Management of A.P.

1. Stable A.P.

Asppirin 75 – 325 mg / d

Intermittent Nitrate Theray

NTG SL TAB 0.3, 0.4, 0.6 mg.

Onset of actopm 1 – 2 min. DurN – 15-40

ISDN SL TAB 2.5 – 5 mg

Onset 2-4 min DURn – 1-2 Hrs.

For Propphylactic use before exertion

NTG T 2.5 and 6.5 mg DASE – 2.5 – 6.5 mg

NTG Skin paste 2% 15 mg / INCH

Dose – 0.25 – 0.5 INCH

T Sorbitrate 5 mg and 10 mg T. Dose – 10-40.

2. MGT of Unstable A.P.

1. Acute Phase (48 – 96 Hrs.)

Aspirin

Heparin

IV Nitrates

B Blockers

Caclium Channel Blockers.

2. Subacute Phase

Oral Nitrates

Heparin

Aspirin

3. Chronic Phase

Aspirin

B Blockers OR

C.C.A.

No smoking, DIET, etc.

MGT of Variant A.P.

IV NTG

C.C.A.

If No Response

Combination Therapy

Amiodaron

Guanethidine

Clonidine

Oral Nitrates for Prophylaaxis

Aspirin

No B Blockers in

Vasospastv Angina

Drug Therapy of A.P. Protocol

Angina

Infrequent Angina

Prophylactic Nitrates for Exert

More Frequent Angina

Angina Frq Limiting Activity

B Blockers

B. B. Contraied

C.C.A.

Angina Still Disabl

Maxlmise Drug Combinations.

Angina Still not Controued

Coronary Angyogr

PTCA CABG

MGI of Myocardial Infarction

1. During 1^st 6 HRS (Hyperacuteph)

Streptokinase

Heparin

Aspirin

2. BETN 6 HRS – 3 Days (Acute Phase)

B Blockers

IV NTG

No.C.C.A.

If B Blockert contraidicated, NON DHP CCA are used.

3. After 3 days (PT is stable)

B Blockers

Oral Nitrates

C.C.A. (Non DHP)

Aspirin.

Advances In Conrol of IHD

1. Pharmacological Advances.
2. Non Pharmacological Advances

Pharmacological Advances

1. Aadvances in Conventional Therapies
2. New Therapies.

1. Advances in Conventional Therapies

1. Nitrates

Preparations Avaliable :

Action :

Prelcad Afterload

Relieve Corcnary spasm

Redistributes Blood along Collateral Channels.

Side Effects :

Headach

Methaemo Globinemia

Hypotension

Syncope

Contrind

Angina by Hypertrophic CMP.

Cardiac Temponade.

Disadv

Tolerance

5. Isosorbide Mononitrate (ISMN) ADV

Completely Bloavallable

Achieves High Blood Conc.

Not converted to Another Active met.

Dose not Undergo Presystemic.

Hepatic Elimination Smaller

Doses Than ISDN Required.

Effect Lasts Longer.

Molsidomine – New Drug

Nitrate like agent that appearc to produce vascular smooth musqe relax by same machanisms as Nitrates.

Undergoing Clinical Trials Recent Studies Show.

NTG Platellet Aggregation INHIB^N

+ VE in folts model

ALSSCC + VE in man in theraputk doses in unstaable angina.

To Avoid Tolerance :

Use Eccentric dosage schedule e.g. BD.

Transdermal patch removed for at Least 8 – 10 Hrs. at night.

Self conrolling Transdermal Patches.

1. Calcium Channel Antagonist

Preparations Available

Action :

Selectively inhibit inward ca 2t current in those Tissues where action Potential has dominant ca 2t dependant upstroke like vascular smooth musue and nodal tissue

Vasodilation

• VE lonotropie Effect

Adverse Effects :

Flushing, Headach, Palpitation

A – V Block, PPT ^N of M.I., Heart Failure.

Contrind :

Sinus Bradycardia, A-V cond Deffects.

Hypotension, Obstr CMP.

Severe Aortic Stenosis.

New Drugs

1. In DHP Nisoldipine, Nitreddipine.
2. In Phenylalkylamines : Gallopamil.
3. In Piperazine : Flunazarine, Panolazine, Tr rmetazodine.

1. & (b) Have same actions as other members in their, class
2. Have some Cytoprctective effects on myocardium

Shown to be Effective as antianginal agents in absence of Haemodynamic Disturbances.

Recent Studies Show :

All C.C.A. Ability of Myocardlum to sustain ischemia

Reversible injury

Delayed by C.C.A.

Reversible injury

They support and protect ischemic fibres during short periods of ischemia

Prevent cumulative damage.

Veradamil Reverses exercise Induced se In coronary resistence, in coronary flob thus improves segmental myocarde. Function verapamil ses Viscocity of Blood Gallopamil prevents sichemia Induced Activation of Neutrophll

Recent studies on C.C.A. and Endothelium show :

CCA also help vasodil ^N through endo thelial mechanism (EDRF) CCA donot affect ca dependent form of No. they interfere e- hypoxia induced damage of endothelium thus no release. They effect of ET₁ induced activ ^N of Mcrophages.

New study in T/t of Aaginagits – Nifedipine :

Gastrointestinal therapeutic system recently developed formul ^N that slowly releases drug in GIT over 24 Hr. Period. When given O.D. same efficacy as S.R. forml ^N of felodipine, verapamil and diltiazem study.

30 – 90 mg of GITS NIF added to existing CCA or B. Blocker therapy.

OBSV ^N Time to onset of angina and extent of st seg. Depression at 24 hr. After 1^st dose

DUR ^N OF Ischemia

Frequency of attacks

NTG of consumption

Advantages :

More effective

Adequate control in stable ang.

Better tolerated in elder.

Can be substituted for conventional T/A

Incidence of adverse R less than con.

Minimum effect on lipid and glucose metabolism.

Reverses L V Hypertrophy

Duration, frequency of attacks.

NTG consumption.

Dosage : start with 30 mg OD

Max 120 mg OD

Disadvantage : Not reported.

Amlodipine :

Current new SHP CCA

Studies show : At 5 – 10 mg /OD )Ther. Dose)

Frequency of attacks

Time of onset.

Consumption of NTG

Total work duration.

Anti anginal efficacy is similar to Diltizem, Nifedipine

B- Blockers + Amlod = Additive effect

Isch. In post infarct.

Advantages :

No adverse effect on rest in HR & BP.

No adverse effect on Cardiac output.

Useful in vasospastic angina.

No adverse effect on lipid and glucose metabolism.

No postural hypotension.

Less tachycardia than nifedipine.

Adverse effect :

Reflex tachycardia.

Antiatherosclerotic effect on CCA.

CCA primarily affect interactions of smooth muscles, endothelial cells, monocytes and platelets which play central role in ATH CCA interact specifically with these cells types and do not allow them to take part in ath. Process.

Recent studies show :

CCA Can lower expression of adhesion molecule in cultured endothelial cell thus redn cell adhesion.

e.g., Nitiendipine lowers surface expression of Adhesion molecule VCAM.

DHP CCA Amlodipine is shown to have antiaggregating effect on platelets mechanism.

Free Ca in platelets.

Release of thromboxane.

CCA can stop process of atherosclerosis and calcification of vessel wall.

Studies :

Animal Study

CCA or prevent deposition of Ca or Cholesterol in vessel wall

Clinical trial :

International Nif. Trial of antiatherotherapy (Intact) :

PTS : Mild / Moderate atherosclerosis tested with nifedipine for 3 years.

Significant effect CN develop of new plaques (P < 0.05)

No resolution of old plaques.

Conclusion from intact :

Ca antagonists may be useful as prophylactic agents in early stages of athesclerosis.

In primary study (1985) (Animal study) CCA retard development of athesclerosis.

CCA & MI

In very acute phase.

Harmful specially in L.V. Dysfunction.

In post infarct period :

Non DHP is useful when used in acute stage of AMI.

Mortality :

Current trend.

No CCA in acute phase of AMI.

After acute stage passed and patient is stable.

Non DHP CCA – Diltiazem, Verapamil used.

Mortality

Sudden death.

Short acting DHP – Nifidipine is harmful in acute phase and postMI

(Because reflex symp. Response TC prediminant vasodilation caused by NIF)

Place of CCA in MI therapy.

Verapamil and Diltiazem : Useful alternative to B blockers when used for secondary prevention in post MI specially with good IV function.

B Blockers

B Blockers available

Seminar Topic

Dr. A. Kumar IGMC, Nagpur

Cogestive Cardiac Failure & Its Pharmacotherapy.

Pharmacotherapy of Cardiac Failure

Reduction in ventricular wall stress by

• Bed rest (Anxiolytics)
• Vasodilators
• Positive inotrapic drugs such as

Digitalis (Also was Wonder Drug in CCF)

Reduction in neurohormonal activation by

• ACE inhibitors

Counteracting Na⁺ retension by

• Restriction of Na⁺ intake
• Promotion of Na⁺ excretion by diuretics.

Digitalis

1. History

1. Cardiac Giycoside comes from laves of plant fozglove family.
2. Effectiveness in CCF was described by withering in 1785.

"Who wrote on the use of the foxglove it has a power over the motion of the heart to a degree yet unobserued in any other medicen."

1. Chemistry

C.P.P Raing = Cylopentano phenanthrene ring

Each glycoside represents a combination of an aglycone or aenin with sugar

Pharmacological activity is present in aglycone or genin

(Cg) 1 x Na⁺ / K A tpage of cell remine with constist of Na⁺ / K⁺ p

1. (Cg) bing to K⁺ binding site of enzyme and pump.
2. This pump causes size in (Na⁺) influx.
3. The rise in (Na⁺) slows down the rute extansion of (IC) cs²⁺ across the numbrune the is 13/0 of esctruesion of intro racellular (IC) Na²⁺ by a Na⁺ / Ca ²⁺ exchange mechanism. Therefore more ca²⁺ is retained inside the all.
4. This introcell (ze) ca²⁺ conc. Causes relese of ca²⁺ frp, sarcp[;isocret tjos ca²⁺ (IC) actiuatus leght chamysoin and this myosin combius with cectino form actomyosin.

Mechanism of Action of Cardiac Glycosides

1. = Volt ghted ca⁺⁺ channel
2. = Triggek
3. = Voltage gated ca⁺⁺ channel
4. = Ca⁺⁺ transportar
5. = Myosin filament
6. = ca⁺⁺ sensitizer
7. = Actin myosin (Ross bridges)

Pharmloical of pigitalis

1. Cardiovascular actions

(I) Contractility

1. Increases speed force of contraction tve inotrapic effect
2. Systolic phase – Rest to heart
3. O₂ consumption by diastolic heart size

Cardiotonic Drug

2) Heart Rate :- Heart rate by vagal action

7) Blood fressure :- No change also not contraineticated in hypertension

1. Coronary Cireulation :- Diastolic Heart size

 

 

2. Digitalis & potassium

Hy pokalimia Digitalis toxicity

10) Digitalis & Calcium

Sumergostical action with ca⁺⁺ IV ca⁺⁺ - cardiac arrest in systole

Extracardiac

Actions of Digitals

1. Kidney :- Causes 2⁰ diurasis casodilataion – GFR – urine

Venous pressure

2. GIT :- Nuasea, vomitting, anorexia action

Diarrhoe rarely

Drug Interactions of digoxin

1. Druges which serum digoxin levels

1. By Bioavailubility

Cholestyramine, kaolin pecting, antacids neomycin, sulfusalazin

Therefor give digoxin 8hr. before the agent

2. By induction of hepatic microsomal enezyme rifampicine

1. Drugs which serum digoxin levels

Propufen, quinidine, verapamil, amiodarne methyledopa, indomethacin

Renal digoxin clearance & volume of distribution 70 – 100 % serum levels

Therefor does of digoxin are by 50 %

2. B – Blocker, verapamil ca⁺⁺ channel blocker flecanamide, disopyramide

They (SA), (AV) Junctional conduction velocity tissue Automaeity

3. Kaliuretic diuretics

They serum K⁺ & tissue K⁺ Automacity

Therefor moiter ECG for arrhymius

Principles of treatment of digitalis

1. Stop digitalis
2. Stop diurectics
3. Estimate serum potassium
4. Treat bradycardia with atropine.
5. Mils toxicity treat with K⁺

Ventricular premature beats or bigemini give : 5 – 7.5 gm of Kcl orally / day in divided doses or 40 meq of Kcl in 500ml of 5 % dextrose IV over 2 – 4 hr. with ECG momitering

6. Supraventricular tachyarrythmias

Give : 10 – 40mg of propranolol ghrly of 0.5 – 1mg of propranolol IV

7. Ventricular tachycardia

Give : Lignocain HCL in initial doses of 1 –2 mg / kg IV followed by similar dose at 30 min interval or by drip at a rate of 1 – 2mg / min.

Of phenytoin 'Na' 250mg IV over 5 min.

8. Sever digitalis toxicity

Give : treat with digitalis antiboies fab fragament (Ddigibind)

9. K⁺ is contra indicated in tnce of AV Blook hyperkalimia, & sever renal insuffeicency.

The cation itself prolongs two (RP) of AV node :- (CI) (DOC) in Ht of tach yarrhythmics. Inss digitals.

Cardiouersion by (PC) is (CI) in contⁿ defects my unmushed by digitals.

Selar taxicity digxin antibodis (rb) digi bind (40 mg) vicl 170 disoxin fab complex in excreta by kidnings.

1. Pigoxin in (HF) with underate (UF)

1. Digitalis VR in AFⁿ beg No. og impulge that pass down fue AU node D bahdle of his.
2. Digoxin the ERP of AV – node by direct indired cm (uargal) D auti (AD) my action the interval het. 2 successive impuls in ed.
3. A degree of AV blook D natarulay that in (AF)ⁿ B to longer ERP of (AV) node. So many impuls (AFⁿ – 500 min) thay die as tacs fall during ERP of AV node Therefore when difitalins is given in (AF)ⁿ the (UR) is in dose dependent maxurer

Preparations

1. Tab Digocin 0.125 mg or 0.25 mg of digoxin (Lonoxin)
2. Digoxin injection digoxin in 70 % also each ml contains 0.25 mg of drug dilute it with 10ml of 0.9 % Nacl give slow over 10 min.
3. Digitoxin tab – 0.1 mg
4. Ourbain aqu. IV. 0.25 mg / ml of drug.

Therapeutic uses of digoxin

1. Congenstive cardiac failure (low out put).
2. Left ventricular failure see 84 – 352
3. Atrial fibrillation with fast ventricular rate.
4. Atril flutter
5. Atrial & AV nodal paroxysmal atrial tachy

Therapeytic utility of digitalis

1. Extremly useful : In CCF with afinton s ventrute
2. Very useful low output failure

In valvular, HT, IHD

3. Useful in shock assi with HF
4. Iimited value in high output HF
5. Not effective in MS, conc. Pericurditis
6. Contraindicated in

AV Block,

Dynamic out flow obstruction as hypertropic cardio myopathy

Slow digitalizations :-

1. Mild to modrate cases of CCF avarg dose of digoxin is 0.25 mg
2. Resporse takes J – 7 days to develop
3. If no respouse is seen with in 1 wk. Then the dose to

Guide :- Impornt of S/S of CCF, HF, Bodycot, Borudy cardi HR C60 . min is an indication for stoping drug.

1. Rapid oral digitellization with few hr.

Digoxin 0.5 – 1 any stat – 0.25 mg / 6hr. it takes 6 – 2 hr.

Digitalisation

1. Digitalisation without loading dose

Digoxin 0.125 – 0.5 0.75 – 1.5 C. 5 – 1.5

Digitoxin 0.05 – 0.2 0.8 – 1.2 C – 8

(Oral) (IV)

Digoxin given as single daily dose max upto 0.25

Larger doses are divided to avoid nauser.

Digitalisation with – Digoxin occurs in 5 – 7 days

Digitoxin – 25 – 30 dy

Nyha class II & III days after randomization

= Placebo ie :- without digoxin (diuretis + ACEI)

= pt on digoxindinrectics + ACEI

with drawal of digoxis & probablity of worse HF in Radiance – Randomazed assesments of digoxis on Inhibition of ACE vyha II – dyspnea on walking flut

III – dyspnea on getting in / out of bed

Type of Vasodilators used in CCF

1. Predominant arterial dilators

1. hydrallazine
2. Phentolamine (AL)
3. Minoxadial

1. Predominant venodilators

1. Nitrates (PL)

1. Balanced dilators ie : arterial & venous dilation

1. Na⁺ nitropussied (AL & PL)
2. Prazosin
3. ACE inhitors

Vasodilators are used in all types of HF ranging from acute to chronic they mortality

Mild to sever

Various vasodilatory vary in

But only ACE inhibitors S/or combination of hydrallazine + Isosarbide dinitrate is useful improved survival in randomised trial.

(VP) not used in hypotensive pts

For Acute HF – (IV) Na Nitroprussied is given

B/o rapid action & short duration of action

CCE ACE Inhibitor are (D.O.C)

1. oral admistration, Action last for > 6hr.
2. Reflex tachycardia not seen
3. Long term control of S/S in CCF
4. Toxic effect of Ag II on myoccadium
5. No tolerance seen
6. Arrest clinical progression in asymptomaticle with LV lysfunction.

Commonly used vasodilators in CCF