PHARMACOLOGY

I. GENERAL PHARMACOLOGY

Pharmacodynamics - What the drug does to the body, physiological and biochemical effects of drugs and their
mechanism of action.

Pharmacokinetics- the body's effect on the drug, deals with time required for drug absorption, distribution in the
body, metabolism, and method of excretion.

DRUG COMPENDIA
• Pharmacopoieas: contain description of chemical structure, molecular weight, physical & chemical
characteristics, solubility, identification and assay methods, stndards of purity, storage conditions and
dosage forms of officially approved drugs in a country. Eg. Indian Pharmacopoiea (I.P)
• Formularies: produced in easily carried booklet form, they list indications, dose, dosage forms,
contraindications, precautions and adverse effects. Contains mixed formulations. National Formulary of India
(NFI) does not include brand names.
• Martindale: the complete drug reference (extra pharmacopoiea) - published every 2-3 years, contains
recently added drugs and their pharmacology.
• Non official compendia: Physician Drug Reference (PDR), Drug- facts & comparisons, etc...

ORPHAN DRUGS
Used for diagnosis/treatment/prevention of a rare disease or condition or a common disease in a resource poor
country.
Examples are:
• Fomepizole • Somatropin
• Liposomal amphotericin - B • Digoxin antibody
• Ancrod • Liothyronine (T3)
• Rifabutin • Sodium nitrite
• Succimer

ESSENTIAL DRUGS (MEDICINES) CONCEPT

• The WHO definition: "those that satisfy the priority healthcare needs of the population".
• They are selected with due regard to public health relevance, evidence on efficacy and safety, and
comparative cost effectiveness.

BIOAVAILABILITY
• The fraction of administered drug that reaches the systemic circulation in the unchanged form.
• When a drug is given orally, some of the drug gets metabolized in the liver. (First pass metabolism or pre-
systemic metabolism) and rest of the drug reaches the systemic circulation.
• Absorption and first pass metabolism are two important determinants of bioavailability.
• It can be calculated by comparing the AUCkiarea under plasma concentration time curve) for i. v. route and
for that particular route. It can also be calculated by comparing the excretion in the urine.

Intra venous/ Intra-arterial: 100%

Intra muscular & Sub cutaneous: 75-100%

Oral & inhalational: 5-100%

Per rectal: 30-100%

Transdermal: 80-100%

RUG DISTRIBUTION
• Lipid soluble drugs  cross the blood vessel wall  high volume of distribution.
• Drug boundto plasma proteins  large molecule & stay in the plasma.  Less volume of distribution.e.g.
diclofenac and warfarin (99% bound) Vd = 0.15 L/kg.
• Lipid-insoluble drugs do not enter cells. Vdapproximates ECF, e.g. streptomycin, gentamicin 0.25 L/kg.
 • Digoxin 6 L/kg
• Propranolol 4 L/kg,
• Morphine 3.5 L/kg, because most of the drug is present in other tissues, and plasma concentration is low.
• Therefore, in case of poisoning, drugs with large volumes of distribution are not easily removed by
haemodialysis.
• Chloroquine is the drug with highest volume of distribution (1300 Li Kg).
• Body compartments in which drue may distribute:
COMPARTMENT LITERS IN DRUG TYPE
VOLUME 70 KG
(L/KG) HUMAN
Plasma 0.045 3 Strongly plasma protein drugs & very large molecules.
Eg: Heparin
ECF 0.20 14 Large water soluble molecules. Eg: mannitol, aminoglycosides
Total Body water 0.60 42 Small water soluble drugs Eg: Ethanol
Tissue >0.70 >49 Drugs that avidly bind to tissue. Eg: chloroquine

• Factors governing volume of drug distribution:

o Lipid: water partition coefficient of the drug.
o pK a value of the drug .
o Degree of plasma protein binding.
o Affinity for different tissues.
o Fat: lean body mass ratio
o Diseases like CHF, uremia, cirrhosis

Redistribution:
• Highly lipid-soluble drugs getinitially distributed to organs with high bloodflow, i.e. brain, heart, kidney, etc.
• Later, less vascular but more bulky tissues (muscle, fat) take up the drug  plasma concentration falls
Etthedrug is withdrawn from these sites.
• Greater the lipid solubility of thedrug, faster is its redistribution.
• Anaestheticaction of IV thiopentone isterminated in few minutes due to redistribution.
• A relatively short hypnotic action lasting 6-8hours is exerted by oral diazepam or nitrazepamdue to
redistribution despite their elimination t1/2 of > 30 hr.

Bioequivalence:
• Two drug formulations with the same bioavailability (extent of absorption) as well as the same rate of
absorption are bioequivalent.
• Must have identical:
o Tmax: time to reach maximum concentration
o Cmax: maximal concentration
o AUC (area under the curve from concentration vs time graphs)
• Bioequivalence depends on both rate and extent of absorption.

DRUGS BOUND TO PLASMA PROTEIN

To Albumin To Alpha-I acid glycoprotein To Lipoproteins
 BarbituratesaBenzodiazepines Atprenalol Amphotericin B
Bilirubin Bupavicaine Cyclosporine
Digoxin Lidocaine Tacrolimus
PenicininsEtProbenecid Methadone
Phenylbutazone Prazocin
Phenytoin & fos phenytoin B-blockers (Propranolol)
Sulfonamides Quinidine
Salicylates Tricyclic antidepressants
Tolbutamide Verapamil
Valproic acid
Warfarin, Tetracyclines

• Phenytoin is extensively (90%) bound to serum proteins, mainly albumin.

• Fosphenytoin is extensively (95-99%) bound to plasma proteins, primarily albumin.
• Valproic acid is highly bound to albumin and can displace phenytoin.
• Roughly 80-90% of the salicylate in plasma is bound to proteins, especially albumin
• Warfarin is almost completely (99%) bound to plasma proteins, principally albumin.
• Acidic drugs generally bind to plasma albumin and basic drugs to al acid glycoprotein.
• Acid glycoprotein is an important binding protein with binding sites for drugs such as quinidine, lidocaine,
and propranolol.
• Dialysis is not effective in the poisoning due to amphetamines, antidepressants, Organophosphates,
antipsychotics, benzodiazepines, digoxin, opioids, Digitalis,Verapamil, Bblockers and quinidine.

DRUG DISPLACEMENTS
• Salicylates displace suifonylureas & methotrexate.
• Indomethacin & phenytoin displaces warfarin.
• Sulfonamides & Vitamin-K displaces bilirubin.

DRUGS CONCENTRATED IN TISSUES

Skeletal muscle, heart Digoxin, emetine (to muscle proteins).
Liver Chtoroquine, mepacrine, tetracyclines, emetine, digoxin
Kidney Digoxin, chloroquine, emetine
Thyroid Iodine
Brain Chlorpromazine, acetazolamide, isoniazid
Retina Chloroquine (to melanin anucleoproteins )
Lungs Benazeprilat
Iris Ephedrine, atropine (to melanin).
Bone and teeth Tetracyclines, heavy metals (to mucopolysaccharides of connective tissue).
Adipose tissue Thiopentone, ether, minocycline, phenoxybenzamine, DDT dissolve in neutral fat due to
high lipid solubility; remain stored due to poor blood supply of fat.
• DDT (chlorophenothane) is concentrated in adipose tissue but produces no known toxic effects there.

ROUTE OF ADMINISTRATION
Enteral
ROUTE ADVANTAGES DISADVANTAGES
Oral • Most convenient • Destruction of drug by enzymes or low pH (e.g.,
• Produces slow, uniform peptides, proteins, penicillin) Poor absorption of large
absorption and charged particles
• Relatively safe • Drugs bind or complex with gastrointestinal contents
• Economical • (e.g., calcium binds to tetracycline)
• Cannot be used for drugs that irritate the intestine
Rectal • Limited first-pass metabolism • Absorption often irregular and incomplete
• Useful when oral route • May cause irritation to rectal mucosa
precluded
Sublingual/ Rapid absorption Absorption of only small amounts (e.g., nitroglycerin,
buccal Avoids first-pass metabolism Isosorbide dinitrate, isoprenaline, ergotamine, clonidine,
buprenorphine, asenapine, desaminooxytocin)

Parenteral
Intravenous • Most direct route • Increased risk of adverse
• Bypasses barriers to absorption (immediate effects from high concentration
effect) immediately after injection
• Suitable for large volumes • Not suitable for oily substances
• Dosages easily adjusted or suspensions
Intramuscular • Quickly and easily administered • Painful
• Possible rapid absorption • Bleeding
• May use as depot • May lead to nerve injury
• Suitable for oily substances and suspensions
Subcutaneous • Quickly and easily administered • Painful
• Fairly rapid absorption • Large amounts cannot be given
• Suitable for suspensions and pellets
Inhalation • Used for volatile compounds ft drugs that can be Variable systemic distribution
• administered by aerosol (e.g., albuterol)
• Rapid absorption d/t large surface area of
alveolar
• membranes & high blood flow through lungs
• Aerosol (2-5 pm) delivers drug directly to site of
action and may minimize systemic side effects.
Topical Application to specific surface (skin, eye, nose, vagina) May irritate surface
allows local effects
Transdermal Allows controlled permeation through skin (e.g., nicotine, May irritate surface
estrogen, testosterone, fentanyl, scopolamine, clonidine)

BIOTRANSFORMATION/ METABOLISM OF DRUG

• Primary site -Liver.
• Biotransformation reactions can be classified into:
o Non-synthetic / Phase 1 / Functionalization reactions: a functional group is generated or exposed-
metabolite may be active or inactive.
o Synthetic/Conjugation/ Phase II reactions: metabolite is mostly inactive; except few drugs, e.g.
glucuronide conjugate of morphine and sulfate conjugate of minoxidil are active.

Glucuronidation Acetylation Methylation Sulfation

• Chloramphenicol • Sulfonamides • Adrenaline • Sex steroids
• Morphine • including dapsone • Histamine • Adrenal steroids
• Salicylates • & PAS • Nicotinamide • Chloramphenicol
• Lorezapam • Hydralazine • Methyldopa
• Metronidazole • Isoniazid (INH) • Captopril
• Procainamide • Mercaptopurine

• Metabolism may occur with the help of microsomal (present in smooth endoplasmic reticulum) or non-
microsomal enzymes.
• Enzyme inducers: Potent inducers of microsomal enzymes include rifampicin, glucocorticoids, griseofulvin,
phenobarbitone, phenytoin, Isoniazid, Carbamazepine, phenylbutazone and chloral hydrate.
 • Enzyme inhibitors: valproate, ketoconazole, cimetidine, INH, ciprofloxacin, erythromycin &
metronidazole.
• Grapefruit juice inhibits CYP3A4 and, thus, drugs such as amlodipine, clarithromycin, alprazolam, triazolam,
midazolam, cisapride, cyclosporine, Atorvastatin and indinavir are not metabolized  accumulation and
toxicity.
• Charcoal-broiled foods and cruciferous vegetables are known to induce CYP1A enzymes.
• Inhibition of P-glycoprotein & gut wall metabolism by grapefruit juice may substantially increase drug
absorption.
• Chronic administration of isoniazid or ethanol induces CYP2E1 that oxidizes ethanol and activates
carcinogenic nitrosamines.
• CYP2D6 substrates: encainide, flecainide, desipramine, nortriptyline and codeine.
• Drugs undergoing acetylation are SHIP: Sulfonamides including dapsone, Hydralazine, Isoniazid and
Procainamide).

MICROSOMAL ENZYME INDUCTION

• Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of microsomal
enzyme protein, especially cytochrome P-450 and UGTs.
• As a result rate of metabolism of inducing drug itself and / or other drugs is increased. Different inducers are
relatively selective for certain cytochrome P-450 isoenzyme families.
Examples:
• Anticonvulsants (phenobarbitone, phenytoin, carbamazepine), rifampin, glucocorticoids induce CYP3A
isoenzymes.
• Phenobarbitone also induces CYP2B1 and rifampin also induces CYP2D6.
• Isoniazid and chronic alcohol consumption induce CYP2E1.
• Polycyclic hydrocarbons like 3-methylcholan-threne and benzopyrene found in cigarette smoke, charcoal,
broiled meat, omeprazole and industrial pollutants induce CYP1A isoenzymes.
• Other important enzyme inducers are: phenylbutazone, griseofulvin, DDT.

Drugs That Enhance Drug Metabolism in Humans.

Inducer Drug Whose Metabolism Is Enhanced
Benzo[a]pyrene Theophylline
Chlorcyclizine Steroid hormones
Ethchlorvynol Warfarin
Glutethimide Antipyrine, glutethimide, warfarin
Griseofulvin Warfarin
Barbiturates Barbiturates, chloramphenicol, chlorpromazine, cortisol, coumarinanticoagulants,
(except secobarbital) desmethylimipramine, digitoxin, doxorubicin, estradiol,phenylbutazone, phenytoin,
quinine, testosterone
Phenylbutazone Aminopyrine, cortisol, digitoxin
Phenytoin Cortisol, dexamethasone, digitoxin, theophylline
Rifampin Coumarin anticoagulants, digitoxin, glucocorticoids,methadone,metoprolol, oral
contraceptives, prednisone, propranolol, quinidine

Drugs That Inhibit Drug Metabolism in Humans

Inhibitor Drug Whose Metabolism Is Inhibited
Allopurinol, Isoniazid Antipyrine, dicumarol, probenecid, tolbutamide
chloramphenicol
Cimetidine Chlordiazepoxide, diazepam, warfarin, others
Dicumarol Phenytoin
Diethylpentenamide Diethylpentenamide
Disulfiram Antipyrine, ethanol, phenytoin, warfarin
Ethanol Chlordiazepoxide (?), diazepam (?), methanol
Grapefruit juice Alprazolam, atorvastatin,cisapride, cyclosporine, midazotam,Triazolam
Ketoconazole Cyclosporine, astemizole, terfenadine
Nortriptyline, Oral Antipyrine
contraceptives
Phenylbutazone Phenytoin, tolbutamide
Secobarbital Secobarbitat
Troteandomycin Theophylline, methylprednisolone

RUGS-ACTIVE FORMS & ACTIVE METABOLITES

Active drug Active metabolite Active drug Active metabolite
Chloral hydrate Trichloroethanol Losartan E 3174
Morphine Morphine-6 glucuronide Diazepam Desmethyl diazepam,
oxazepam
Cefotaxime Desacetyl cefotaxime Digitoxin Digoxin
Allopurinol Alloxanthine Imipramine Desipramine
Procainamide N-Acetyl procainamide Amitriptyline Nortriptyline
Primidone Phenobarbitone,phenyle Codeine Morphine
thylmalonamide
Spironolactone Canrenone

Prodrug Active form

Levodopa Dopamine
Mercaptopurine Methyl Mercaptopurine ribo nucleotide
a-Methyl dopa α-Methyl Nor epinephrine
Dipivefrine Epinephrine
Sulindac Sulfide metabolite
Prednisone Prednisolone
Sulfasalazine 5-Amino salicylic Acid
Cyclophosphamide Aldophosphamide, acrolein, phosphoramide mustard
Fluorouracil Fluoro-uridine monophosphate
Proguanil Cycloguanil
Acyclovir Acyclovir triphosphate
Bacampicillin, hetacillin, talampicillin, Ampicitlin
pivampicillin

• All ACE inhibitors are prodrugs except captopril & lisinopril.

• Hofmann elimination: inactivation of the drug in the body fluids by spontaneous molecular rearrangement
without the agency of any enzyme, e.g. atracurium.

FIRST PASS (PRESYSTEMIC) METABOLISM

• Metabolism of a drug during its passage from the site of absorption into the systemic circulation.
• All oral drugs are exposed to metabolizing enzymes in the intestinal wall and liver (where they first reach
through the portal vein)
• GIT is the initial site for first-pass metabolism of drugs.
• Liver is the major "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid
hormones, fatty acids, and proteins), and xenobiotics.
• CYP3A4 are found in intestinal mucosa, accounting for first-pass metabolism of drugs such as chlorpromazine
and clonazepam.
• Approximately half of that absorbed from rectum passes through liver.

Extent of first pass metabolism of some important drugs

Low Intermediate High-not given orally High-high oral dose
Phenobarbitone Aspirin Isoprenaline Propranolol
Phenylbutazone Quinidine Lidocaine Alprenolol
Tolbutamide Desipramine Hydrocortisone Verapamil
Theophylline Nortriptyline Testosterone Salbutamol
Pindolol Chlorpromazine Glyceryl trinitrate
Isosorbide Pentazocine Morphine
mononitrate Metoprolol Pethidine

KINETICS OF DRUG ELIMINATION

• Changes in urinary pH affect tubular reabsorption of drugs that are partially ionized.
• Weak bases ionize more and are less reabsorbed in acidic urine.
• Weak acids ionize more and are less reabsorbed in alkaline urine.

Clearance (CI)
Volume of blood cleared of the drug per unit time.
Clearance= Rate of elimination of drug/plasma drug concentration.
Total Body Cl = Cl hepatic + Cl renal + Cl pulmonary + Cl other

Half-life (t1 /2)

• Time required for plasma concentration of drug to decrease by one-half after absorption and distribution are
complete; t1 /2 = (0.693 x Vd)/(Cl)
• Drug left after two half-lives: 25%
• Drug left after three half-lives: 12.5%

Steady state (Css)

• Steady state is reached when the rate of drug influx into the body = the rate of drug elimination out of the
body;
• Css = plasma concentration of drug at steady state.

Volume of distribution (V d) Drug administered IV  (LD)/(CSS)

Clearance (CL)
Rate of elimination (Re)
Half-life (t 1/2 )
Loading Dose
Maintenance Dose
Therapeutic Index (TI)
Infusion rate (K0)
Plasma concentration
Rate of elimination of a drug (Re)
Plasma concentration
Amount of drug eliminated
Time taken
0.693 x V d
CL
Vd x Target plasma Concentration
CL x Target plasma Concentration
Median Lethal Dose (LD50)
Median Effective Dose (ED50)
Cl x Css

• If the infusion rate is doubled, Steady state concentration is also doubled; as dose and concentration are
directly proportional (linear kinetics); Css x k0/Cl
• If a drug is protein bound, then Cl renal =GFR x free fraction (of drug).

During constant infusion, percent of steady state reached after:

• One half-life: 50%
• Two half-lives: 75%
• Three half-lives: 87.5%
 • Four half-lives: 94%

CLcr (patient) Dose rate to be reduced to

50-70 ml/min 70%
30-50 ml/min 50%
10-30 ml/min 30%
5-10 ml/min 20%

KINETICS OF METABOLISM

First Order Kinetics (Exponential Kinetics) Zero order kinetics (non-linear/saturation

The amount of drug eliminated is directly
proportional to the concentration of drug in the
plasma i.e., Constant fraction of drug is
eliminated per unit time
Rate of elimination is proportional to plasma
concentration
Clearance remains constant.
Half life remains constant
Most of the drugs follow first order kinetics
kinetics) /capacity limited /Michaelis-Menten
elimination
Constant amount of the drug is eliminated per unit
time.
Rate of elimination is independent of plasma
concentration
Clearance is more at low concentrations and less at
high concentrations
Half life is less at low concentrations and more at
high concentrations.
Very few drugs follow pure zero order kinetics E.g.
phenytoin and saticylates at high doses, ethanol,
heparin,

Pseudo zero order Rate of metabolism depresses as the substrate concentration increases, E.g: Phenytoin,
ethanol, aspirin

• Change of kinetics from first order to zero order at higher doses: Phenytoin, tolbutamide, Warfarin,
theophylline.

DRUGS UNDERGOING ZERO ORDER (LINEAR) KINETICS

• Ethanol
• Phenytoin
• Propafenone Tolbutamide Theophylline
• Salicylates in high doses.
• Warfarin
HIT AND RUN DRUGS: (Effect of the drug lasts much longer than the drug itself)
• Reserpine, Guanethedine, MAO inhibitors & Omeprazole

pKa of a drug
• The lower the pKa of a drug, the more acidic it is. Higher the pKa, the more basic is the drug

THERAPEUTIC WINDOW PHENOMENON

• Optimal therapeutic effect is exerted only over a narrow range of plasma concentrations or drug doses.
• Tricyclics like imipramine: 50-15Ong/ml
• Clonidine lowers BP in a concentration of 0.2-2.Ong/ml, increases BP if concentration 2.0ng/ml
• Glipizide exerts poorer glycemic control at doses over 25mg/day.
• Others: digoxin, theophylline, lidocaine, cyclosporine, Phenytoin & aminoglycosides.

DOSE RESPONSE CURVE:

• Slope- if the DRC is steeper, response will increase dramatically with slight increase in dose.
• Thus, drug having steeper DRC have narrow therapeutic index (like barbiturates) than those having less steep
curves (benzodiazepines)
• ED50 - the dose that will produce half of the maximum response. More the ED50 lower is the potency.
• LD50 - the dose that will result in death of 50% of the animals receiving the drug. More the LD50 safer is the
drug.
• EC50 is that concentration of drug that produces a response one-half of the maximum response.
• Lower the EC50 higher the potency.

THERAPEUTIC INDEX
• It is a measure of safety of drug.
 • Calculated as a ratio of LD50 to ED50, drugs having high T.I are safer whereas those having low T.I are more
likely to be toxic.
• Therapeutic index= LD50/ED50

Drugs with narrow therapeutic index (low margin of safety):

• Lithium • Anti convulsants. Eg. Phenytoin
• Theophylline • Cyclosporine.
• Amino glycosides and other • Antiarrhythmics
antimicrobials • Tricyclic anti-depressants
• Digoxin
• Lignocaine

Therapeutic drug monitoring (TDM) is useful in:

• Drugs with low safety margin
• If individual variations are large-antidepressants, lithium.
• Potentially toxic drugs used in the presence of renal failure-aminoglycoside antibiotics, vancomycin.
• In case of poisoning.
• In case of failure of response without any apparent reason-antimicrobials.
• To check patient compliance-psychopharmacological agents

AFFINITY, SPECIFICITY, EFFICACY AND POTENCY

POTENCY EFFICACY
Amount of drug needed to produce a response. Maximum response that can be elicited
by the drug.
Antagonist acts by decreasing the potency of drug. Non -competitive antagonist acts by decreasing
the efficacy.
Potency refers to EC50 (or) EDSO of a drug to produce 50%
maximum effect.
Potency depends upon affinity of the receptor for binding the Depends upon drug's interaction with receptor.
drug and in part on the efficiency with which drug receptor
interaction is coupled to response.

Affinity:
The extent of binding of a drug to a receptor, the greater the affinity the more the binding and consequently more
the action.
• Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signalling
compounds are termed agonists.
• Antagonists, bind to receptors without regulatory effect, but their binding, blocks the binding of the
endogenous agonist.
• Agents that are only partly as effective as agonists no matter the dose employed are termed partial agonists.
• Agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that
agonist is termed inverse agonists.

Specificity:
Defined as the ability of the drug to produce an action at the specific site.

MECHANISM OF ACTION OF DRUGS

Type 1 : Ilgand ion Type 2: G-protein- Type 3: receptors Type 4: nuclear
channels coupled receptors kinases receptors
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Channel or enzyme Protein kinases Gene transcription
Coupling Direct G-protein Direct Via DNA
Examples Nicotinic Muscarinic Insulin. growth Steroid receptors
acetylcholine acetyicholine factors, cytokine
receptor. GAE3AA receptor. receptors
receptor adrenoceptors
Structure Ofigomenc assembly Monomeric or Single Monomeric
of subunits oligomeric transmembrane structure with
surrounding central assembly of helix linking separate receptor-
pore subunits extracellular and DNA-binding
comprising seven receptor domain to domains
transmembrane intracellular kinase
helices with
intracellular G-
proteincoupling
domain

G protein coupled receptors

• Receptors coupled to G proteins are often called "G proteincoupled receptors" (GPCRs), "seven-
transmembrane" (7-TM), or "serpentine" receptors.
• Receptors for adrenergic amines, serotonin, acetylcholine (muscarinic but not nicotinic), many peptide
hormones, odorants, and even visual receptors (in retinal rod and cone cells) all belong to the GPCR family.
• All were derived from a common evolutionary precursor.
• A few GPCRs (eg, GABA B and metabotropic glutamate receptors) require stable assembly into either
homodimers (complexes of two identical receptor polypeptides) or heterodimers (complexes of different
isoforms) for functional activity.
DRUG ANTAGONISM
Physical Based upon physical Charcoal adsorbs alkaloids and can prevent
properties of the drug their absorption
Chemical Two drugs react and form an KMnO4 oxidises alkaloids tannins + alkaloids
inactive product chelating agents nitrites form
methemoglobinemia.
• Heparin (acid) antagonised by protamine
sulphate (alkali)
• Gastric acid antagonised by antacids(AI
hydroxide, Mg hydroxide)
• Heavy metal antagonised by chelating
agents
Physiological/ The drugs react with different Histamine and adrenaline on bronchial
functional receptors and exert different muscles Hydrochlorothiazide and triamterene on
effects urinary K+ excretion
Receptor Antagonist interferes with
binding of agonist on receptor

• For physiological antagonism both drugs must act on different receptors.

• Protamine binds to heparin and deactivates it, hence not physiological antagonism.
• PG-I2& Thromboxane A2 acts on different receptors but their actions are exactly opposite  physiological
antagonism.
• Adrenaline and phenoxybenzamine act on same receptors but are antagonists, hence not physiological.
• Acetylcholine and physostigmine also are antagonists on same receptors.
• Pharmacological antagonist- Produce opposite action by binding to the same receptors. Eg beta blockers.

COMPETITIVE INHIBITION
• Equilibrium type-Km is increased, Vmax is unchanged
• Non-Equilibrium type-Km is increased, Vmax is reduced. Eg: Methotrexate & Oranophosphates.

COMPETITIVE
Parallel, Right shift of the DRC
Maximum response remains the same
Reversible by addition of agonist
Eg: Ach & Atropine at muscarinic receptors
NON-COMPETITIVE
Non-Parallel, Right shift of the DRC
Maximum response is much reduced
Irreversible a Unsurmountable by addition of agonist
Eg: Phenoxybenzamine at alpha receptors

Suicide inhibitors (inactivators that attack the heme or the protein moiety):
• Ethinyl estradiol • Allylisopropylacetylurea
• Norethindrone • Diethylpentenamide
• Spironolactone • Ethchlorvynol
• Fluroxene • Carbon disulfide
• Allobarbital • Propylthiouracil

Competitive inhibitor Competes with Enzyme

Physostigmine, Neostigmine Acetyl choline Cholinesterase
Sulfonamides PABA Folate synthetase
Moclobemide Catecholamines MAO-A
Captopril Angiotensin-1 ACE
Finasteride Testosterone 5 α reductase
Letrozole, Anastrozole Androstenedione & testosterone Aromatase
Allopurinol Hypoxanthine Xanthine oxidase
Sulfadiazine Para-amino benzoic acid (PABA) Bacterial folate synthase
 Carbidopa, methyldopa Levodopa Dopa decarboxylase

• Non -competitive inhibitors: (kM is unchanged, Vmax is reduced)

Non – Competitive inhibitor Enzyme Non –Competitive inhibitor Enzyme
Acetazolamide Carbonic anhydrase Omeprazole WK.* ATPase
Aspirin, indomethacin Cyclooxygenase Digoxin Na+K+ ATPase
Disulfiram Aldehyde dehydrogenase Theophylline, Sildenafil Phosphodiesterase
Propyl thiouracil Thyroid peroxidase Lovastatin HMG CoA reductase

DRUG SCHEDULE
• As per drug and cosmetic rule 1945, drugs are scheduled as:

Schedule-C Biological and special products

Schedule-E Poisons
Schedule-F Vaccine and sera
Schedule-G Hormone preparations, anti-histamines, anti-cancer
Schedule-H Drugs and poisons to be sold only by the prescription of a registered medical practitioner
Schedule-J List of diseases for the cure and prevention of which, no drugs should be advertised. (cataract,
epilepsy, hydrocele, blindness)
Schedule-I Antibiotics and other recent chemotherapeutic agents

PHASES IN CLINICAL TRIALS

Phase Done in
0/0.5 Micro dosing 10-15 • Done in healthy volunteers to obtain preliminary pharmacokinetic
subject data.
s • Single dose (1/100th of proposed therapeutic dose to a maximum of
10Oμg) is given.
• No ethical concern.
Human 20-50 • Healthy volunteers or volunteer patients (Anti-cancer/ anti retro
pharmacolog subject viral drug), according to the class of drug and its safety.
y & safety s • Pharmacokinetics (absorption, distribution, metabolism, excretion).
• Pharmacodynamics (biological effects) where practicable,
tolerability, safety, efficacy.

II Therapeutic 50-300 • Pharmacokinetics and pharmaco dynamic dose-ranging, in carefully

exploration & Patients controlled studies for efficacy and safety, which may involve
dose ranging comparison with placebo.
III Therapeutic 250- • Randomized controlled trials
confirmation 1000+P • Efficacy on a substantial scale; safety; comparison with existing
& comparison atients drugs.
IV Therapeutic 2000- Post marketing surveillance for safety and efficacy: further formal
use (post- 10000+ therapeutic trials, especially comparisons with other drugs, marketing
licensing studies and pharmaco economic studies. Detects uncommon side effects,
studies) drug interactions a newer indications.

DRUG CATEGORIZATION
Schedule I (CI) DRUGS Schedule II (CII) DRUGS
 • High potential for abuse • High potential for abuse,
• No currently accepted medical use in • Currently accepted medical use in treatment in USA, or has
treatment in USA, or has no accepted a currently accepted medical use but with severe
safe use under medical supervision. restrictions, and abuse of the drug or other substances
• Examples: heroine, marijuana and a may lead to severe psychological or physical dependence.
host of designer-drugs • Examples: morphine, oxycodone, hydromorphone,
meperidine, codeine, anabolic steroids
Schedule III (CIII) DRUGS Schedule IV (CIV) DRUGS
• Has a potential for abuse less than the • Has a low potential for abuse relative to the drugs or other
drugs or other substances in schedules I substances in schedule III,
and II. • Has a currently accepted medical use in treatment in USA,
• Currently accepted medical use in and abuse of the drug or other substance may lead to
treatment in USA, abuse of the drug or limited physical dependence or psychological dependence
other substance may lead to moderate relative to the drugs or other substances in schedule III.
or low physical dependence or high • Examples: benzodiazepines (Valium, Ativan, etc),
psychological dependence. propoxyphene combinations
• Examples: hydrocodone, codeine and
others in combination with other drugs.
Schedule V (C V) DRUGS
• Low potential for abuse relative to the drugs or other substances in schedule IV,
• Currently accepted medical use in treatment in the United States, and abuse of the drug or other substance
may lead to limited physical dependence or psychological dependence relative to the drugs or other
substances in schedule IV.Examples: Diphenoxylate combination, cough syrups

SALIENT POINTS
• Molecular size of drugs: very small- lithium ion (MW 7) & very large- alteplase (59,050)
• Vast majority of drugs have molecular weights between 100 and 1000.
• P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in brain, testes and drug-resistant
neoplastic cells.
• Multidrug resistance-associated protein-type 2 (MRP2) transporters plays an important role in excretion of
some drugs or their metabolites into urine and bile.

• Drugs that attain high concentrations in bile: erythromycin, ampicillin, rifampin, tetracycline, OCPs &
Phenolphthalein.
• Weak acids are usually excreted faster in alkaline urine; weak bases are usually excreted faster in acidic
urine.
• Venous drainage from the mouth is to SVC, which protects highly soluble drugs like nitroglycerin from rapid
hepatic first-pass metabolism.
• Irritating drug solutions can be given only IV because the drug is diluted by the blood.
• Four most important parameters governing drug disposition: clearance, volume of distribution, elimination
t1/2 and bioavailability.
• "Maximal dose" strategy: doses well in excess of the average required will ensure efficacy and prolongs drug
action. Typically used for penicillins.
• Flavin monooxygenase-Ziegler's enzyme
• Drugs such as chlorpromazine are calmodulin inhibitors.
• B-arrestins recruit proteins such as PDE4, ctathrin and B2-adaptin.
• Drugs whose action is not mediated by receptors: cholesterol binding resins, mannitol etc...
• Vectorial transport: Asymmetrical transport across a monolayer of polarized cells, such as the epithelial and
endothelial cells of brain capillaries.
• Placebo: inert substance which works by psychological means and produces responses equivalent to active
drug.
 • Commonly used placebo: lactose tablets/ capsules and distilled water injection.
• Nocebo: converse of placebo, negative psychodynamic effect evoked by loss of faith in the medication
and/or the physician.
• Enzymatic blood brain barrier: formed by cholinesterase, MAO & other enzymes in capillary walls & do not
allow some drugs to enter brain.
• Maximum permitted shelf life of any drug: 5 years.
• Only drug known to be toxic after expiry date: Tetracycline (Fancony syndrome).
• In coeliac disease, absorption of amoxicillin is decreased but that of cephalexin & cotrimoxazole are
increased.
• Tachyphylaxis: Responsiveness diminishes rapidly after administration of a drug.
o Rapid development of tolerance
o Indirect acting amines (tyramine, amphetamine) exert their effects by releasing monoamines.
o Several doses given over a short time deplete the monamine pool, reducing the response to successive
doses.
• Pharmacogenomics: use of genetic information to guide the choice of drug and dose on an individual basis.
o It intends to identify individuals who are either more likely or less likely to respond to a drug, as well as
those who require altered dose of certain drugs.

Idiosyncrasy
• It is genetically determined abnormal reactivity to a chemical.
• The drug interacts with some unique feature of the individual, not found in majority of subjects and
produces the uncharacteristic reaction.
• Barbiturates cause excitement and mental confusion in some individuals.
• Quinine/ quinidine cause cramps, diarrhoea, purpura, asthma and vascular collapse in some patients.
• Chloramphenicol produces non dose-related serious aplastic anaemia in rare individuals.

ADVERSE DRUG REACTIONS

These are noxious or unintended effects produced by drugs. These may be classified as
• Type A:Augmented pharmacologic effects - Dose dependent and predictable e.g. hypoglycemia caused by
anti-hyperglycemic drugs like sulfonylureas
• Type B: Bizarre effects (or idiosyncratic) - Does independent and unpredictable e.g. allergic reactions caused
by penicillins
• Type C: Chronic effects e.g. peptic ulcer caused by chronic use of NSAIDs
• Type D: Delayed effects e.g. teratogenicity caused by thalidomide
• Type E: End-of-treatment effects e.g. withdrawal response to morphine
• Type F: Failure of therapy

Pulmonary Toxicants
Drugs Chemicals
Amiodarone Asbestos Ozone
Bleomycin Beryllium Paraquat
Busulfan Cadmium oxide Phosgene
Cyclophosphamide Chlorine gas Silica
Methotrexate Nitrogen dioxide Sulfur dioxide

Renal Toxicants
Drugs Chemicals
Cephalexin Gentamicin Choloform
Cephalothin Ifosfamide Citrinin
Cisplatin NSAIDs Hexachlorobutadiene
Cyclosporine Streptozocin Mercuric chloride

Hepatotoxicants
Drugs Chemicals
Acetaminophen Isoniazid Allyl
Chlorpromazine Nitrofurantoin Beryllium
Estrogens Phenylbutazone Carbon tetrachloride
Ethanol Urethane Vinyliden chloride
Halothane 6-Mercaptopurine

Central Neurotoxicants
Drugs Chemicals
Cocaine Lead
Ethambutol Mercury
Quinine Methanol
Organochlorine insecticides

Peripheral Neurotoxicants
Drugs Chemicals
Doxorubicin Acrylamide
Isoniazid Carbon disulfide
Nitrofurantoin Lead
n-Hexane
 II. AUTONOMIC NERVOUS SYSTEM AND AUTACOIDS

• Parasympathetic (trophotropic): leading to growth, ''rest and digest''.

• Sympathetic system (ergotropic): leading to energy expenditure, "fight or flight."
• Fibres of sympathetic system originate from thoracic and lumbar spinal cord (thoraco lumbar outflow).
• Parasympathetic system originates from cranial nerves (III, VII, IX and X) and sacral (S2,3.4) spinal cord
(craniosacral outflow).
• In sympathetic system, postganglionic fibres are either equal or longer than Preganglionic fibres
• In parasympathetic system, Preganglionic fibres are much longer than postganglionic fibres.
o Acetylcholine (ACh) is the principal NT at NMJ as well at all preganglionic fibres.
o In parasympathetic system, NIT release at postganglionic fibres is also ACh.
o In sympathetic system, at most of post ganglionic fibres NT secreted is NA but it can be dopamine
(renal & mesenteric vasculature), ACh (sweat glands; sympathetic cholinergic) or Adr (adrenal medulla).

Autonomic Receptor Types

Locations Agonists Antagonists
M1 CNS neurons, sympathetic postganglionic MCN-343A, Pirenzepine, Telenzepine
neurons, some presynaptic sites, Gastric glands Oxotremorine
M2 Myocardium, smooth muscle, some presynaptic Methacholine Methoctramine, Tripitramine
sites
M3 Exocrine glands, vessels (smooth muscle and Bethanechol Hexahydrosiladifenidol, Darifenacin
endothelium)
NN Postganglionic neurons, some presynaptic DMPP, Nicotine Hexamethonium, Trimethaphan
cholinergic terminals, adrenal medulla
NM Neuromuscular junction PTMA, Nicotine Tubocurarine,a -Bungarotoxin

• M4 receptor: facilitation/inhibition of transmitter release in certain areas of brain.

• M5 receptor: facilitate dopamine release and mediate reward behavior.

DRUGS AFFECTING MUSCARINIC ACTIVITY

Cholinergicf parasympathomimetic drugs Anticholinergic/ parasympatholytics drugs
Direct acting: Acetyl Choline, Pilocarpine Non-selective antagonists : Atropine, Hyoscine
Indirect acting: Receptors selective antagonists:
Physostigmine, M1 blocker (Pirenzepine, Telenzepine)
Neostigmine M2 blocker (Tripitramine, methoctramine); M3 blocker (Darifenacin)
Drugs acting by other mechanisms:
Decrease choline uptake (Hemicholinium)
Decrease vesicular uptake of ACh (Vesamicol)
Decrease release of ACh (Botulinum toxin)

PARASYMPATHOMIMETIC DRUGS
DIRECTLY ACTING DRUGS INDIRECTLY ACTING DRUGS (anticholinesterase)
Reversible Anticholinesterases Irreversible
Natural alkaloids: ACh, muscanne,
nicotine, pilocarpine and arecoline
Synthetic derivatives: methacholine,
carbachol and bethanechol
Methacholine  maximum action on
myocardium.
Bethanechol  action on urinary
bladder (has no nicotinic activity) &
increase the tone of LES in GERD.
Pilocarpine is used in glaucoma due to
its pupillary constrictor (miotic) action.
Pilocarpine & Cevimeline: used to treat
dry mouth in Sjogren's syndrome.
Acetylcholine is metabolized quickly by
cholinesterases & is not effective even
by i.v. route.
Lipid soluble: Physostigmine, tacrine, Donepezil, Organophosphates
Galantamine and rivastigmine (Malathion,
Water soluble: neostigmine, pyridostigmine, parathion,
edrophonium ecothiophate &
Physostigmine is used in glaucoma and in diflos) & carbamates
belladonna (atropine) poisoning as a specific (carbaryl and
antidote. propoxur).
Neostigmine is preferred for the treatment of Except ecothiophate
myasthenia gravis, cobra bite, post operative these are not used
paralytic ileus, atony of urinary bladder and reversal therapeutically.
of competitive skeletal muscle relaxants,
Ecothiophate is
Pyridostigmine is longer acting than neostigmine
useful in glaucoma
and can be used for all these indications.
Edrophonium is a short acting synthetic
anticholinesterase and used in the diagnosis of
myasthenia gravis (Tensilon test).
Tacrine, rivastigmine, donepezil & galantamine:
was used in Alzheimer's disease.

• The carbamates and phosphates respectively carbamylate and phosphorylate the esteratic site of the
enzyme.
• The acetylated enzyme reacts with water extremely rapidly and the esteratic site is freed in a fraction of a
millisecond.
• The carbamylated enzyme (reversible inhibitors) reacts slowly and the phosphorylated enzyme (irreversible
inhibitors) reacts extremely slowly or not at all
• True acetyl cholinesterase- present in all cholinergic sites, RBC, gray matter.
• Drugs metabolized by cholinesterase: acetylcholine, methacholine.
Choline Ester Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action
Acetylcholine ++++ +++ +++
Methacholine + ++++ None
Carbachol Negligible ++ +++
Bethanechol Negligible ++ None

• Pseudo (Butyryl) cholinesterase, present in plasma, liver, intestine a white matter has lower specificity for
Ach.
PHYSOSTIGMINE NEOSTIGMINE
Source Is the only natural alkaloid Synthetic
Chemistry Tertiary amine Quaternary ammonium
Oral absorption Good Poor
CNS action Present Absent
Applied to eye Penetrates cornea Poor penetration
Direct action on cholinoceptors Absent Present
Prominent actions Autonomic On skeletal muscles
Important use Miotic (glaucoma) Myasthenia gravis
Duration of action 4-6 hours (eye:6-24 hours) 3-4 hours

• Major contraindications to the use of the muscarinic agonists are asthma, hyperthyroidism, coronary
insufficiency and acid-peptic disease.
• Atropine is an antidote of choice for both organophosphate and carbamate poisoning.
• Ach esterase contains 2 binding sites- anionic site & esteratic site. Carbamates occupy both the sites
whereas OPC attaches only to esteratic site.
 • Oximes in OPC poisoning: binds to anionic site & reactivate it.
• Enzyme reactivators like pralidoxime, obidoxime (more potent) and diacetylmonoxime can be used to
regenerate AChE in OPC poisoning but contra-indicated in the carbamate poisoning.
• Diacetylmonoxime can cross BBB & regenerate AChE whereas pralidoxime and obidoxime cannot cross.
• Di iso propyl fluoro phosphate (DFP) is an anti-cholinesterase that inhibits the action of Ach esterase  Ach
is preserved at the site for longer time. It is an ingredient of some pesticides and nerve gas poisons.
• Many of the organophosphates (except-ecothiophate ion) are highly lipid-soluble liquids.
• Soman is an extremely potent "nerve gas." Other nerve gases: Tabun & Sarin.
• Chronic exposure to certain OPCs causes neuropathy associated with demyelination of axons.
• Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade, and in Datura
stramonium, also known as jimsonweed (Jamestown weed) or thorn apple.
• Scopolamine (hyoscine) occurs in Hyoscyamus nigeror henbane.
• Features of anti Cholinesterase poisoning: DUMBELS (Diarrhea, Urination, Miosis and Muscle
Weakness, Bronchospasm, Excitation, Lacrimation and Seizures, Sweating and Salivation).

ANTI-CHOLINERGIC DRUGS

Natural Semi-Synthetic Synthetic Compounds

Alkaloids derivatives
Atropine Homatropine Mydriatics Anti secretory - anti spasmodics Anti-Parkinsonian
Hyoscine Atropine Cyclopentolat Quaternary compounds: Trihexiphenidyl,
methonitrate e Tropicamide Propantheline, Oxyphenonium, Procylidine,
Hyoscine butyl Clidinium, Pipenzolate, Biperidin,
bromide Isopropamide, Glycopyrrolate. Benztropine,
Ipratropium Tertiary amines: Cycrimine,
bromide Dicyclomine, Oxybutynin, Ethopropazine.
Tiotropium Flavoxate, Pirenzepine,
bromide Telenzepine, Valethamate

• Drugs blocking NM receptors are called neuromuscular blocking agents and those blocking NN are called
ganglion blockers.
• Atropine's effect declines rapidly in all organs except the eye.
• Effects on the iris and ciliary muscle persist for 72 hours.
• Tissues most sensitive to atropine are the salivary, bronchial and sweat glands.
• Secretion of acid by the gastric parietal cells is the least sensitive.
• In adults, body temperature is elevated if large doses are administered, but in infants and
• children even ordinary doses may cause "atropine fever."

ACTIONS OF ANTIMUSCARINIC AGENTS

• CNS: Atropine is a CNS stimulant whereas scopolamine causes CNS depression.
o Hyoscine induces "twilight sleep", used as lie detector or truth serum drug in suspects.
o Transdermal patch of scopolamine  prevents motion sickness.
o Central anticholinergic agents like trihexiphenidyl (benzhexol), benztropine and biperidin: DOC in
treatment and prevention of drug induced Parkinsonism.
• Eye: (Atropine, homatropine, cyclopentolate and tropicamide) cause mydriasis and cycloplegia.
o Atropine: long duration of action (3-5 days) (it has shorter action in other organs).
o Tropicamide is the shortest acting mydriatic.
o Anticholinergic agents are contra-indicated in glaucoma.
• Respiratory system: reversal of bronchoconstriction caused by stimulation of M3 receptors.
o Ipratropium and tiotropium (selective M3 receptors antagonists) useful in COPDand bronchial asthma.
o Acts on receptors located in larger central airways (sympathomimetics act on peripheral bronchioles).
o Glycopyrrolate is used as a pre-anesthetic medication
 • GIT: decrease the motility, tone and secretion in gastrointestinal tract.
o Pirenzepine and telenzepine (selective M1 blockers) useful in peptic ulcer disease.
o Hyoscine, Dicyclomine, propanthetine, oxyphenonium and clidinium are useful as antispasmodic agents
for the treatment of intestinal colic.
o Darifenacin is selective M3 blocker useful for irritable bowel syndrome and overactive bladder.
• Genitourinary tract: decrease the motility of urinary tract and result in urinary retention (therefore contra-
indicated in BHP).
o Dicyclomine, flavoxate and oxybutynin used in urinary incontinence and renal colic.
o Tolterodine (selective M3 antagonist) is also useful for urinary incontinence.
Atropine is contra-indicated in BHP & in children d/t the risk ofhyperthermia (due to decreased sweating).
Other uses:
o Atropine is the DOC for early mushroom poisoning due to inocybe species.
o It is contra-indicated in poisoning due to Amanita muscaria. Thiotic acid is useful for late mushroom
poisoning due to Amanita phalloides.
o It is also the DOC for organophosphate poisoning.
o It is used along with neostigmine (to decrease its muscarinic side effects) for the treatment of
Myasthenia gravis.
• Phenylephrine less effect on ciliary muscles, not a proper cycloplegic agent.
• Atropine - strongest cycloplegic agent, indicated for children, effect last for 10-14 days.
• Homatropine - moderately effective unstable cycloplegic, effect last for 48-72 hours.
• Cyclopentolate: Potent, rapidly acting Mydriasis Et cycloplegia occurs in 30-60 min and lasts for day.
• Tropicamide: Briefest (3-6 hours) action, quickest (20-40 mins) onset. Relatively less cycloplegic

MUSHROOM POISONING
Early mushroom poisoning (muscarine type): d/t Inocybe & clitocybe species. Symptoms d/t cholinergic activation.
DOC: atropine.
Amanita muscaria (Hallucinogenic type); no cholinergic symptoms, atropine is contraindicated.
Delayed mushroom poisoning (Phalloidin type): due to Amanita phalloides & Galerina species.
Principal toxin is amatoxins (Act by inhibiting mRNA synthesis). Treatment is largely supportive & penicillin. Thioctic
acid & Silbinin may be effective antidotes.

Common cycloplegic and mydriatic drugs

Drug Age when indicated Peak effect Duration of action Tonus allowance
Atropine 1% ointment < 5 years 2 -3 days 10 - 20 days 1D
Homatropine 2% drops 5 - 8 years 60 -90 mins 48 - 72 hours 0.5D
Cyclopentolate 8 - 20 years 80 - 90 mins 6 - 18 hours 0.75D
1 %drops
Tropicamide 1%drops Only mydriatic 20 - 40 mins 4 - 6 hours _
Phenylephrine drops Only mydriatic 30 - 40 mins 4 - 6 hours _

DRUGS ACTING ON AUTONOMIC GANGLIA

GANGLIONIC STIMULANTS
• Selective nicotinic agonists: nicotine (small dose), lobeline, Dimethyl Phenyl Piperazinium (DMPP),
Tetramethyl ammonium (TMA), Varenicline.
• Non selective/muscarinic agonists: Ach, Carbachol, Pilocarpine, Anticholinesterases, MCN 343-A

Note
• Varenicline: NN subtype nicotinic partial agonist to reduce craving and nicotine withdrawal symptoms in
those who stop smoking.
GANGLION BLOCKING AGENTS
Competitive blockers
• Quaternary ammonium compounds: Hexamethonium, Pentolinium
• Amines (secondary/tertiary): Mecamylamine, Pempidine
• Monosulfonium compound: Trimethaphan camforsulfonate
Persistent depolarising blockers
• Nicotine (large dose)
• Anticholinesterases (large dose)
Trimethaphan: ultra-short acting, occasionally infused i.v. to produce controlled hypotension and in hypertensive
emergency due to aortic dissection.

Mecamylamine: Either alone or in combination with nicotine patch, it has been tried for smoking cessation. It
appears to block the reward effect of nicotine and improve abstinence rate compared to placebo. Constipation
occurred in many subjects, and is not an approved drug.

DRUGS FOR SMOKING CESSATION

• Nicotine (gum, patch, nasal inhaler, oral inhaler)
• Clonidine (oral, patch)
• Varenicline
• Nortriptyline
• Amfebutamone
• Bupropion
• Rimonabant
• Mecamylamine

SYMPATHOMIMETIC DRUGS
SYMPATHETIC RECEPTORS
Raymond Ahlquist (1948) discovered & termed that catecholamines acted via α and β receptors
A B
α1 (smooth muscles) α2 β-1 β-2 β-3
α-1 A α-1B/1D PRE SYNAPTIC POST SYNAPTIC Heart JG cells Bronchi, eye Adipose tissue
Posterior GIT, Uterus, Coronary
Prostatic Blood vessels Tends to inhibit Blood vessels pituitary Liver, Bladder vessels
urethra Sympathetic Brain Skeletal muscle
Eye system Blood vessels

ADRENERGIC RECEPTORS
Receptor Mechanism of Examples of Tissue Distribution Examples of Action
Type Action
α1 ↑ IP3 and Ca++, Sympathetic postsynaptic nerve Increase vascular smooth muscle
DAG terminals contraction
α2 ↓cAMP Sympathetic presynaptic nerve Inhibit norepinephrine release;
terminals; β cell of pancreas inhibit insulin release
β1 ↑- cAMP Heart, JG cells in kidney Increase cardiac output
β2 ↑ cAMP Liver; smooth muscle of Increase hepatic glucose output;
vasculature, bronchioles, GIT, eye decrease contraction of blood
and uterus vessels, bronchioles, and uterus
β3 ↑ cAMP Liver; adipose tissue (lipocyte) Increase hepatic glucose output;
increase lipolysis

Dopamine receptors
D1 (DA1), D5 Brain; effector tissues, especially Stimulation of adenylyl cyclase
smooth muscle of the renal vascular bed and increased cAMP
D2 (DA2) Brain; effector tissues especially smooth Inhibition of adenylyl cyclase;
muscle; presynaptic nerve terminals increased potassium conductance
D3 Brain Inhibition of adenylyl cyclase
D4 Brain, cardiovascular system

SOME ACTIONS OF CATECHOLAMINE HORMONES

β: Epinephrine > Norepinephrine α: Norepinephrine > Epinephrine
↑Glycogenolysis ↑Gluconeogenesis (α1)
↑ Gluconeogenesis (β2) ↑Glycogenolysis (α1)
↑ Lipolysis (β3) (β2) ↓Insulin secretion (α2)
↑Calorigenesis (β1) ↑T Cardiac contractility (α1)
↓ Glucose uƟlizaƟon ↑Arteriolar vasoconstriction
↑ Insulin secreƟon (β2) & / Giucagon secretion (β2) ↑-BP (α1) (splanchnic, renal, cutaneous, genital)
↑ Muscle K. uptake (62) ↑Gastrointestinal & Urinary Sphincter contraction (α1)
↑Cardiac contracƟlity, ↑ Heart rate (β1) ↑Platelet aggregation (α2)
↑ ConducƟon velocity (β1) ↑Sweating ("adrenergic")
↑ Arteriolar dilaƟon: ↓ BP (βz) ↑Dilation of pupils (α1)
↑ Muscle relaxaƟon (β2): Gastrointestinal, Urinary &
Bronchial

DIRECTLY ACTING SYMPATHOMIMETICS INDIRECTLY ACTING MIXED ACTION

Catecholamines Non catecholamines SYMPATHOMIMETICS SYMPATHO-
MIMETICS
Endogenous α1 agonists: • Act by increasing the • Enhance the
catecholamines: • Phenylephrine and methoxamine: release of NA in the release of NA
Adrenaline, nasal decongestants. synaptic cleft & activates α
Noradrenaline and • Phenylephrine used as mydriatic • Tyramine  cheese and β
Dopamine. (no reaction (in patients receptors.
• cycloplegia). on MAO inhibitors) • Ephedrine and
Exogenous α2 agonists: • Methylphenidate DOC pseudo-
catecholamines: • Clonidine & α methyldopa: - for attention deficit ephedrine:
Isoprenaline, treatment of hypertension. hyperkinetic disorder nasal
Dobutamine, • Guanfacine, guanabenz. (ADHD). decongesta nts
Dopexamine and • Apraclonidine and brimonidine: • Other drugs are • Ephedrine: in
Fenoldopam • selective α2 agonists used topically amphetamines and bronchial
for treatment of glaucoma. pemoline. vasopressor of
Non • Tizanidine: used as muscle • Amphetamines are choice in
Catecholamines : relaxant. basic drugs; urinary pregnancy.
Xylometazolin • Dexmeditomidine is used for pre- acidification (with
Clonidine anesthetic medication & sedation NH4Cl) is employed for
Phenylephrine in ventilated patients, provides the treatment of their
Salbutamol akin to natural sleep. toxicity.
Methoxamine β1 agonists: prenaltrenol - used for • Amphetamines are
reversal of β blockade. included in the "dope
β2 agonists: test" for athletes.
• Salbutamol (albuterol), • Modafinil:used in
metaproterenol (Orciprenaline), Narcolepsy, in shift
terbutaline, pirbuterol, salmeterol, workers & an adjunct
arformoterol, carmoterol, in obstructive sleep
indacterol and formoterol: useful in apnea
bronchial asthma.
• Ritodrine and isoxsuprine are
agonists useful as tocolytic.
THERAPEUTIC CLASSFICATION OF ADRENERGIC DRUGS
• Pressor agents: Noradrenaline, Ephedrine, Dopamine, Phenylephrine, Methoxamine, Mephentermine
• Cardiac stimulants: Adrenaline, Isoprenaline, Dobutamine
• Bronchoditators: Isoprenaline, Salbutamol (Albuterol), Terbutaline, Salmeterol, Formoterol, Bambuterol.
• Nasal decongestants: Phenylephrine, Xylometazoline, Oxymetazoline, Naphazoline, Pseudoephedrine,
Phenyl propanolamine
• CNS stimulants: Amphetamine, Dexamphetamine, Methamphetamine
• Anorectics: Fenfluramine, Dexfenfluramine, Sibutramine
• Uterine relaxant and vasodilators: Ritodrine, Isoxsuprine, Salbutamol, Terbutaline

IMPORTANT FACTS:
• Prolonged use of naphazoline, oxymetazoline & xylometazoline: prolonged use leads to atrophic rhinitis
(rhinitis medicamentosa.)
• Oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect.
• Metaproterenol, terbutaline, and fenoterol: class of resorcinol bronchodilators & resistant to methylation by
COMT.
• Formoterol is approved for treatment of asthma, bronchospasm, prophylaxis of exercise-induced
bronchospasm and COPD.
• Long-acting inhaled B-receptor agonist (salmeterol, formoterol) is more effective than doubling the dose
of the inhaled corticosteroid in case of asthmatics refractory to treatment.
• Sympathomimetics as ophthalmic drops are useful in localizing the lesion in Horner's syndrome.
o Postganglionic lesion: indirectly acting sympathomimetics will not dilate the abnormally constricted
pupil (catecholamines are lost from the nerve endings in the iris) whereas the pupil will be dilated by
phenylephrine (acts directly on the receptors of iris.
o Preganglionic lesion: shows a normal response to both drugs.
• Salmeterol or formoterol are the agents of choice for nocturnal asthma.
• Salmeterol is metabolized by CYP3A4 to α -hydroxy-salmeterol.
• Phenylpropanolamine {α1 agonist} was banned due to risk of hemorrhagic stroke.
• Long-acting (>12 hrs) β2-selective agonists: salmeterol and formoterol.
• Mirabegron is a new drug approved for overactive bladder. It acts by stimulating β3 receptors.
• Midodrine [α1 agonist}, (active metabolite: desglymidodrine) is used to treat orthostatic hypotension.
• Metaraminol: used in hypotensive states or off-label to relieve attacks of paroxysmal atrial tachycardia
associated with hypotension.
• Most important side effect of salbutamol: muscle tremor> tachycardia and arrhythmias.
• Ephedrine: first orally active sympathomimetic drug. It is found in Ma-huang, a popular herbal medication.
• The main urinary metabolite of methylphenidate is ritatinic acid, which accounts for 80% of the dose.
• Methylphenidate is contraindicated in patients with glaucoma.
• Dexfenfluramine, selective 5-HT agonist, an appetite suppressant was withdrawn because of cardiac valve
toxicity.
• Appetite suppression is d/t agonist action at 5-HT 2C receptors in the CNS.

CATECHOLAMINES:
Adrenaline: α1 + α2 + β1 + β2 and weak β3 action
Nor adrenaline: α1 + α2 + β1 + β2 but no β2 action
Nor adrenaline: β1 + β2 + β3 + but no α action

• α 2-receptor agonists cause platelet aggregation and a decrease in platelet cAMP Levels.
• cAMP is the major second messenger of β-receptor activation.
• Catecholamines are inactivated by catechot-O-methyltransferase (COMT), an enzyme found in gut and liver.
• Almost pure α activity-methoxamine
• Almost pure β activity-isoproterenol.

Effect of cteholamines on the heart rate and blood pressure:

SBP DBP Heart Rate
(β1) (β2 and α) Direct Action (β1) Reflex Action (M2) Net effect
 Adr ↑↑ ↑↓ ↑ Nil ↑
NA ↑↑ ↑↑ ↑ ↓↓ ↓
Iso ↑ ↓↓ ↑ ↑ ↑↑

Adrenaline:
• DOC in anaphylactic shock. (0.5 ml of 1:1000 solution (i.e. 0.5 mg) 1.m. /S.C. injection).
• Prolongs the duration of action & decrease the systemic toxicity of local anesthetics.
• Contraindicated in hypertension, hyperthyroid, angina & during halothane anesthesia.
• Concentration of adrenaline for different routes and indications.

Route and indication Concentration of Adrenaline required

Bronchial asthma, inhalational 1:100
Anaphylactic shock, intramuscular 1:1000
Anaphylactic shock, subcutaneous 1:1000
Anaphylactic shock, intravenous 1:10000
Cardiac arrest, intravenous 1:1000
With Local anaesthetics, subcutaneous 1:200000

• Dopamine is the DOC for cardiogenic shock with oliguric renal failure.
• It cause renal vasodilatation by acting on D1 receptors and maintains renal perfusion and GFR.
• The D1 receptors in renal and mesenteric blood vessels are the most sensitive.
• IV infusion of low dose of DA dilates these vessels (by raising intracellular cAMP).
• Moderately high doses produce a positive inotropic (direct B1 and D1 action + that due to NA release), but
little chronotropic effect on heart.
• Vasoconstriction (al action) occurs only when large doses are infused.
• lbopamine is similar to dopamine.
• Dobutamine is relatively selective β1 agonist with no action on DA receptors.
• Dopexamine - combines β-2 & D-1 agonist activity with NA reuptake inhibitory action.
• Fenoldopam is D1 agonist useful in hypertensive emergencies.

TREATMENT OF NEUROGENIC SHOCK

• Simultaneous approach to the relative hypovolemia and to the loss of vasomotor tone.
• Excessive volumes of fluid may be required to restore normal hemodynamics if given alone.
• Once hemorrhage has been ruled out, norepinephrine or a pure a-adrenergic agent (phenylephrine) may be
necessary to augment vascular resistance and maintain an adequate MAP.

Effect of receptors on pupil size:

Receptor Location Action
M3 Sphincter papillae Miosis
α1 Dilator pupillae Mydriasis

SYMPATHOLYTIC DRUGS
ALPHA BLOCKERS
• Non Equilibrium Type
o Beta halo alkylamines - Phenoxybenzamine
• Non selective
o Ergot Alkaloids - Ergotamine, Ergotoxin
o Hydrogenated Ergot Alkaloids - Dihydroergotamine, Dihydroergotoxin
o Imidazolines - Tolazoline, Phentolamine
o Miscellaneous - Chlorpromazine
• Selective
o Alpha-1 selective Prazosin, Terazosin, Doxazosin, Tamsulosin
o Alpha-2 selective Yohimbine
Nonselective α-Blockers
• Phenoxybenzamine: irreversible antagonist,
used to prevent hypertensive episodes during
operative manipulation of tumor in
pheochromocytoma.
• Phentolamine & tolazoline: reversible blockers,
agents for the treatment crisis in clonidine
withdrawal and cheese reaction.
• Vasomotor reversal of Dale. IV of adrenaline
normally cause increase in BP (α effect) followed
by prolonged fall (β2 effect). If it is administered
after giving α bockers, only fall in BP is seen.
Selective α1-Blockers
(Prazosin, terazosin, doxazosin and alfuzosin)
• Decrease in blood pressure with lesser
tachycardia.
• All subtypes of al receptors are blocked equally
by prazosin.
• Favorable effect on lipid profile (increase HDL
and decrease LDL and TG)
• DOC for patients with hypertension and benign
hyperplasia of prostate (BHP).
• Major adverse effect: postural hypotension.
(First dose effect) & Inhibition of ejaculation.
• Doxazosin (t1/2 -22h) is used in hypertension
and BPH.
• Tamsulosin, alfuzosin & Silodosin selectively
inhibits subtype of α1 receptors present in the
prostate (α1A/D) without affecting those present
in the blood vessels, preferred for the treatment
of BHP.
• Terazosin: used in BHP, has apoptosis promoting
effecting on prostate.
• Tamsulosin: Causes 'floppy iris syndrome'
during cataract surgery.
• Indoramin & Urapidil: used in hypertension.
• Others: pinacidil & cromakalim.

Indoramin:
• Competitive α1 antagonist & antagonizes H1 and 5-HT receptors.
• Lowers BP with minimal tachycardia & decreases incidence of attacks of Raynaud's phenomenon. Selective
α2-Blockers: Yohimbine, Rauwolscine and idazoxan

Idazoxan:
• Acts as both a selective α2 adrenergic antagonist, and an antagonist for the imidazoline receptor.
• Idazoxan has been under investigation as an antidepressant & as an adjunctive treatment in schizophrenia.
• Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics.

BETA BLOCKERS
• First s nthesized β-blockendichloroiso roterenol.
Nonselective β- Blockers Propranolol, Timolol, Sotalol, • Myocardial oxygen demand is decreased
Nadolol, Pindolol, Alprenolol, • Coronary vasoconstriction
Oxprenolol (contraindicated in variant angina).
• Bronchoconstriction(β2 blockade)
• Dyslipidemia, hypotension, Hypoglycemia
β-Blockers with Intrinsic Celiprolol, Oxprenolol, Pindolol, Preferred in patients prone to develop severe
Sympathomimetic Penbutotol, Alprenolol, Acebutolol bradycardia with beta blocker therapy a in
Activity (ISA) asthmatics
Cardio selective (Selective Betaxolol, Bisoprolol, Atenolol, Preferred in patients with diabetes mellitus,
β1) β - Blockers (IInd gen.) Esmolol (Shortest acting), bronchial asthma, peripheral vascular disease or
Acebutolol, Nebivolol (Most cardio hyperlipidemia
selective), Metoprolol Celiprolol
β-Blockers with Propranolol (maximum), Posses Na' channel blocking (local anesthetic)
Membrane Stabilizing Metoprolol, Labetalol, Acebutolol activity. It can contribute to antiarrhythmic
Activity Pindolol action. should be avoided in glaucoma due to the
risk of corneal anesthesia
Lipid Insoluble β- Blockers Nadolol (longest acting β blocker), Excreted by kidney and are therefore
Sotalol, Atenolol, Acebutolol, contraindicated in renal failure
Betaxolol, Bisoprolol, Celiprolol

Another system classifies beta blockers into 3 generations.

First generation Second generation Third generation
Older, nonselective Β1 selective With additional α blocking and/or
vasodilator property
Propranolol Metoprolol Labetalol
Timolol Atenolol Carvedilol
Sotalol Acebutolol Celiprolol
Pindolol Bisoprolol Nebivolol
Esmolol Betaxolol

• Celiprolol: Selective β1 blocker having additional weak β2 agonistic activity  reduces vascular resistance &
safe in asthmatics.
• Carvedilol: β1 + β2 + α1 adrenoceptor blocker; produces vasodilatation due to al blockade as well as calcium
channel blockade, and has antioxidant property.

THIRD GENERATION β-BLOCKERS

• Possess additional vasodilatory property.
• Third-Generation B Rece tor Antagonists with Additional Cardiovascular Actions:
Nitric Oxide β receptor α 1 receptor Ca channel blockers K channel Anti-oxidant
production agonism antagonism opening activity

Celiprolol Celiprolol Labetalol, Bevantolol Titisolol Carvedilol

Carteolol Carteolol carvedilol Betaxolol
Bopindolol Bopindolol Bucindolol Carvedilol
Nipradilol. Bevantolol
Nebivolol Nipradilol

ACTIONS OF BETA BLOCKERS

• CVS:Decreases heart rate, force of contraction and cardiac output & prolongs systole by retarding
conduction.
• Blood vessels: On prolonged administration BP gradually falls in hypertensive subjects but not in
normotensive. Total peripheral resistance is increased initially and cardiac output is reduced-little change in
BP.
• Blocks cardiac stimulant action of adrenergic drugs but not that of digoxin, Ca2+, methytxanthines or
glucagon.
• Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension.
• Respiratory tract: increased bronchial resistance by blocking B2 receptors.
• Metabolism: blocks adrenergically induced lipolysis and consequent increase in plasma free fatty acid levels.
• Plasma triglyceride level and LDLIHDL ratio is increased.
• It also inhibits glycogenolysis in heart, skeletal muscles and in liver (inconsistently).
• Glucagon stimulates the heart via glucagon receptors, which are not blocked by antagonists.Prophylaxis for
musicians with performance anxiety ("stage fright"): low doses of propranolol.
• Nadolol with isosorbide mononitrate: more efficacious than scierotherapy in preventing re-bleeding in
esophageal varices.
• Resting bradycardia and bradycardia during exercise are indicators of propranolol's blocking effect.

USES OF β-BLOCKERS
Cardiac (due to β1 blockade) Extra cardiac (due to β2 blockade)
Hypertension Pheochromocytoma (after α blockade)
Classical angina Hyperthyroidism
Myocardial infarction Performance anxiety
Supraventricular arrhythmias Tremors
Chronic CHF Akathisia
Hypertrophic obstructive cardiomyopathy (DOC) Prophylaxis of migraine
Emergency management of symptoms of TOF Glaucoma (timolol and betaxolol)
Mitral valve prolapse Alcohol and opioid withdrawal
Prophylaxis of bleeding in portal hypertension

• Greatest utility of β blockers has been shown in mild to moderate (NYHA class II, III) cases of dilated
cardiomyopathy with systolic dysfunction.
• Encouraging results (upto 35% decrease in mortality) in class IV.
• There is no place for B blockers in decompensated patients.
• β blockers should be stopped during an episode of acute heart failure

ADVERSE EFFECTS OF BETA BLOCKERS

• Nonselective blockers like propranolol block β2 receptors in bronchial smooth muscle 
bronchoconstriction  contraindicated in asthmatics.
• Nonselective β blockers blunt the responses and delay recovery from hypoglycemia in type 1 (insulin-
dependent) diabetes mellitus, but infrequently in type 2 diabetes mellitus. Also B blockade leads to
decreased glycogenolysis and decreased glucagon secretion.
• Abrupt discontinuation of chronic B blocker therapy can lead to "rebound" symptoms, including
hypertension, increased angina, and arrhythmias; thus, b receptor antagonist therapy is tapered over 2
weeks.
• Accentuates myocardial insufficiency: can precipitate CHF and edema by blocking sympathetic support to
the heart, especially during cardiovascular stress.
• Bradycardia
• Propranolot is contraindicated in partial and complete heart block: arrest may occur.

CONTRAINDICATIONS OF BETA BLOCKERS

• Decompensated CCF
• Bradycardia, HR<60/min
• COPD, Asthma
• Variant angina
• Carbohydrate intolerance
• Hyperlipidemia
• Atherosclerosis
• Partial and complete heart block
• Raynaud's disease

COMBINED ALPHA AND BETA BLOCKERS

• Labetalol and carvedilol  control of hypertensive episodes in pheochromocytoma.
• Carvedilol: commonly used beta blocker in chronic CHF (antioxidant and anti mitogenic) Other drugs:
medroxalol and bucindolol.

AUTACOIDS
• Amine - Histamine, Serotonin
• Lipid - Prostaglandins, Leukotrienes, Platelet activating factor
• Peptide - Bradykinin, Angiotensin, Kallidin
The classical autacoids are-
• Amine autacoids: Histamine, 5-Hydroxytryptamine
• Lipid derived autacoids: Prostaglandins, Leukotrienes, Platelet activating factor
• Peptide autacoids: Plasma kinins (Bradykinin, kallidin), Angiotensin

SEROTONIN
• Over 90% of the serotonin in the body is found in enterochromaffin cells in GIT.
 • Serotonin is a powerful vasoconstrictor except in skeletal muscle & heart.
• On i.v. injection, it produces triphasic response on BP.
o Phase-I: Early sharp fall in blood pressure (due to Bezold Jarisch reflex),
o Phase-II: brief rise in blood pressure (due to vasoconstriction)
o Phase-III: prolonged fall in blood pressure (due to arteriolar dilatation)
• Powerful stimulator of smooth muscles. It increase peristalsis and constricts bronchi.
• It has gastro protective action by decreasing acid secretion and increasing mucus production.
• Involved in regulation of sleep, cognition, behavior and mood.
• Increases platelet aggregation.

5 HT1 5 HT 2A / 2C 5HT3 5 HT4

• 5 HT1A – presynaptic • Responsible for • Inotropic receptor • Present in GIT
autoreceptor, partial most of the direct • Mediates most of the and is
agonists of the receptor actions of reflex and indirect responsible for
(buspirone, ipsapirone, serotonin. actions of serotonin the increase in
gespirone) are useful as ANTAGONISTS: • Stimulation is peristalsis
antianxiety drugs. • Ketanserin a responsible for • Agonists
• 5 HT1B/1D cause ritanserin: vomiting induced by (cisapride,
constriction of cranial antihypertensive anticancer drugs renzapride,
vessels & agonists agents. • 5 HT3 antagonists like tegaserod) are
(sumatriptan, • Clozapine and ondansetron, useful in GERD.
naratriptan) are useful risperidone are granisetron and • Tegaserod-
for the treatment of atypical • tropisetron are the Used in
acute migraine antipsychotics. DOC for chemotherapy treatment of
attacks,but not used in induced vomiting constipation.
prophylaxis.

• Sumatriptan- most effective by oral route.

Others: Almotriptan, Rizatriptan
Contraindications:
• Naratriptan and eletriptan - severe hepatic/ renal impairment or peripheral vascular syndromes;
• Frovatriptan - peripheral vascular disease
• Zolmitriptan - Wolff-Parkinson-White syndrome.

NON SELECTIVE DRUGS

• Cyproheptadine: It blocks 5HT 2A, H1 and muscarinic receptors. It increases appetite  used in children to
promote weight again.
• Methysergide: It is a 5HT 2A /2c antagonist and a 5HT1 agonist indicated for the prophylaxis of migraine attacks
but prolonged use can result in pulmonary, endocardial and retroperitoneal fibrosis.
• LSD: It is an ergot derivative and a powerful hallucinogen. It acts as an agonist at several serotonin receptors
including 5HT-1A, 5 HT 2A/2C and 5 HT5-7

ERGOT ALKALOIDS
• Ergot poisoning was called St. Anthony's fire.
• These are derived from a fungus Claviceps purpurea.
• Partial agonistic and antagonistic effects at 5HT, and dopaminergic receptors.
• Can cause vasoconstriction (α blockage & partial agonistic activity on a and 5 HT2 receptors.
• Ergot derivatives can cause dry gangrene of hand and feet as well as coronary vasospasm.
• Ergotamine and dihydroergotamine are used for the treatment of attack of migraine.
• Dihydroergotoxine (codergocrine) is useful for the treatment of dementia.
• Bromocriptine is useful in Parkinsonism, Hyperprolactinemia and Acromegaly.
• Methyl ergometrine (methergine) is used in the prophylaxis of postpartum hemorrhage
• Methysergide: used for prophylaxis of migraine attacks.

TREATMENT OF MIGRAINE
 • Mild & moderate attacks: NSAIDs
• Severe attacks: ergot alkaloids or triptans.
• Ergotamine  to abort acute attack of migraine, usually combined with caffeine enhances the absorption
of ergotamine and is a powerful vasoconstrictor. These drugs increase the nausea and vomiting during
migraine.
• Sumatriptan (subcutaneous) is the DOC for aborting acute attack of migraine. It suppresses the vomiting of
migraine. It is a short acting drug and has low oral bioavailability.
• Frovatriptan is the longest acting and rizatriptan is the most potent and fastest acting congener.
• Other drugs useful are zolmitriptan, eletriptan, naratriptan and almotriptan. All of these drugs can cause
coronary vasospasm and are contraindicated in ischemic heart disease.
• Triptans and ergotamine should not be administered within 24 hours of each other.
• Prophylaxis of migraine is required if the attacks are frequent (>2-3 per month).
• Drugs useful for prophylaxis are:
o Propranolol is the most commonly used drugs for prophylaxis of migraine attacks. Metoprolol and
nadolol can also be used but the drugs with intrinsic sympathetic activity (e.g. pindolol) are ineffective.
o Calcium channel blockers like flunarizine, verapamilis also effective.
o Methysergide, Cyproheptadine and TCAs like amitriptyline can also be used
o Clonidine can be used orally for the prophylaxis of migraine attacks.
o Recent drugs: Topiramate, valproate, gabapentin, Onabotulinum toxin-A.

HISTAMINE
Synthesized from histidine & stored in the mast cells.
It acts mainly on H1 and H2 receptors. Recently H3 (presynaptic) and H4 receptors have also been isolated.
Actions
• Vasodilatation  hypotension; Increases capillary permeability  edema (H1 receptors.)
• Intradermal injection may result in triple response (H1 response)
o Red reaction (due to vasodilatation),
o Wheal (exudation of fluid due to increased permeability)
o Flare (spreading redness due to axon reflex).
• H1 receptor stimulation has negative dromotropic effect whereas H2 stimulation increases the force of
contraction of isolated heart. Effect on intact heart is not prominent.
• Bronchoconstriction & abdominal cramps (H1 receptors). Increases gastric secretion (H2 receptors.)
• Stimulates nerve endings and may result in pruritic and pain.
• Stimulates reticular activating system and maintains wakefulness (H, receptors).
• Mediator of inflammation and immediate type of hypersensitivity reactions.
• Rote in chemotaxis of white blood cells.
• Histamine content of tissues is directly related to their mast cell content.
• Mast cells in skin and basophils (not in lungs) show a negative feedback mechanism mediated by
H2 receptors.
o Betahistine is an oral histamine analogue used to control vertigo in Meniere's disease.
o Drugs that cause histamine release: d-tubocurarine, morphine, atropine, stilbamide, vancomycin,
polymyxin-B etc.

Receptor Location Agonist Antagonist

H1 Smooth muscles, CNS, endothelial Histamine Chlorpheniramine
cells
H2 Gastric parietal cells, cardiac Dimaprit Ranitidine
muscles, mast cells, brain
H3 CNS, myenteric plexus Histamine Thioperamide, Clobenpropit
H4 Eosinophils, neutrophils, CD4 T cells Clobenpropit , Thioperamide
clozapine

H1 ANTIHISTAMINICS:
First Generation Anti-histaminics
 • Penetrate blood brain barrier and thus result in sedation and psychomotor impairment.
• Contraindicated in truck drivers etc...
• Has additional anticholinergic adv. Effects
Highly sedating: Diphenhydramine, Dimenhydrinate, Promethazine, Hydroxyzine, Doxepin
Moderately sedating: Pheniramine, Cyproheptadine, Meclizine, Buclizine, Cinnarizine
Mildly sedating: Chlorpheniramine, Mepyramine, Cyclizine, Clemastine, triprolidine

Second Generation Anti-histaminics

• Lack sedation (can be used in truck drivers) & anticholinergic Adv. Effects
• Terfenadine: fastest acting antihistaminic, causes torsades de' pointes (blocks cardiac K+ channels.*
prolongation of QTc interval). Its active metabolite "fexofenadine" lacks K+ channel blocking property.
• Astemizole: slowest acting agent & possess arrhythmogenic activity. Should not be administered with
ketoconazole, erythromycin, clarithromycin and itraconazole.
• Loratidine: longest acting second generation antihistaminic, metabolized to desloratidine
• Cetirizine: active metabolite of a first generation antihistaminic drug, hydroxyzine. Levocetirizine is l-isomer
of cetirizine that is more potent and less sedative
• All second generation antihistaminics are metabolized to active products except cetirizine and mizolastine.
• Azelastine: maximum topical activity and can be given by nasal spray for allergic rhinitis.
• Other drugs: Mizolastine, ebastine, levocabastine, rupatidine, olapatidine and acrivastine

• Burimamide (H2 blocker) improgran (no effect on H1, H2, or H3) has significant analgesic action when
administered into the CNS.
• Few H1 antagonists (terfenadine, acrivastine) inhibit the P-glycoprotein transporter found in cancer cells, the
epithelium of the gut and capillaries of the brain.
• Rupatadine: recently introduced anti histaminic with additional PAF antagonism.
• Ebastine: converted to carbostine
• Doxepin, a TCA, is one of the most potent antihistamines; -800 times more potent than diphenhydramine.

OTHER FACTS
• Rate-limiting step in biosynthesis of catecholamines (tyrosine to dopa) is inhibited by metyrosine.
• Metyrosine is useful in symptomatic patients with inoperable or metastatic pheochromocytoma.
• Solifenacin is newly approved for overactive bladder with a favorable efficacy: side effect ratio.
• Stress urinary incontinence has been treated with some success with duloxetine.
• Methacholine challenge test used to diagnose airway hyper reactivity.
• Cevimelineis a newer muscarinic agonist available orally for use in treatment of xerostomia.
• Edrophonium test: 1-2 mg i.v. dose of edrophonium improve skeletal muscle activity if the weakness is due
to myasthenia whereas it will worsen the condition if it is due to cholinergic crisis.
• DOC for acute mountain sickness: Acetazolamide
• DOC for morning sickness: Dicyclomine, Promethazine
• DOC for sea sickness: Meclizine
• DOC for motion sickness: Hyoscine.
• Promethazine, diphenhydramine, dimenhydrinate and cyclizine have prophylactic value in milder types of
motion sickness.
• Pharmacological stress testing: done by infusion of dobutamine- increases myocardial oxygen demand
• Bradykinin is predominant kinin in plasma, while lysylbradykinin is the major urinary form.
• Icatibant is a second generation Bradykinin -2 (B2) receptor antagonists.
• Adrenergic drugs may directly protect neuronal cells in the retina.
• Physiological antagonist: Adrenaline.
• Most universally distributed autacoid: eicosanoids
• treatment of choice in β- blocker poisoning: isoproterenol / Glucagon (glucagon stimulates the heart via
glucagon receptors, which are not blocked by B antagonists)
• Drugs for acute muscle spasm: carisoprodol, chlorphenesin, chlorzoxazone,
• cyclobenzaprine,metaxalone, methocarbamol and orphenadrine

MANAGEMENT OF ANAPHYLACTIC SHOCK

 • Syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension.
• Usually responds rapidly to the parenteral administration of epinephrine, 0.3-0.5 mg (0.3-0.5 mL of 1:1000
epinephrine solutions).
• IM route may be preferred, since skin blood flow may be unpredictable.
• In some patients with impaired cardiovascular function, very cautious intravenous injection of epinephrine
may be required.
• Epinephrine is the agent of choice because it activates α, β1, and β2 receptors.
• Glucocorticoids and antihistamines may be useful as secondary therapy.
• Urotensin II is potent than endothelia 1, making it the most potent known vasoconstrictor.

MANAGEMENT OF ERECTILE DYSFUNCTION

• Ejaculation is mediated by a -receptor (and possibly purinergic receptor) in ductus deferens, seminal vesicles
and prostate.
• The detumescence following ejaculation is also brought about by norepinephrine (and possibly neuropeptide
Y) released from sympathetic nerves.
• Alpha activation has a similar detumescent effect on erectile tissue in female animals.

Drugs Used:
• Sildenafil (Viagra) increases cGMP by inhibiting its breakdown by phosphodiesterase - 5.
• Sildenafil potentiates the action of nitrates used for angina'  severe hypotension and MI.
• Indicated by a "black box" warning on product labeling.
• Should not be given within 6 hours of nitrate treatment.
• Sildenafil also has effects on color vision, causing difficulty in blue-green discrimination.
• Other PDE-5 inhibitors: tadalafil, vardenafil, Udenafil & Avanafil
• Drug most commonly used in patients not responding to sildenafil: alprostadil, a PGE1 analog.
• Other drugs: phentolamine & apomorphine

Sildenafil
• PDE-5 inhibitors lower pulmonary arterial pressure as NO is an important regulator of pulmonary vascular
resistance.
• Sildenafil is more selective for pulmonary circulation than vardenafil.
• Metabolized largely by CYP3A4 and an active metabolite is produced.
• Sildenafil is ineffective in men who have lost libido,in spinal cord injury or damaged nervi erigentes.
• Sildenafil is the DOC for pulmonary hypertension as it is the only PDE-5 inhibitor shown to improve arterial
oxygenation.

MANAGEMENT OF VERTIGO
• Labyrinthine suppressants: suppress end organ receptors or inhibit central cholinergic pathway:
o Antihistaminics (with anticholinergic action as well) - cinnarizine, cyclizine, dimenhydrinate,
diphenhydramine, promethazine.
o Anticholinergics-atropine, hyoscine.
o Antiemetic phenothiazines-prochlorperazine, thiethylperazine.
• Vasodilators: improve blood flow to labyrinth and brain stem-betahistine, codergocrine, nicotinic acid,
naftidrofuryl.
• Diuretics: decrease labyrinthine fluid pressure -acetazolamide, thiazides, furosemide.
• Anxiolytics,antidepressants: modify the sensation of vertigo-diazepam, amitriptyline.
• Corticosteroids: suppress intralabyrinthine edema due to viral infection or other causes.
Parenteral prochlorperazine is the most effective drug for controlling violent vertigo and vomiting.

PROSTAGLANDINS
Arachidonic acid  Prostaglandins & thromboxanes [by cyclooxygenase (COX)].
• COX-I - constitutive, housekeeping functions of the cells, found in GIT, kidneys and platelets.
• COX-II - Inducible & participates in inflammation
• COX-III- isolated from cerebral cortex. Involves in pain perception & fever but not in inflammation.
o Platelets contain thromboxane synthetase & produces TXA2
 o Vascular endothelium contains prostacyclin synthase & produces PGI2.

ACTIONS OF PROSTAGLANDINS:
CVS • PGE2 and PGF2α cause vasodilatation in most vascular beds. In isolated preparations, they
are more potent vasodilators than ACh or histamine.
• PGF2α constricts larger veins.
• PGI-2: potent vasodilator
• TXA2 consistently produces vasoconstriction.
• PG endoperoxides are inherently vasoconstrictor.
Platelets TXA2 - vasoconstriction and potent inducer of aggregation and release reaction.
PGI- 2 (less extent by PGD-2) is a potent inhibitor of platelet aggregation.
Uterus PGE-2 & PGF-2α (more potent): contract human uterus, pregnant & non pregnant invivo.
CNS • PGE2 and PGI2 sensitize the peripheral nerve endings to painful stimuli by lowering the
• threshold of nociceptors.
• Centrally, PGE2 can increase excitability in pain transmission neuronal pathways in the
spinal cord. Hyperalgesia also is produced by LTB4.
Bronchial • PGE-2 & PGI-2: bronchial smooth muscle relaxation.
muscle • PGF-2α & TX A-2: bronchoconstrictors
GIT • PGE-2 & PGI-2: decreases gastric acid secretion & increases mucus production.
• PGE-2 & PGF-2α: contraction of longitudinal muscle of GIT
Kidney • PGE-2 & PGI-2: natriuresis, renal vasodilatation, inhibit ADH action to promote water
clearance
• TX-A2: renal vasoconstriction
Male • PGE is 20 times PGF-2α in a fertile semen.
reproductive • PGE-1 enhances penile erection & increases sperm motility from vagina to uterus.
system
CNS • PGE-1 & PGE-2 are pyrogenic.
• PGI-2 & PGE-2sensitise pain receptors at afferent nerve endings.
Endocrine • PGE-2 facilitates release of growth hormone, TSH, ACTH, FSH, LH and prolactin
Eye PGF-2α & also PGE-2 lower intraocular pressure
Cancer PGE-2 & TXA-2 are likely procarcinogenic mediator

• Chemicals that excite the chemical type of pain are bradykinin, serotonin, histamine, potassium ions, acids,
AMP, acetylcholine, and proteolytic enzymes.
• Pain enhancers:Prostaglandins & sub-P enhance the sensitivity of pain endings without exciting them.
• In cirrhosis, liver produces large amounts of potent vasoconstrictor 8-epi-PGF2α (play a pathophysiologic
role in hepatorenal syndrome).
• PGE1 and PGE2 increase body temperature, probably via EP3 receptors.
• PGD2 induces natural sleep.
• PGs (especially PGE2, acting on EP4 receptors) in vivo increase bone turnover, ie, stimulation of bone
resorption and formation.
• Adverse effects: nausea, vomiting, watery diarrhoea, uterine cramps, unduly forceful uterine contractions,
vaginal bleeding, flushing, shivering, fever, malaise, fall in BP, tachycardia and chest pain.

Uses:
Epoprostenol (PGI2) & Pulmonary hypertension
Treprostinil (PGI2)
Alprostadil (PGE1) & Keeps ductus arteriosus patent before surgery -
Epoprostenol (PGI2)
Epoprostenol (PGI2) Anti platelet aggregator in hemodialysis, blood storage & cardio pulmonary bye-pass
Dinoprostone (PGE2) Cervical ripening
Carboprost (PGF2α) To control post partum hemorrhage
Misoprostol (PGE1) Induction of abortion
 Aerolised PGE2 Acute attacks of asthma
Misoprostol Specific drug for NSAID induced gastric ulcer. (DOC: Proton pump inhibitors)
Alprostadil (PGE1) Penile erectile dysfunction
Lantanoprost (PGF2α) Glaucoma

• NSAIDS like aspirin & Indomethacin can close the ductus.

• Regular use of aspirin or Celecoxib decreases the risk of carcinoma Colon.
• Use of misoprostol in pregnancy  Moebius syndrome (abnormal development of cranial nerves-VI & VII).
• Barter syndrome: characterized by excess PG's lead to hyperreninemia, excess aldosterone, Hypokalemia &
alkalosis. Treatment is Indomethacin.

LEUKOTRIENES
• Synthesized from arachidonic acid by the enzyme 5-lipooxygenase.
• The leukotrienes are produced by the 5-LOX present in leukocytes (neutrophils, basophils, eosinophils, and
monocyte-macrophages) and other inflammatory cells such as mast cells and dendritic cells.
• LTC4 & LTD4 - slow reacting substances of anaphylaxis (SRS-A), potent chemoattractants for eosinophils.
• LTB4- powerful chemo tactic agent for neutrophils, mediator of all types of inflammation.
• Both lipoxin A and lipoxin B inhibit natural killer cell cytotoxicity.
• Annexins or lipocortins inhibit phospholipase A2 activity, by interfering with phospholipid binding and
preventsthe release of arachidonic acid.
• LTs inhibited by steroids, Lipo-oxygenase inhibitors (Zileuton), LT receptor antagonists (Zafirlukast,
Montelukast, Pranlukast, Iralukast)

PLATELET ACTIVATING FACTOR (PAF)

• Most potent agent known to increase the capillary permeability.
• Apafant & Lexipafant -PAF antagonists- used in acute pancreatitis.

FIROMBOXANE A21
• Daltroban & sulotroban are TXA2 receptor antagonists.
• Dazoxiben inhibits the enzyme thromboxane synthetase.
LICOFELONE-: combined COX-LOX inhibitor- disease modifying anti-osteo arthritis drug. (DMAOAD)
NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• Acts by inhibiting COX enzyme and prostaglandin synthesis.

CLASSIFICATION
A. Nonselective COX inhibitors (traditional NSAIDs)
• Salicylates: Aspirin
• Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
• Fenamate: mephenamic acid.
• Enolic acid derivatives: Piroxicam, Tenoxicam.
• Acetic acid derivatives: Ketorolac, Indomethacin, Nabumetone.
• Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
B. Preferential COX-2 inhibitors:
Nimesulide, Diclofenac, Aceclofenac, Meloxicam, Etodolac.
C. Selective COX-2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic - antipyretics with poor anti-inflammatory action
• Paraaminophenol derivative: Paracetamol (Acetaminophen)
• Pyrazolone derivatives: Metamizol (Dipyrone), propiphenazone.
• Benzoxazocine derivative: Nefopam.

Features of nonselective COX inhibitors and selective COX-2 inhibitors.

Action
Analgesic
Antipyretic
Anti-inflammatory
Antiplatetet aggregatory
Gastric mucosal damage
Renal salt/water retention
Delay/ prolongation of labour
Ductus arteriosus closure
Aspirin sensitive asthma precipitation
COX-1/COX-2 inhibitors COX-2 inhibitors
+ +
+ +
+ +
+ -
+ -
+ +
+
+ ?
+ -

NON SELECTIVE COX INHIBITORS

Paracetamol (acetaminophen):
• It is a selective COX 3 inhibitor in the brain.
• It is metabolized to N-acetyl parabenzo quinoneimine (NAPQI) by microsomal enzymes.
• Safe drug because sulfhydryl groups in glutathione produced by the liver combines with NAPQI to detoxify it.
• Paracetamol poisoning:
o Occurs in larger doses (> 150mg/kg). Fatal dose: > 250mg/kg.
o Liver damage occurs if plasma concentration is greater than 200μg/ml at 4 hours & 30 μg/ml after 15
hours of ingestion.
o Manifests as centri lobular hepatic necrosis after 12-28 hours of ingestion & may be accompanied by
Renal Tubular Acidosis & hypoglycemia, leading to coma. Infants & alcoholics are prone for toxicity.
o treatment consists of activated charcoal lavage & infusion of N- Acetyl Cysteine (specific antidote)

Salicylates:-
• Irreversible inhibitors of COX enzyme.
• Apart from antipyretic, analgesic and anti inflammatory effects, aspirin has several other indications.
• At lowest doses (40-325 mg): antiplatelet action  prophylaxis of myocardial infarction and stroke. It acts
by inhibiting cyclooxygenase enzyme  decreasing the synthesis of TXA2, it also inhibits PGI2 (anti-
aggregator) synthesis at higher doses.
• Aspirin is used to inhibit niacin induced flushing, dysrnenorrhea and pre-eclampsia.
• Fecal blood loss of 3m1 is routinely associated with aspirin administration.
• Daily dose of aspirin: < 2g: increases while >4 g decreases serum uric acid levels.
• Metabolic pathways for salicylates- get saturated when the total body toad exceeds 600 mg.
 • Aspirin triad: asthma, nasal polyps and rhinitis
• Adverse Effects
o Salicylism: characterized by headache, vertigo, tinnitus, vomiting, hyperventilation & electrolyte
imbalance.
o Respiratory alkalosis and Compensatory metabolic acidosis. (More in infants as early symptoms like
tinnitus & vertigo are frequently missed).
o At therapeutic doses, it can cause hyperuricemia therefore should not be used in patients with gout.
o Aspirin is contraindicated in children (<12 yrs old) due to increased risk of Reye's syndrome.
o Treatment: Salicylate poisoning is treated by supportive measures, gastric lavage, correction of
metabolic acidosis and urinary Alkalinization to increase the excretion.

Plasma salicylate Effect Complications

concentration (mg/dl)
0-10 Analgesic, antipyretic, Gastric intolerance, bleeding, hypersensitivity,
antiplatelet impaired hemostasis
10-50 Anti-inflammatory, Uricosuric
50-80 Mild intoxication Tinnitus, central hyperventilation
80-110 Moderate intoxication Fever, dehydration, metabolic acidosis
110-160 Severe intoxication Vasomotor collapse, coma, hypoprothrombinemia
>160 Lethal Renal & respiratory failure
• Nonacetylated Salicylates: Magnesium choline salicylate, sodium salicylate and salicylsalicylate.

OTHER NON- SELECTIVE COX INHIBITORS

• Indomethacin: inhibits PLP-A2; immunosuppressive, used in Barter syndrome. Causes GI upset, headache
(analgesic causing headache) and sedation.
• Indomethacin should be avoided in patients with nasal polyps or angioedema, in whom asthma may be
precipitated.
• Phenylbutazone: causes agranulocytosis
• Propionic acid derivatives include ibuprofen, Ketoprofen and flurbiprofen. Ketoprofen possesses additional
lysosomal stabilizing action & flurbiprofen can be used topically as eye drops.
• Ibuprofen can be used for pediatric patients.
• Naproxen & Oxaprozin: long acting drugs, inhibit leucocyte migration.
• Meclofenamate and mefenamic acid inhibit both COX and phospholipase A2 & enhances the effect of oral
anticoagulants.
• Mefenamic acid (PG receptor antagonistic and PLPA2 inhibitory activity) it is very useful in dysmenorrhoea.
• Mefenamic acid should not be used for longer than 1 week and should not be given to children.
• Meclofenamate is contraindicated in pregnancy.
• Phenacetin (prodrug of paracetamol) is implicated in causing analgesic nephropathy.
• Ketorolac is the only NSAID that can be used i.v. It is also available as eye drops.
• Piroxicam and tenoxicam are longest acting NSAIDs due to enterohepatic cycling.
• Nefopam (benzoxazocine derivative) does not inhibit PG synthesis, acts rapidly in traumatic & post-
operative pain.
• Nimesulide weakly inhibits PG synthesis.
• Apazone: potent uricosuric activity.
• Paracetamol has no anti-inflammatory action.
• All NSAIDS are racemic mixtures except naproxen & diclofenac.
• All are equally efficacious except Tolmetin (ineffective in gout) It aspirin (ineffective in ankylosing
spondylitis).
• Diclofenac + misoprostol decreases UGI ulceration but result in diarrhea.
• Diclofenac + omeprazole effective in prevention of recurrent bleeding, but renal adverse effects were
common.
• Diclofenac at a dosage of 150 mg/d impairs renal blood flow and GFR.
• A topical gel containing 3% dictofenac is effective for solar keratoses.
• Aceclofenac: COX-2 selective congener has chondroprotective property by enhancing glycosaminoglycan
synthesis.
 • Diflunisal: effective for cancer pain with bone metastases and for pain control in dental (third molar) surgery.
• 2% diflunisal oral ointment useful analgesic for painful oral lesions. Can result in pseudoporphyria.
• Flurbiprofen: associated with cogwheel rigidity, ataxia, tremor, and myoclonus
• Oral Ibuprofen is effective in closing PDA in preterms, with much the same efficacy and safety as
indomethacin.
• Concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin.
• Nabumetone- very expensive NSAID can cause pseudoporphyria and photosensitivity.
• Naproxen: only NSAID marketed as a single enantiomer, it's free fraction is 41% higher in women than in
men.
• Oxaprozin: mildly uricosuric, potentially more useful in gout than other NSAIDs.
• Sulindac suppresses familial intestinal polyposis & inhibit the development of colon, breast, and prostate
cancer in humans. Can cause Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia,
agranulocytosis and nephrotic syndrome
• Others: Tenoxicam, Tiaprofen, Tolmetin, Azapropazone & Carprofen.
• Fries toxicity index: indomethacin, tolmetin & meclofenamate were associated with the greatest toxicity,
while salsalate, aspirin and ibuprofen were least toxic.

PREFERENTIAL COX-2 INHIBITORS SELECTIVE COX-2 INHIBITORS

• These drugs have more inhibitory action of COX-2
than COX-1.
• E.g: Nimesulide, meloxicam, nabumetone
(prodrug), etodolac and diclofenac.
• All NSAIDs are acidic in nature except
nabumetone.
• Celecoxib, Rofecoxib and valdecoxib are
sulfonamide derivatives, thus can cause rash
and hypersensitivity.
• Etoricoxib is longest acting coxib; Lumiracoxib
is a newer drug, more active in acidic medium.

• Clinical trials have established that at least three selective inhibitors of COX-2—rofecoxib, valdecoxib &
celecoxib—confer an increased risk of heart attack and stroke.
• Celecoxib is a highly selective COX-2 inhibitor—about 10-20 times more selective for COX-2.
• Etoricoxib: acute treatment osteoarthritis, rheumatoid arthritis, acute gouty arthritis and for relief of
acute musculoskeletal pain.
• Rofecoxib: associated with occasional edema and hypertension.
• Valdecoxib: indicated for primary dysmenorrhea, serious reactions have been reported in sulfonamide-
sensitive individuals.
• Parecoxib is a prodrug of valecoxib that can be administered parenterally.
• Some tNSAIDs [traditional NSAIDs], such as meloxicam and diclofenac resemble celecoxib in terms of
their selectivity.

TREATMENT OF RHEUMATOID ARTHRITIS

Disease modifying anti rheumatoid drug (DMARDs) slow the progression of disease but act slowly (take few
months).
DMARDs Biological response modifiers (BRMs) Adjuvant drugs
• TNF- α blocking agents: Corticosteroids
• Immunosuppressants:
etanercept, adalimumab and
Methotrexate, Azathioprine,
infliximab
Cyclosporine
• IL-1 antagonist: Anakinra
• Sulfasalazine
• Chloroquine or Hydroxychloroquine
• Leflunornide
• Gold sodium thiomalate, auranofin
• d-Penicillamine

• Methotrexate: It is the first choice DMARD, used in doses of 7.5mg weekly.

• Sulfasalazine: It is metabolized to sulfapyridine and 5-arninosalicylic acid. Former is the active moiety in RA
and latter is useful for ulcerative colitis. Used when methotrexate is contraindicated.
 • Leflunomide: inhibits the enzyme Dihydro orotate dehydrogenase. It is faster acting (action is manifested in
4 weeks as compared to 3 months with other DMARDs) alternative to methotrexate.
• Old drugs: Gold and d-Penicillamine are highly efficacious DMARDs but are rarely used now due to severe
toxic reactions. Gold salts can be used orally (auranofin) as well as intramuscularly (aurothiomalate).
Dermatitis is the most common adverse effect seen with gold salts. These can also results in kidney and liver
damage, peripheral neuropathy, pulmonary fibrosis, encephalopathy and bone marrow depression.
• Nitritoid reactions (sweating, flushing, and headaches) can occur, especially with gold thiomalate and are
presumably due to the vehicle rather than the gold salts.
• Chloroquine and hydroxy Chloroquine: Hydroxychloroquine is preferred over Chloroquine due to less
chances of retinal damage.
• Other immunosuppressants: Azathioprine, mycophenolate mofetil, cyclosporine and cyclophosphamide can
also be used as DMARDs.
• Triple-therapy regimenin RA: methotrexate, sulfasalazine and hydroxychloroquine.
• TNF- α blocking agents:etanercept, adalimumab and infliximab
o Infliximab is also indicated in Crohn's disease, psoriatic arthritis, Wegener's granulomatosis sarcoidosis.
o Golimumab: once a month drug.
• Corticosteroids decrease the symptoms but do not slow down the progression of the disease (not DMARDs).
• Abatacept is a co stimulation inhibitor indicated for severe refractory RA.
• Tocilizumab (monoclonal antibody against IL-6 receptor).
• NSAIDs: only symptomatic relief, no effect on the progression of the disease.

DISEASE MODIFYING ANTI-OSTEOARTHRITIS DRUGS (DMAOAD)

• Osteoarthritis is treated by NSAIDs but these do not arrest the disease progression or joint destruction
• Diacerin (IL-1 antagonist) and Licofelone (combined COX-LOX inhibitor)

TREATMENT OF GOUT
• Hyperuricemia: serum urate concentration more than 7.0 mg/dL.
• Fluids with urate content greater than 7.0 mg/dL are supersaturated with urate  urate crystal
precipitation.
• Attacks tend to be associated with rapid increases, and more often decreases, in the concentration of urate
in synovial fluid.
• These concentrations mirror the fluctuations seen in the serum.
• The greatest utility of measuring serum urate is in monitoring the effects of urate-lowering therapy.
• The 24-hour urine uric acid measurement is not required in all patients with gout but is useful for
determining potential causes of hyperuricemia Et determining whether uricosuric therapy can be effective,
since this form of therapy is effective only in underexcreters.
• The goal of treatment is to maintain the serum urate level at 5.0 mg/dL or less.
• Excretion of >800 mg of uric acid per 24 h on a regular diet suggests the cause of overproduction.

ACUTE GOUT:
• NSAIDs like Indomethacin are DOC due to better tolerability. Aspirin is not used as it may cause
hyperuricemia.
• Colchicine is more effective and faster acting.
o It causes metaphase arrest. Most common and dose limiting toxicity is diarrhoea.
o It can also cause kidney damage, myopathy and bone marrow depression.
o Other indications of colchicine: Hyperuricemia, Cirrhosis, Mediterranean fever, Sarcoid arthritis.
• Intra-articular corticosteroids can be used in the refractory cases.

CHRONIC GOUT:
Drugs Decreasing Synthesis of uric acid (inhibitors of Xanthine oxidase):
• Allopurinol: used during inter- attack periods, along with anti-cancer drugs & also as an adjunct to sodium
stibogluconate in kala azar. Contraindicated in acute gout due to interference with release of cytokines.
• The incidence of acute attacks of gouty arthritis may increase during the early months of allopurinol therapy
d/t mobilization of tissue stores of uric acid.
• Febuxostat
 • In patients excreting large amounts of uric acid, uricosuric agents should be avoided so as not to precipitate
the formation of uric acid calculi.
• Aside gout, allopurinol is used as an antiprotozoal agent & indicated to prevent the massive uricosuria
following therapy of blood dyscrasias.
• Allopurinol can bind to lens, resulting in cataracts.
Drugs Increasing Excretion (Uricosurics): Probenecid, Sulfinpyrazole and benzbromarone
Drugs Increasing Metabolism:
• Recombinant urate oxidase is now available as Rasburicase & Pegloticase: catalyzes the
enzymatic oxidation of uric acid into the soluble and inactive metabolite allantoin.
• ACTH (i.m) effective in acute polyarticular refractory gout or in those with a contraindication for using
colchicine or NSAIDs.
 III. CARDIOVASCULAR SYSTEM

TREATMENT FOR HYPERTENSION

DIURETICS
• First Line drugs. According to JNC-VIII, thiazides are the first choice diuretics unless contraindicated.
• Diuretics are effective in lowering blood pressure by 10-15 mm Hg in most patients.
• Indapamide is longer acting & more potent than hydrochlorothiazide. Can be used in diabetic patients.
• Indapamide: reduces risk of further stroke in post stroke patients.
• Indacrinone can be used in patients with gout as it inhibits uric acid reabsorption in the nephrons.
• Loop diuretics are indicated in severe hypertension with CHF and renal dysfunction.

DRUGS INHIBITING CENTRAL SYMPATHETIC OUTFLOW

• Clonidine and α- methyl dopa act as α2 agonists in the brain.
• α methyl dopa is a prodrug and converted to a methyl nor epinephrine in the brain.
• These drugs can cause sedation. Abrupt discontinuation of clonidine rebound hypertension (treated by
phentolamine);
• Methyl dopa can cause hemolytic anemia. Both of these drugs are safe in pregnancy (a methyl dopa is the
DOC).
• New drugs: moxonidine and rilmenidine are congeners of clonidine with longer half lives.
• Side effects: sodium and water retention. Diuretics can be added to ameliorate these effects.
• Off-label uses of clonidine:
o Atrial fibrillation o Mania
o Attention-deficit/hyperactivity disorder o Post hepatic neuralgia
(ADHD), o Psychosis
o Constitutional growth delay in children o Restless leg syndrome
o Cyclosporine-associated nephrotoxicity o Ulcerative colitis
o Tourette's syndrome Hyperhidrosis o Allergy-induced inflammatory reactions in
patients with extrinsic asthma.

GANGLION BLOCKERS
• Trimethaphan- used along with nitroprusside as a slow iv infusion for hypertensive emergencies and in
aortic dissection & to produce controlled hypotension during neurosurgery.
• Mecamylamine: used for smoking cessation.
• Others: Pentolinium, pempidine, Hexamethonium.

ADRENERGIC RECEPTOR ANTAGONISTS

ALPHABLOCKERS
• Phenoxybenzamine, phentolamine and tolazoline are non-selective alpha blockers (α1 both al and α2
receptors).
• Phenoxybenzamine is used for hypertensive crisis in pheochromocytoma and off-label to control the
manifestations of autonomic hyperreflexia in patients with spinal cord transection.
• Phentolamine and tolazoline DOC in clonidine withdrawal and cheese reaction.
• Papaverine/ Phentolamine Induced Penile Erection (PIPE): therapy for impotence.
• A major adverse effect of alpha blockers is first dose hypotension.
• Can be used in patients with DM, CAD (improves lipid levels) and gout (do not affect uric acid).

BETA BLOCKERS
• Cardio selective beta (β1) blockers can be used in conditions like diabetes mellitus, variant angina, bronchial
asthma, Raynaud's disease and in patients having hyperlipidemia.
• Beta blockers can lead to severe bradycardia, but not with Celiprolol, oxprenolol, pindolol, alprenolol and
acebutolot (beta blockers with intrinsic sympathomimetic activity).
• All beta blockers can lead to rebound hypertension on sudden withdrawal after prolonged use.

VASODILATORS
POTASSIUM CHANNEL OPENERS: (hydralazine, minoxidil and diazoxide)
• Hydralazine also acts by releasing nitric oxide (NO) from the endothelium.
• Hydralazine is the DOC for hypertensive emergencies during pregnancies.
• Minoxidil and hydralazine can be given orally for the treatment of severe hypertension.
• Diazoxide is administered in hypertensive emergencies as rapid i.v. injection.
• Minoxidil can cause abnormal hair growth in females (hirsutism) and used for treatment of alopecia.
• Diazoxide is a thiazide derivative and can cause hyperuricemia and hyperglycemia (by inhibiting insulin
release from beta cells of pancreas). The latter effect has lead to its use in insulinoma.
Note: other K+ channel openers are nicorandil, cromakalim & pinacidil.
NITRATES (NITRIC OXIDE RELEASERS)
• Venodilation  peripheral pooling of blood  decrease in preload & end diastolic pressure.
• DOC in angina.
• Causes favorable redistribution of blood flow to ischemic area without change in coronary circulation.
• Nitroglycerine & Isosorbide dinitrate: Sublingually aborts the attack & used orally for prophylaxis of angina.
• Pentaerythritol tetranitrate: longest acting; amyl nitrate: shortest acting.
• Relaxes smooth muscles, hence used in biliary colic & oesophageal spasm.
• Sodium nitroprusside and hydralazine act by releasing nitric oxide from the endothelium,
• Nitroprusside (DOC in hypertensive emergencies) is a very short acting drug & leads to hypothyroidism (due
to accumulation of thiocyanate).
• Nitroprusside is rapidly metabolized by RBCs with liberation of cyanide.
• Cyanide is metabolized by the mitochondrial enzyme rhodanase to the less toxic thiocyanate.
• Thiocyanate toxicity: weakness, disorientation, psychosis, muscle spasms and convulsions, and the diagnosis
is confirmed by finding serum concentrations > 10 mg/dL.
• Recent drug: Molsidomine- no tolerance.

DOPAMINE AGONIST
• Fenoldopam is dopamine D1 receptor agonist that causes dilation of peripheral arteries and natriuresis.
• It can be used i.v. for short control of blood pressure in hypertensive emergencies.

CALCIUM CHANNEL BLOCKERS (CCBS)

• These are the drugs that block L-type of voltage gated calcium channels present in blood vessels and heart.
• Four groups of CCBs include
o Phenylalkylamines (verapamil, Nor-verapamil)
o Benzothiazepines (diltiazem)
o Dihydropyridines (nifedipine, nicardipine, nimodipine, nimodipine, nitrendipine, isradipine, lacidipine,
felodipine and amlodipine).
o Diarylaminopropylamine ether (Bepridil)
• Decrease in frequency of opening of calcium channels  vasodilatation
• Verapamil and diltiazem have strong direct cardio depressant (verapamil > diltiazem) activity.
• CCBs tend to cause reflex tachycardia.
• Nifedipine: increase the risk of angina (increase in cardiac work & tachycardia) whereas sustained release
preparation of nifedipine and amlodipine are safer.
• Nifedipine can cause hyperglycemia & voiding difficulty in elderly.
• Nimodipine: cerebro-selective vasodilator, thus used in sub-arachnoid hemorrhage.
• Verapamil: for the treatment of angina, PSVT, hypertension and HOCM.
• Diltiazem: has lesser effect on the heart than verapamil and indicated for hypertension and
• angina.
• Women may be more sensitive than men to the hypotensive action of diltiazem.
• Verapamil & CCBs block the P170 glycoprotein that transports foreign drugs out of cancer (and other) cells
 partially reverse the resistance of cancer cells to chemotherapeutic drugs.
• These drugs are especially suitable for elderly patients, patients with low renin hypertension,
• and patients with diseases like asthma, migraine or peripheral vascular disease and in cases of isolated
systolic hypertension.
• DHP's are safe in pregnancy.
• CCB's are avoided in conditions involving decreased conductivity like sick sinus syndrome, CHF etc…..
 • Clevidipine: ultrashort acting DHP, approved for hypertensive emergencies.
• Bepridil blocks cardiac Na+> Ca2+ & K+ Channels.
• Bepridil prolongs the cardiac action potential  torsade de pointes (contraindicated in patients with serious
arrhythmias or prolonged QT syndrome).

DRUGS DECREASING THE ACTION OF RAAS

• Angiotensinogen secreted from the liver is converted to Angiotensin-I with the help of renin.

• Angiotensin II acts on AT, (main action) and AT2 (less important) receptors.
• RAAS system results in vasoconstriction, salt and water retention +increase in blood pressure. Therefore,
RAAS inhibitors can be used for decreasing the blood pressure.
• NSAIDs, centrally acting sympatholytic drugs and B blockers decrease renin release.
• ACE inhibitors, angiotensin receptor blockers (ARB5), and renin inhibitors increase renin release.
• B blockers, renin inhibitors, ACE inhibitors, AT, and Aldosterone antagonists act by decreasing the activity of
RAAS.
Drugs which increase plasma renin activity Drugs which lower plasma renin activity
• Diuretics • β blockers
• Vasodilators • Clonidine
• CCBs, ACE inhibitors • Methyldopa

Renin inhibitors:
• Orally active, first generation: enalkiren, zankiren, CGP38560A, and remikiren, has low potency, poor
bioavailability, and short t1/2.Not approved.
• Second generation, low molecular weight renin inhibitor: Aliskiren, remikiren and enalkiren
o Can be used orally for the treatment of chronic hypertension
o Renoprotective.
o Decrease in plasma BNP levels, urinary BNP, and aldosterone levels
o Favorable neurohormonal effects of aliskiren in heart failure when added to standard therapy

Angiotensin Converting Enzyme Inhibitors (ACEI)

• Decrease the activity of RAAS and potentiate the vasoditatory action of Bradykinin.
• Commonly lowers BP in hypertensives, except in primary aldosteronism.
 • Classification:
o Sulfhydryl-containing ACE inhibitors related to captopril.
o Dicarboxyl-containing ACE inhibitors related to enalapril (e.g., lisinopril, benazepril, quinapril, moexipril,
ramipril, trandolapril and perindopril)
o Phosphorus-containing ACE inhibitors related to fosinopril.

• Captopri I is less potent, has fast onset and short duration of action and less absorption in presence of
food in GIT. Because of short and fast action, it can cause postural hypotension which is not seen with
other ACEI.
• All ACEI are prodrugs except captopril and lisinopriI. Other drugs like enatapril are converted to its active
metabolite (enalaprilat) and thus are slow acting.
• Preeclampsia is associated with the development of agonistic auto-antibodies against the AT1 receptor.
• Benazeprilat, in vitro is more potent
• All are eliminated primarily by the kidneys except fosinopril and moexipril.
• Enalaprilat is available as a separate drug meant for use in hypertensive emergencies by i.v. route.
• Ramiprilat displays triphasic elimination kinetics with ti /2 of 2-4 hours, 9-18 hours, and 50 hours. This is due
to extensive distribution to all tissues (initial t1 /2), clearance of free ramiprilat from plasma (intermediate t1
/2) and dissociation of ramiprilat from tissue ACE (terminal t1 /2).
• Plasma concentration of temocaprilat (temocapril) remains unchanged even in renal failure.
• Adverse effects: dry cough, hyperkalemia & angioedema (due to elevated levels of Bradykinin).
• Prevent left ventricular remodeling in patients with CHF.
• Aspirin and iron supplementation reduce cough induced by ACE inhibitors.
• Once ACE inhibitors are stopped, the cough disappears, usually within 4 days.
• K+-sparing diuretics and K+ supplements may exacerbate ACE inhibitor-induced hyperkalemia.
• Other adverse effects include rashes, dysgeusia (altered taste sensation), and acute renal failure (if used in
bilateral renal artery stenosisor stenosis of the renal artery of a solitary kidney). These drugs are contra-
indicated in pregnancy (teratogenic in second half of pregnancy) and when serum creatinine is more than
3.5 mg/dl.

Angiotensin Receptor Blockers (ARB):

• Losartan, valsartan, irbesartan, candesartan, telmisartan & eprosartan act by antagonizing the action of
Angiotensin II at AT1 receptors.
• Losartan is a competitive antagonist of the thromboxane A2 receptor and attenuates platelet aggregation.
• Irbesartan and losartan are approved for diabetic nephropathy.
• Losartan is used for stroke prophylaxis and is safe and highly effective in the treatment of portal
hypertension with cirrhosis without compromising renal function.
• Valsartan is approved for heart failure patients who are intolerant of ACE inhibitors.
• ARBs are pregnancy category C for the first trimester and category D for the second and third trimester.
• Like ACE inhibitors it can cause hypotension & hyperkalemia, but first dose hypotension is uncommon.

TREATMENT OF HYPERTENSION WITH CO-EXISTING CONDITIONS

Concomitant condition Drugs preferred Drugs to be avoided
Angina β blocker ,CCB Vasodilators
BHP α-blocker
Diabetes and hyperlipidemia ACEI, ARB, CCB, α-blocker β-blocker, diuretics
Elderly and isolated systolic hypertension Diuretics, CCB
Low renin hypertension Diuretics, CCB
High renin hypertension ACE1, ARB, B-blocker
Asthma CCB, diuretics, ACEI, ARB β-blocker
CHF ACE1, diuretics CCB
Post MI β-blocker, ACEI
DM with CRF/proteinuria ACEI
Peripheral Vascular Disease CCB, α-blocker β-blocker
Thyrotoxicosis B-blocker Vasodilators
ABCD of the BHS (British Hypertension Society) rule:
• A-ACE inhibitor/ARB
• B- Beta blocker
• C- Calcium Channel Blocker
• D- Diuretics
A & B are preferred in youngers (>55years), C & D are preferred in the elderly for monotherapy.

Recommendations of JNC-8 (Joint National Committee)

• >60 years of, not diabetic/ not CKD: , target BP level; <150/90 mmHg
• 18 to 59 years without major comorbidities + >60 years with DM/ CKD/Both; goal is <140/90 mmHg.
• First-line medications: thiazide-type diuretics, calcium channel blockers (CCBs), ACEIs, and ARBs
• Second- and third-line: higher doses or combinations of ACEIs, ARBs, thiazide-type diuretics, and CCBs.
• Later-line alternatives: Beta-blockers, Alpha-blockers, Alphal /beta-blockers (eg, carvedilol), Vasodilating
beta-blockers (eg, nebivolol), Central alpha2-adrenergic agonists (eg, clonidine), Direct vasodilators (eg,
hydralazine), Loop diuretics (eg, furosemide), Aldosterone antagonists (eg, spironolactone), Peripherally
acting adrenergic antagonists (eg, reserpine),
• When initiating therapy, patients of African descent without chronic kidney disease should use CCBs and
thiazides instead of ACEIs.
• Use of ACEIs and ARBs is recommended in all patients with CKD.
• ACEIs and ARBs should not be used in the same patient simultaneously.
• CCBs and thiazide-type diuretics should be used instead of ACEIs and ARBs in patients over the age of 75 with
impaired kidney function due to the risk of hyperkalemia, increased creatinine, and further renal
impairment.

Preferred Parenteral Drugs for Selected Hypertensive Emergencies

Hypertensive encephalopathy
Malignant hypertension (for IV therapy)
Stroke
Myocardial infarction/unstable angina
Acute left ventricular failure
Aortic dissection
Adrenergic crisis
Postoperative hypertension
Preeclampsia/eclampsia of pregnancy
Nitroprusside, nicardipine, labetalol
Labetalol, nicardipine, nitroprusside, enalaprilat
Nicardipine, labetalol, nitroprusside
Nitroglycerin, nicardipine, labetalol, esmolol
Nitroglycerin, enalaprilat, loop diuretics
Nitroprusside, esmolol, labetalol
Phentolamine, nitroprusside
Nitroglycerin, nitroprusside, labetalol, nicardipine
Hydralazine, labetalol, nicardipine

CONGESTIVE HEART FAILURE (CHF)

• Low output failure: decreased contractility of the heart  decreased cardiac output.
• High output failure: increased body demand, not met even with increased cardiac output in states like
severe anemia, thyrotoxicosis & thiamine deficiency.
• Systolic failure: abnormality in cardiac contraction. Eg: ischemic heart disease & dilated Cardiomyopathy.
• Diastolic failure: abnormality in ventricular relaxation. Eg: hypertension & hypertrophic Cardiomyopathy.
• Acute/decompensated CHF: inability of the heart to pump; amenable to treatment with positive ionotropes.

TREATMENT OF ACUTE CHF

• DIURETICS: especially loop diuretics will decrease the preload & decrease the symptoms. Do not alter the
basic pathology no effect on mortality, except spironolactone which decreases the mortality.
• INOTROPIC DRUGS:
o Dobutamine (IV): increases cAMP increased cardiac contractility.
o Dopamine: dose dependent increase in cardiac contractility.
 1-2μg/kg/min: stimulates dopamine receptors  renal vasodilatation
 2-10μg/kg/min: stimulates the heart by acting on β-1 receptors.
 >10 μg/kg/min: stimulates α receptors  intense vasoconstriction.
 o Inodilators (both Inotropic & vasodilatory actions): Inamrinone (Amrinone), milrinone & Vesnarinone.
Inhibits phopshodiesterase-III a increases cAMP in heart & blood vessels. Indicated for short term iv use in
severe & refractory CHF. Major side effect: thrombocytopenia (rare with milrinone). Levosimendan:
another agent that sensitizes the myocardium to calcium apart from inhibiting phopshodiesterase.
o Cardiac glycosides: Digoxin, digitoxin, Strophanthin & Ouabain.
 Positive ionotropes but do not increase heart rate or oxygen consumption.
 Can be used in both acute treatment& maintenance therapy.
 Do not alter the basic pathology & unable to decrease the mortality.
 Acts by inhibiting Na-K pump.

Digitoxin Digoxin
Source Digitoxin purpurea Et D. lanata D. lanata
Plasma protein 95% 25%
binding
Oral absorption 90-100% 60-80%, can be given IV also
Vd 38L/70kg 500L/70kg
Plasma t1/2 5-7 days 36 hours
Elimination Hepatic (contraindicated in liver failure) Renal (contraindicated in renal failure)
Uses Maintenance Routine treatment & for emergencies

• Earliest appearing adverse effect: GI symptoms (d/t gastric irritation & CTZ stimulation).
• Can cause any type of cardiac arryhthmia except Mobitz-II & atrial flutter.
• M/c arrhythmia: ventricular premature beats & bigeminy.
• Most characteristic: non paroxysmal supra ventricular tachycardia with variable AV block.

Digitalis dosage
Therapeutic plasma concentration 0.5-1.5 ng/mL
Toxic plasma concentration > 2 ng/mL
Daily dose (slow loading/ maintenance) 0.25 (0.125-0.5) mg
Rapid digitalizing dose (rarely used) 0.5-0.75 mg every 8 hours for three doses

• Immunotherapy with purified Fab fragments from ovine antidigoxin antisera (DIGIBIND) is an effective
antidote for life threatening digoxin or digitoxin toxicity.
• Istaroxime: steroid that acts by inhibiting Na+ K+ pump.
• Nesiritide: recombinant Brain Natri uretic peptide (BNP) differentiates cardiac & pulmonary causes of
dyspnea.
TREATMENT OF COMPENSATED/ CHRONIC CHF
• VASODILATORS: Drugs may cause vasodilatation by
o Opening potassium channels,
o By releasing nitric oxide,
o By blocking calcium channels
o By acting as agonists of dopamine receptors.

Mainly venodilators
Primarily decreases preload
Nitrates:
Glyceryl trinitrate
Isosorbide dinitrate
Mainly arteriolar dilators
Primarily decreases after-load
Hydralazine, minoxidil, diazoxide,
fenoldopam, Ca2+ channel blockers
(Nifedipine) Pot. channel openers
(Nicorandil)
Dilate both arterioles and venules
Decreases both preload & after-load
ACE Inhibitors, ARBs, Prazosin,
Amrinone, Milrinone &
Nitroprusside

Major adverse effect: tachycardia and headache (due to dilatation of cerebral blood vessels).
• ACE INHIBITORS AND ARB'S: indicated in all grades of CHF, can decrease mortality.
• ALDOSTERONE ANTAGONISTS: reduces mortality by antagonizing aldosterone effects. (reversal of
remodeling).
• BETA BLOCKERS: increase the longevity of CHF patients. Drugs used - carvedilol, metoprolol & bisoprolol.
Usually indicated in mild to moderate heart failure with dilated Cardiomyopathy & absolutely
contraindicated in decompensated heart failure. Should be started at very low doses and increased
gradually if needed.
• VASOPEPTIDASE INHIBITOR: Inhibits ACE & neural endopeptidase. Omapatrilat It sampatrilat are the oral
drugs used in chronic CHF. Major limiting factor: Angioedema.

Agents that decrease the mortality (prolongs survival) Relief of congestive/low output symptoms &
 restoration of cardiac performance
• ACE inhibitors • Inotropic drugs
• Angiotensin Receptor Antagonists • Diuretics
• Beta blockers • Vasodilators
• Aldosterone antagonist • Beta blockers

ANTI ARRYTHMIC DRUGS

VAUGHAN WILLIAM'S CLASSIFICATION OF ANTI ARRYTHMIC DRUGS

Class Mechanism Drugs
Class- la Quinidine, procainamide, disopyramide
Class-lb Na+ channel blockers Lignocaine , Mexiletine, tocainaide, phenytoin
Class-lc Encainide, moricizine, Flecainide, propafenone
Class-II Beta blockers Esmolol, propranolol, metoprolol & Sotalol
+
Class-III K channel blockers Amiodarone, Bretylium, Sotalol, Ibutilide, dofetilide
Class-IV Blockers of L type Ca2+ channels Verapamil, Diltiazem
Class-V Miscellaneous Digoxin, magnesium, adenosine, potassium & atropine

Antiarrhythmic drugs that do not fit in the Vaughn-Williams classification system:

• Digoxin
• Adenosine
• Magnesium

PROPERTIES:
• Class la: highly prone to cause torsades de' pointes.
• Class lb: possess additional potassium channel opening property, used only for ventricular arrhythmia.
• Class lc: have maximum pro-arrhythmic activity, indicated only for resistant & life threatening arrhythmias.
• Class III: prone to cause torsades de' pointes, due to prolongation of QT interval

Quinidine:
• May cause profound hypotension, hypoglycemia, and cinchonism (headache and tinnitus) & may precipitate
digitalis toxicity.
• W/c side effect is diarrhea & Diarrhea-induced hypokalemia may potentiate the risk of torsades de pointes.
• Most common immunological reaction is thrombocytopenia.
• Hepatitis, bone marrow depression and lupus syndrome occur rarely.
Procainamide:
• Orally active derivative of procaine, long term therapy results in drug induced lupus(DLE)
Lignocaine:
• Most commonly used LA, DOC for arrhythmias due to digitalis toxicity.
Mexiletine:
• Orally active lignocaine derivative, also used in diabetic neuropathy (off-label), myotonia congenita etc...
• In doses of 450 750 mg/d orally, significantly relieves chronic pain, especially pain due to diabetic
neuropathy and nerve injury.
Phenytoin:
• Can be used as an alternative to lignocaine for arrhythmias due to digitalis toxicity.
Tocainaide:
• Not widely used d/t risk of agranulocytosis.
Amiodarone:
• Longest acting anti-arrhythmic drug.
• Structural analog of thyroid hormone
• Narrow therapeutic index
• Possesses actions of all the four classes.
• Has widest anti-arrhythmic spectrum.
• Less chances of causing prolongation of Q-T interval
 • Contains iodine a can cause both hypothyroidism & hyperthyroidism.
• Other toxicities are hepatotoxicity (pseudo alcoholic liver injury), peripheral neuropathy, myocardial
depression, Lung fibrosis, corneal micro deposits (reversible on discontinuation) and Photosensitivity.
• Dronedarone: similar to amiodarone, but lacks iodine.
• Celivarone: noniodinated benzofuran derivative under trial for preventionof ventricular tachycardia
recurrence.
Bretylium: Adrenergic neuron blocking drug used parenterally for arrhythmias. Major adverse effect: postural
hypotension.
Sotalol: Have both class II & class III actions.
Dofetilide: pure class Ill anti arrhythmic.
Ibutilide: Only drug approved for conversion of atrial fibrillation to sinus rhythm.
Vernakalant: Multi ion channel blocker for converting recent onset atrial fibrillation to sinus rhythm.

Type of Drugs for acute therapy Drugs for chronic therapy Remarks
arrhythmia
Atrial Flutter Propranolol Ibutilide, Quinidine, Cardioversion is treatment of
Atrial Esmolol Digoxin choice.
Fibrillation Amiodarone Verapamil Only Ibutilide is indicated for
conversion to sinus rhythm
PSVT Adenosine Verapamil Sotalol Propranolol
Amiodarone
Ventricular Lignocaine Sotalol Amiodarone
tachycardia Magnesium Quinidine
Ventricular Lignocaine Amiodarone Electrical defibrillation is the
fibrillation Bretylium treatment of choice
WPW syndrome Flecainide Propranolol Amiodarone Laser ablation of aberrant pathway
is definitive treatment
Torsades de' Magnesium Propranolol Amiodarone should not be used
pointes
Digitalis Lignocaine Propranolol For brady arrhythmias atropine
induced Phenytoin can be used.
ventricular
arrhythmia

• Dofetilide maintains normal sinus rhythm & restores it in atrial fibrillation.

Adenosine
• Administered by rapid i.v. injection (over 1-3 sec)
• More than 90% episodes of PSVT involving the A-V node are terminated within 30 sec.
• It activates ACh sensitive K+ channels and causes membrane hyperpolarization.
• Indirectly reduces the Ca+ current in AV node
• Reduction of re entrant circuit through AV node- responsible for termination of PSVT
• Coronary dilatation occurs transiently.
• Adenosine has a very short t1/2 in blood (10 sec) due to uptake into RBCs and endothelial cells where it is
converted to 5-AMP and inosine.
• Injected ATP is rapidly converted to adenosine.
• Dipyridamole potentiates its action by inhibiting uptake.
• Theophylline / caffeine increases its action by blocking adenosine receptors.
• Patients on carbamazepine are at risk of developing heart block.
• Complete elimination occurs in single passage through coronary circulation
• Action lasts less than one minute, therefore adverse reactions are transient
• No hemodynamic deterioration- can be given in hypotension, CHF or those receiving β blockers
Other uses of adenosine:
• Diagnosis of tachycardias
• To induce brief coronary vasodilatation during diagnostic/interventional procedures.
• To produce controlled hypotension during surgery.

ANTI ANGINAL DRUGS

• Nitrates
o Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)
o Long acting: Isosorbide dinitrate (short acting by sublingual route), Isosorbide mononitrate, Erythrityl
tetranitrate, Pentaerythritot tetranitrate
• β-Blockers: Propranolol, Metoprolol, Atenolol and others.
o Decrease in myocardial oxygen consumption d/t negative chronotropic effect (particularly during
exercise), a negative inotropic effect, and a reduction in arterial blood pressure (particularly systolic
pressure) during exercise.
o The decreases in heart rate and contractility  increases in the systolic ejection period and left
ventricular end-diastolic volume; these alterations tend to increase O2 consumption.
o Net effect of ¤ adrenergic receptor blockade is usually to decrease myocardial O2 consumption,
particularly during exercise.
• Calcium channel blockers
o Phenyl alkylamine: Verapamil
o Benzothiazepine: Diltiazem
o Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine,
Lercanidipine, Benidipine
• Potassium channel opener:Nicorandil
• Others : Dipyridamole, Trimetazidine (metabolic modulator),Ranolazine, Ivabradine & Oxyphedrine.
• Ranolazine: congener of trimetazidine, LC3-KAT inhibitor, is a metabolic modifier.
o Spares fatty acid oxidation and shifts ATP production to more 02 efficient carbohydrate oxidation.
o Also inhibits late INa+ current in the myocardium which indirectly facilitates Ca2+ entry

Clinical classification
• Used to abort or terminate attack : GTN,lsosorbide dinitrate (sublingually).
• Used for chronic prophylaxis : All other drugs.

MANAGEMENT OF ANGINA
• The nitrates (nitroglycerin) are the mainstay of therapy for the immediate relief of angina.
• Vasodilators (calcium channel blockers) & β -blockers, which are not vasodilators, are important for
prophylaxis.
• The total amount of "ischemic time" per day is reduced by long-term therapy with a β-blocker.
• β -blockers reduce the myocardial oxygen demand.
• Concurrent use of a receptor antagonists with either verapamil or diltiazem may be problematic.
• A CCB is indicated only when coronary spasm is not effectively counteracted by the nitrate.
• Fatty acid oxidation inhibitors alter myocardial metabolism.
• Other antianginal drugs:
o Dipyridamole: failure drug due to coronary steal phenomenon.
o Trimetazidine: no effect on HR/BP, but improves cellular tolerance to ischemia, can cause reversible
Parkinsonism.
o Drug for chronic resistant angina: Ranolazine (LC-3 KAT inhibitor & metabolic modifier-spares fatty acid
oxidation).
o Oxyphedrine.

Recommended Drug Therapy for Angina in Patients with Other Medical Conditions
Condition Recommended treatment (and alternatives) for Drugs to avoid
angina
Medical Conditions
Systemic hypertension,
Migraine/ vascular
headaches
Asthma or COPD with
bronchospasm
Hyperthyroidism
Raynaud's syndrome
Insulin-dependent diabetes
mellitus
Non-insulin-dependent
diabetes mellitus
Depression
Mild peripheral vascular
disease
Severe peripheral vascular
disease with rest ischemia
Cardiac Arrhythmias and Conduction Abnormalities
Sinus bradycardia Dihydropyridine Ca2+ channel antagonists
Sinus tachycardia (not due
to heart failure)
Supraventricular tachycardia
Atrioventricular block
Rapid atrial fibrillation (with
digitalis)
Ventricular arrhythmias
Left Ventricular Dysfunction
Congestive heart failure
Mild (LVEF >40%)
Moderate to severe (LVEF
<40%)
Left-sided valvular heart disease
Mild aortic stenosis
Aortic insufficiency
Mitral regurgitation
Mitral stenosis
Hypertrophic cardiomyopathy
β receptor antagonists (Ca2+ channel antagonists)
Verapamil or diltiazem β receptor
β receptor antagonists
Long-acting, slow-release Ca2+ antagonists β receptor antagonists
β receptor antagonists (particularly if prior MI) or
long-acting, slow-release Ca2+ channel antagonists
β receptor antagonists or long-acting, slow-release
Ca2+ channel antagonists
Long-acting, slow-release Ca2+ channel antagonists β receptor antagonists
β receptor antagonists or Ca2+ channel antagonists
Ca2+ channel antagonists β receptor antagonists
β receptor antagonists,
diltiazem, verapamil
β receptor antagonists
Verapamil, diltiazem, or β receptor antagonists
Dihydropyridine Ca2+ channel antagonists β receptor antagonists,
diltiazem, verapamil
Verapamil, diltiazem, or β receptor antagonists
β receptor antagonists
β receptor antagonists
Amlodipine or felodipine (nitrates)
β receptor antagonists
Long-acting, slow-release dihydropyridines
Long-acting, slow-release dihydropyridines
β receptor antagonists
β receptor antagonists, non-dihydropyridine Ca2+ Nitrates, dihydropyridine
channel antagonists Ca2+ channel antagonists

TREATMENT OF MYOCARDIAL INFARCTION

• Thrombolytic therapy should be instituted as early as possible, preferably with in first 3 hours.
• Pentazocine and pethidine should not be used for pain (tachycardia and can worsen the symptoms).
• Aspirin should be started at low doses (40-325 mg) for its antiplatelet action.
• If aspirin is contra-indicated clopidogrel can be used.
• Beta blockers like metoprolol reduce infarct size, prevent reinfarction and decrease the incidence of
arrhythmias. Oral anticoagulants can be administered to prevent thrombus extension and embolism.
• Statins can be added to reduce associated dyslipidemia.

DRUGS FOR PERIPHERAL VASCULAR DISEASES

 • Cyclandetate
• Xanthinol nicotinate
• Pentoxifylline/Oxpentifylline- has rheological action (dealing with the property of flow rather than action).
Other uses of pentoxifylline: non-hemorrhagic stroke, chronic cerebrovascular insufficiency, TIA, intermittent
claudication, trophic leg ulcers, gangrene, male infertility (improves sperm motility).

SCLEROSING AGENTS
Irritants, cause inflammation, coagulation and fibrosis, when injected locally into haemorrhoids or varicose vein
mass.
• Phenol (5%) in almond oil or peanut oil
• Ethanolamine oleate (5% in 25% glycerine and 2% benzyl alcohol)
• Sodium tetradecyl sulfate (3% with benzyl alcohol 2%)
• Polidocanol (3% injection)

Drugs that prolong Q-T interval (Have potential to precipitate Torsades de pointes)
• Anti-arrhythmics: Quinidine, procainamide, disopyramide, propafenone, amiodarone
• Anti-malarials: Quinine, mefloquine, artemisinin, halofantrine
• Anti-bacterials: Sparfloxacin, moxifloxacin
• Anti-histaminics: Terfenadine, astemizole, ebastine
• Anti-depressants: Amitryptyline and other tricyclics
• Anti-psychotics: Thioridazine, pimozide, aripiprazole, ziprasidone
• Pro-kinetic: Cisapride
 IV. EXCRETORY SYSTEM

DIURETICS

High efficacy/ Medium efficacy diuretics Weak/ adjunctive diuretics

loop diuretics Thiazides Thiazide like Carbonic Potassium Osmotic
anhydrase sparing diuretics diuretics
inhibitors
Furosemide Clopamide, Benzthiazide Metolazone Acetazolamid Aldosterone Mannitol
aumetanide Hydrochtorothiazide Indapamide e antagonists: Glycerol
Torsemide, Bendroflumethiazide, Xipamide Spironolactone, Isosorbid
Indacrinone Chlorothiazide Clopamide eplerenone e
Ethacrynic. A Hydroflumethiazide Quinethazone Renal epithelial
Mersalyl methiclothiazide, most Chlorthalidon Na channel
potent:polythiazide & e (long acting blockers:
trichtormethiazide thiazide) Triamterene
Amiloride

LOOP DIURETICS (faster acting)

• Inhibits Na+ K+2Cl- symporter in loop of Henle & are the diuretics of choice in renal failure.
• Furosemide- Vasodilator - used in LVF & Pulmonary edema, cerebral edema & hypercalcemia of malignancy.
• Bumetanide -most potent loop diuretic.
• Ethacrynic acid: highly ototoxic with steep DRC.
• Longest half life: Torsemide.

MEDIUM EFFICACY DIURETICS

• Inhibits Na+Cl- symporter in the DCT & are used as first line drug in hypertension
• Cause more Hypokalemia than loop diuretics.
• Thiazides and loop diuretics enhance digitalis toxicity by causing Hypokalemia.
• Incidence of erectile dysfunction is greater with thiazides.
• Metolazone: used in severe renal failure (even if GFR< 15ml/min).
A/E common to both loop & thiazide diuretics: ECF depletion, hypotension, hypokalemia, hyponatremia,
hypochloremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, and hyperuricemia. Hyperglycemia &
hyperlipidemia are minimal at low doses.

CARBONIC ANHYDRASE INHIBITORS (Acetazolamide, Dichlorphenamide, methazolamide)

• Acetazolamide is a sulfonamtcle derivative which noncompetitively but reversibly inhibits CAse in proximal
tubule.
• Acetazolamide- used in gitaucoma, epilepsy, mountain sickness, hypokalemic periodic paralysis, metabolic
alkalosis, urinary alkalinization & increases PO4 excretion in hyperphosphatemia.
• Self limiting diuretic action.
• Dorzolamide and Brinzolamide- topical use.
• At equally natriuretics doses, potassium excretion is maximum with CA inhibitors.
• Acetazolamide-cause bone marrow suppression and metabolic acidosis & more prone for Hypokalemia.
• All of them are contraindicated in liver disease as they can precipitate hepatic coma.

Extra renal actions of acetazolamide are:

• Lowers intraocular tension due to decreased formation of aqueous (aqueous is rich in HCO3-)
• At heavy doses, decreases gastric HCI and pancreatic NaHCO3 secretion.
• Raised level of CO2 in brain and lowering of pH  sedation and elevation of seizure threshold.
• Alteration of CO2 transport in lungs and tissues. These actions are masked by compensatory mechanisms.

POTASSIUM SPARING DIURETICS

• Acts in late DCT and collecting duct to preserve K+.
Epithelial Sodium channel inhibitor: Amiloride & Triamterene
• Amiloride -It is more potent and longer acting.
o DOC for Lithium induced DI.
o Used as an aerosol in cystic fibrosis (decreased secretion).
o Decreases Calcium & magnesium excretion & increases urate excretion.
o Used in Liddle syndrome.
• Triamterene: causes megaloblastic anemia, interstitial nephritis & renal stones.

Aldosterone antagonists: Spironolactone, Canrenone, potassium canreonate & epierenone.

• Act from the interstitial site of tubular cell (all other diuretics act from lumina) side).
• Spironolactone is converted to canrenone & it increases calcium excretion, causes gynecomastia, impotence.
• Spironolactone decreases mortality when used in congestive heart failure.
• Spironolactone blocks human ether-a-go-go-related gene (HERG) K+channels  antiarrythmic effects of
spironolactone in heart failure.
• Mostly useful in states of mineralocorticoid excess, due to primary hypersecretion (Conn's syndrome,
ectopic ACTH production) or to secondary aldosteronism (from heart failure, hepatic cirrhosis, nephrotic
syndrome) and hirsutism.
• It is given orally in one or moredoses totalling 100-200 mg.
• Maximum diuresis isdelayed for up to 4 days.
• If after 5 days response isinadequate, dose may be increased to 300-400 mg/d.
• 0.5-1 mg/kg are required in treating hypertension.
• The oestrogenic side effects of spironolactone arethe major limitation to its long-term use.
• Epleronone: lacks anti-androgenic side effects.

OSMOTIC DIURETICS
• Acts on both proximal tubule & loop of Henle.
• Mannitol: Used to maintain GFR- contraindicated in ARF and bleeding cerebral hemorrhage; can be used in
osmotic diarrhea.
 • Urea & mannitol is used for dialysis disequilibrium syndrome.
• Isosorbide & Glycerol: used in the treatment of glaucoma & cerebral edema.

Loop diuretics Increases excretion of Leads to hypocalcemia, hypercalciuria & urolithiasis

calcium Used in treating hypercalcemia
Thiazides Decrease calcium excretion Can lead to hypercalcemia & Hypocalciuria
Used in recurrent urolithiasis
• Indacrinone (Ticynafen) is used in gout as it inhibits reabsorption of uric acid in the nephron.
• Mersalyl (Organo mercurial): withdrawn due to risk of kidney damage.

ANTI DIURETICS

• Antidiuretic hormone (ADH, Vasopressin), Desmopressin, Lypressin, Terlipressin

• Thiazide diuretics, Amiloride.
• Miscellaneous: Indomethacin, Chlorpropamide & Carbamazepine.

ANTI - DIURETIC HORMONE (ADH)

Acts via3 receptors V1, V2 and V3
V-1 V2 V3
Vas smooth muscle/ platelet/ CT (kidney) Ant, pituitary
hepatocyte
Vas endothelium
Vasoconstriction  Antidiuretic Release of ACTH
Vascular smooth muscle con-  Increase release of factor VIII, von
traction willebrand factor
Platelet aggregation glycogenolysis  vasodilatation
PLC/IP3-DAG- Ca++ Adenyl cyclase Same as V1
Arginine vasopressin desmopressin Arginine vasopressin

Actions of ADH:
• ADH increases the permeability of CD by its action on V2 receptors.
• Stimulation of these receptors elevates cAMP levels that increase aquaporins on the apical membrane of CD
• V2 receptor activation also increases permeability of CD to urea by stimulating the urea transporter.
• Vasoconstrictor action is mediated by the activation of V1 (also called V1a) receptors. This action requires
much higher concentration than V2 receptor activation.
• V2 receptor mediated vasodilatory action (due to the release of NO) has also been demonstrated.
• ADH is also involved in the release of vWF and factor VIII from the endothelium. This action is also
mediated by V2 receptors.
• Acts on V3 receptors and increases ACTH release.

Uses:
• Major indication of ADH is only central DI.
• Desmopressin: longer acting and Vzselective analogue of vasopressin and is the DOC for central DI. It can
be administered orally or intranasally.
• Desmopressin can also be used for nocturnal enuresis and bed wetting in children.
• Another V2 receptor mediated use of desmopressin is in hemophilia and von Willebrand's disease. It acts
by releasing factor VIII and vWF from the endothelium.
• AVP has vasoconstrictor action that can be utilized to stop bleeding in esophageal varices. Lypressin has
longer duration of action but is non-specific (action on both VI and V7). Terlipressin (prodrug of vasopressin)
is the preferred agent for this indication.
• Felypressin: used along with local anesthetics to prolong their duration of action.

Drugs Receptor Uses

Desmopressin V2 Neurogenic Diabetes insipidus
Nocturnal enuria
Renal concentration test
Hemophilia and von willebrand's disease
Lypressin: β-Lysine vasopressin Both V1 and V2 Neurogenic diabetes insipidus
Terlipressin V1a, V1b, V2 Gastrointestinal bleeding

VASOPRESSIN ANTAGONISTS
• Tolvaptan: It is an orally active nonpeptide selective V2 receptor antagonist.
o Introduced for the treatment of hyponatraemia due to CHF, cirrhosis of liver or SIADH.
o It increases free water clearance by the kidney (aquaretic) and helps to correct the low plasma Na+
levels.
o In clinical trials symptoms of worsening heart failure were improved.
o Too rapid correction of hyponatraemia can lead to thrombotic complications due to
haemoconcentration. The most frequent side effect is thirst and dry mouth.
o The t1/2 is 6-8 hours, and it is given once daily.
• Mozavaptan (V2 selective antagonist) and Conivaptan (V1a+V2 antagonist) are the other antagonists.
• Conivaptan (i. v) is used in treatment of euvotemic hyponatremia in hospitalized patients who do not have
congestive heart failure.
• Reicovaptan is selective V1 antagonist whereas lixivaptan, mozavaptan and tolavaptan are V2 selective
antagonists.

OTHER ANTIDIURETICS
• Thiazides: exert paradoxical effect (decrease urine formation) in both central as well as Nephrogenic DI.
• Chiorpropamide and Carbamazepine: increase the action of ADH on the kidney& useful only in central DI.
• Amiloride: It is the agent of choice for the treatmentof lithium induced Dl.

Drugs causing Hypokalemia Drugs causing Hyperkalemia

Thiazides, Furosemide
NSAIDs, SCh, ACE inhibitors
Carboxolone, lithium,
Potassium sparing diuretics (spironolactone, amiloride and
Corticosteroids, amphotericin B
triamterene), Salt substitutes, ARBs (tosartan), Pentamidine, digoxin
Gentamicin, insulin
overdose, cyclosporine cytotoxics, trimethoprim heparin, β- blockers
Mannitot, theophylline
(initially)
Carbonic anhydrase inhibitor
 V. DRUGS AFFECTING BLOOD AND BLOOD FORMATION

HAEMATINICS
Main haematinics are iron, folic acid and vitamin B12, copper, pyridoxine etc.

IRON
• Daily requirement of iron is 1 mg in adult male, 2 mg in menstruating female and 3-5mg in pregnancy.

Formulations:
• Oral preparations include ferrous sulphate (20% elemental iron), gluconate, succinate etc.
• For treatment of iron deficiency the dosage recommended is 200 mg elemental iron daily that can be
obtained by giving 1000mg of ferrous sulphate daily.
• Rise of hemoglobin level of blood by 0.5-1g/ dl per week is considered adequate response to iron therapy.
• For prophylaxis of iron deficiency, 200 mg ferrous sulphate once daily is enough.
• In pregnancy, iron should be started in the second trimester.
• Parenteral iron preparations are iron-dextran and iron-sorbitol-citrate.
• Intramuscular injections are usually given by Z- technique to avoid staining and pigmentation of skin.
• Ferric carboxymaltose: It is the latest formulation of iron in which a ferric hydroxide core is stabilized by a
carbohydrate shell.
• The macromolecule is rapidly taken up by the RE cells, primarily in bone marrow (upto 80%), as well as in
liver and spleen.
• Iron is released and delivered subsequently to the target cells.
• It is administered either as daily 100 mg i.v. injection, or upto 1000 mg is diluted with 100 ml saline (not
glucose solution) and infused i.v. taking 15 min or more.
• Infusion may be repeated after a week.

FOLIC ACID
• It consists to pteridine, Paraaminobenzoic acid (PABA) and glutamic acid.
• THFA participates in many carbon transfer reactions.
• Deficiency is best determined by increased amount of FIGLU in the urine.
• Deficiency of folic acid results in megaloblastic anemia similar to vitamin B12 deficiency.
• Folic acid is indicated in megaloblastic anemia, in pregnancy to prevent neural tube defects in the fetus.
• It should be started as soon as the pregnancy is diagnosed. (Recommended dose- 400 μg/d)
• Leucovorin (folinic acid, formyl THFA or citrovorum factor) can be used to prevent the toxicity of
methotrexate.

VITAMIN B12
• Used for treatment of megaloblastic anemia (I.m. or S.C. for pernicious anemia due to deficiency of intrinsic
factor and orally for other causes).
• For correcting neurological abnormalities in diabetics etc. (methylcobalamine is used) and also for treatment
of tobacco amblyopia (hydroxy Cobalamin is used, it combines with cyanide of tobacco  cyanocobalamine)

Causes of Megaloblastic Anemia

• Cobalamin deficiency or abnormalities of cobalamin metabolism (see Tables 105-3 and 105-4)
• Folate deficiency or abnormalities of folate metabolism (see Table 105-5)
• Therapy with antifotate drugs (e.g., methotrexate)
• Independent of either cobalamin or folate deficiency and refractory to cobalamin and folate therapy:
o Some cases of acute myeloid leukemia, myelodysplasia
o Therapy with drugs interfering with synthesis of DNA [e.g., cytosine arabinoside, hydroxyurea, 6-
mercaptopurine, azidothymidine (AZT)]
o Orotic aciduria (responds to uridine)
o Thiamine-responsive

HEMATOPOIETIC GROWTH FACTORS

 • RBC - EPO, Recombinant human erythropoietin (Epoietin). Adverse effect: polycythemia & hypertension.
• Darbopoietin is a long acting congener.
• Peginesatide is a new drug called erythropoiesis stimulating agent (ESA). It acts by stimulating
erythropoietin receptors. It is indicated for treatment of anemia due to CRF in patients on dialysis.
• WBC - granulocyte colony stimulating factor G-CSF & granulocyte monocyte colony stimulating factor GM-
CSF
• Platelets - thrombopoetin and IL-11
• Recombinant G-CSF is filgrastim and recombinant GM-CSF is sargramostim.These areused for leucopenia
induced by cancer chemotherapy and are also useful for harvesting peripheral blood stem cells.
• High doses of filgrastim can lead to intractable bone pains.
• Oprelvekin is recombinant IL-2 and is used for the prevention and treatment of thrombocytopenia induced
by cancer chemotherapy.
• Romiplostim: member of a new group of drugs called "PEPTIBODIES"- Peptides linked to antibodies. Acts as
an agonist of thrombopoietin receptor & indicated for chronic ITP.
• Its half-Life is inversely proportional to serum platelet count (Longer in patients with thrombocytopenia and
shortest in patients whose platelet count has recovered to normal)
• Eltrombopag: new orally active thrombopoietin agonist approved for ITP.
• Molgramostim is a colony stimulating factor. Injected daily beginning one day after last dose of
myelosuppressant chemotherapy, it hastens recovery of neutrophil count.

Blood cell Growth factor Drug Indications

RBC Erythropoietin Epoietin Anemia in CRF, myelosuppressive drug use
Darbopoietin (zidovudine and cancer chemotherapy)
WBC G-CSF Filgrasin Neutropenia due to anti-cancer drugs
Peg-filgrastim Severe chronic neutropenia, stem cell transplantation,
Lenograstim mobilization of peripheral blood stem cells.
GM-CSF Sargramostim
Molgramostim
Platelets IL-11 Oprelvekin Thrombocytopenia due to anti- cancer drugs
Thrombopoietin Rorniplastim ITP
Eltrombopag ITP

ANTIPLATELET / ANTI THROMBOTIC DRUGS

• TXA2 is generated by blood platelets, while PGI2 is produced by vascular endothelium.
• TXA2 is a potent vasoconstrictor. It also initiates the release reaction, followed by platelet aggregation.
• PGI2 is a vasodilator, especially potent in coronary circulation. It also inhibits platelet aggregation by virtue
of stimulation of platelet adenyl cyclase.
• A balance between formation and release of PGI2, TXA2 and /or cyclic endoperoxides in circulation is of
utmost importance for the control of intra-arterial thrombi formation and possibly plays a role in the
pathogenesis of atherosclerosis.
• Both thromboxane and prostacyclins act on different receptors, but their actions are exact opposite, hence
they are physiological antagonists.

Irreversible cyclooxygenase inhibitors Acetylsalicylic acid/Aspirin, Aloxiprin, Carbasalate calcium Indobufen,

Adenosine diphosphate (ADP) receptor
inhibitors
Glycoprotein IIB/IIIA inhibitors (intravenous
use only)
Prostaglandin analogue (PG-I2)
Phosphodiesterase inhibitors
Thromboxane synthase inhibitors
Thromboxane receptor antagonists
Triflusal
Clopidogret, Prasugrel, Ticlopidine, Cangrelor, Elinogrel Ticagretor
Abciximab, Eptifibatide, Tirofiban
Beraprost, Prostacyclin, Iloprost, Treprostinit
Cilostazol, Dipyridamole, Triflusal
Dipyridamole, Picotamide
Terutroban
• Main anti platelet drugs are:
o TXA2 synthesis inhibitor (aspirin)
o ADP antagonists (Clopidogrel and ticlopidine)
o Gp Ilb / IIIA antagonists (abciximab, tirofiban, eptifibatide).

• Aspirin inhibits COX enzyme irreversibly and thus results in decreased synthesis of TXA2 (at low doses) as
well as PGI2 (at high doses).
• Aspirin inhibits thromboxane synthesis.
• Dazoxiben inhibit the enzyme thromboxane synthetase.
• For anti-platelet action lowest doses of aspirin are required (60 - 325 mg).
• Dipyridamole acts by inhibiting phosphodiesterase (which breaks down cAMP) resulting in increased cAMP
that potentiates prostacyclins and thus anti- aggregation.
• Gp lib /IIIa antagonists are strongest antiplatelet drugs as they block aggression induced by all agonists.
• Ticlopidine, Clopidogrel Ft prasugrel: antagonists of P2Y12 receptor of ADP. Common side effect: GI
symptoms.
• Prasugrel: latest, most potent and faster acting. Suitable for STEMI, contraindicated in stroke & hemorrhage.
• Ticlopidine causes thrombocytopenia & less commonly used, whereas Clopidogrel is better tolerated.
• Ticlopidine: inhibits both ADP & fibrinogen induced platelet aggregation.
• Concomitant administration of clopidogrel and proton pump inhibitors, which are inhibitors of CYP2C19,
produces a small reduction in the inhibitory effects of clopidogrel on ADP-induced platelet aggregation.
• Abciximab is a monoclonal antibody against Gpllb/Illa receptor and is not antigenic.
• Eptifibatide blocks platelet aggregation in vitro after intravenous infusion.
• Used to treat acute coronary syndrome and for angioplastic coronary interventions  reduces MI and death
by -20%.
• Eptifibatide does not react with the vitronectin receptor.
• Eptifibatide generally is administered in conjunction with aspirin and heparin.
• Ticagretor and cangrelor are direct - acting reversible P2 Y12 receptor antagonists.
• Ticagretor is orally effective.
o As compared to clopidogrel, it produces greater and more predictable antiplatelet action.
o It also has more rapid onset and offset of action as compared to clopidogrel.
o It is the first new antiplatelet drug to demonstrate a greater reduction in cardiovascular death than
clopidogrel in patients with acute coronary syndromes.
• Cangrelor is intravenous reversible P2 Y12 receptor antagonist in late stages of development.
• Vorapaxar and atopaxar are orally active inhibitors of thrombin receptors on platelets called protease-
activated receptor 1 (PAR-1). These are currently undergoing clinical trials
• Major adverse effect: Bleeding.
 • Antiplatelet drugs are used for prophylaxis of MI (aspirin is used most commonly), cerebrovascular disease
and in artificial heart valves (dipyridamole + warfarin is preferred).
• Cilastazole: phosphodiesterase-Ill inhibitor  increased cAMP, reduces platelet aggregation & possess
additional peripheral vasodilator action. Used in the treatment of intermittent claudication.

Aspirin Vs ADP receptor inhibitors

Aspirin ADP receptor inhibitor
Polypharmacological effects Single receptor targeting agent
Produces both platelet and vascular effects Only produces platelet mediated response
Multiple actions (analgesic,anti- inflammatory) Only produces inhibition of platelets

Feature Abciximab Eptifibatide Tirofiban

Specificity for Gp Ilb/Illa No Yes Yes
Plasma t1/2 Short (min) Long (2.5 hr) Long (2 hr)
Platelet bound t1/2 Long (days) Short (s) Short (s)
Renal clearance No Yes Yes

• In addition to targeting the GPIlb/Illa receptor, abciximab also inhibits the closely related αv β3receptor,
which binds vitronectin and αmβ2, a leukocyte integrin.
• In contrast, eptifibatide and tirofiban are specific for GPIlb/111a.
• Inhibition of αv β3 and αm β3 may endow abciximab with anti-inflammatory and/or antiproliferative
properties that extend beyond platelet inhibition.

ANTICOAGULANTS
Used in vivo Parenteral Indirect thrombin inhibitors Heparin, Low molecular weight heparins,
anticoagulants Fondaparinux, Danaparoid
Direct thrombin inhibitors Lepirudin, Bivalirudin, Argatroban
Oral Coumarin derivatives Bishydroxycoumarin (dicumarol), Warfarin sod,
anticoagulants Acenocoumarol (Nicoumalone),
Ethylbiscoumacetate
Indandione derivative Phenindione
Direct factor Xa inhibitors Rivaroxaban
Oral direct thrombin inhibitor Dabigatran etexilate
Used in vitro Heparin 150 U to prevent clotting of 100 ml blood
Calcium complexing 1.65 g for 350 ml of blood; used to keep blood in the fluid state for transfusion
agents like
Sodium citrate

ORAL ANTI-COAGULANTS
• Warfarin, bishydroxycoumarin (dicumarol), acenocoumarin, phenindione etc.
• Warfarin (Wisconsin Alumni Research Foundation, with "arin" from coumarin), discovered in the 1950s.
• Phenindione causes orange coloured urine as well as liver and kidney damage.
• Inhibits the activation of vitamin K dependent clotting factors II, VII, IX and X as well as anti-clotting
proteins, protein C and protein S.
• Protein C has shortest half life  first factor to decline and its deficiency may lead to dermal vascular
necrosis and hyper coagulation (protein C is anti-clotting).
• Among clotting factors, first to disappear is factor VII (t1/2=6 hours) and last to disappear is factor II (t1/2=60
hours).
• Warfarin can also be given intravenously without dose modification.
• Intramuscular injection is not recommended because of the risk of hematoma formation.
• The half life of warfarin ranges from 25 to 60 hours (mean -40 hours); the duration of action is 2-5 days.
• Cirrhosis or passive congestion of the liver can increase sensitivity to warfarin by decreasing synthesis of the
liver-dependent coagulation factors.
 • A polymorphism of CYP 2C9 affects up to 30% of people and results in slow metabolism (and risk of toxicity)
of warfarin, tolbutamide and losartan.
• M/C adverse effect: Bleeding.
• Treatment of over dosage: FFP  treatment of choice but specific antidote  vitamin K1 (but the action will
be delayed).
• Warfarin  Teratogenecity (contradi syndrome): hypoplastic nasal bridge, chondrodysptasia, CNS
malformations.
• Drug interactions:
INCREASING THE EFFECT OF WARFARIN DECREASING THE EFFECT OF WARFARIN
Prolongs the bleeding time, Needed dose reduction Require increase in dose of warfarin
Broad spectrum antibiotics, cephalosporins, aspirin, Enzyme inducers like rifampicin, griseofulvin & OCP's
phenylbutazone and microsomal enzyme inhibitors like
erythromycin, cimetidine etc...

• Prothrombin time is used to adjust the dose of warfarin.

• Better test for monitoring: INR (international normalized ratio). INR= (PT of patient/ PT of reference)ISI
• International normalized ratio (INR) was adopted to monitor warfarin concentration.
• The normal INR is typically about 0.9 to 1.1
• The risk of serious bleeding: INR values >4 and is highest during initiation of warfarin therapy.
• The goal of warfarin therapy is an INR of 2 to 3 for most indications and 2.5 to 3.5 in patients with
mechanical heart valves.
• Warfarin resistance is most commonly seen in patients with advanced cancers, typically of gastrointestinal
origin (Trousseau's syndrome).

Guidelines for anti-coagulation

• INR 2.0-2.5 Prophylaxis of deep vein thrombosis including surgery on high-risk patients (2.0-3.0 for hip
surgery and fractured femur operations).
• INR 2.0-3.0 Treatment of deep vein thrombosis; pulmonary embolism; systemic embolism; prevention of
venous thromboembolism in myocardial infarction; mitral stenosis with embolism; transient ischaemic
attacks; atrial fibrillation.
• INR 3.0-4.5 Recurrent deep vein thrombosis and pulmonary embolism; arterial disease including myocardial
infarction; mechanical prosthetic heart valves.

INDIRECT THROMBIN INHIBITORS

• Includes unfractionated heparin, low molecular weight heparin (enoxaparin, dalteparin, tinzaparin,
pamparin, ardeparin, nadroparin & reviparin) and fondaparinux and idraparinux.
• Heparin (discovered by McLean in 1916) is the strongest organic acid present in the body.
• Acts by activating antithrombin III in plasma.
• Unfractionated heparin inhibits both factor Ila and Xa.
• LMW heparins & fondaparinux only cause conformational changes in AT-III and thus inhibit only factor Xa.
• Fondaparinux does not cause HIT because it does not bind to PF4.
• There is no antidote for fondaparinux.
• Heparin is given either by S.C. or i.v. routes (i.m. route is contra-indicated d/trisk of hematoma formation).
• It does not cross the placenta and is thus anticoagulant of choice during pregnancy.
• At higher does, heparin also exerts anti platelet action.
• LMW heparin and fondaparinux do not require monitoring and once daily S.C. doses are sufficient.
• Specific antidote of heparin is protamine (highly basic drug that can cause release of histamine).

Advantages of LMWH over Heparin

Advantage Consequence
Better bioavailability and longer half-life Can be given subcutaneously once or twice daily for both prophylaxis
after subcutaneous injection and treatment
Dose-independent clearance Simplified dosing
Predictable anticoagulant response Coagulation monitoring is unnecessary in most patients
Lower risk of heparin-induced Safer than heparin for short- or long-term administration
thrombocytopenia
Lower risk of osteoporosis Safer than heparin for extended administration

HEPARIN ORAL ANTICOAGULANTS

Route of administration Parenteral (i.v, s.c) Oral
Onset of action Rapid Delayed (1-3 days)
Activity In vitro and in vivo In vivo only
MOA Activates antithrombin III ↓ activation of II,VII,IX,X
Monitoring by APTT PT
Antagonist Protamine sulphate Vit.K, (phytonadione)
Placental barrier Does not cross placenta Fetal warfarin syndrome

DIRECT THROMBIN INHIBITORS

• Includes hirudin, lepirudin, bivalirudin, argatroban, melagatran and ximelagatran.
• Ximelagatran is a prodrug of melagatran, can be given orally but withdrawn d/t hepatotoxicity.
• All other drugs used parenterally.
• Argatroban is metabolized by the liver  has a greater safety margin in renal failure patients, but should be
avoided in patients with liver disease.
• These drugs directly inactivate factor Ila (thrombin).
• These are the anticoagulant of choice for heparin induced thrombocytopenia.

USE OF ANTICOAGULANTS
• Warfarin: chronic atrial fibrillation (to prevent the thromboembolism).
• Aspirin and heparin in combination: unstable angina.
• Heparin: disseminated intravascular coagulation (def. brination syndrome)

Bleeding Specific antidote

Heparin therapy Protamine sulfate
Anticoagulants (warfarin) Vitamin K1 (phytonadione)

• Heparin and oral anticoagulant drugs do not affect the fibrinolytic mechanism.
• 100 units of heparin in the patient is neutralized by 1 mg of IV protamine sulfate.
• 1 mg of protamine sulfate partially neutralize 1 mg of enoxaparin.
• Protamine will not reverse the activity of fondaparinux.
• Excess danaparoid can be removed by plasmapheresis.

NEWER ANTI-COAGULANTS
• Heparinoids: Heparan sulphate, danaparoid, lepirudin & ancrod.
• Danaparoid: 84% heparan sulfate + 12% dermatan sulfate + 4% chondroitin sulfate. Used in prophylaxis of
DVT & HIT syndrome
• Rodenticides contain long acting anti coagulants: bromadiolone, brodifacoum, dephenadione,
chlorphenacinone & pindone. Treatment is Vit. K
• Drotrecogin alpha: recombinant form of human activated protein C, decreases mortality in sepsis.
• Rivaroxaban: new oral anti coagulant acts by reversibly inhibiting factor Xa.
• New oral anticoagulants include dabigatran etexilate, rivaroxaban and apixaban. These do not require
monitoring.
• Dabigatran etexilate is a prodrug and its active metabolite is a direct thrombin inhibitor whereas rivaroxaban
and apixaban are factor Xa inhibitors.
• Rivaroxaban has maximum (80%) whereas dabigatran etexilate has minimum (6%) oral bioavaitability.
• Other new oral anticoagulants include edoxaban, betrixaban, YM150, and TAK-442, which are oral factor Xa
inhibitors, and AZD0837, which is an oral thrombin inhibitor

HITT: HEPARIN INDUCED THROMBOCYTOPENIC THROMBOSIS

 • Occur due to formation of IgG antibodies against complexes of heparin with platelet factor 4 that can result
in paradoxical thrombosis.
• These complexes activate platelets by binding to Fcgl la receptors, which results in platelet aggregation,
release of more platelet factor 4, and thrombin generation. Platelet count <150,000/mL or a 50% decrease
from pretreatment value occurs typically 5-10 days after initiation of therapy with standard heparin
• The incidence of thrombocytopenia is lower with low-molecular-weight heparin
• Venous thromboembolism occurs most commonly, but arterial thromboses causing limb ischemia,
myocardial infarction, and stroke also occur.
• Bilateral adrenal hemorrhage, skin lesions at the site of subcutaneous heparin injection, and a variety of
systemic reactions may accompany heparin-induced thrombocytopenia.
• Warfarin is contraindicated.
• LMW heparin or fondaparinux should not be used.
• Anticoagulant of choice for HIT syndrome is direct thrombin inhibitors like lepirudin.
Features Details
Thrombocytopenia Platelet count of <100,000/pL or a decrease in platelet count of >50%

Timing Platelet count falls 5-10 days after starting heparin

Type of heparin More common with unfractionated heparin than low-molecular-weight heparin
Type of patient More common in surgical patients and patients with cancer than general medical
patients. More common in women than in men
Thrombosis Venous thrombosis more common than arterial thrombosis

Management of Heparin-Induced Thrombocytopenia

Stop all heparin
Give an alternative anticoagulant, such as lepirudin, argatroban, bivalirudin, or fondaparinux
Do not give platelet transfusions
Do not give warfarin until the platelet count returns to its baseline level. If warfarin is administered, give vitamin K to
restore the INR to normal
Evaluate for thrombosis, particularly deep-vein thrombosis

FIBRINOLYTICS / THROMBOLYTICS
• Activates plasminogen to form plasmin  lysis of thrombus.
• Major adverse effect: bleeding.
• Important drugs: streptokinase, urokinase, alteplase, tenecteplase and reteplase.
• Main indication of these drugs is treatment of acute myocardial infarction, for which these should be
administered i.v. within 12 hours preferably within first 3-6 hours.
• The currently recommended ("accelerated") regimen for coronary thrombolysis is a 15 mg intravenous
bolus, followed by 0.75 mg/kg of body weight over 30 minutes.
• These are also indicated in severe, life threatening pulmonary embolism.
• Epsilon amino caproic acid (EACA) and tranexaemic acid are specific antidotes for over dosage.

Streptokinase Alteplase (t-PA) Reteplase Tenecteplase (TNK-tM)

Source Group C Streptococcus Recombinant DNA Recombinant DNA Recombinant DNA
T1\2 20minutes 5minutes 15minutes 20minutes
Clot selectivity Low High High High
Fibrinogenolysis +++ + + +
Bleeding + + + +
Hypotension +++ + + +
Allergy ++ 0 0 +
Re-occlusion 5-20% 10-30% - 5-20%

Contraindications for thrombolysis:

 • Recent trauma, surgeries, biopsies
• Recent stroke, Peptic ulcers
• Severe hypertension, aneurysms
• Bleeding disorders
• Acute pancreatitis
ANTIFIBRINOLYTICS: Drugs which inhibit plasminogen activation and dissolution of clot. Epsilon amino caproic acid
(EACA) and tranexaemic acid.

COAGULANTS
• Main coagulant in the body is vitamin K. (K1 (phytonadione), K2 (menaquinone) and K3 (menadione).)
• Vitamin K is involved in the activation of various clotting factors (like II, VII, IX, X) as well as anti-clotting
proteins (like protein C and S).
• It carries out the final step in activation of these factors i.e. gamma carboxylation of glutamate residues.
• For most of the indications, vitamin Kl is used.
• Menadione (K3) is contra-indicated in patient with G-6-PD deficiency (causes hemolysis) and in newborn
(more chance of kernicterus)

MANAGEMENT OF HYPERTRIGLYCERIDEMIA
• There is increased CHD risk associated with the presence of triglyceride levels >150 mg/dL
• Weight loss, increased exercise, and alcohol restriction are important.
• If triglycerides remain >200 mg/dL after the LDL-C goal is reached, further reduction in triglycerides may be
achieved by increasing the dose of a statin or of niacin.
• Combination therapy (statin plus niacin or statin plus fibrate) may be required, but caution is necessary with
these combinations to avoid myopathy.
• Therapeutic intervention may be graded as:
o Plasma TG <150 mg/dl (Normal): No TG lowering needed; treat as per Cholesterol levels.
o PlasmaTG 150-499 mg/dl (High): Life style modification; treatment of cause if identified, specific TG
lowering drug (fibrate/nicotinic add) may be considered if
I. CAD present
II. family history of premature CAD
III. non HDL-Cholesterol: 190 mg/dl
IV. HDL < 40 mg/ dl
V. genetic dysbetalipoproteinemia (type Ill) or familial combined hyperlipemia (type v)
VI. multiple risk factors present.
o Plasma TG >500 mg/di (very high):Vigorous measures to lowerTG level needed since risk of acute
pancreatitis is high;
I. Control diabetes and other causes.
II. Institute very low fat diet; reduce weight; curtail alcohol; specific TG lowering drugs strongly
indicated.

DYSLIPIDEMIA

Type of Lipo Proteins Lipids elevated Risk of CAD treatment

disorder increased
Tri Glycerides Cholesterol
I CM +++ Normal No None
Ila LDL Normal ++ +++ Statins
Ilb VLDL and LDL ++ ++ +++ Statins, fibrates, nicotinic acid
III IDL and CM ++ ++ ++ Fibrates
IV VLDL ++ Normal ++ Fibrates, nicotinic acid
V VLDL and CM ++ Normal No None

• TG is elevated in all except type Ila; Cholesterol is elevated only in type II (Ila, lIb) and type III.
• Type II is treated with statins and III and IV with fibrates.
• I and V do not increase the risk of atherosclerosis and require no treatment.
 Desirable Borderline to high High
Total cholesterol < 200 200-239 >240
LDL cholesterol <130 130-159 >160
HDL cholesterol >60
Men >40
Women >50
Triglycerides <150 150-199 >200

CAUSES OF:
Hypercholesterolemia Hypertriglyceridemia
• Hypothyroidism • Diabetes mellitus • Estrogens
• Early nephrosis • Alcohol ingestion • Uremia
• Resolving lipemia • Severe nephrosis • Corticosteroid excess
• Immunoglobulin • Immunoglobulin-lipoprotein • Myxedema
• lipoprotein complex • complex disorders • Glycogen storage
• disorders • Lipodystrophy • disease
• Anorexia nervosa • Isotretinoin • Hypopituitarism
• Chotestasis • Protease inhibitors • Acromegaly
• Hypopituitarism
• Corticosteroid excess

ANTI - DYSLIPIDEMIC DRUGS

• HMG-CoA reductase inhibitors (Statins): Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin,
Pitavastatin
• Bile acid sequestrants(Resins): Cholestyramine, Colestipol.
• Lipoprotein lipase activators (PPARa activators, Fibrates): Clofibrate, Gemfibrozil, Bezafibrate, Fenofibrate.
• Lipolysis and triglyceride synthesis inhibitor: Nicotinic acid
• Sterol absorption inhibitor: Ezetimibe.
• First line drugs include statins, bile acid binding resins and intestinal cholesterol absorption inhibitors.
• Second line drug include fibrates and niacin.

STATINS: (HMG CoA reductase inhibitor)

• Most powerful LDL lowering agents, also lower TG, IDL and VLDL and increases HDL slightly.
• No effect on lipoprotein (a).
• Have pleotropic effects (antioxidant, anti-inflammatory and anti-proliferative properties).
• In response to the reduced free cholesterol content within hepatocytes, synthesis of LDL receptors is
increased and their degradation is reduced.
• The greater number of LDL receptors on the surface of hepatocytes increases removal of LDL from the blood,
• Most potent statin is rosuvastatin> atorvastatin >ftuvastatin and lovastatin(least potent)
• Activity of HMG CoA reductase is maximum at night, so these drugs are administered at night.
• Rosuvastatin (t1/2 =14 hours) -long acting drug,
• Pravastatin: decreases plasma fibrinogen levels.
• Lovastatin and simvastatin are administered as prodrugs.
• All drugs except Pravastatin are metabolized extensively by hepatic microsomal enzymes.
• Major adverse effect - myopathy (high when combinedwith fibrates or niacin) and hepatotoxicity.
• Myopathy can proceed to rhabdomyolysis with resultant renal shutdown.
• These drugs are the first line drugs for type Ila, type llb and secondary hyperlipoproteinemia.
• PLEIOTROPIC EFFECTS OF STATIN:
• Improved endothelial function • Stabilisation of atherosclerotic plaque
• Reduced vascular inflammation • Antithrombotic action & Enhanced fibrinolysis
• Reduced platelet aggregability • Inhibition of germ cell migration during
• Increased neovascularisation of ischaemic tissue development
• Increased circulating endothelial progenitor • Immune suppression
cells • Protection against sepsis.
BILE ACID BINDING RESINS
• Bind to bile acids in the intestinal lumen  decrease its reabsorption  depletion of cholesterol pool of
liver
• Bile acids inhibit TG production in the liver and their deficiency results in elevation of TGs.
• Bile acid binding resins are used only for type Ila disorder (TGs are normal in this condition). Drugs in this
group include cholestyramine, colestipol and colesevelam (better compliance).
• Major adverse effect of these drugs is constipation.

FIBRATES
• Inhibits lipoprotein lipase by activating a nuclear receptor, PPARa (peroxisome proliferators activated
receptor alpha).
• Major effect of the fibrates is to reduce TG (contained in VLDL) and to increase HDL.
• Clofibrate  malignancies, post cholecystectomy complications & did not prevent MI (banned
• now).
• Gemfibrozil, fenofibrate and bezafibrate are currently available.
• Fenofibrate is a prodrug with longest half life. It has maximum LDL cholesterol lowering action.
• Risk of myopathy is lower & also reduce plasma fibrinogen level.
• DOC in hypertriglyceridemia (type III and IV) and can be used with other drugs in type Ilb (fenofibrate, as it
has maximum LDL reducing action).
• DOC for treating type III hyperlipoproteinemia as well as subjects with severe hypertriglyceridemia
(triglycerides >1000 mg/dL) who are at risk for pancreatitis.
• Fenofibrate is uricosuric  can be used in hyperuricemia.
• GI distress and elevation of aminotransferases are important adverse effects of fibric acid derivatives.
• Risk of myopathy is increased if used with statins (except bezafibrate).

NICOTINIC ACID
• Niacin is an inexpensive drug (vitamin B3) that produces decreases in LDL, VLDL and triglycerides along with
increase in HDL cholesterol.
• Acts by inhibiting lipolysis in the adipose tissue.
• Among all hypolipidemic drugs, niacin has maximum HDL increasing property.
• Niacin is the only lipid-lowering drug that reduces Lp(a) levels significantly, by -40%;
• It is useful for type Ilb, Ill and IV disorders.
• Adverse effects: cutaneous flushing, pruritic, GI toxicity and hyperuricemia. Niacin can also lead to
hepatotoxicity which is manifested by fall in both LDL as well HDL cholesterol.

INTESTINAL CHOLESTEROL ABSORPTION INHIBITOR

• Ezetimibe acts by inhibiting the absorption of cholesterol by the intestine by blocking uptake via the
Neimann-Pick C-like 1 protein.
• Can be used alone or combined with statins for type Ila and Ilb hypertipoproteinemia.

MISCELLANEOUS DRUGS
• Probucol inhibits oxidation of LDL and cause reduction in levels of both HDL and LDL cholesterol.
• Gugulipid causes modest decrease in LDL & slight increase in HDL. Diarrhea is the adverse effect.
• a-tocopherol acetate (vitamin E) has no effect on lipid levels but is a powerful antioxidant.
• Niacin is the best agent available for increasing HDL (increments of 30-40%); it also ↓ triglycerides by 35-
45% (as effectively as fibrates & statins) and ↓ LDL levels by 20-30%.
• Changes in plasma lipoprotein levels, particularly increases in high-density lipoprotein (HDL), have been
associated with the protective effects of ethanol.
• Factors associated with elevation of plasma FFA followed by increased output of triacylglycerol and
cholesterol into the circulation in VLDL includeemotional stress and coffee drinking.
• Red wine increases HDL, because of its content of antioxidants.
• Regular exercise lowers plasma LDL but raises HDL.

NEWER DRUGS
 • Avasimibe is an inhibitor of enzyme ACAT-1 (acetyl coenzyme A: cholesterol acetyl transferase -1) which
forms cholesterol ester from cholesterol.
• Torcetrapib, Anacetrapib: increases HDL by inhibiting cholesterol ester triglyceride transport protein.

PLASMA EXPANDERS
• HMW substances acting by increasing the colloid osmotic pressure.
• Retains in the vascular compartment following IV administration.
• Eg: human albumin, dextran, degraded gelatin polymer, hydryethyl starch, polyvinyl pyrrolidone

IMPORTANT FACTS
• Prothrombin complex concentrates (PCC) - Bebulin and Proplex T
• Dipyridamole with 25 mg of aspirin: secondary prophylaxis of cerebrovascular disease.
• Transmission of viral diseases such as hepatitis B and C and AIDS is reduced or eliminated by pasteurization
and by extraction of plasma with solvents and detergents.
• Humate-P is a factor VIII concentrate for the treatment of bleeding in von Willebrand disease.
• Preparations of factor IX concentrate: Autoplex (with factor VIII correctional activity) and Feiba (with factor
VIII inhibitor bypassing activity).
• Aprotinin is a serine protease inhibitor ("serpin") that inhibits fibrinotysis by free plasmin. Reduces bleeding
by 50% in extracorporeal circulation for open heart procedures and liver transplantation.
 VI. ENDOCRINOLOGY

ANTERIOR PITUITARY HORMONES

GROWTH HORMONE (GH) AND GROWTH HORMONE RELEASING HORMONE (GHRH)

• GH controls growth of all organs except brain and eye.
• Acts by liberating somatomedins (insulin like growth factors (IGF-land 1GF-2).
• Dopamine increases GH release in normal subjects but decreases it in acromegalics.
• Genetic GH deficiency may present in the newborn with hypoglycemic seizures.
• Criteria for diagnosis of GH deficiency include
o A growth rate below 4 cm per year
o Absence of a serum GH response to two growth hormone secretagogues.
• Patients with Turner's syndrome have an increased risk of otitis media while taking GH.
• GH treatment is contraindicated in a patient with a known malignancy.
• Recombinant growth hormones (somatrem and somatropin) used in pituitary dwarfism, short bowel
syndrome & AIDS related wasting.
• Mecasermin: recombinant human IGF-1 & IGF- binding protein-3. Indicated for growth failure due to
deficiency of IGF-1, not responding to GH. Major adverse effect: hypoglycemia.
• Tesamorelin: synthetic analogue of growth hormone releasing factor indicated to reduce excess abdominal
fat in HIV infected patients with lipodystrophy.
• Sermoreline and hexarelin are recombinant GHRH analogs that are used for pituitary dwarfism.

• Sermorelin diagnostic test for pituitary GH reserve: after 1 pg/kg sermorelin IV, Serum GH levels must reach
a peak of over 2 ng/mL.
• Sermorelin is given to children who have had a positive growth hormone response to the diagnostic test and
who have a bone age of less than 7.5 years (girls) or 8 years (boys).
• Pegvisomant is a GH receptor antagonist indicated for the treatment of Acromegaly.

SOMATOSTATIN: secreted by hypothalamus as well as by δ-cells of pancreas.

• It inhibits the secretion of GH, TSH, Prolactin, insulin, glucagon, gastrin, and Ha
• Indicated for the management of Acromegaly, islet cell tumors, bleeding due to esophageal varices and
secretory diarrhea but has the disadvantage of short duration of action.
• Octreotide is a somatostatin analogue having high potency and long duration of action. It is preferred over
somatostatin for all the indications.
• Sinus bradycardia & Vitamin B12 deficiency may occur with long-term use of octreotide.
• Octreotide is a drug of choice for diarrhea in HIV
• Lanreotide (given I.M. in slow release formulation), Vapreotide & Seglitide are other somatostatin analogs.
• Pasireotide is a new somatostatin analog approved for treatment of Cushing's disease.

PROLACTIN
• D2 blockers like antipsychotics and metoclopramide can cause Hyperprolactinemia.
• Bromocriptine is a dopamine agonist useful in the treatment of Hyperprolactinemia (amenorrhea,
impotence, galactorrhea and sterility in males). Although less effective than Octreotide, it can also be used in
the treatment of Acromegaly.
• Other uses of bromocriptine include Parkinsonism and suppression of lactation.
• Cabergoline is a longer acting dopamine agonist that is better tolerated than bromocriptine.
• Quinagolide is a non-ergot dopamine agonist having less adverse effects.

GnRH ANALOGUES
• Buserelein, goserelin, leuprolide, Naferelin & histrelin are more potent & longer acting than natural GnRH.
• These drugs stimulate gonadotropin secretion when given in pulsatile manner whereas inhibit the release
on continued administration.
• Synthetic GnRH- gonadorelin is used to differentiate b/w pituitary & hypothalamic defect in
hypogonadotropic hypogonadism.
 • Pulsatile therapy: anovulatory infertility, hypogonadotropic hypogonadism, delayed puberty &
cryptorchidism
• Continuous therapy: precocious puberty, endometriosis, prostatic carcinoma, PCOD and uterine fibroids.
• Most are used by S.C. route whereas Naferelin can be used by nasal route and goserelin can be used as S.C.
implant.
• GnRH analog therapy for pituitary suppression  transient rise in sex hormone concentration during first 2
weeks of treatment. This can be deleterious in treatmentof prostate cancer, precocious puberty and
infertility.

GnRH ANTAGONISTS
Cetrorelix, ganirelix and abarelix are administered subcutaneously for the treatment of uterine fibroids
endometriosis, in-vitro fertilization & to prevent premature spontaneous ovulation.

DRUGS USEFUL FOR HYPERTHYROIDISM

A. Inhibitors of Sodium iodide symport:

• Thiocyanate, perchlorate, pertechnate and nitrates. These drugs are very toxic.

B. Thyroid peroxidase inhibitors (Anti-thyroid drugs/Thioamides):

• Leaves an intact thyroid gland.
• Carbimazole, methimazole and propylthiouracil act by inhibiting this enzyme.
• Carbimazole is a prodrug and acts after conversion to methimazole.
• The most common adverse effect is a maculopapular pruritic rash (4-6%)
• The most dangerous complication is agranulocytosis
A & B are collectively called "goitrogens"

Propytthiouracil Carbimazole
Dose to dose less potent About 3 times more potent
Highly plasma protein bound Less protein bound
Less transferred across placenta & milk Larger amounts cross to fetus & in milk
Plasma t1/2 :1-2 hours Plasma t1/2 : 6-10 hours
Acts for 4-8 hours Acts for 12-24 hours
No active metabolite The active metabolite is methimazole
Multiple doses needed Single daily dose is sufficient
Inhibits peripheral conversion of T4  T3 Does not inhibit conversion of T4 T3
Used only in Thyroid storm, Pregnancy & lactation Used routinely.

C. Inhibitors of thyroid hormones release:

• Sodium iodide, potassium iodide and Lugol's solution act as 'thyroid constipating agents' by inhibiting the
release of T3 and T4.
• Used in preoperative preparation of thyroid gland, thyroid storm.
• Potassium iodide is available as a saturated solution (SSKI, 38-mg iodide per drop) or as Lugol's solution,
containing 6.3 mg of iodide per drop.
• Lugol's solution (5% iodinein 10% potassium iodide solution)
• Chronic overdose of iodides is called iodism. Major symptoms are inflamed mucus membranes, increase in
secretions (salivation, lacrimation and rhinorrhoea), headache, rashes and gastrointestinal distress.

D. Drugs causing the Destruction of Thyroid Gland:

• I131 is the most commonly used radioactive iodine with a half-life of 8days (stable isotope of iodine
• is I127).
• Thyroid peroxidase inhibitors are administered to make the patient euthyroid.
• After a gap of 5 days (after stopping anti-thyroid drugs), radioactive iodine is given and thyroid peroxidase
inhibitor treatment is resumed till the effect of I131 starts.
 • Radioactive iodine therapy is primarily indicated for patients older than 35 years and in the presence of
other contra-indications of surgery. These drugs are not suitable for young children and in the pregnancy.
• Another disadvantage of radioactive iodine is that if hypothyroidism develops, it is permanent.

Off label use of thyroxine:

• Refractory anemia
• Menstrual disorders
• Infertility
• Chronic non healing ulcers
• Obstinate constipation

Thyrotoxic crisis/ thyroid storm

• Life-threatening exacerbation of hyperthyroidism, accompanied by fever, delirium, seizures, coma, vomiting,
diarrhea and jaundice.
• The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with
treatment.
• Usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially
on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism.

• Management of thyroid storm:

 Intensive monitoring and supportive care, identification and treatment of the precipitating cause, and
measures that reduce thyroid hormone synthesis.
 Large doses of propylthiouracil (antithyroid drug of choice), (600 mg loading dose and 200300 mg
every 6 h) should be given.
 One hour after the first dose of propylthiouracil, stable iodide is given to block thyroid hormone
synthesis via the Wolff-Chaikoff effect (the delay allows the antithyroid drug to prevent the excess iodine
from being incorporated into new hormone).
 A saturated solution of potassium iodide (5 drops SSKI every 6 h), or ipodate or iopanoic acid (500 mg
per 12 h), may be given orally. (Sodium iodide, 0.25 g IV every 6 h, is an alternative but is not generally
available.)
 Propranolol should also be given to reduce tachycardia and other adrenergic manifestations
 Additional therapeutic measures include glucocorticoids (e.g., dexamethasone, 2 mg every 6 h),
antibiotics if infection is present, cooling, oxygen, and intravenous fluids.

DRUGS ACTING ON CALCIUM HOMEOSTASIS

Drugs useful for the Treatment of Osteoporosis

Drugs inhibiting bone resorption Bisphosphonates, Donesumab, Cinacalcet, calcitonin, oestrogen,
SERM's, Gallium nitrate
Drugs stimulating bone formation Teriparatide, calcium, Calcitriol, fluoride
Both the actions Strontium ranelate

• Bisphosphonates: accelerate apoptosis of osteoclasts by inhibiting lnterleukin-6

• Used in treatment of osteoclast-mediated bone resorption, including post menopausal a steroid induced
osteoporosis, Paget's disease, hypercalcemia of malignancy, breast and prostate cancer and hypercalcemia.
• First generation: medronate, clodronate, etidronate
• Second generation: alendronate, ibandronate, pamidronate
• Third generation: risedronate, zoledronate (most potent)
• Intravenous bisphosphonates: pamidronate, zoledronate.
• All bisphosphonates can cause gastric irritation except etidronate.
• Zoledronate: used as an adjunct in Philadelphia chromosome positive CML.
• Zoledronate infusion of 5mg once yearly has been approved for treatment of osteoporosis.
• M/C: adverse effect: esophageal irritation, others: osteonecrosis of jaw, osteomalacia
• Principal toxicity of etidronate - osteomalacia.
 • Continuous administration of PTH or high circulating PTH levels causes bone demineralization and
osteopenia.
• Paradoxically, intermittent PTH administration promotes bone growth.
• Teriparatide: recombinant PTH1-34-. In low & pulsatile doses stimulate bone formation but causes resorption
in excess.
• Teriparatide and strontium ranelate can stimulate osteoclast whereas most other agents used for
osteoporosis act by inhibiting osteoclast.
• Donesumab: monoclonal antibody against RANK (Receptor for Activated Nuclear factor- K, expressed by
osteoclasts), used in osteoporosis. Osteoprotegerin acts as a decoy receptor for RANK ligand & prevents
osteoporosis.
• Cinacalcet: catcimimetic drug acts by directly activating calcium sensing receptors on parathyroid gland.
o Approved for treatment of hypercalcemia d/t secondary hyperparathyroidism & parathyroid carcinoma.
• Statins & amino bisphosphonates blocks farnesyl pyrophosphate synthase, an enzyme in the
mevalonate pathway (critical for osteoclast survival & important in bone cell function).
• Hypervitaminosis D: only condition that requires emergency lowering of serum calcium.
• Gallium nitrate: acts by inhibiting bone resorption, used for management of hypercalcemia of malignancy
and treatment of advanced Paget's disease.Nephrotoxic
• Calcium gluconate is the preferred parenteral form of calcium as it is less irritating to veins.
• Calcium and calcitriol (vitamin D) can be used in the prophylaxis and treatment of osteoporosis.
• Calcium can be life saving in extreme hyperkalemia (>7 mEg/L). It can reverse some of the cardiotoxic effects
of K+.
• Calcium is also approved for i.v. treatment of black widow spider envenomation and magnesium toxicity.
• Fluorides are used for prevent dental caries but their usefulness in osteoporosis is uncertain.
• Thiazides inhibit the renal excretion of Ca+ and thus can be used for the treatment of osteoporosis. (apart
from their use in recurrent calcium stones due to hypercalciurea).
• Calcitonin inhibits resorption of bone thus can be used for the treatment of osteoporosis. It can be
administered by nasal route for this indication.

Management of hypercalcemia: (In order of preference)

• Hydration with saline
• Forced diuresis ( saline + loop diuretic)
• Bisphosphonates: 1st- etidronate, 2ndpamidronate, 3rd- zolidronate.
• Calcitonin
• Gallium nitrate
• Plicamycin
• Phosphate
• Glucocorticoids
• Dialysis

MANAGEMENT OF DIABETES MELLITUS

CLASSIFICATION OF ANTI-DIABETIC DRUGS

• Enhance Insulin secretion
o Sulfonylureas (KATP Channel blockers)
 First generation: Tolbutamide, chlorpropamide, tolazamide, acetohexamide
 Second generation: Glibenclamide (glyburide), Glipizide, Gliclazide, Glimepiride
o Glinides/Meglitinides/phenylalanine analogues(KATP Channel blockers/prandial glucose regulators):
Repagiinide, Nateglinide
o Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs):Exenatide, Liraglutide
o Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin
• Overcome Insulin resistance
o Biguanide (AMPK activator): Metformin
o Thiazolidinediones (PPARY activator):Pioglitazone
• Miscellaneous antidiabetic drugs
o α -Glucosidase inhibitors: Acarbose, Miglitol, Voglibose
 o Amylin analogue: pramlintide
o Dopamine-D2 receptor agonist: Bromocriptine
o Sodium-glucose cotransport-2 (SGLT-2) inhibitor: Dapagliflozin, canaglifozin

Improve insulin availability Overcome insulin resistance

• Exogenous insulin • Biguanides
• Sulfonylureas • Thiazolidinediones
• Meglinitinide/ phenyl.alanine analogues • Alpha glucosidase inhibitors
• Dipeptidyl peptidase-4 inhibitors (DPP-41s)
Major limitations (except for DPP-41s) Major limitations
• Hypoglycaemic episodes • Inability to achieve normoglycaemia by
• Weight gain themselves in many patients, especially
• Concern about premature Atherosclerosis d/t moderate-to-severe cases
hyperinsulinaemia

INSULIN
• Discovered by Banting and Best in 1921.
Preparations: Conventional preparations are obtained from pork and beef. Addition of zinc makes it long acting.
Insulin may be:
o Ultra short acting (insulin lispro, glulisine and aspart)
o Short acting (regular insulin and semi lente).
o Intermediate acting (lente insulin and neutral protamine hagedron).
o Long acting (ultra lente and protamine zinc insulin).
o Ultra long acting (insulin detemir and glargine)
• Single peak insulin and mono component insulin: less immunogenic.
• Rapid-acting and short-acting insulins are clear solutions at neutral pH and contain small amounts of zinc to
improve their stability and shelf-life.
• All others except insulin glargine are dispensed as turbid suspensions at neutral pH with either protamine in
phosphate buffer (neutral protamine Hagedorn [NPH] insulin) or varying concentrations of zinc in acetate
buffer (ultralente and lente insulins).
• Insulin glargine is the only soluble, "peakless" ultralong- acting insulin analog.
• When lente insulin is mixed with regular insulin, some of the regular insulin may form a complex with the
protamine or Zn2+
• D/t its acidic pH, insulin glargine cannot be mixed with other insulin preparations that are formulated at
neutral pH.
• Prevalence of hypoglycemia is reduced by 20-30% with insulin lispro, and glucose control, as assessed by
HbA1c, is modestly but significantly improved.
• Continuous Subcutaneous Insulin Infusion Devices: most physiologic method of insulin replacement.

Route of administration
• All preparations can be given by S.C. route.
• Only regular (crystalline zinc) insulin can be given i.v.
• Inhalational route (Exubera) is being tried.

Basal-bolus regimen:
• 3-4 daily injections.
• A long-acting insulin (glargine) is injected once daily either before breakfast or before bed-time for basal
coverage along with 2-3 meal - time injections of a rapid acting preparation (insulin lispro or aspart).

Complications of insulin therapy

• Most common complication is hypoglycemia.
• Lipodystrophy (less with highly purified and recombinant forms)
• Allergic reactions can occur with conventional preparation
• Short lived edema due to Na+ retention.
 ORAL HYPOGLYCEMIC AGENTS

DRUGS ACTING BY THE RELEASE OF INSULIN

• This group includes Sulfonyl ureas and meglitinides. These drugs inhibit ATP sensitive K+ channels and cause
depolarization of B cells resulting in the release of insulin.
• These drugs are effective only if 30% or more of the B cells in the pancreas are available.
• Major limitation of these drugs is hypoglycemia.

Sulfonylureas:
• These may be first generation (Tolbutamide, chlorpropamide) or second generation (glibenclamide, glipizide,
gliclazide and glimipride) compounds.
• Tolbutamide is the shortest acting whereas chlorpropamide is the longest acting sulfonylurea.
• Second generation drugs are most the potent.
• They can cause weight gain (less chance with glipizide and gliclazide).
• Chlorpropamide has additional actions like dilutional hyponatremia (ADH like action), cholestatic jaundice
and disulfiram like reaction (intolerance to alcohol).
• Glimipride: Have beneficial effects in regard to ischemic preconditioning.
• Glibenclamide(glyburide): higher incidence of hypoglycemia, sequestered in beta cells.
• Gliclazide has additional antiplatelet action.

Meglitinides: Nateglinide and repaglinide (mainly for post prandial hyperglycemia).

• There is no sulfur in its structure  repaglinide may be used in type 2 diabetics with sulfuror sulfonylurea
allergy.

DRUGS ACTING BY OTHER MECHANISMS

Biguanides:
• Metformin and phenformin: preferred agents for obese patients (cause weight loss).
• Decreases the production (inhibit gluconeogenesis and glycogenolysis) and increasing the utilization
(stimulation of glycolysis and tissue uptake of glucose).
• These drugs also inhibit the intestinal absorption of glucose.
• Lactic acidosis (more with phenformin) and Megaloblastic anemia (more with metformin) due to vitamin B12
deficiency are the major adverse effects of these drugs.
• Lactic acidosis is more likely to occur in the presence of hepatic and renal impairment or alcohol ingestion.
• Metformin is used in PCOD & it is the only drug that reduces macrovascular complications in type-II DM.

Thiazolidinediones;
• Troglitazone, pioglitazone and rosiglitazone act as agonists of peroxisorne proliferator activated receptor
gamma (PPARy). These drugs increase HDL.
• These drugs are used to reverse insulin resistance in type II DM.
• Troglitazone was withdrawn d/t serious hepatotoxicity and monitoring of hepatic function is recommended
for other glitazones also.
• Glitazones are avoided in CHF due to the risk of edema.
• Rosiglitazone is associated with increased incidence of MI & Pioglitazone with bladder Ca.

α-Glucosidase inhibitors:
• Inhibitors of a glucosidase (voglibose, acarbose and miglitol) decrease carbohydrate absorption from the
GIT.
• Not as potent as other oral agents in lowering the A1C but is unique because it reduces the postprandial
glucose rise even in individuals with type 1 DM.
• Major adverse effect of these drugs is flatulence due to fermentation of unabsorbed carbohydrates.

GLP-1 AGONISTS
• Exenatide: a recombinant glucagon like peptide (GLP) analogue.
o GLP is normally secreted (in GIT) when food enters the stomach and it stimulates release of insulin.
o GLP is normally metabolized by dehydro peptidyl peptidase 4 (DPP-4).
 o Exenatide is a GLP analogue resistant to DPP-4 and can be used for the treatment of DM.
o Can be associated with pancreatitis.
• Liraglutide:
o Long-acting GLP-1 agonist, closely related to the native peptide but its tight binding to plasma proteins
extends t1/2 to > 12 hours and duration of action to >20 hours.
o MC adverse effects: nausea and diarrhea.
o Use of liraglutide  weight loss & being evaluated as an antiobesity drug even for nondiabetics.
o Carries a black box warning because of an increased risk of thyroid C-cell tumors in rodents.
o Contraindicated in medullary carcinoma of the thyroid and MEN syndromes.
o Hypoglycaemia is rare with exenatide/liraglutide mono-therapy.

DPP-4 INHIBITORS
• Sitagliptin, Vidagliptin & Saxagliptin: It is a DPP-4 inhibitor and thus decreases the metabolism of
endogenous GLP.
• Sitagliptin achieves peak concentrations within 1-4 hours, and has a half-life of approximately 12 hours.
• The usual dosage is 100 mg orally once daily.
• Sitagliptin can be used as monotherapy and in combination with metformin, sulfonylureas, and Tzds.
• Therapy with sitagliptin has resulted in HbA lc reductions of between 0.5% and 1.0%.
• Boosts post prandial insulin release & decreases glucagon secretion.
• Adverse effects are rare.
• Nasopharyngitis & cough can occurd/t prevention of Substance-P degradation.
• Pancreatitis is rare.

NEWER DRUGS
• Pramlintide, an analogue of amylin: given parenterally, delays gastric emptying and suppresses glucagon
secretion.
o Reduce postprandial glycemic excursions in type 1 and type 2 diabetic patients taking insulin.
• Bromocriptine mesylate: alter insulin resistance by acting on hypothalamus & bromocriptine targets D-2
receptors.
• Dapagliflozin: produces round-the-clock glucosuria and lowers blood glucose levels. Resulting glycosuria can
predispose to urinary and genital infections, electrolyte imbalance and increased urinary frequency.
• Colesevelam hydrochloride: Initially developed as a bile acid sequestrant and cholesterol-lowering drug, is
now approved as an antihyperglycemic therapy for persons with type 2 diabetes who are taking other
medications or have not achieved adequate control with diet and exercise.
• Epalrestat:
o Sorbitol is a minor metabolite of glucose generated by the enzyme aldose reductase.
o In diabetics, excess sorbitol is deposited in nerves and other tissues  diabetic neuropathy and other
complications.
o Epalrestat is an aldose reductase inhibitor- delays sorbitol accumulation & delays progression of
diabetic neuropathy.
o Nausea, vomiting and elevation of liver enzymes are the adverse effects.

Important facts:
• Glucose-lowering agents other than insulin (with the exception of amylin analogue and α-glucosidase
inhibitors) are ineffective in type 1 DM.
• All others are used only in type 2 DM
• The only bile acid binding resin approved for type 2 DM is cholesevelam.
• D2 agonist approved for type 2 DM is Bromocriptine
• Weight gain is seen with—Insulin, insulin secretagogues (sulfonyi ureas, meglinitinides), thiazolidinediones
• Weight reduction is seen with - Metformin, pramlintide, GLP-1 agonist
• Weight neutral- DDP4 inhibitors
• Alpha glucosidase inhibitor will reduce the progression of impaired glucose tolerance to type 2 DM.
 Mechanism HbA1C Advantages Disadvantages Contraindications
of Action Reducti
on (%)
Biguanides ↓Hepatic 1-2 Weight neutral, Diarrhea, nausea, Serum creatinine
Glucose Do not cause lactic acidosis >1.5, CHF, radiographic
production hypoglycemia, contrast studies,
inexpensive seriously ill patients,
acidosis
α- Glucosidase ↓GI glucose 0.5-0.8 Reduce postprandial GI flatulence, liver Renal/liver disease
inhibitors absorption glycemia function tests
Dipeptidyl Prolong 0.5-0.8 Do not cause Reduce dose with renal
peptidase IV endogenous hypoglycaemia disease
inhibitors GLP-1 action
Insulin ↑ Insulin 1-2 Inexpensive Hypoglycemia, weight Renal/liver disease
secretagogue secretion gain
s: Sulfonylurea

Insulin ↑insulin 1-2 Short onset of Hypoglycemia Renal/liver disease

secretagogue secretion action, lower
s: Non- postprandial
sulfonylureas glucose
Thiazolidine ↓Insulin 0.5-1.4 Lower insulin Peripheral edema, CHF, liver disease;
dionesb resistance, requirements CHF, weight gain,
↑glucose fractures, macular
utilization edema; rosiglitazone
may increase
cardiovascular risk
Bile acid Bind bile 0.5 Constipation, Elevated plasma
sequestrants acids; dyspepsia, triglycerides
mechanism abdominal pain,
of glucose nausea, Ttri-
lowering not glycerides, interfere
known with absorption of
other drugs, intestinal
obstruction
Insulinb.c ↑ Glucose Not Known safety Injection, weight gain,
utilization, limited profile hypoglycemia
↓Hepatic
glucose
production,
and other
anabolic
actions
GLP-1 receptor ↑Insulin, 0.5-1.0 Weight loss, do Injection, nausea, Renal disease,
agonistsb ↓glucagon, not cause ↑ risk of hypoglycemia agents that also slow
slow gastric hypoglycaemia with insulin GI motility;
emptying, secretagogues,
satiety pancreatitis, renal
failure
Amylin Slow gastric 0.25-0.5 Reduce Injection, nausea, ↑risk Agents that also slow GI
agonistsb.c emptying, postprandial of hypoglycemia with motility
↓ glucagon glycemia; weight insulin
loss
Medical ↓Insulin 1-3 Other health Compliance difficult,
nutrition resistance, benefits long-term success
therapy and ↑insulin low
physical secretion
activityb,c

a
• A1C reduction (absolute) depends partly on starting A1C.
b
• Used for treatment of type 2 diabetes.
c
• Used in conjunction with insulin for treatment of type 1 diabetes.

GENERALISATIONS IN OHA USAGE

• Insulin secretagogues, biguanides, GLP-1 receptor agonists, and thiazolidinediones improve glycemic control
to a similar degree (1-2% reduction in A1C) and are more effective than aglucosidase inhibitors and DPP-IV
inhibitors.
• Assuming a similar degree of glycemic improvement, no clinical advantage to one class of drugs has been
demonstrated, and any therapy that improves glycemic control is likely beneficial.
• Insulin secretagogues, GLP-1 receptor agonists, DPP-IV inhibitors, and a -glucosidase inhibitors begin to
lower the plasma glucose immediately, whereas the glucose-lowering effects of the biguanides and
thiazolidinediones are delayed by several weeks.
• Not all agents are effective in all individuals with type 2 DM (primary failure)
• Biguanides, α -glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, and thiazolidinediones do
not directly cause hypoglycemia.
• Most individuals will eventually require treatment with more than one class of oral glucose-lowering agents
or insulin, reflecting the progressive nature of type 2 DM.
• Durability of glycemic control is slightly less for glyburide compared to metformin or rosiglitazone.

AGENTS FOR OBESITY

Feeding centre: Arcuate nucleus in the mediobasal hypothalamus
Substances playing important role in the regulation of food intake:
• Orexins: acts on orexin receptor & increases food intake.
• Ghrelin: Acts directly on the Arcuate nucleus to stimulate food intake.
• Neuro peptide Y & Agouti related peptide: These peptides; NPY and AgRP, stimulate food intake, reduced
energy expenditure and promote weight gain.
• Melanocyte Stimulating Hormone (MSH) and CART (cocaine and Amphetamine Related Transcript): Both
MSH and CART reduce food intake by eventually causing activation of 5-HT2c (serotonin) receptors.
• Insulin and Leptin: These signals are increased in obesity. These are inhibitory to NPY and AgRP neurons
and facilitatory to MSH and CART neurons.
• Cannabinoids: The endo cannabinoids act on their receptor CBI and CB2 to stimulate the anabolic pathway
(NPY and AgRP). They also inhibit the catabolic pathways (CART and MSH)  excessive food intake and
obesity.

ANORECTICS:
• Noradrenergic agents: Phentermine, phenylpropanolamine, diethylpropion, mazindol.
• Serotonergic agents: Fenfluramine, dexfenfluramine.
• Noradrenergic/serotonergic agent: Sibutramine

THERAPIES FOR THE MANAGEMENT OF OBESITY

• Phentermine acts by increasing dopamine and norepinephrine levels in the brain.
• Sibutramine blocks the reuptake of serotonin, norepinephrine, and dopamine into presynaptic nerve
terminals in the brain.
o Phentermine and sibutramine are associated with tachycardia, hypertension, headache, insomnia, dry
mouth& constipation.
o MAO inhibitors, SSRIs and dextromethorphan should be avoided in patients taking sibutramine
o Fen-phen (combination of fenfluramine and phentermine) can cause pulmonary hypertension and heart
valve abnormalities. Hence, Fenfluramine was removed from the markets.
 • Orlistat is an antiobesity agent that inhibits gastric and pancreatic lipase, thereby inhibiting breakdown of
dietary fat.
o Adverse effects of orlistat are Oily spotting, abdominal discomfort,flatus with discharge, fatty stools,
fecal urgency & increased defecation.
o Fat-soluble vitamins supplementation is recommended in patients taking orlistat.
• Rimonabant: it is a cannabinoid receptor antagonist which acts on CB1 receptor.
o It blocks the orexigenic action of ghrelin and cause reduction in appetite.
o It also causes lipolysis and increases basal metabolic rate.
• Four types of diets are recommended for weight loss. These are
o Atkins (very low carbohydrate)
o Traditional (lifestyle, exercise, attitudes, relationship, nutrition {LEARN}
o Ornish (very high carbohydrate)
o Zone (low carbohydrate)

CORTICOSTEROIDS

Features Steroid
Maximum glucocorticoid activity Dexamethasone, Betamethasone
Maximum mineralocorticoid activity Aldosterone
Glucocorticoid with maximum mineralocorticoid activity Hydrocortisone
Maximum topical activity Triamcinolone acetonide
Least potent glucocorticoids Cortisone
Most potent glucocorticoids Betamethasone
Selective mineralocorticoid action (no glucocorticoid activity) DOCA
Selective glucocorticoid action (no mineralocorticoid activity) Triamcinolone, paramethasone, dexamethasone,
Betamethasone

Compound Gluco Mineralo Equivalent dose

(anti- inflammatory)
Glucocorticoids Short acting Hydrocortisone (cortisol) 1 1 20mg
(t1/2< 12hr)
Intermediate Prednisolone 4 0.8 5 mg
acting Methyl preclnisolone 5 0.5 4mg
(t1/2< 12- Triamcinolone 5 0 4mg
36hr)
Long acting Dexamethasone/betamethasone 25 0 0.75mg
Mineralocorticoids Equiv. Salt retaining
dose
Desoxycorticosterone acetate (DOCA) 0 100 2.5mg (sublingual)
Fludrocortisone 10 150 0.2mg
Aldosterone 0.3 3000 Not used clinically

Glucocorticoid and Mineralocorticoid Potency of Natural Corticosteroids and Some Synthetic

Analogues
Glucocorticoid Mineralocorticoid
Hydrocortisone 1 1
Corticosterone 0.5 1.5
Prednisone (1.2 double bond) 4 <0.1
6α-Methylprednisone (Medrol) 5 <0.1
9α-Fluoro- 16α- hydroxypred nisolone (triamcinolone) 5 <0.1
9α-Fluoro-16α-methylprednisolone (dexamethasone) 30 <0.1
Aldosterone 0.25 500
Deoxycorticosterone 0.01 30
9α-Fluorocortisol 10 500

Contraindications of steroid therapy

• Peptic ulcer • Herpes simplex keratitis
• Diabetes mellitus • Psychosis
• Hypertension • Epilepsy
• Viral and fungal infections • CHF
• Tuberculosis and other infections • Renal failure
• Osteoporosis

GLUCOCORTICOID SYNTHESIS INHIBITORS

• These drugs are useful in the diagnosis of adrenal diseases and in the treatment of Cushing's syndrome.

Metyrapone
• Inhibits 11β hydroxylase enzyme (involved in the synthesis of Cortisol and cortisone) and results in the
reduced glucocorticoid activity.
• It was used for diagnostic purposes and for the treatment of Cushing's syndrome.
• It is the only drug safe in pregnancy.

Aminoglutethimide:
• Inhibits the conversion of cholesterol to Pregnenotone  inhibits the synthesis of all corticosteroids.
• It also inhibits the enzyme Aromatase and is useful in breast carcinoma.

Mitotane: Causes atrophy of zona fasciculata and reticularis without affecting zona glomerulosa.
Trilostane:
• Inhibits 3 β hydroxysteroid dehydrogenase enzyme, which is involved in the production of adrenal and
gonadal hormones. It is also an Aromatase inhibitor.
Ketoconazole: is an antifungal agent that can be used for the treatment of Cushing's syndrome due to the inhibitory
actions on 17α hydroxylase and 3β hydroxysteroid dehydrogenase enzymes.

MANAGEMENT OF ADRENAL INSUFFICIENCY

• Immediate management of acute adrenal insufficiency: IV NS supplemented with 5% glucose and
corticosteroids.Appropriate therapy for precipitating causes such as infection, trauma, or hemorrhage.
• Initial IV bolus of 100 mg, hydrocortisone (cortisol) should be given by continuous infusion at a rate of 50-
100 mg every 8 hours.
• For suspected but unconfirmed acute adrenal insufficiency, 4 mg of dexamethasone sodium phosphate can
be substituted for hydrocortisone, since dexamethasone does not cross-react in the cortisol assay.

CORTICOSTEROID RECEPTOR ANTAGONISTS

• Mifepristone is an antagonist at the glucocorticoid and progesterone receptors.
• Spironolactone and eplerenone are Aldosterone receptor antagonists that are used as K+ sparing diuretics.
• Drosperinone: a progestin, used in contraceptive pill & also has anti mineraiocorticoid activity.
• Eplerenone: has no effect on androgen receptors.

SEX HORMONES
• Most of the actions of androgens are mediated by DHT whereas testosterone is itself active at few sites.
Actions of DHT
• Development and
maturation of external
genitalia (scrotum, penis,
urethra etc.) in male
• Male behaviour and changes
of puberty
Actions of testosterone
• F - Fedback inhibition of LH
• I - Internal genitilia
development
• S - Spermatogenesis
• H - Hematopoiesis
Actions of both testosterone and
DHT
• Increase in mass and
strength of skeletal muscle
and bone
• Epiphyseal fusion
 • Growth and hypertrophy of
prostatein the elderly.
• Growth of hair follicles
(pubic, axillary and beard)
during puberty
• Loss of scalp hair in adults.
• Activation of sebaceous
glands.

Androgens Methyl testosterone, Fluoxymesterone

Anabolic steroids
Anti-androgens
5-a reductase inhibitor
Estrogens
Anti- estrogens
Progesterone
Anti progestins
Nandrolone, Oxymetholone, Stanozolol, Methandienone
Danazot, Cyproterone acetate, Flutamide, Bicalutamide, Abiraterone
Weak anti-androgens: Ketoconazole, Cimetidine, Spironolactone, Progesterone
Finasteride, Dutasteride
Natural: Estrone, Estriol, Estradiol
Synthetic Steroidal: Ethinylestradiol, Mestranot, Tibolone
Synthetic Non steroidal: dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol,
methalenestril and chlorotrianisene.
SERD  Selective Estrogen Receptor Down regulator(Pure Estrogen antagonist ):
Fulvestrant
SERM  Selective Estrogen Receptor modulator: Tamoxifen citrate, Clomiphene
citrate, Toremifene, Raloxifene, Ormeloxifene(Centchroman)
Aromatase inhibitor: Aminoglutethimide(Ist generation); Letrozole, Anastrazole,
fadrozole, vorozole, formestane and Exemestane(Ilnd generation);
Progesterone derivatives: Medroxyprogesterone acetate, Megestrol acetate,
Dydrogesterone, Hydroxyprogesterone caproate, Nomegestrol acetate(Newer drug)
19-nortestosterone derivatives; Norethindrone, Lynestrenol, Allylestrenol,
Levonorgestrel, Desogestrel, Norgestimate, Gestodene
Mifepristone, Onapristone, Gestinone

Major therapeutic applications:

• Finasteride, Dutasteride  BHP, male baldness.
• Clomiphene citrate  infertility due to failure of ovulation, invitro fertilization, Azoospermia. Major adverse
effect is hyperstimulation leading to multiple pregnancy.
• Fulvestrant, Tamoxifen, Letrozole, Anastrazole & Exemestane  breast cancer.
• Raloxifene  osteoporosis mainly in postmenopausal state,
• Ormeloxifene  treatment of Dysfunctional Uterine Bleeding (DUB).
• Mifepristone  termination of pregnancy, cervical ripening, post coital. contraception
• SERD's, SERM & AROMATASE INHIBITORS are used for chemotherapy in Ca. Breast.
• Fulvestrant  used in post menopausal women with hormone receptor positive metastatic Ca. breast that
has progressed in spite of anti-oestrogen therapy.
• Selective progesterone receptor modulator- Asoprisnil: was tested for myomas. Discontinued d/t
endometrial hyperplasia.
• Finasteride is approved for use in the treatment of male pattern baldness.
• Finasteride is as effective as flutamide or the combination of estrogen and cyproterone in the treatment of
hirsutism.
• Tamoxifen: antagonist on estrogen receptors in mammary tissue but agonist on ER in bone.
• Danazol:
o Derivative of the progestogen, ethisterone.
o It has partial agonist androgen activity  Impeded' androgen; it has little progestogen activity.
o Selective inhibitor of pituitary gonadotrophin secretion (LH, FSH) affecting the surge in the mid-
menstrual cycle more than basal secretion.
o This reduces ovarian function, which leads to atrophic changes in endometrium, both uterine and
elsewhere (ectopic), i.e. endometriosis.
 o In mates it reduces spermatogenesis.
o Androgenic unwanted effects occur in women (acne, hirsutism and, rarely, enlargement of the clitoris).
o It is chiefly used for: endometriosis, fibrocystic mastitis, gynaecomastia, precocious puberty,
menorrhagia and hereditary angioedema.
o Gestrinone is similar.
• Tibolone: synthetic steroid with weak oestrogenic, progestogenic and androgenicproperties.
o It is administered as a daily oral dose of 2.5 mg to suppress vasomotor symptomsand to prevent
postmenopausal osteoporosis.
o The main adverse effect is vaginal bleeding.
o Vasomotor menopausal symptoms may occasionally be helped by low doses of clonidine.
o Can be used continuously without cyclical progesterone (avoiding the inconvenience of withdrawal
bleeding).
• Impeded androgens: Synthetic Progestins-"19-nortestosterone" third-generation agents: more effective
gonadotropin inhibitors with minimal estrogenic, androgenic or anabolic activity.

Androgen receptor antagonists

• Inhibit testosterone binding to the androgen receptors or inhibit 5α-reductase
• Flutamide & Bicalutamide  palliation in metastatic prostatic carcinoma.
• For maximal clinical efficacy, these are not indicated as monotherapy as routine but used in combination
with leuprolide to reduce tumour flareup symptoms.
• Flutamide is used to treat hirsutism in women.
• Bicalutamide and nilutamide have longer plasma half lives  once daily oral dosing.
• Elevation of hepatic transaminase above twice normal is a signal for stopping the drug.
• Adverse effects: Nausea, hot flushes, mild gynaecomastia and transient elevation of liver enzymes.
• Combined use of orchiectomy or leuprolide plus flutamide  total androgen blockade.

UTERINE STIMULANTS (Oxytocics, Abortifacients)

These drugs increase uterine motility, especially at term.
• Posterior pituitary hormone: Oxytocin, Desamino oxytocin
• Ergot alkaloids: Ergometrine (Ergonovine), Methylergometrine
• Prostaglandins: PGE2, PGF2α, 15-methyl PGF2α, Misoprostol
• Miscellaneous: Ethacridine, Quinine.

TOCOLYTIC AGENTS
Drugs that decrease uterine motility.
• Agent of choice: Nifedipine(Calcium channel blocker)
• Contraindicated in heart disease  pulmonary edema: Ritodrine & Isoxsuprine (Selective B2 agonists)
• Safest tocolytic agent: Atosiban (oxytocin antagonist)
• Most efficacious tocolytic agent: Nifedipine
• Tocolytic in heart disease: Atosiban> MgSO4
• Other drugs: progesterone, ethanol & NSAIDs

IMPORTANT FACTS:
• Abiraterone: orally acting prodrug inhibits 17-α hydroxylase  reduces synthesis of cortisot & steroids
used in refractory prostate cancers.
• Vitamin-D & calcitonin can be used to treat osteoporosis; PTI-1 excess leads to osteoporosis.
• Excess of vitamin-D: stored in adipose tissue.
• Doxercalciferol & Paricalcitol: approved for treatment in secondary hyperparathyroidism in CKD.
• Calcitriol affects maturation and differentiation of mononuclear cells  tried in cancers.
• Topical calcipotriol (calcipotriene): approved in psoriasis.
• Fludrocortisone-most commonly prescribed salt-retaining hormone.
• DHEA-beneficial in patients with systemic lupus erythematosus.
• Lilopristone- potent progesterone inhibitor and abortifacient with antigtucocorticoid activity.
• Danazol does not inhibit aromatase.
• The prototypical steroidal inhibitor of aromatase is testolactone.
• Fadrozole is a newer oral nonsteroidal (triazole) inhibitor of aromatase activity.
• Hypokalemia is the major adverse effect and may lead to transient paralysis with gossypol treatment.
• Drugs inhibiting insulin release: Diazoxide, phenytoin, vinblastine & colchicine.
• Safest sulfonylurea for use in elderly diabetics: totbutamide.
• Metformin therapy decreases the risk of macrovascular as well as microvascular disease.
• Thiazolidinediones acts on adipose tissue, where the drug promotes glucose uptake and
• utilization.
• Troglitazone was withdrawn because of hepatic toxicity.
• "Gut Glucagon"/ Enteroglucagon: Insulinotropin (GLP-1) - considered as a potential therapeutic
• agent in type 2 diabetes.
• Fibroblast growth factor-23 (produced by osteociasts ft osteoblasts) inhibits Calcitriol production &
phosphate reabsorption in kidney.
 VII. CENTRAL NERVOUS SYSTEM

ANTIEPILEPTIC DRUGS

Adenosine is an endogenous antiepileptic substance

MECHANISM OF ACTION OF ANTI- EPILEPTIC

• Inhibition of use dependent Na+ channels: Phenytoin, carbamazepine, valproate, topiramate, lacosamide
lamotrigine.
• Increase in inhibitory neurotransmission: Barbiturates, Ganaxolone and benzodiazepines. Drugs can also
act by increasing the synthesis of GABA (Gabapentin), decreasing its metabolism (vigabatrin) or inhibiting its
uptake in neurons (Tiagabine).
• Decrease in excitatory neurotransmission: Felbamate acts by inhibiting NMDA receptors.
• Inhibition of T-type Ca2+ channels: (ethosuximide, valproate, lamotrigine) useful in petit mal epilepsy.

BARBITURATES
• Phenobarbitone: antiepileptic DOC in pregnant patients.

BENZODIAZEPINES
• Diazepam, lorazepam & Clonazepam: used in acute seizures & status epilepticus (Lorazepam is DOC).
• Diazepam (P/R): DOC for febrile seizures.
• Tolerance develops to the anti-epileptic effect, so not indicated in long term use.

PHENYTOIN
• It is a non sedating oral antiepileptic drug.
• Potent enzyme inducer.
• It has been found to enhance wound healing.
• Fosphenytoin: administered parenterally for status epilepticus, digitalis induced arrhythmia.
• Fosphenytoin: water soluble prodrug, rapidly converted into phenytoin by phosphatases in liver & RBC's.
• A/ Es of rapid IV administration of Fosphenytoin: cardiac arrhythmias (m/c), Cerebellar atrophy.
• Fosphenytoin is extensively (95-99%) bound to plasma proteins, primarily albumin.
• Fosphenytoin displaces phenytoin from binding sites.
• Fosphenytoin: useful for adults with partial/generalized seizures when IV/IM administration is indicated.
• Therapeutic level of phenytoin: 10 to 20 μg/mL.
• Congeners of phenytoin: mephenytoin and ethotoin.
• Ethotoin: recommended for patients who are hypersensitive to phenytoin, but larger doses are required.
• Metabolite of mephenytoin-nirvanol contributes most of the antiseizure activity.
• Most reliable test of thyroid function in patients taking phenytoin: measurement of TSH.

Adverse Effects of Phenytoin (Dilantin):

At therapeutic level
• Hyperglycemia, Hirsutism, Acne
• Hypertrophy of gums - Commonest 20%,
• Megatoblastic anemia (folate deficiency),
Vitamin D & K deficiency
• Fetal hydantoin syndrome: cleft lip, cleft palate,
hypoplastic phalanges, microcephaly and
congenital heart disease.
• Hypersensitivity reaction - Rashes, DLE
Dose related toxicity
• Drowsiness, behavioral alterations, mental
Confusion and hallucination
• Ataxia, Vertigo, Diplopia, Nystagmus
• Rapid IV injection, local vascular injury-edema &
discoloration
• Fall in B.P and cardiac arrhythmias

CARBAMAZEPINE AND OXCARBAZEPINE

• Oxcarbazepine has similar efficacy but less toxicity than carbamazepine (CBZ).
• Metabolism of carbamazepine is induced by phenobarbitone, phenytoin, valproate and vice versa.
 • Erythromycin, cimetidine, fluoxetine, isoniazid inhibits metabolism & increases the blood level of
carbamazepine.
• Eslicarbazepine acetate (ESL) is a prodrug that has been approved as adjunctive therapy in adults with
partial-onset seizures, with or without secondary generalization.
• ESL is more rapidly converted to S (+)-licarbazine (eslicarbazine) than is oxcarbazepine; dearly both prodrugs
have the same metabolite as active product.

USES:
• DOC in partial seizures and can also be used in GTCS.
• DOC for trigeminal neuralgia & in glossopharyngeal and post herpetic neuralgia.
• Bipolar disorder (manic depressive psychosis) & as an antidiuretic in DI.
• Major adverse effects of these drugs include dizziness, headache, ataxia, vertigo and diplopia.

VALPROIC ACID
• It is a broad spectrum antiepileptic drug effective in all types of seizures.
• It acts by several mechanisms including blockade of use dependent Na+ channels, ↑ acYvity of GABA (by
↑ synthesis due to sYmulaYon of glutamic acid decarboxylase and decreasing metabolism by inhibiYng
GABA transaminase), inhibition of T type Ca2+ channels and decrease in release of glutamate in the brain.
• It is the DOC in GTCS, juvenile myoclonic, myoclonic, atonic, clonic and tonic seizures.
• It is also effective in Lennox Gestaut syndrome, absence seizures, infantile spasms and partial seizures.
• Other uses of this drug include bipolar disorder, prophylaxis of migraine and as an alternative to
carbamazepine in trigeminal neuralgia.
• Adverse effect of this drug includes weight gain, alopecia, tremors and hepatotoxicity (more in children<3yrs
old).
• Other adverse effects include acute pancreatitis & hyperammonemia.
• It is DOC for absence seizures (petit mal epilepsy) in patients older than 3years.
• Valproate associated with a substantial increase in the incidence of spina bifida in the offspring of women
who took vatproate during pregnancy.

ETHOSUXIMIDE AND TRIMETHADIONE

• Useful only in absence seizures (petit mal epilepsy). Ethosuximide is DOC for this condition in children <
3years
• Characteristic adverse effect of trimethadione is hemarlopia (photophobia and glare effect).

OTHER ANTIEPILEPTIC DRUGS

Vigabatrin
• It is the DOC for infantile spasms (previously ACTH was DOC).
• It can result in irreversible visual field defects due to retinal atrophy.

Lamotrigine: broad spectrum antiepileptic useful for various seizures including absence seizures and myoclonic
epilepsy.
• It is specifically indicated for depressive phase of manic depressive psychosis.
• Steven Johnson syndrome and toxic epidermal necrolysis may be seen.

Gabapentin
• It is useful is GTCS and partial seizures.
• Non epileptic uses include diabetic and post herpetic neuralgia and pain associated with multiple sclerosis.

OTHER DRUGS
• Ganaxolone, neurosteroid: effective for absence seizures, infantile spasms and catamenial epilepsy (seizures
occurring during menstruation).
• Topiramate acts by blocking Na' channels, increasing GABA transmission and inhibiting kainate receptors.
• It is useful is GTCS, partial seizures and Lennox Gestaut syndrome.
 • Zonisamide (another antiepileptic drug) and topiramate can cause renal stones due to their carbonic
anhydrase inhibitory activity.
• Felbamate (analogue of an obsolete anxiolytic drug, meprobamate) is an NMDA blocker useful in drug
resistant epilepsies but its use is limited due to hepatotoxicity and aplastic anemia.
o Limited to intractable epilepsy (e.g. in children with Lennox-Gastaut syndrome).
• Carisbamate, a new drug similar to felbamate that does not cause aplastic anaemia.
• Levetiracetam is another antiepileptic drug useful for partial seizures.
• Magnesium sulphate is DOC for treating the convulsions during labour (eclampsia).
• Tiagabine: indicated for adjunctive treatment of partial seizures. Rationally designed drug -inhibitor of GABA
uptake.
• Lacosamide: used for adjunctive therapy of partial onset seizures. Acts by blocking Na channels & CRMP-2
(Coltapsin- Response Mediator Protein-2).
• Rufinamide: used for adjunctive therapy of seizures associated with Lennox- Gestaut Syndrome. Acts by
blocking Na channels.
• Stiripentol: used with clobazam and valproate in the adjunctive therapy of refractory generalized tonic-clonic
seizures in patients with severe myoclonic epilepsy of infancy (SMEI, Dravet's syndrome).

SELECTION OF ANTI- EPILEPTIC DRUGS

Drug First line of choice in
Ethosuximide Absence seizures in children
Valproate Absence seizures in adults, GTCS, Atypical absence seizures, Myoclonic seizures, Atonic
seizures, Tonic, clonic seizures
Carbamazepine Partial seizures
Vigabatrin Infantile spasms
Diazepam P/R Febrile seizures
Lorazepam IV Status epilepticus
Phenobarbitone Epilepsy in pregnancy
Magnesium sulfate Eclamptic seizures
Clonazepam Seizures in porphyria

• Valproic acid is particularly effective in absence, myoclonic, and atonic seizures and is therefore the drug of
choice in patients with generalized epilepsy syndromes having mixed seizure types.

Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs

Generic Name Principal Uses Systemic Adverse Effects
Phenytoin Tonic-clonic Gum hyperplasia,Lymphadenopathy
(diphenyl- Focal-onset Hirsutism, Osteomalacia, Facial coarsening
hydantoin Skin rash
Carbamazepine Aplastic anemia, Leukopenia,Gastrointestinal
irritation,Hepatotoxicity
Hyponatremia
Valproic acid Tonic-clonic,Absence Hepatotoxicity,Thrombocytopenia
Atypical absence,Myoclonic Gastrointestinal irritation
Focal-onset,Atonic Weight gain,Transient alopecia
Hyperammonemia
Lamotrigine Focal-onset,Tonic-clonic Skin rash
Atypical absence,Myoclonic Stevens-Johnson syndrome
Lennox-Gastaut syndrome
Ethosuximide Absence Gastrointestinal irritation,Skin rash
Bone marrow suppression
Gabapentin Focal-onset Gastrointestinal irritation,Weight gain
Edema
Topiramate Focal-onset Renal stones (avoid use with other carbonic
Tonic-clonic,Lennox-Gastaut anhydrase inhibitors),Glaucoma,Weight
syndrome loss,Hypohidrosis
Tiagabine Focal-onset Gastrointestinal irritation
Phenobarbital Tonic-clonic, Focal-onset Skin rash
Primidone
Clonazepam Absence,Atypical absence Anorexia
Myoclonic
Felbamate Focal-onset Aplastic anemia,Hepatic failure
Lennox-Gastaut syndrome Weight loss, Gastrointestinal irritation
Tonic-clonic
Levetiracetam Focal-onset Anemia,Leukopenia
Zonisamide Focal-onset Anorexia,Renal stones,Hypohidrosis
Oxcarbazepine Tonic-clonic
Lacosamide Focal-onset GI irritation,Cardiac conduction (PR interval
prolongation)
Rufinamide Lennox-Gastaut syndrome GI irritation,Leukopenia
Cardiac conduction (QT interval prolongation)

MANAGEMENT OF STATUS EPILEPTICUS

OPIOIDS
• Serturner in 1803 isolated the pure alkaloid morphine from Papaver somniferum (poppy plant).
• Morphine acts by agonistic activity on μ, K and δ receptors.
• Receptor for opioid system - G protein-coupled orphanin opioid-receptor-like subtype1 (ORL1).
• Its endogenous ligands are nociceptin /orphanin FQ (N/OFQ System).
• Nociceptin: similar to dynorphin but acts only at the ORL1 receptor.

Opioids Natural opioids Morphine, Codeine

Semisynthetic opioids Diacetyl morphine (Heroin), Pholcodeine
 Synthetic opioid Pethidine(Meperidine), Fentanyl, Methadone, Dextropropoxyphene,
Tramadol
Complex Agonist- antagonist Nalorphine, Pentazocine, Dezocine, Meptazinol, Butorphanol
Action opioid Partial/weak μ Buprenorphine
& antagonists agonist + K antagonist
Pure antagonists Naloxone, Naltrexone, Nalmefene

ACTIONS MEDIATED BY OPIOID RECEPTORS

μ (mu)
• Analgesia (supraspinal μ1 +
spinal μ2)
• Respiratory depression (μ2)
• Sedation
• Euphoria
• Miosis
• Muscular rigidity
• Reduced g.i. motility (μ2)
• Physical dependence
• (morphine type)
K (kappa)
• Analgesia (spinal K1)
(supraspinal- K3)
• Respiratory depression (lower
ceiling)
• Dysphoria, psychotomimetic
• Miosis (lower ceiling)
• Sedation
• Physical dependence
(nalorphine type)
• Reduced G.I. motility
δ (delta)
• Analgesia (spinal + affective
component of supraspinal)
• Respiratory depression
• Affective behaviour
• Reinforcing actions
• Reduced G.I. motility
• Proconvulsant

ACTIONS OF OPIOIDS:
CNS actions
• Spinal and supraspinal analgesia
• Respiratory depression & cough
suppression.
• Miosis (pin point pupil is a valuable sign
in diagnosis of opioid poisoning).
Peripheral effects
• Pethidine & pentazocine  increase heart rate (contra
Indicated in MI)
• Fall in BP
• Increase intra biliary pressure, Constipation
• Aggravate broncho constriction by releasing histamine

• Atropine partially prevents morphine-induced biliary spasm, but opioid antagonists prevent or relieve it.
• Nitroglycerin (0.6-1.2 mg) administered sublingually also decreases the elevated intrabiliary pressure.
• Opioids stimulate the release of ADH, prolactin, and somatotropin but inhibit release of LH.
• Morphine in the hypothalamus inhibits the release of most of the hormones except thyrotropin.
• NK cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids.

CLINICAL USES:
• Order of potency (relative to morphine) is: sufentanil (1000x) > remifentanil (300x) > fentanyl (100x) >
alfentanil (15x) > morphine (1x) > meperidine (0.1x).
• Normal adult dosage: Intravenous morphine: 1-3 mg/kg, fentanyl: 100-150μg/kg.
• Most opioids have no significant direct effects on the heart other than bradycardia.
• Exception to this: meperidine- tachycardia.
• Meperidine and its congeners  serotonin syndrome should not be used in patients taking MAO
inhibitors.
• Pentazocine: first agonist antagonist to be used as an analgesic.
• Most potent: Sufentanil
• Least potent: meperidine (pethidine) and propoxyphene.
• Morphine is metabolized to morphine -3- glucuronide (M3G)  accumulation can lead to renal failure.
• Pethidine is metabolized 4meperidinic acid a norpethidine.4 Accumulation can lead to seizures.
• Pethidine: acts on a2 receptors a can reduce shivering after anesthesia.
• Alvimopan: peripheral opioid antagonist  used in paralytic ileus.
• Morphine: myocardial infarction, pre-anesthetic medication, acute pulmonary edema.
• Utricaria d/t morphine & meperidine treatment: mediated by histamine release & won't be reversed by
naloxone.
• Codeine, noscapine: cough suppressant.
• Analgesic effect of codeine is due to its conversion to morphine.
 • Loperamide and diphenoxylate (active metabolite- difenoxin): non-infective diarrhea.
• Buprenorphine: analgesic & in opioid withdrawal.
• Butorphanol: analgesic & sedative. Only opioid available in nasal formulation.
• Meptazinol: partial opioid agonist used in treatment of Jarisch Hexheimer reaction in louse borne relapsing
fever.
• Ziconotide: blocks voltage gated N type Ca channels, approved for intra thecal analgesia.
• Tramadol: weak p agonist also inhibits reuptake of NA & 5-HT, responsible for analgesic actions, which can
be abolished by 5-HT3 antagonists. At high doses, can lead to seizures.
• Tapentadol: newer analgesic with NA reuptake inhibiting a p receptor agonistic action.
• Heroin (diacetylmorphine) is a potent and fast acting opioid but carries high risk of abuse potential.
• The most commonly abused drug among health professionals—meperidine.
• Methadone: Agonist at p receptors, also blocks NMDA receptors & reuptake of monoamines. Have long
t1/2 and high oral parenteral activity ratio & used in opioid abuse.
• Methadone relieves neuropathic & cancer pain that are not relieved by morphine.
• Long acting methadone analog, L-acetylmethadol, used for thrice a week dosing.
• The most frequently employed opioid are fentanyl and its congeners, sufentanil or remifentanil, because
they induce analgesia more rapidly than morphine does, given intravenously, epidurally, or intrathecally.
• Morphine remains the opioid of choice in pain of terminal illness and cancer pain.
• Satisfactory analgesia in cancer patients is associated with a plasma steady-state concentrations of morphine
at 16-364 ng/mL.

PRECAUTIONS FOR MORPHINE USE

• Infants & elderly- risk of respiratory depression.
• Morphine is absolutely contraindicated in head injury.
• Accentuates sleep apnea  sudden death
• Can precipitate bronchial asthma.
• Elderly males: chances of urinary retention
• Hypothyroidism, liver and kidney patients  more sensitive

FENTANYL
• Can be given epidurally, also available as transdermal patch & a transoral mucosa( preparation.
• Analgesic activity is beneficial in Cancer patients.

EFFECTS AND TOXICITY

• Tolerance develops to most of the actions of opioid except miosis, constipation and convulsions.
• Triad of opioid poisoning: coma, pinpoint pupils and depressed respiration.
• Psychological & physical dependence.
• Withdrawal syndrome: rhinorrhoea, lacrimation, yawning, chills, mydriasis, vomiting, diarrhea and anxiety.

Characteristics of Opioid Withdrawal:

Symptoms Signs
Regular withdrawal
Craving for opioids Pupillary dilation
Restlessness, irritability Sweating Piloerection ("gooseflesh")
Increased sensitivity to pain Tachycardia
Nausea, cramps Vomiting, diarrhea
Muscle aches Increased blood pressure
Dysphoric mood Yawning
Insomnia, anxiety Fever
Protracted withdrawal
Anxiety Cyclic changes in weight, pupil size,
Insomnia respiratory center
Drug craving sensitivity

• Naloxone: DOC in acute opioid poisoning & used in neonatal resuscitation

 • Meperidine & Codeine show cross tolerance with morphine & would not be effective in this condition.
• Naltrexone: maintenance drug for opioid addicts. It is also used to decrease craving in chronic alcoholics.
• Recently modified analogs of naloxone and naltrexone:
o Methylnaltrexone bromide for treatment of constipation in patients with late-stage advanced illness.
o Alvimopan for the treatment of postoperative ileus following bowel resection surgery.

TREATMENT OF OPIOID ADDICTION

• To treat withdrawal symptoms: clonidine & beta blockers
• To prevent withdrawal symptoms: methadone
• To prevent relapse: Naltrexone

USES OF NALOXONE
• Morphine poisoning
• Neonatal asphyxia
• To reverse respiratory depression
• Management of opioid induced constipation
• Intra spinal opioid analgesia
• Diagnosis of opioid dependence
• Reverses alcohol intoxication/ prevention of relapse
• Elevate BP in shock

ALCOHOLS

ETHYL ALCOHOL (ETHANOL)

• Local actions: mild rubefacient, astringent & counter irritant
• CNS: neuronal suppressant & sleep inducer
• CVS:
o Mild doses: cutaneous a gastric vasodilation, no effect on BP
o Moderate doses: tachycardia & mild rise in BP
o Large doses: myocardial & vasomotor suppression, fall in BP
• Blood: raise HDL levels & decrease LDL oxidation.
• Chronic alcoholism  megaloblastic anemia
• RS: reflex stimulant but central depressant
• Kidneys: diuresis due to inhibition of ADH secretion. No renal impairment.
• Endocrine effects: increased adrenaline release & hyperglycemia, hypoglycemia in acute intoxication.
• Plasma concentration >300 mg/dl  death.
• Uterus relaxation: was used for the suppression of premature labor in the past.
• Acute intake of large doses: hypotension, hypoglycemia (chronic alcohol consumption: hypertension and
dilated cardiomyopathy).
• M/c hematologic disorder seen in chronic drinkers: mild anemia d/t folic acid deficiency.
• Ethanol is metabolized to acetaldehyde (by alcohol dehydrogenase) and finally acetic acid (by aldehyde
dehydrogenase).
• Disulfiram (antabuse), chlorpropamide, cefoperazone, moxalactam, cefamandole, metronidazole,
griseofulvin etc.) cause inhibition of aldehyde dehydrogenase resulting in accumulation of acetaldehyde.
Acetaldehyde may lead to severe distressing symptoms known as disulfiram like reaction.

TREATMENT OF ALCOHOL DEPENDENCE

• Benzodiazepines (chlordiazepoxide and diazepam): in withdrawal.
• Naltrexone: to reduce alcohol craving.
• Acamprostate (NMDA antagonist): maintenance therapy of alcohol abstinence.
• Disulfiram can be used in psychologically dependent person who are motivated to quit alcohol. It is
contraindicated in physically dependent individuals.
OTHER DRUGS: Topiramate-for treating alcohol dependence & Ondansetron reduces alcohol consumption.

METHYL ALCOHOL (METHANOL)

 • Metabolized to formaldehyde (by alcohol dehydrogenase) and finally to formic acid (by aldehyde
dehydrogenase).
• Accumulation of formic acid may result in lactic acidosis, blindness and death.
• Specific toxicity of formic acid is retinal damage leading to blindness.
• Poisoning can be treated by supportive measures, gastric lavage and sodium bicarbonate (to treat acidosis).
• Methanol concentrations > 50 mg/dL - absolute indication for hemodiatysis and ethanol treatment.
• Formate blood levels are a better indication of clinical pathology.
• A decrease in serum bicarbonate is a uniform feature of severe methanol poisoning.
• Ethanol is useful because it competitively inhibits the conversion of methanol to formic acid.
• Fomepizole: specific inhibitor of alcohol dehydrogenase.

ETHYLENE GLYCOL
• It is used as a solvent and as an anti-freeze in industry.
• At toxic levels, it can cause renal tubular acidosis with excretion of oxalate crystals in the urine.
• DOC: Fomepizole

SEDATIVE HYPNOTIC DRUGS

• Sedative is a drug that calms a person whereas hypnotics induce sleep.

BARBITURATES
• Act by increasing the CI- conductance across GABAA-BZD-CI- channel complex.
• Indications: epilepsy (phenobarbitone) & anesthesia (thiopentone).
• Narrow therapeutic index due to steep dose response curve.
• No specific antidote. Treatment for overdose is gastric lavage & forced alkaline diuresis, hemodialysis.
• Adverse effects: Hangover, distortion of sleep (decreases the duration of REM and stage 3 and 4 sleep and
increasing the duration of stage 2 sleep).
• These are absolutely contraindicated in acute intermittent porphyria.
• Glutethimide (a piperidinedione) and meprobamate (a carbamate) are practically equivalent to barbiturates.

BENZODIAZEPINES
Hypnotic Diazepam, flurazepam, flunitrazepam, temazepam, triazolam, quazepam,midazolam
Anti-convulsants Diazepam, clonazepam, clobazam and lorazepam
Anti-anxiety Diazepam, oxazepam, lorazepam, alprazolam, chlordiazepoxide
Muscle relaxant Diazepam

• Short acting and do not accumulate on repeated administration.

• Bicuculline binds to GABA-A receptor & acts as a competitive inhibitor of GABA & non competitive inhibitor
of benzodiazepines.
• β- carboline is an inverse agonist at benzodiazepine site  convulsions
• BZD's have flat dose response curve, causes less hangover & less distortion of sleep architecture.
• Can be safely administered in liver disease.
• Estazolam, lorazepam, oxazepam, temazepam & triazolam are directly conjugated to active products.
• Midazolam produces minimal venous irritation & is the BZD most frequently used in the perioperative
period.
• Oral midazolam is useful for sedation of young children.
• Short acting drugs are Triazolam, Temazepam, Oxazepam, Lorazepam and Estrazolam (STOLE).
• Triazolobenzodiazepines: triazolam and alprazolam.
• Flunitrazepam is tasteless  used as a date rape drug (cause dose dependent amnesia).
• Recent drug used for "date rape"- gamma-hydroxybutyric acid (GHB).
• Drugs with short half life are used in sleep onset insomnia whereas long acting drugs are used in anxiety.
• Benzodiazepine Antagonist: Flumazenil: administered i.v. for the treatment of BZD poisoning (specific
antidote), also inhibits the action of β-carboline.

NEWER HYPNOTIC DRUGS

Zopiclone: stimulates GABAA receptors prolongs stage 3 and 4 sleep and does not affect REM sleep.
Zolpidem:
• It binds selectively to α1 subtype of benzodiazepine receptors and increases GABA mediated neuronal
inhibition.
• Abuse potential of zolpidem is very low. It is also indicated for the short term treatment of insomnia.

Zaleplon:
• Acts by selectively binding to α1 subtype of benzodiazepine receptors.
• It decrease sleep latency without affecting total sleep time or sleep architecture (therefore useful in persons
having difficulty to fall asleep).
• Withdrawal symptoms are minimal with zolpidem and zaleplon.

Effect of BZDs & older sedative-hypnotics on patterns of normal sleep:

• Latency of sleep onset is decreased (time to fall asleep).
• Duration of stage 2 NREM sleep is increased.
• Duration of REM sleep is decreased.
• Duration of stage 4 NREM slow-wave sleep is decreased.

MELATONIN
• It increases the sleep during night but has no effect on latency or duration of sleep.
• It is used to reduce symptoms of jet lag.
• Ramelteon: agonist of MT1 & MT2 receptors of melatonin in Suprachiasmatic nucleus. Approved for long
term use in treatment of sleep onset insomnia.
• Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due
to extensive first-pass metabolism.
• Common adverse effects: dizziness, fatigue, somnolence & increase prolactin levels.
• Agomelatine, which has agonist actions at MT1 and MT2 receptors as well as antagonist actions at 5-HT2c
receptors, is a novel antidepressant drug.
• Sedative autonomic drugs: hydroxyzine, promethazine.
• Mandrax: Hypnotic + antihistaminic.

TREATMENT OF NEURODEGENERATIVE DISEASES

TREATMENT OF PARKINSONISM
DRUGS INCREASING BRAIN DOPAMINERGIC ACTIVITY:
Dopamine precursors: Levo-dopa
• Metabolized by dopa decarboxylase (contains pyridoxine as co-factor) to dopamine.
• Levo-dopa is always given in combination with peripheral dopadecarboxylase inhibitors like carbidopa or
benserazide.
• Co-careldopa/ Sinemet: preparation containing carbidopa & levodopa in fixed proportion (1:10 or 1:4).
• A drug holiday (for 3-21 days) may alleviate some of the neurologic and behavioral adverse effects of
levodopa.
• Levodopa is contraindicated in psychotic patients, angle-closure glaucoma, history of melanoma or with
suspicious undiagnosed skin lesions

Adverse effects:
• Nausea and vomiting. (Domperidone but not Metoclopramide can be used for the treatment of this
vomiting).
• Wearing off effect and on-off phenomenon: 'On' means patient is having no symptoms and "Off" means
patients has full blown symptoms
• Abnormal choreiform movements.
• Hallucinations, vivid dreams, sleep disturbance & mydriasis (Contra indicated in angle closure glaucoma).
• Pyridoxine decreases the effectiveness of Levo-dopa.

DRUGS INHIBITING METABOLISM OF DOPAMINE:

 • Dopamine is metabolized by MAO and COMT (catechol-o-methyl transferase).
• COMT inhibitors: Tolcapone (periphery & brain) and entacapone (only in the periphery).
• Adverse effects of tolcapone: diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, orange
discoloration of the urine.
• Tolcapone  increase in liver enzyme levels  death from acute hepatic failure.

MAO-A: located in the syncytiotrophoblast layer of term placenta and liver.

MAO-B: located in platelets, osteocytes around blood vessels, lymphocytes and liver.
In brain: MAO-A is highest in the locus ceruleus; MAO-B is prominent in the nucleus raphe dorsalis, filial cells &
posterior hypothalamus.

MAO-B Inhibitors: Selegiline and rasagiline

• At normal doses selegiline inhibits only MAO-B and thus has no interaction with cheese or tricyclic
antidepressants.
• Selegiline (metabolite -desmethylselegiline) may cause insomnia when taken tater during the day.
• Contraindicated with meperidine, TCAs & SSRI because of the risk of acute toxic interactions.
• At high doses, it also inhibits MAO-A & leads to hypertensive crisis (cheese reaction) with tyramine
containing foods and serotonin syndrome with TCAs.
• Both selegiline and rasagiline incorporate a propargyl ring that provides antiapoptotic effects.
• Rasagiline is more potent than selegiline and used as a neuroprotective agent in MPTP-induced
Parkinsonism.

DOPAMINE AGONISTS
• Directly activate D2 receptors.
• Bromocriptine, pergolide and cabergoline: short acting, can cause digital vasospasm (leading to gangrene)
and erythromelalgia.
• Pramipexole (D3 agonist) & ropinirole (D2 receptor): long acting and do not cause gangrene.
• These are now the first choice drugs for Parkinsonism in young patients. (Preferred over levodopa).
• Can cause excessive day time Somnolescence.
• Rotigotine: dopamine agonist, given as a dermal patch, discontinued d/t crystal formation.
• Apomorphine: given as s.c.., for temporary relief of off-periods.Highly nauseating drug.

DRUGS INCREASING DOPAMINE LEVELS AT SYNAPSE:

Amantadine
• Possesses anticholinergic and antiglutaminergic activity.
• Adverse effects of these drugs include nausea, insomnia, ankle edema and livido reticularis.

DRUGS INHIBITING BRAIN CHOLINERGIC TRANSMISSION

• Central anticholinergic drugs like trihexiphenidyl (benzhexol), procyclidine, benztropine, orphenadrine and
biperidin: DOC in drug induced Parkinsonism. Other drugs used for this indication: first generation anti-
histaminics with high anti muscarinic activity like promethazine a diphenhydramine.
• D2 receptors blockers in the brain  Parkinsonism (like antipsychotics, Metoclopramide etc.)

Note: Drugs-Inducing Parkinsonism - Reserpine, tetrabenazine, haloperidol, 1-methyl-4-phenyl 1,2,3,6

etrahydropyridine (MPTP) and phenothiazines.

TREATMENT OF OTHER NEURO-DEGENERATIVE DISEASES

Alzheimer's disease Anticholinesterases (Donepezil, rivastigmine and galantamine), Tacrine -more
hepatotoxic.
Acetyl-l-carnitine: antioxidant & increases cholinergic transmission (slows the
progression)
Memantine: NMDA antagonist that slows down the progression
Huntington's chorea D2 blockers like chlorpromazine, haloperidol as well as Olanzapine.
Tetrabenazine(dopamine depleter) & reserpine
 Amyotrophic lateral Riluzole (NMDA antagonist); Idrocilamide -inhibition of glutamatergic transmission in
slerosis CNS.
Multiple sclerosis Frequency of relapse can be decreased by: beta-interferon or glatiramer
Spasticity can be decreased by: baclofen or tizanidine
Monoclonal antibody: natalizumab (A.E: progressive multifocal leuco encephalopathy)
Fingolimod: sphingosine-1 phosphate receptor modulator- used in relapsing forms of MS
Dalfampridine: oral K channel Mocker, improves walking in patients with MS.
Wilson's disease D-Penicillamine, Trientine, Zinc sulphate and potassium sulfide

RESTLESS LEG SYNDROME

• The four core symptoms for diagnosis:
o An urge to move the legs, usually caused or accompanied by an unpleasant sensation in the
o legs;
o Symptoms begin or worsen with rest;
o Partial or complete relief by movement;
o Worsening during the evening or night.
• In 80% of patients, RLS is associated with periodic leg movements (PLMs)
• Involuntary movements are brief, lasting no more than a few seconds, and recur every 5-90 seconds.
• Primary RLS is genetic, with an autosomal dominant pattern of inheritance.
• The mean age of onset in genetic forms is 27 years.
• Secondary RLS may be associated with pregnancy or a range of underlying disorders, including
• anemia, ferritin deficiency, renal failure, and peripheral neuropathy.
• The pathogenesis probably involves disordered dopamine function.
• General measures to improve sleep hygiene and quality should be attempted first.
• Low doses of dopamine agonists, e.g., pramipexole (0.25-0.5 mg) and ropinirole (1-2 mg), are given 1-2
hours before bedtime.
• Other drugs: Levodopa, Rotigotine, pergolide, Benzodiazepines, carbamazepine and gabapentin.

IMPORTANT FACTS:
• Brain cells couple arachidonic acid with ethanolamine to form anandamide, which has cannabinoid action.
• Principal endocannabinoid synthesized in brain: anandamide
• Treatment of apnoea in new born when morphine is given to mother during labour: Naloxone -10 μg/ kg via
umbilical cord.
• Lethal dose of morphine: 250mg.
• β-funaltrexamineis a selective but irreversible p antagonist.
• Norbinaltorphimine: selective K antagonist.
• Naltrindole: selective δ antagonist.
• K3 receptors mediate lower ceiling supraspinal analgesia.
• Blindness caused by methanol is due to its oxidative products.
• Drug that increases suicide behavior: Reserpine, an adrenergic neuron blocker (decreases brain serotonin
levels).

DRUGS AFFECTING THE GABAA RECEPTOR GATED CHLORIDE CHANNE

GABA Endogenous agonist
Muscimol Agonist at the receptor
Bicuculline Competitive antagonist at GABAA receptors
Picrotoxin Blocks chloride channel noncompetitively
Barbiturate Agonist at allosteric site, prolong opening of chloride channel
Alcohol, inhalational anesthetics, propofol Direct chloride channel opening
Benzodiapines Agonist at allosteric BZP site, increase frequency of chloride
channel opening
Beta carboline Inverse agonist at BZP site
Flumazenil Competitive antagonist at BZP site
 VIII. RESPIRATORY SYSTEM

DRUGS FOR COUGH

• Pharyngeal demulcents: Lozenges, cough drops, linctuses containing syrup, glycerine, and liquorice.
• Expectorants (Mucokinetics)
o Bronchial secretion enhancers: Sodium or Potassium citrate, Potassium iodide, Guaiphenesin, balsum of
Tolu, ammonium chloride.
o Mucolytics: Bromhexine, Ambroxol, Acetyl cysteine, Carbocisteine.
• Antitussives (Cough centre suppressants)
o Opioids Codeine, Pholcodeine.
o Nonopioids Noscapine, Dextromethorphan, Chlophedianol.
o Antihistamines Chlorpheniramine, Diphenhydramine, Promethazine.
• Adjuvant antitussives: Bronchodilators-Salbutamol, Terbutalin.

Expectorants
• Potassium iodide acts directly (by irritating
bronchial glands) & indirectly (by gastric
irritation) to increase bronchial secretion.
• Bromhexine, acetyl cysteine & Ambroxol
(metabolite of bromhexine) makes the mucus
less viscid (mucolytic).
Anti-tussives
• Cough suppressants, either by acting directly in
the CNS or by inhibiting cough impulse. These
drugs should be used only for dry (non
productive) cough.
• Anti tussives include codeine, pholcodeine,
noscapine, chlophedianol and
dextromethorphan.

MANAGEMENT OF BRONCHIAL ASTHMA

• Drugs mostly used are B agonists ("relievers" or bronchodilators) and inhaled corticosteroids ("controllers"
or anti-inflammatory agents).

Treatment of acute attack of bronchial asthma(bronchodilators)

Sympathomimetics Parasympatholytics Methyl xanthines
• Fastest acting drugs by inhalational • Less efficacious and slower • Includes caffeine,
route. acting bronchodilators Aminophylline,
• Adrenaline, isoprenaline and • More effective for COPD theophylline and
ephedrine. than bronchial asthma theobromine.
• Selective β2 agonists (Salbutamol • Ipratropium and • Act by blockade of
(albuterol), metaproterenol, tiotropium are adenosine receptors and by
pirbuterol and terbutaline) are used anticholinergic drugs inhibiting
for aborting an attack of acute (selective m3 antagonists) phosphodiesterase
asthma. that can be used by • Caffeine causes
• Not suitable for prophylaxis because inhalational route vasoconstriction of cranial
of shorter duration of action. • Bronchodilators of choice vessels (so useful in
• Salmeterol, bambuterol and in patients of bronchial migraine).
formoterol are long acting B2 asthma on β blocker • Theophylline can be used to
selective agonists. therapy reduce the frequency of
• Sitosterol: prodrug activated to form apnea in premature infants
colterot by lung esterases.

• Tiotropium bromide (M1 and M3) has a longer duration of action with lower affinity for M2 receptors.
• Adrenergic drugs cause bronchodilatation through β2 receptor stimulation.
• Roflumilast,has recently been approved by the FDA as a treatment for COPD, though not for asthma.

THEOPHYLLINE
• Obesity and prematurity are associated with reduced rates of elimination.
• Tobacco smoking enhances theophylline clearance by inducing hepatic P450 enzymes.
 • Enzyme inhibition by erythromycin, cimetidine, ciprofloxacin, allopurinol or oral contraceptives, Hepatic
cirrhosis, congestive heart failureincreases the plasma concentration of theophylline.
• Enzyme inducers such as carbamazepine, barbiturates, phenytoin and rifampicin reduce the concentration.
• Theophylline activates histone deacetylases in the nucleus  anti-inflammatory action.

DRUGS INHIBITING IgE ACTION

• Omalizumab- a monoclonal antibody against IgE to prevent the attack.

MAST CELL STABILIZERS: (Sodium cromoglycate and nedocromil)

• Indicated only for prophylaxis of bronchial asthma. These are given by inhalational route.
• Cromolyn solution is also useful in reducing symptoms of allergic rhinoconjunctivitis.
• Ketotifen has additional antihistaminic action, specially indicated for patients with multiple disorders (atopic
dermatitis, perennial rhinitis, conjunctivitis etc.).

DRUGS DECREASING THE ACTION OF LEUKOTRIENES

Corticosteroids
• These are potent anti inflammatory drugs and also decrease bronchial hyper reactivity and mucosal edema.
• Used in severe chronic asthma and in status asthmaticus.
• These are not bronchodilators but increase the sensitivity to β2 agonists.
• Inhaled steroids include beclomethasone, budesonide, fluticasone, flunisolide and triamcinolone.
• Hoarseness of voice and oro pharyngeal candidiasis is very common adverse effects.
• Ciclesonide: inhaled steroid metabolized in the lungs.

Lipo-oxygenase inhibitors (Zileuton)

Inhibits synthesis of LTB4 (chemotactic) and LTC4 & LTD4 (bronchoconstrictor). Short acting & more hepatotoxic.

LT receptor antagonists (Montelukast and Zafirlukast)

• They competitively antagonize cysLT1 receptor mediated bronchoconstriction.
• Used as prophylactic agents for bronchial asthma.
• May be associated with churg Strauss syndrome (vasculitis with eosinophilia).

DRUGS USED FOR ACUTE ASTHMA

• Inhaled beta 2 agonists
• Subcutaneous beta 2 agonists - adrenaline, terbutaline
• Inhaled anticholinergics - ipratropium
• Aminophylline - loading dose 5-6 mg/kg and maintenance 1mg/kg/hr
• Prednisolone (oral)
• Hydrocortisone - 10mg/kg bolus IV followed by 5mg/kg/6th hrly
• Methyl prednisolone 4mg/kg single dose
• MgSO4

Note:
• Salmeterol is a long acting beta agonist. It is used for maintenance therapy.
• Only short acting inhaled beta agonists and inhaled anticholinergic drugs are used for acute exacerbation of
asthma treatment.
• Early initiation of oral steroids reduces the duration and severity of asthma episodes.
• Mandel's paint: (1.25% iodine dissolved with the help of Pot. iodide forming soluble ions) is applied on sore
throat

ANALEPTICS (RESPIRATORY STIMULANTS) -Doxapram & Prethcamfde

• Drugs which stimulate respiration in sub convulsive doses.
• Margin of safety is narrow.
• Acts by promoting excitation of central neurons, more selective for the respiratory centre.
• Respiration is also stimulated through carotid and aortic body chemo receptors.
 IX. DRUGS ACTING ON GASTRO INTESTINAL TRACT

TREATMENT OF PEPTIC ULCER DISEASE

ANTACIDS : (Immediate relief from ulcer pain)

• Sodium bicarbonate is rapidly acting systemic antacid, not indicated for long term use because of its toxicity.
• Aluminium hydroxide, magnesium trisilicate, megaldrate and magnesium hydroxide are non systematic
antacids.
• These are slower but longer acting drugs. Rebound acidity does not occur.
• Aluminium salts causes constipation whereas magnesium salts are responsible for diarrhea.
• Simethicone: inert anti-foaming agent. It reduces gastric flatulence, can also be used to prevent bed sores.

DRUGS DECREASING ACID SECRETION

Proton pump inhibitors (PPIs)
• Prodrugs (active moiety is sulfenamide) acting by irreversible inhibition of H+K+ATPase in parietal cells.
• Omeprazole, pantoprazole, esomeprazole, lansoprazole and rabeprazole.
• Given orally in early morning empty stomach (just before breakfast).
• Pantoprazole, lansoprazole & Esomeprazole are given i.v. lansoprazole is the most potent & safe in
pregnancy.
• These drugs have short tla but can inhibit acid secretion for more than 24 hours (hit and run drugs).
• Prolonged PPI usage can lead to:
o Subnormal B12 levels
o Increased risk of hip fracture in older women(Due to decreased Ca absorption).
o Increased risk of both community- acquired respiratory infections and nosocomial pneumonia among
patients taking proton pump inhibitors.
o There is a 2- to 3-fold increased risk for hospital- and communityacquired Clostridium difficile infection.
• Tenatoprazole is a PPI containing an imidazopyridine ring instead of a benzimidazole ring, which promotes
irreversible proton pump inhibition.
o This agent has a longer half-life than the other PPIs and may be beneficial for inhibiting nocturnal acid
secretion, which has significant relevance in GERD.
• Potassium-competitive acid pump antagonists (P-CABs): inhibit gastric acid secretion via potassium
competitive binding of the H+ K+-ATPase.
• PPIs are the drugs of choice for: Peptic ulcer disease (PUD) due to any etiology (even NSAID induced),
esophagitis, Gastroesophageal reflux disease (GERD) & Zollinger Ellison Syndrome (ZES).

H2 receptor antagonists
• These drugs competitively inhibit H2 receptors in parietal cells, thus inhibiting the acid secretion.
• DOC for stress induced GI bleeding.
• Cimetidine, ranitidine, famotidine, roxatidine, nizatidine and loxatidine (non competitive blocker).
• These drugs can be used for GERD, PUD, ZES and prevention of stress induced ulcers.
• Famotidine is most potent I-H2 blocker
• Nizatidine: has anti-AChE activity, can cause bradycardia & enhances GI emptying.
• H2 blockers produce rapid andmarked pain relief (within 2.3 days); 85% ulcers heal at 4 weeks and 70-95%
ulcers at 8 weeks.
• Cimetidine is not used routinely because it causes:
o Impotence in males, mental changes
o Gynecomastia and galactorrhoea.
o Inhibits CYP enzyme and increase plasma concentration of warfarin, theophylline etc...
o It is the least potent H2 blocker.

Anticholinergics
• Non-selective anti-muscarinic drugs like propantheline and oxyphenonium decreases gastric acid secretion.
• Pirenzepine and telenzepine are selective M1 blockers that are preferred antimuscarinic agents.
DRUGS INCREASING PROTECTIVE FACTORS
• PGE1, PGE2 and PGI2: increases mucus and bicarbonate release & increases the mucosal blood flow.
• PGs also inhibit H+ K+ ATPase and decrease the acid production.
• Misoprostol (PGE1 analogue) is the most specific drug for treatment and prevention of NSAID induced
peptic ulcer (DOC is PPI). Enprostil and rioprostil (PGE2 analogue) are other drugs in this group.
• Commonest side effect: diarrhea & colicky abdominal pain.

ULCER PROTECTIVE AGENTS

Forms a covering over the ulcer bed that prevents its exposure to gastric acid.
Sucralfate:
• It is aluminium salt of sulfated sucrose.
• At pH below 4, its molecules polymerize to form a sticky layer that covers the ulcer base and acts physical
barrier to prevent acid exposure.
• It can bind phosphates also and can result in hypophosphatemia.
• It should not be given with antacids because it acts only in acidic medium (antacids raise the pH
neutralizing the gastric acid).
• Milk alkali syndrome (hypercalcemia, renal insufficiency & metabolic alkalosis) may be caused by excessive
doses of Na2CO3 or CaCO3 (milk).

Colloidal bismuth subcitrate:

• It also forms an acid resistance coating over the ulcer.
• It also dislodges H.pylori from the surface of gastric mucosa and kills it.
• Adverse effects include blackening of tongue and bismuth toxicity (osteodystrophy and encephalopathy).

Rebamipide & ecabet: cytoprotective drugs acting by increasing PG synthesis & by scavenging free radicals.

ULCER HEALING DRUGS

• Carbenoloxone is obtained from the roots of liquorice.
• It causes epithelialization of ulcer without decreasing acid production.

ANTIHELICOBACTER PYLORI DRUGS

• Metronidazole/tinidazole
• Amoxicillin
• Clarithromycin
• Tetracycline
• Colloidal bismuth subcitrate
• Omeprazole/ Lansoprazole

NOTE:
• These are used as three drug combination (triple therapy) for 2 weeks (one week regimen is less effective).
• US-FDA approved regimen is lansoprazole (30 mg) + amoxicillin (1000 mg) + clarithromycin (500 mg) for 2
weeks.
• Triple therapy 14 days: [Proton pump inhibitor + clarithromycin 500 mg + (metronidazole 500 mg or
amoxicillin 1 g)] twice a day. (Tetracycline 500 mg can be substituted for amoxicillin or metronidazole.)
• Quadruple therapy 14 days: Proton pump inhibitor twice a day + metronidazole 500 mg three times daily +
(bismuth subsalicylate 525 mg + tetracycline 500 mg four times daily) or H2 receptor antagonist twice a day
+ (bismuth subsalicylate 525 mg + metronidazole 250 mg + tetracycline 500 mg) four times daily

Recommended Treatment Regimens for Helicobacter pylori

First-Line Treatment
Regimen 1: OCA (7-14 days) Regimen 2: OCM ((7-14 days)
 • Omeprazote (20 mg bid) • Omeprazole (20 mg bid)
• Clarithromycin (500 mg bid) • Clarithromycin (500 mg bid)
• Amoxiciain (1 g bid) • Metronidazole (500 mg bid)
Second - Line Treatment: Regimen 3: OBTM (14 days)
• Omeprazole (20 mg bid)
• Bismuth subsalicylate (2 tabs qid)
• Tetracycline HCI (500 mg qid)
• Metronidazole (500 mg tid)

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Drugs used for increasing the GI motility are known as prokinetic drugs.
These drugs can also be used for the treatment of gastroparesis, post operative paralytic ileus and -constipation.

Metoclopramide (Central & peripheral D2 blocker, agonist on 5HT4 & antagonist at 5HT3)
Central D2 blocking is responsible for its antiemetic effects. Increases gastric emptying and LES tone.
• Mainly used as an antiemetic agent & to enhance gastric emptying for emergency general anesthesia.
• D2 blockage leads to extra pyramidal side effects (muscle dystonia, Parkinsonism etc.) and
Hyperprotactinemia. Latter may lead to gynecomastia (in males) and galactorrhoea (in females).

Domperidone
• D2 receptor antagonist.
• Antiemetic (less efficacious than metoclopramide) & devoid of extrapyramidal/hyperprolactinemic adverse
effects.
• It decreases I-dopa induced vomiting without interfering with its efficacy.

5HT4 Agonists
Cisapride, mosapride, renzapride, prucalopride and tegaserod are 5-HT4 agonistic drugs with no action on D2
receptors (no antiemetic property). These drugs increase whole GI motility including colon.
• Cisapride has been withdrawn due to its QT prolonging action. It is metabolized by CYP 3A4.
• Mosapride and renzapride do not prolong QT interval.
• Tegaserod can be used for irritable bowel syndrome.

Other Prokinetic Drugs

• Levosulpiride is a newer D2 blocker having prokinetic activity.
• Loxiglumide is a CCK1 receptor antagonist.

EMETICS
These are drugs used to evoke vomiting.
• Act on CTZ : Apomorphine
• Act reflexly and on CTZ : Ipecacuanha

Apomorphine:
• A semisynthetic derivative of morphine.
• Acts as a dopaminergic agonist on the CTZ.
• Injected i.m./s.c. in a dose of 6 mg, it promptly (within 5 min) induces vomiting.
• It should not be used if respiration is depressed, as it has inherent respiratory and CNS depressant actions.
• Oral use of apomorphine is not recommended because the emetic dose is larger, slow to act and rather
inconsistent in action.
• Apomorphine has a therapeutic effect in Parkinsonism, but is not used due to side effects.
• Profound hypotension and loss of consciousness occurs when apomorphine is administered with
ondansetron, hence the combination is contraindicated.

ANTI EMETIC DRUGS

 • Drugs for motion sickness: Hyoscine. Antihistaminics like Promethazine, Diphenhydramine, Cyctizine or
Meclizine can also be used for prophylaxis.
• Cinnarizine (antihistaminic with anticholinergic & anti serotonergic drugs) is used treatment of vertigo.
• Combination of doxylamine (antihistaminic) with pyridoxine (Vit B6): safest anti-emetic drug in pregnancy
• Chemotherapy & radiotherapy Induced vomiting: 5HT3 blockers like ondansetron, granisetron,
palonosetron, ramosetron and dolasetron are DOC.
• Alosetron is a highly potent and specific antagonist of the 5-HT3 receptor.
• Vomiting due to cisplatin (most emetogenic anti cancer drug) can occur within 24 hours or it may be delayed
(after 2 days). DOC for the former condition is 5HT3 blocker whereas for the latter condition, DOC is
aprepitant (substance P antagonist).
• Fosaprepitant- IV prodrug of aprepitant_
• Aprepitant is a highly selective NK-1 receptor antagonist, orally active & enter the brain.
• Cannabinoids: Dronabinol & nabilone: possess anti-emetic activities by stimulating CB-1 receptors. Used in
cancer chemotherapy and to stimulate appetite in AIDS patients. It also reduces intraocular pressure in
glaucoma.
• Post Operative Vomiting: 5HT3 antagonists are preferred over other drugs.

LAXATIVES
CLASSIFICATION AND COMPARISON OF REPRESENTATIVE LAXATIVES
Class Example Effect & latency
Bulk forming laxative (increasing Bran, Psyllium preparations Softening of Feces 1-3
stool bulk and transit) Methylcellulose Days
Calcium polycarbophil
Hyperosmolar agents Polyethylene glycols (PEGs) Soft or Semifluid Stool
(osmotically drawing water into the Sorbitol, Lactulose, Mannitol 24-48 hours
lumen)
Stimulant / irritant laxatives (direct Diphenylmethane derivatives (Bisacodyl, Soft or Semifluid Stool 6-
effects on enterocytes, enteric Sodium picosulfate) 8 Hours
neurons, & GI smooth muscle by Anthraquinone derivatives (Senna, Cascara
inducing low-grade inflammation) sagrada) Castor oil, Diphenyl methane
derivatives
Saline / Osmotic laxative (osmotically Sodium phosphates Watery Evacuation 1-3
mediated water retention, which then Magnesium sulfate Hours
stimulates peristalsis) Milk of magnesia (Mg hydroxide)
Magnesium citrate, Polyethylene glycol-
electrolyte preparations
Surfactant laxatives/emollients Docusates, Poloxamers Softening of Feces 1-3
(lower the surface tension of the Lactulose, Sorbitol, Mineral oil days
stool)
Chloride channel activator Lubiprostone

• The usual oral daily dose of bisacodyl is 10-15 mg for adults and 5-10 mg for children 6-12 years old.
• The drug requires hydrolysis by endogenous esterases in the bowel for activation, and so the laxative effects
after an oral dose usually are not produced in <6 hours; taken at bedtime, it will produce its effect the next
morning.
• Suppositories work within 30-60 minutes.
• Due to the possibility of developing an atonic nonfunctioning colon, bisacodyl should not be used for more
than 10 consecutive days.
• Laxatives containing magnesium cations or phosphate anions commonly are called saline laxatives.
• Magnesium-containing laxatives may stimulate the release of Cholecystokinin, which leads to intraluminal
fluid and electrolyte accumulation and to increased intestinal motility.
• For every additional mEq of Mg in the intestinal lumen, fecal weight increases by -7 g.
 TREATMENT OF INFLAMMATORY BOWEL DISEASE
Aminosalicylates
• 5-aminosalicylic acid (formulations known as mesalamine): acts topically in the colon.
• Sulfasalazine (5-ASA + sulphapyridine), olsalazine (5-ASA+5-ASA) and balsalazide (5-ASA+ amino benzoyl
Alanine) are effective for the treatment of ulcerative colitis.
• 5-ASA is the first line treatment for mild ulcerative colitis.

Glucocorticoids
Prednisone, hydrocortisone, prednisolone and budesonide: in moderate to severe ulcerative colitis and Crohn's
disease.

Purine analogs
• Azathioprine and 6-MP: maintenance for remission of ulcerative colitis and Crohn's disease.
Methotrexate: induction and maintenance of remission of Crohn's disease but not ulcerative colitis.
Anti TNF α therapy: Infliximab, adalimumab and certolizumab are useful in Crohn's disease.
Natalizumab: targeted against α-4 subunit of integrins. Should not be used with other immunosuppressants due to
the risk of progressive multifocal leukoencephalopathy.

DRUGS FOR IRRITABLE BOWEL SYNDROME:

DIARRHEA DOMINANT IBS CONSTIPATION DOMINANT IBS
Loperamide, Diphenoxylate Clonidine Tegaserod, prucalopride: : 5-HT4 agonist
Fedotozine: K opioid receptor antagonist Loxiglumide
Mebeverine: reserpine analog Lubiprostone
Alosteron: 5-HT3 antagonist

• Racecadrotil: converted to thiorphan, an enkephalinase inhibitor with anti diarrheal effect.

• Clonidine: used in diabetics with chronic diarrhea.
• Hexahydrosiladifenidol: selective M3 inhibitor.

DRUGS FOR DIARRHEA

Class Drug Use
Absorbants Ispaghula, Psyllium, Methyl Irritable bowel syndrome (IBS),
cellulose Ileostomy/colostomy diarrhea
Anti-secretory Sulfasalazine, Mesalazine ulcerative colitis & other IBD's
Bismuth subsalicylate, Traveller's diarrhea
Octreotide carcinoid, VIP secreting tumour, diarrhea in AIDS
Atropine Nervous, drug induced diarrhea
Racecadotril Acute secretory diarrhea
Anti-motility Codeine, Diphenoxylate-atropine, Noninfective or mild travellers' diarrhoea;
(opioids) also loperamide Idiopathic diarrhoea in AIDS
anti- secretory After anal surgery, colostomy

Non-diarrhoeal uses of ORT:

• Postsurgical, postburn and post-trauma maintenance of hydration and nutrition (in place of i.v. infusion).
• Heat stroke.
• During changeover from parenteral to enteral elimentation.

Super ORS
• In addition to rehydrating may lead to decrease in purging rates and improvement in diarrhoea by enhanced
absorption.
• Improvement in ORS by adding certain actively transported amino acids (alanine, glycine which cotransport
Na+ ) has been tried.
• Their efficacy is marginal, and not extended to noncholera diarrhoea; cost-effectiveness may not be
favourable.
INDICATIONS FOR USE OF MAGNESIUM
• Replacement therapy for hypomagnesemia.
• First-line antiarrhythmic agent for torsades de pointes in cardiac arrest and for managing quinidine-induced
arrhythmias.
• As a bronchodilator after beta-agonist and anticholinergic agents have been tried.
• It is commonly administered via the intravenous route for the management of severe asthma attacks.
• Magnesium sulfate can be used to treat eclampsia in pregnant women.
• Magnesium sulfate can also delay labor (tocolysis).
• Intravenous magnesium sulfate prevents cerebral palsy in preterm babies.
• Magnesium sulfate is administered intravenously as a bolus and as an infusion due to its inhibition of skeletal
muscle contraction and vasodilatory properties for the management of Chironex fieckeri or Box Jellyfish
envenomation that is unresponsive to antivenom therapy, or for treatment of Irukandji syndrome.
• Solutions of sulfate salts such as Epsom salt may be given as first aid for barium chloride poisoning.
 X. ANTI-BACTERIAL AGENTS

CDK (concentration Killing effect of a drug is high when ratio Aminoglycosides,

dependent killing) of peak concentration to MIC is more. Fluoroquinolones
TDK (time dependent Killing effect of a drug depends on the Beta lactams macrolides
killing) length of time the concentration remains Glycopeptides.
above MIC
PAE (Post Antibiotic Signifies the inhibitory effect of antibiotics Aminoglycosides,
effect) even when their concentration is below Fluoroquinolones
MIC Beta lactams

CLASSIFICATION OF ANTIBIOTICS ACCORDING TO ITS MECHANISM OF ACTION:

Bacteriostatic Protein synthesis Tetracyclines (bind to 30S ribosomes, inhibit aminoacyl-tRNA)

inhibitors Chloramphenicol(bind to 50S ribosomes, inhibit peptidyl transferase)
Macrolides & Lincosamides (bind to 30S ribosomes, inhibit
translocation of peptide chain)
Linezolid: binds to 23S fraction of 50S ribosomes
Drug affecting DNA Nitrofurantoin, Novobiocin
Drug affecting Sulfonamides ,Trimethoprim , Ethambutol
metabolism
Bactericidal Protein synthesis Aminoglycosides (bind to 30S & 505 ribosomes, misreading of mRNA),
inhibitors Streptogramins
Polypeptide antibiotics Polymyxin B, Colistin, Amphotericin B
Drug affecting DNA Quinolones (DNA gyrase inhibitor), metronidazole
Cell wall synthesis Fosfomycin, Cycloserine, Bacitracin, Vancomycin, Penicillins,
inhibitors Cephalosporins
First line ATT Drugs Rifampicin, Isoniazid, Pyrazinamide, Streptomycin
(except Ethambutol)

FACTORS AFFECTING THE CHOICE OF AN ANTIMICROBIAL AGENT

Age
• Chloramphenicol in new born may cause grey baby syndrome (decreased RBC's, cyanosis & cardiac collapse).
• Sulfonamides in new born cause kernicterus.
• Half life of aminoglycosides is prolonged in the elderly.
• Tetracyclines are contra-indicated in children < 8 years as it accumulates in the developing teeth and bone.
Pregnancy: Penicillins, most cephalosporins and erythromycin appear safe.
Impaired host defenses: Bactericidal drugs are must in immuno compromised patient.
Genetics factors: Antimicrobials producing hemolysis in glucose-6-phosphate dehydrogenase (G-6PD) deficient
patients are primaquine, chloramphenicol, nitrofurantoin, fluoroquinolones and sulfonamides etc.

Renal disease Liver disease

Contra indicated drugs Dose reduction done Contra indicated Dose reduction to be done
Cephalothin, Cephaloridine Aminoglycosides Erythromycin estolate Chloramphenicol
Nitrofurantoin, Nalidixic acid Amphotericin B Tetracyclines Isoniazid
Tetracyclines (except doxycycline) Vancomycin Pyrazinamide Rifampicin
Ethambutol Pefloxacin Clindamycin
• Penicillins and rifampicin do not require dose adjustment in renal disease

IMPORTANT MECHANISMS OF DRUG RESISTANCE:

GROUPS MECHANISM OF RESISTANCE
Beta lactams Inactivating enzyme (beta lactamase)
Tetracyclines Efflux pump (decreased concentration in the cell)
Chloramphenicol Inactivating enzyme (acetyl transferase)
 Fluoroquinolones Altered DNA gyrase with reduced affinity
Sulfonamides For large amount of PABA, Decreased activity of folate synthase
Aminoglycosides Inactivating enzyme
Macrolides Decreased permeability or efflux pumps

• Transfer of resistance is plasmid mediated except for fluoroquinolones (due to chromosomal mutation).
• Enterococci and staphylococci are gram-positive bacteria that also transfer antibiotic resistance by
conjugative transfer.

BETA-LACTAM ANTIBIOTICS
Bactericidal drugs containing β- lactam ring et act by inhibiting the cell wall synthesis and include
• Penicillins
• Cephalosporins
• Monobactams e.g. aztreonam
• Carbapenems e.g.imipenem
These bind to penicillin binding proteins (PBPs) on bacterial membrane and inhibit transpeptidase enzyme
responsible for the cross linking of peptidoglycan chains.

PENICILLINS
• Commercially obtained from penicillium chrysogenum.
• Semi-Synthetic penicillins:
Acid-resistant alternative to Penicillinase-resistant penicillins Extended spectrum penicillins
penicillin G
Phenoxymethyl penicillin (Penicillin Methicillin, Cloxacillin, Dicloxacillim • Aminopenicillins: Ampicillin,
V) Bacampicillin, Amoxicillin.
• Carboxypenicillins: Carbenicillin,
Ticarcillin.
• Ureidopenicillins: Piperacillin,
Mezlocillin

• β-lactamase inhibitors: Clavulanic acid, Sulbactam, Tazobactam

Narrow spectrum Wide spectrum Penicillinase susceptible

Penicillinase Penicillinase resistant Aminopenicillins: Amoxycillin, ampicillin, bacampicillin
susceptible Carboxy penicillins - carbenicillin, ticarcillin
Ureidopenicillins- piperaciltin, azlocillin, mezlocillin
Penicillin G Methicillin, Nafcillin, Oxacillin
Mecillinam
Penicillin V Cloxacillin, dicloxacillin
• Antipseudomonal penicillin: Carbenicillin, ticarcillin, azlocillin, mezlocillin, piperacillin.

Clinical uses
• Penicillin G: DOC in syphilis. Benzathine or procaine penicillin (DOC in neurosyphilis) is used.
• Pen-G is now the DOC for meningococcus, actinomycosis, tetanus, gas gangrene, Past. multocida, rat bite
fever, yaws, leptospirosis, streptococci & anaerobic bacteria except bacteroides.
• Acid resistant & orally active: penicillin-V, oxaciltin, Dicioxacillin, Cloxacillin, Amoxycillin & Ampicillin
• Methicillin, nafcillin, oxacillin and cloxacillin: staphylococcus aureus infections.
o Methicillin resistance due to the formation of alternative penicillin binding proteins.
o Organisms resistant to methicittin (MRSA) are resistant to all other beta lactam drugs.
o These resistant organisms are treated by vancomycin or teicoplanin (α glycopeptide antibiotic mixture
of related compounds).
o Vancomycin resistant staphylococcus (VRSA) can be treated by linezolid or streptogramins.
• Ampicillin, amoxycillin: these are wide spectrum penicillinase sensitive antibiotics. In addition to gram
positive organism, these are also effective against enterococci, listeria and haemophilus organism.
• Ampicillin is the DOC for listeria meningitis & UTI caused by E.fecalis.
 • Piperacillin, ticarcillin, carbenicillin, azlocillin and mezlocillin: possess activity against gram negative rods
including pseudomonas. These are used with beta lactamase inhibitors and with aminoglycosides.

Toxicity
• Main toxicity: hypersensitivity, serum sickness, Anaphylaxis.
• M/c drug implacted in drug allergy: Penicillin-G(highest with procaine penicillin)
• Topical penicillins are highly sensitizing and are banned for use except in case of gonococcal ophthalmia.
• If a patient develops severe hypersensitivity reaction to a penicillin, all other beta lactam antibiotic are
contra-indicated except aztreonam (cross sensitivity is not present)
• Ampicillin causes maculopapular skin rash in infectious mononucleosis.
• Methicillin is the most common antibiotic causing interstitial nephritis.
• Procaine penicillin  seizures; Oxacillin  hepatitis; nafcillin  neutropenia; carbenicillin  bleeding.

BETA LACTAMASE INHIBITORS

• Penicillinase is a beta lactamase responsible for the breakdown of beta lactam ring (resistance to
penicillins).
• Clavulanic acid, sulbactam & tazobactam overcome the resistance.
• "Suicide" inhibitor that irreversibly binds β-lactamases from a wide range of gram-positive and gram-
negative microorganisms.
• Most active against Ambler class A B-lactamases (plasmid-encoded transposable element [TEM] lactamases
in particular) such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E
coli, and K pneumoniae.
• Inhibit chromosomal lactamases of legionella, bacteroides, and branhamelta.
• Not good inhibitors of class C -B lactamases, produced by enterobacter, citrobacter, serratia, and
pseudomonas.
• MRSA is not susceptible to B-lactam antibiotics.

POLYMYXIN B AND COLISTIN

• Polymyxins are elaborated by Bacillus polymyxa.
• Colistin is produced by Bacillus colistinus.
• Colistin (polymyxin E) is available as colistin sulfate for oral use.
• They are active against gram negative bacteria only; all except Proteus, Serratia and Neisseria are
inhibited.
• Both have similar range of activity, but colistin is more potent on Pseudomonas, Salmonella and Shigella.
• Colistimethate sodium for parenteral administration (not recommended).
• They are cleared renally, and dose modification is required with impaired renal function.
• Polymyxin B sulfate is available for ophthalmic, otic, and topical use.
• Colistin is available as otic drops
• External otitis, frequently due to Pseudomonas, may be cured by the topical use of the drug.
• P. aeruginosa is a common cause of infection of corneal ulcers; local application or subconjunctival
injection of polymyxin B often is curative.
• Because of their extreme nephrotoxicity, these drugs are rarely if ever used except topically.
• Hypersensitization with Polymyxin B is uncommon with topical use.
• Neurological reactions include muscle weakness and apnea, paresthesias, vertigo & slurred speech.
• Polymyxins are nephrotoxic, and coadministration with aminoglycosides should be avoided.

CEPHALOSPORINS
1st GENERATION Oral Cephalexin , Cefadroxil, Cephradine & Cephaloridine
Parenteral Cephalothin, Cefazolin & Cephapirin
2nd GENERATION Oral Cefaclor, Cefuroxime Axetil , Loracarbef & Cefprozil
Parenterai Cefuroxime, Cefotetan, Cefoxitin, Cefmetazole, Ceforanide, Cefonicid &
Cefamandole
3rd GENERATION Oral Cefixime, Cefpodoxime proxetil, Cefdinir, Ceftibuten, ceftamet pivoxil
&Cefditoren
 Parenteral Cefotaxime, Ceftizoxime, Ceftriaxone, Ceftazidime, Cefoperazone & Moxalactam

4th GENERATION Parenteral Cefepime & Cefpirome

Pharmacokinetics
• Most cephalosporins are excreted via kidney through tubular secretion.
• Ceftriaxone and cefoperazone are excreted mainly in the bile.
• Nephrotoxicity of these drugs is increased with loop diuretics.

CLINICAL USES:
• First generation: better activity against gram positive organisms.
• Later compounds: against gram negative aerobic organisms.

First generation:
• Active against gram positive cocci including staphylococci.
• Cefazolin is the DOC for surgical prophylaxis.
• Cephradine: available in both oral & parenteral forms.

Second generation:
• Less active against gram positive organism but has extended gram negative coverage.
• Cefotetan, Cefuroxime, cefmetazole and Cefoxitin: active against anaerobes like bacteroides fragilis.
• Cefuroxime: attains higher CSF levels.

Third generation
• Active against gram negative organism resistant to other beta-lactam antibiotics.
• Penetrates the blood brain barrier (except cefoperazone and cefixime).
• Ceftazidime (maximum) and cefoperazone are active against pseudomonas.
• Ceftazidime: DOC for melioidiosis.
• Ceftriaxone: DOC for gonorrhea, salmonellosis, E.coli sepsis, proteus, serratia, hemophilus & empirical
treatment in bacterial meningitis.
• Ceftizoxime has maximum activity against bacteroides.

Fourth generation:
• Active against gram negative organism (including pseudomonas) resistant to 3rd generation cephalosporins.
• Not active against anaerobes.

OTHERS:
• Cefotaxime and ceftriaxone are most active cephalosporins against penicillin resistant pneumococci.
• No cephalosporin is active against Entercococcus fecalis and listeria monocytogenes.
• Ceftazidime plus aminoglycoside is the treatment of choice for pseudomonas infections.
• Ceftobiprole: fifth generation cephalosporin, effective against MRSA & Pseudomonas.
• Ceftaroline: fifth generation cephalosporin, effective against MRSA & community acquired pneumonia.
• Loracarbef: similar to cefaclor, used orally.
• Beta-lactam antibiotics with activity against methicillin-resistant staphylococci are currently under
development.
• Ceftaroline fosamilis the prodrug of the active metabolite ceftaroline.
• Ceftaroline has increased binding to penicillin-binding protein 2a,which mediates methicillin resistance in
staphylococci.

Toxicity
• Cefamandole, cefoperazone, moxalactam & cefotetan: hypoprothrombinemia & disulfiram like reaction.
• Ceftazidime: Neutropenia, thrombocytopenia, increase in plasma transaminases & blood urea.

MONOBACTAMS
 • Aztreonam: active against gram negative rods including pseudomonas but no activity against gram positive
organisms and anaerobes.

CARBAPENEMS
• Imipenem, doripenem, meropenem, faropenem & ertapenem.
• Wide spectrum of activity against gram positive cocci, gram negative rods & anaerobes.
• DOC for enterobacter, klebsiella & acinetobacter species. Only drugs effective against ESBL (extended
spectrum beta lactamase) producing organisms.
• Imipenem is rapidly inactivated by renal dehydropeptidase-I, so it is combined with cilastatin.
• Meropenem: is a derivative of thienamycin, not hydrolysed by renal peptidase; does not need to be
protected by cilastatin.

VANCOMYCIN
• With the exception of flavobacterium, vancomycin is active only against gram-positive bacteria.
• Rapid infusion of vancomycin can cause "red man/red neck" syndrome (diffuse flushing due to histamine
release).
• Telavancin is potentially teratogenic, so administration to pregnant women must be avoided.
• Enterococcal resistance to vancomycin is due to a plasmid mediated alteration of the dipeptide target site,
reducing its affinity for vancomycin.
• These strains typically are resistant to multiple antibiotics, including streptomycin, gentamicin, and
ampicillin. Resistance to streptomycin and gentamicin is of special concern, because the combination of an
aminoglycoside with a cell-wall-synthesis inhibitor is the only reliably bactericidal regimen for enterococcal
endocarditis.
• The Van A phenotype: resistant to both teicoplanin and vancomycin.
• The Van B phenotype: low level of resistance to vancomycin susceptible to teicoplanin.

NOTE: gentamicin resistant enterococci is d/t inactivating enzyme.

• Vancomycin derivatives: Oritavancin, Telavancin & Dalbavancin: used in MRSA & VRSA infections.
• Dalbavancin is not active against most strains of vancomycin-resistant enterococci.
• Dalbavancin has an extremely long half-life of 6-11 days, which allows for onceweekly intravenous
administration.

FLUOROQUINOLONES
• Inhibits DNA gyrase (to oisomerase II & IV) resulting in the inhibition of DNA.

1st generation Norfloxacin, lomefloxacin Narrow spectrum, active against

gram negative
2nd generation Ciprofloxacin and oftoxacin
3rd generation Levofloxacin, gatifloxacin, pefloxacin, sparfloxacin Active against gram positive
4th generation Moxifloxacin, fleroxacin, garenoxacin, gemifloxacin and Broad spectrum
trovafloxacin

• Dose adjustment is necessary in renal disease for all quinolones except pefloxacin, moxifloxacin &
trovafloxacin.
• Greatest activity against pseudomonas (maximum: ciprofloxacin)
• Norfloxacin: least active against both gram-negative and gram-positive organisms
• Used in adolescent patients with cystic fibrosis who have pulmonary exacerbations.
• Norfloxacin is superior to tetracyclines in decreasing the duration of diarrhea in cholera.
• Ciprofloxacin: DOC for prophylaxis & treatment of anthrax & for prophylaxis of meningococcal meningitis.
• Ciprofloxacin and oftoxacin cure most patients with enteric fever caused by S. typhi, as well as bacteremic
nontyphoidal infections in AIDS patients.
• Respiratory fluoroquinolones: levofloxacin, gatifloxacin, gemifloxacin & moxifloxacin.
• Gatifloxacin: hyperglycemia in diabetics and hypoglycemia in patients receiving oral hypoglycemic agents.
 • Pruliftoxacin: converted to ulifloxacin, a broad spectrum antibiotic active against both gram positive and
gram negative bacteria, including many resistant strains.do not prolong QT interval.
• Pefloxacin attains higher concentration in CSF and used for meningitis.
• Moxifloxacin & trovafloxacin- wide spectrum against gram negative, gram positive & anaerobic organisms.
• Gatifloxacin and moxifloxacin-excellent activity against S. pneumoniae and have shown efficacy comparable
to β-lactam antibiotics. (community acquired pneumonia)
• Most potent fluroquinolone against M.tuberculosis: moxifloxacin.
• WC side effect: GI distress, followed by CNS side effects.
• May cause cartilage problems, tendon rupture & tendonitis.
• Maximum phototoxicity: lomefloxacin & sparfloxacin.
• Sparfloxacin & Gatifloxacin prolong QTc interval, grepafloxacin was withdrawn d/t arrhythmias.
• Norftoxacin does not achieve adequate systemic concentrations.
• Quinolones are also used in traveler's diarrhea & shigellosis.
• Quinolones induce the Shiga toxin in vitro  should not be used for Shiga toxin-producing E. coll.
• Ciprofloxacin and ofloxacin are less effective in treating episodes of peritonitis occurring in patients on
chronic ambulatory peritoneal dialysis, due to their higher MICs for coagulase-negative staphylococci.

AMINOGLYCOSIDES
Systemic aminoglycosides Topical aminoglycosides
Streptomycin, gentamicin, Kanamycin, Neomycin and framycetin
Tobramycin, amikacin, sisomicin, netilmicin, paromomycin
• Bind to 30S ribosomes and freeze initiation, inhibit translocation and cause misreading of mRNA code.
• All aminoglycosides except amikacin and netilmicin are susceptible to inactivating enzymes.
• Exert a long and concentration dependent 'postantibiotic effect'.
• Aminoglycosides have concentration-dependent killing.

Clinical uses
• Gentamicin, tobramycin and amikacin: gram negative organisms including pseudomonas. Not reliable for
gram positive organism if used alone. All are inactive against anaerobes,
• Gentamicin -PMMA (poly methyl methacrylate) special drug delivery system for osteomyelitis.
• Streptomycin: DOC for tuberculosis, Plague and tularemia.
• Amikacin: second line drug for tuberculosis and is also used for the MDR tuberculosis.
• Netilmicin: used for serious infections only.
• Neomycin and framycetin: used topically for their high toxicity.
• Neomycin: used orally for gut sterilization in hepatic encephalopathy.
• Spectinomycin: single dose treatment for penicillinase producing Neisseria gonorrhea.

Toxicity
• Maximum nephrotoxic aminoglycoside is Neomycin>gentamicin. Streptomycin is least nephrotoxic.
• Cochlear toxic aminoglycosides are amikacin (Maximum), kanamycin & neomycin.
o Cochlear damage is irreversible.
o A high-pitched tinnitus often is the first symptom of toxicity and can persist for days to weeks.
• Vestibulotoxic aminoglycosides are streptomycin (maximum) & gentamicin.
• Maximum neuromuscular blocking aminoglycoside is Neomycin>streptomycin. Leads to respiratory
depression. (risk factors: hypocalcemia, peritoneal administration, use of neuromuscular blockade & pre
existing respiratory depression)
• Netilmicin is least ototoxic.
• Oral neomycin damages intestinal  malabsorption syndrome, diarrhea & steatorrhea.
• Parenterally administered aminoglycosides are not associated with pseudomembranous colitis.
• Neomycin can cause apnea by its muscle paralyzing action, when applied to serous cavities.

TETRACYCLINES
Bind to 30S ribosomal subunit & inhibit the binding of aminoacyl-tRNA to the A site.
Classified into three groups:
 • Group I: Tetracycline, chlortetracycline, oxytetracycline
• Group II: Demeclocycline, lymecycline
• Group III: Doxycycline, minocycline
• Glycylcycline: Tigecycline

Pharmacokinetics
• Crosses the placenta and affect the fetus.
• Excreted in the urine except Doxycycline. Doxycycline excreted in the feces  can be used in renal failure.
• Half life of Doxycycline and minocycline is longer than other tetracyclines.
• Resistance occurs d/t development of efflux pumps.

Clinical uses
First choice drug for
• Lymphogranuloma venereum (LGV)
• Granuloma inguinale
• Atypical pneumonia due to mycopiasma
• Cholera, Brucellosis & Plague prophylaxis
• Relapsing fever, Lyme's disease
• Rickettsia infections
Other uses
• Peptic ulcer by H. pylori (tetracycline)
• Amoebiasis, leprosy
• Meningococcal carrier state (minocycline)
• Amoebiasis ( Doxycycline)
• Malaria prophylaxis (Doxycycline)
• Syndrome of inappropriate ADH secretion
(Demeclocycline)

Toxicity:
• Teratogenic effect: fetal tooth enamel dysplasia and irregularities in the fetal bone growth.
• Young children: dentition abnormalities.
• Outdated tetracyclines: Fanconi's syndrome (a type of renal tubular acidosis).
• Demeclocycline (maximum) and Doxycycline can result in photosensitivity.
• Minocycline: dose dependent vestibular toxicity.

SULFONAMIDES
• Bacteriostatic agents & act by inhibiting folate synthase competitively.
• Undergo hepatic metabolism by ACETYLATION, ineffective in the presence of pus d/t abundance of PABA.
• May result in crystalluria (minimum risk with sulfisoxazole).
• Sulfadoxine is longest acting and sulfacytine is the shortest acting sulfonamide.

Classification:
For systematic use of oral agents Short acting Sulfacytine, sulfisoxazole, sulfa
methiazole
Intermediate acting Sulfamethoxazole, sulfadiazine
Long acting Sulfadoxine
For use in GIT Sulfasalazine, olsalazine
For topical use Sulfacetamide, silver sulfadiazine, mafenide

Clinical use
• Sulfacetamide: ocular infections, mafenide & silver sulfadiazine are used in burn patients as topical agents.
• Sulfadiazine can be used for nocardiasis and sulfisoxazole for urinary tract infections.
• Sulfasalazine and olsalazine are used for the treatment of ulcerative colitis.
• Sulfadoxine plus Pyrimethamine is used for malaria.
• Sulfadiazine and Pyrimethamine combination can be used for the treatment of toxoplasmosis and
prophylaxis of pneumocystis jiroveci pneumonia in AIDS patients.
• M/c adverse effect: skin rash; also causes granulocytopenia, thrombocytopenia & aplastic anemia (common
in HIV).

COTRIMOXAZOL
• Fixed dose combination of sulfamethoxazole (400mg) & trimethoprim (80) in 5:1 ratio (reaches a plasma
conc. ratio of 20:1)
 • Double strength: 160 mg trimethoprim + 800 mg sulfamethoxazole.
• Trimethoprim easily crosses the BBB Et placenta, sulfamethoxazole can't.
• Effective in UTI, respiratory tract infections, MRSA, middle ear & sinus infections d/t hemophilus &
moraxella.
• DOC in pneumocystocis & nocardiosis.
• Alternative to penicillin in protecting agranulocytosis patients.
Cotrimazine: combination of trimethoprim with sulfadiazine.
Trimethoprim as such is effective only in UTI infemales & Prostatitis.

MACROLIDES
• Erythromycin, roxithromycin, clarithromycin, spiramycin & azithromycin.
• More active in alkaline medium.
• Narrow spectrum activity, includes mostly gram positive & a few gram megative organisms.
• Macrolides are the DOC for Chancroid, Legionella, Atypical pneumonia & whooping cough.
• Resistant enterobacteriaceae produce erythromycin esterase.
• Azithromycin is not an enzyme inhibitor & is free of drug interactions.
• Erythromycin is used as a prokinetic agent in diabetic gastroparesis, to improve gastric emptying in short
term.
• Erythromycin is the preferred drug in children for diarrhea d/t C.jejuni
• Mechanism of resistance of macrolides:
o Drug efflux by an active pump mechanism
o Ribosomal protection by production of methylase enzymes that modify the ribosomal target
o and decrease drug binding.
o Macrotide hydrolysis by esterases produced by Enterobacteriaceae
o Chromosomal mutations that alter a 50S ribosomal protein.
• Adverse Effects:
o Erythromycin stimulates motilin receptors  gastric contractions hastens gastric emptying & promotes
intestinal motility.
o Reversible hearing impairment in high doses.
o Hepatitis with cholestatic jaundice occurs with estolate ester after 1-3 weeks.
o Incidence is higher in pregnant women.
o Clarithromycin: pseudomembranous enterocolitis, hepatic dysfunction or rhabdomyolysis

MACROLIDE LIKE ANTIBIOTIC

• Ketolides: Telithromycin inhibits CYP1A2.
 Active against S pyogenes, S pneumoniae, S aureus, H influenzae,Moraxella catarrhalis, mycoplasma,
legionella, chlamydia, H. pylori, N. gonorrhoeae, Bacteroides fragilis, T gondii and nontuberculosis
mycobacteria.
• Lincosamides:
 Clindamycin (used against anaerobes like bacteroides & propionobacterium, along with penicillin in
invasive group-A streptococci, m/c antibiotic associated with pseudo membranous colitis)
 Lincomycin.

 Pseudomembranous colitis due to overgrowth of toxin-producing C. difficile presents with severe diarrhea,
fever, and stools containing mucous membrane neutrophils.
 Discontinuation of the drug, combined with the oral administration of metronidazole or vancomycin, usually
is curative.

CHLORAMPHENICOL
• Active against anaerobes, may cause superinfection diarrhea, dose dependent reversible bone marrow
suppression & idiosyncratic irreversible myelosuppression.
• Resistance is d/t formation of inactivating enzyme acetyl transferase.
• Inhibits hepatic microsomal enzymes that metabolize several drugs.
 • Half-lives of these drugs are prolonged, and the serum concentrations of phenytoin, cyclophosphamide,
tolbutamide, chlorpropamide and warfarin are increased.
• Concurrent administration of phenobarbital or rifampin, which potently induce CYPs, shortens
chloramphenicol's t1/2 and may result in subtherapeutic drug concentration failure of therapy.

OTHERS:
• Glycylcyclines: tigecycline, similar to tetracyclines. Has a broad spectrum against MRSA, VRSA, streptococci,
enterococci, and rapidly growing mycobacteria. Ineffective against proteus pseudomonas. Indicated in
complicated, severe skin & intra abdominal infections.
• Streptogramins: Quinpristin-dalfopristin: effective against penicillin resistant pneumococci, MRSA, VRSA,
methicillin resistant Enterococcus faecium. M/c side effect: venous irritation; can also cause arthralgia
myalgia syndrome.
• Urinary antiseptics: nitrofurantoin, nalidixic acid, methenamine (hexamine), mandelamine &
phenazopyridine.
• Oxazolidinones (Linezolid): binds to 235 part of 50S ribosomal subunit. Active against MRSA, VRSA &
vancomycin resistant Enterococcus faecium as well as fecalis. Major A.E: thrombocytopenia & neutropenia.
Inhibits MAO-A & cause serotonin syndrome if used along with SSRI or other serotonergic drugs.
• Retapamulin: a pleuromutilin inhibits protein synthesis by binding to 505 ribosomes, used for topical
treatment of impetigo d/t MRSA or streptococcus pyogenes.
• Oxolinic acid and cinoxacin are similar in structure and function to nalidixic acid.
• Dihydro Folate Reductase (DHFR) inhibitors: trimethoprim, pyrimethamine, methotrexate, proguanil &
pentamidine.
• All can cause megaloblastic anemia.
• Trimethoprim: attains high concentrations in prostate a vaginal fluids. Usually combined with sulfonamides.
• Iclaprim- recent analogue of trimethoprim.
• Daptomycin: lipopeptide bactericidal drug, acts by causing depolarization of bacterial cell membranes with
K+ efflux & rapid cell death. Used for serious gram positive infections including penicillin resistant
pneumococci, MRSA, VRSA & organisms resistant to linezolid & streptogramins. Surfactant antagonizes
daptomycin  not used in pneumonia.
• Peptide antibiotics: Bacitracin and gramicidin, active against gram-positive organisms such as streptococci,
pneumococci, and staphylococci.
• Use of bacitracin in the anterior nares may temporarily decrease colonization by pathogenic staphylococci.
• Bacitracin can induce contact urticaria syndrome.
• Mupirocin & Fusidic acid: blocks protein synthesis, used topically for staphylococcal infections.
• Recommended treatment regimen is twice-daily application for 5 days.

SURGICAL WOUNDS
Classification of operative wounds
Clean Clean- contaminated Contaminated Dirty
Elective, non Otherwise clean but emergency Gross spillage from GIT, Opening of abscess or
traumatic surgery, no surgery, elective with opening of opening of infected bitiary or purulent site, pre
viscera or tract any viscera/tract but minimal genitor urinary tract, operative perforation e.g.
entered, no infection spillage, no contact with infected penetrating injury< 4 hours, GI/ respiratory/Genito
at site, no break in material, minor break in grafting on open wound, urinary tract/Penetrating
technique technique major break in technique injury > 4 hours

• Incidence of post operative infection is higher if duration of surgery> 2hours

• For most of the procedures, oral antibiotics are given 1 hour prior to the procedure & IV drugs, just before/
after the anesthesia.

KlPIROCIN
• Available as a 2% cream for dermatologic use and as a 2% ointment for intranasal use.
• Indicated for traumatic skin lesions and impetigo secondarily infected with S. aureus or S. pyogenes.
• Systemic absorption through intact skin or skin lesions is minimal.
 • Any mupirocin absorbed is rapidly metabolized to inactive monic acid.
• Mupirocin is effective in eradicating S. aureus carriage.
• Benificial in patients with proven S. aureus nasal colonization plus risk factors for distant infection or a
history of skin or soft tissue infections.

MANAGEMENT OF INFECTIONS:
Pathogen
Gram-negative cocci (aerobic)
Moraxella (Branhamella)
Catarrhalis
Neisseria gonorrhoeae
Neisseria meningitides
Gram-negative rods (aerobic)
E coli, klebsiella, proteus
Enterobacter, citrobacter, Serratia TMP-SMZ, quinotone
Shigella
Salmonella
Campylobacter jejuni
Brucella species
Helicobacter pylori
Vibrio species
Pseudomonas aeruginosa
Burkholderia cepacia (formerly
Pseudomonas cepacia)
Stenotrophomonas maltophilia
(formerly Xanthomonas
maltophilia)
Legionella species
Gram-positive cocci (aerobic)
Streptococcus pneumoniae,
penicillin-susceptible (MIC <2)
Penicillin-resistant
Streptococcus pyogenes (group A) Penicillin, clindamycin
Streptococcus agalactiae (group
B)
Viridans streptococci
S.aureus
Drugs of First Choice Alternative Drugs
TMP-SMZ, cephalosporin (second- or Erythromycin, quinotone,
third-generation) clarithromycin, azithromycin
Ceftriaxone, cefixime Spectinomycin, quinolone
Penicillin G Chloramphenicol, cephalosporin (third-
generation)
Cephalosporin (first- or second- Quinolone, aminoglycoside
generation), TMP-SMZ
Imipenem
Antipseudomonal penicillin,
aminoglycoside, cefepime
Quinolone TMP-SMZ, ampicillin
TMP-SMZ, quinolone, cephalosporin Chloramphenicol, ampicillin
(third generation)
Erythromycin Tetracycline, quinolone
Doxycycline + rifampin or Chloramphenicol + aminoglycoside or
aminoglycoside TMP-SMZ
Bismuth + metronidazole + Proton pump inhibitor + amoxicillinand
tetracycline oramoxicillin clarithromycin
Tetracycline Quinolone, TMP-SMZ
Antipseudomonal Antipseudomonal penicillin +
penicillin + quinolone; cefepime, ceftazidime,
aminoglycoside imipenem, or aztreonam ±
aminoglycoside
TMP-SMZ Ceftazidime, chloramphenicol
TMP-SMZ Minocycline, ticarcillin-clavulanate,
Quinolone
Azithromycin + rifampin Clarithromycin, erythromycin, .
or quinolone + rifampin Doxycycline
Penicillin Doxycycline, ceftriaxone, cefuroxime,
erythromycin, imipenem, meropenem,
linezolid
Ceftriaxone, vancomycin Carbapenems, linezolid
Erythromycin, cephalosporin (first
generation)
Penicillin (+ aminoglycoside) Vancomycin
Penicillin Cephalosporin (first- or thirdgeneration),
vancomycin
Beta-lactamase-negative
Beta-lactamase-positive
Methicillin-resistant
Enterococcus species
Gram-positive rods (aerobic)
Bacillus species (nonanthracis)
Listeria species
Nocardia species
Anaerobic bacteria
Gram-positive (clostridia,
peptococcus, actinomyces,
peptostreptococcus)
Clostridium difficile
Bacteroides fragilis
Fusobacterium, prevotella,
Porphyromonas
Spirochetes
Leptospira species
Treponema species
Penicillin Cephalosporin (first-generation),
vancomycin
Penicillinase-resistant Penicillin Cephalosporin (1st-gen), vancomycin
Vancomycin TMP-SMZ, minocycline, linezolid,
quinupnstin-dalfopristin
Penicillin ±aminoglycoside Vancomycin ± aminoglycoside
Vancomycin Imipenem, quinolone, clindamycin
Ampicillin (± aminoglycoside) TMP-SMZ
Sulfadiazine, TMP-SMZ Minocycline, imipenem, amikacin
Penicillin, clindamycin Vancomycin, imipenem, Chloramphenicol
Metronidazole Vancomycin, bacitracin
Metronidazole, clindamycin Chloramphenicol, imipenem, betalactam-
beta-lactamase-inhibitor combinations
Metronidazole, clindamycin, penicillin
Penicillin Tetracycline
Penicillin Tetracycline, azithromycin, Ceftriaxone

PROPHYLACTIC USE OF ANTIBIOTICS

UTI, toxoplasmosis Cotrimoxazole Surgical prophylaxis Cefazolin
Pneumocystis Cotrimoxazole/dapsone/ Bacterial Erythromycin ophthalmic
jiroveci atovaquone Conjunctivitis ointment
Cholera Tetracycline > Diphtheria Erythromycin /penicillin
Furazolidone / Single dose
Doxycycline
Rheumatic fever Benzathine penicillin Endocarditis Amoxycillin/ clindamycin
Tuberculosis Isoniazid + nfampicin Herpes simplex Acyclovir
Meningococcal Rifampicin / Ciprofloxacin Ampicillin
Group-B streptococci
meningitis
Gonorrhea / Procaine penicillin H. influenza B Rifampicin
syphilis
Rickettsia! Tetracyclines MAC Azithromycin/clarithromyan
infections
Malaria Chtoroquine / mefloquine Otitis media Amoxycillin
!nth A & B( Bird flu) Oseltamivir Pertussis Erythromycin
Anthrax Ciprofloxacin/Doxycycline Plaque Tetracycline

URINARY ANTISEPTICS AND ANALGESICS

• Methenamine is a urinary tract antiseptic and prodrug that owes its activity to its capacity to generate
formaldehyde.
o The agent is most useful when the causative organism is E. coil.
• Nitrofurantoin is a synthetic nitrofuran that is used for the prevention and treatment of infections of the
urinary tract.
o Nitrofurantoin is active against many strains of E. coil and enterococci.
o Nitrofurantoin is bacteriostatic for most susceptible microorganisms at concentrations of 320g/ml or
less and is bactericidal at concentrations of 100 mg/ml and more.
o The antibacterial activity is higher in an acidic urine.
• Phenazopyridine hydrochloride has an analgesic action on the urinary tract and alleviates symptoms of
dysuria, frequency, burning, and urgency.
o The usual dose is 200 mg three times daily. The compound is an azo dye, which colors urine orange or
red.
 XI. ANTI-MYCOBACTERIAL AGENTS

ANTI TUBERCULAR DRUGS

First line Essential: Isoniazid (H), Rifampin (R), Pyrazinamide (Z), Ethambutol (E),
Drugs Supplementary: Streptomycin (S), Rifabutin, Rifapentine
Second Line Old Drugs: Thiacetazone, Paraaminosalicylic acid, Ethionamide , Cycloserine, Kanamycin, Amikacin,
Drugs Capreomycin, Ciproftoxacin, Oftoxacin, Levofloxacin, Moxifloxacin, Linezolid
All first line Anti tubercular drugs are bactericidal except Ethambutol which is static.

• Isoniazid: bacteriostatic against resting & bactericidal against rapidly multiplying organisms.
o Effective against intracellular & extracellular organisms.
o Resistance occurs d/t mutation in Kat G (gene for catalase peroxidase) or INH-A
• Rifampicin: excreted in feces  safe in renal failure. Bactericidal against dormant organisms.
o Effective against intracellular & extracellular organisms.
• Ethambutol: inhibits the synthesis of arabinogalactan (cell wall component), d/t inhibition of arabinosyl
transferase.
• Pyrazinamide: active against intracellular bacteria only & in acidic media.
• Streptomycin: active against extracellular bacteria only, given as IM, contraindicated in pregnancy.

Drug Mechanisms of Action and esistance Adverse effects

Isoniazid Inhibit mycolic acid synthesis
High level resistance mutation in gene coding for
Catalase peroxidase
Rifampicin Inhibits DNA dependent RNA polymerase
Resistance due to mutation in repo B gene
Ethambutol Inhibits synthesis of arabinogalactan (cell wall
component)
Pyrazinamide Action similar to that of INH Resistance due to
mutation in the gene which encodes for enzyme
generation in the active metabolite.
Streptomycin Protein synthesis inhibitor
Hepatitis, Peripheral neuritis
(always given in combination with
pyridoxine), Hemolysis in G6PD
deficiency, SLE in slow acetylators,
cheese reaction
Proteinuria, Hepatitis, Flu-like
syndrome, Red orange urine,
Thrombocytopenia. Potent
microsomal enzyme inducer;
Contraindicated in patients on ART
Dose dependent retro bulbar
neuritis, 'visual acuity and Red - reen
blindness
Polyarthralgia, myalgia, Hepatitis &
Rash Hyperuricemia, phototoxicity,
↑ porphyrin synthesis, non gouty
arthritis (40%)
Deafness, Vestibular dysfunction &
Nephrotoxicity.

• Isoniazid: prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.

• The target of the isoniazid derivative is enoyl-ACP reductase of fatty acid synthase II.
• Fast acetylators: (30--40% of Indians) t1 /2 of INH: 1 hr.
• Slow acetylators: (60-70% of Indians t1 /2 of INH: 3 hrs.
• Isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier
protein synthetase, which blocks mycolic acid synthesis.
• Isoniazid penetrates well into caseous material and persists in therapeutic concentrations.
• Main excretory products in humans result from acetylation (acetylisoniazid) and hydrolysis (isonicotinic acid).
• Hepatitis is d/t the metabolite acetylhydrazine.
• Isoniazid induced peripheral neuritis - more common in slow acetylators.
• Mental abnormalities may appear, including euphoria, transient memory impairment, loss of self-control,
and psychosis.
• Approximately 1 in 106tubercle bacilli will be genetically resistant to isoniazid.
 • The other congener of hydrazine- iproniazid is found to be a mood elevator.

Rifampicin toxicity
• Major adverse effect
o Hepatitis, a, is dose-related and is reversible on discontinuation.
o 'Respiratory syndrome': breathlessness associated with shock and collapse.
o Purpura, haemolysis, shock and renal failure.
• Minor reactions: not requiring drug withdrawal and more common with intermittent regimens are:
o 'Cutaneous syndrome': flushing, pruritus + rash (especially on face and scalp), redness and watering of
eyes.
o 'Flu syndrome': with chills, fever, headache, malaise and bone pain.
o 'Abdominal syndrome': nausea, vomiting, abdominal cramps with or without diarrhoea.
o Orange discolouration of soft contact lenses.

Other uses of rifampin

• Prophylaxis of Meningococcal and H. influenzae meningitis and carrier state.
• Second/third choice drug for MRSA, diphtheroids and Legionella infections.
• Combination of doxycycline and rifampin is the first line therapy of brucellosis.

DERIVATIVES OF RIFAMPICIN
RIFABUTIN: (Ansamycin)
• Similar in action to rifampicin and shows cross resistance to rifampicin.
• Mild inducer of cytochrome P-450 unlike rifampicin & rifapentin. Causes pseudojaundice.
• Indicated in the treatment of tuberculosis in HIV patients on anti retroviral therapy due to less toxicity.
• Rarely, it can cause anterior uveitis, hepatitis, clostridium difficile-associated diarrhea, diffuse polymyalgia
syndrome, yellow skin discoloration (Pseudo-jaundice) and pancytopenia. Unlike rifampicin

Rifabutin (as compared to rifampicin) is

• Less effective against TB
• More effective against MAC
• Longer acting, t1/2 (45 hours)
• Less potential to induce microsomal enzymes
• Donot require dose adjustment in liver disease

RIFAPENTIN:
• Similar in action to rifampicin and shows cross resistance to rifampicin.
• Potent Inducer of cytochrome P-450. Can cause light chain proteinuria.
• Metabolized to 25-desacetyl rifapentin.
• Should not be used in HIV individuals as it leads to drug resistance a more prone for toxicity.
RIFAXIMIN: indicated for traveler's diarrhea (E.coli) & hepatic encephalopathy.

OTHER DRUGS
• Thiacetazone: tuberculostatic drug. Major adverse effects include hepatitis, bone marrow suppression and
Steven Johnson syndrome (not used in HIV positive patients).
• Para amino salicylic acid (PAS): bacteriostatic. It can cause kidney, liver and thyroid dysfunction.
• Ethionamide: tuberculostatic can cause hepatitis, optic neuritis and impotence. Also used in leprosy.
o Ethionamide also inhibit mycolic acid biosynthesis with consequent impairment of cell-wall synthesis.
o Resistance can develop rapidly in vivo when ethionamide is used as a single-agent treatment, including
low-level cross-resistance to isoniazid.
• Cycloserine is a cell wall synthesis inhibiting drug and can cause neuropsychiatric adverse effects.
• Kanamycin, capreomycin and amikacin are injectable aminoglycosides, used in MDR tuberculosis.
• Fluoroquinolones: ciprofloxacin, ofloxacin, moxifloxacin & sparfloxacin. Effective against MAC in AIDS
patients.
• Azithromycin and clarithromycin are effective against non-tubercular atypical mycobacteria.
 • Bedaquiline is an inhibitor of mycobacterial ATP synthase. It is indicated as a part of MDT in adults with
pulmonary MDR-TB. It can cause QT prolongation.

MULTI DRUG RESISTANT TUBERCULOSIS

• Resistance to both Isoniazid & Rifampicin and may be any number of other anti-TB drugs.
• Treatment is mainly based on culture sensitivity.
• Usually fluoroquinolones are added.
• For H resistance: RZE is given for 12 months.
• For H+R resistance: ZE + S/ Kanamycin/Amikacin/ Capreomycin + cipro/Ofloxacin + Ethionamide.

EXTENSIVELY DRUG RESISTANT TUBERCULOSIS (XDR-TB)

• Resistance to four most effective drugs: H, R1 a fluoroquinolone, one of Kanamycin/Amikacin/ Capreomycin
and may be any number of other anti-TB drugs
• Virtually untreatable: high mortality, particularly among HIV positive patients.

TREATMENT OF ATYPICAL MYCOBACTERIA

Species Clinical Features Treatment Options
M kansasii Resembles Ciprofioxacin, clarithromycin,ethambutol, isoniazid,rifampin,
tuberculosis trimethoprimsulfamethoxazole
M marinum Granulomatous cutaneous Amikacin, clarithromycin,ethambutoi, doxycycline,
disease minocycline, rifampin,trimethoprimsulfamethoxazole
M scrofulaceum Cervical adenitis in children Amikacin, erythromycin (or other macrolide), rifampin,
streptomycin (Surgical excision is often curative and the
treatment ofchoice.)
M avium Pulmonary disease in patients Amikacin, azithromycin,clarithromycin,
complex with chronic lung disease; ciprofloxacin,ethambutol, rifabutin
Disseminated infection in AIDS
M chelonae Abscess, sinustract, ulcer; Amikacin, doxycycline, imipenem, macrolides, tobramycin
bone,joint, tendon infection
M fortuitum Abscess, sinustract, ulcer; bone, Amikacin, cefoxitin,ciprofloxacin, doxycycline, ofloxacin,
joint, tendon infection trimethoprimsulfamethoxazole
M ulcerans Skin ulcers Isoniazid, streptomycin,rifampin, minocycline (Surgical
excision may beeffective.)

ANTI - LEPROTIC DRUGS

Rifampicin, dapsone, clofazimine, ethionamide, ofloxacin, minocycline & clarithromycin.

RIFAMPICIN
Bactericidal, most effective & prevents resistance to Dapsone.

DAPSONE
• Bacteriostatic for Mycobacterium leprae, Inhibits rotate synthesis via dihydropteroate synthetase inhibition.
• It can cause methemoglobinemia and hemolysis in G-6-PD deficient patients.
• Acedapsone is given as a single IM injection that maintains dapsone in tissue for up to 3 months.
• Alternative drug for the treatment of pneumocystis jiroveciinfection in AIDS patients.
• DOC in dermatitis herpetiformis.

CLOFAZIMINE
• It is a drug with leprostatic and anti-inflammatory activity.
• Concentrated in fat.
• It interferes with the template function of DNA. It can cause gastrointestinal irritation, icthyosis of skin and
discoloration of skin and secretions. Can be used for lepra reaction.

OTHER DRUGS
• Ethionamide has antileprotic activity but causes hepatotoxicity in 10% patients.
 • Ofloxacin, pefloxacin, sparfloxacin, minocycline and clarithromycin can also be used in leprosy.

MULTIDRUG THERAPY FOR LEPROSY (WHO RECOMMENDED REGIMEN)

Drug Multi bacillary Pauci bacillary Leprosy
Rifampicin 600mg once a month 600mg once a month supervised
Dapsone 100mg daily self administered 100mg daily self administered
Clofazimine 300mg once a month & 50mg OD
Duration 12 months 6months

Single lesion single dose therapy utilizes 600mg rifampicin + 400mg ofloxacin + 100 mg minocycline (ROM regimen)
as a single dose for patients with solitary lesion PBL.

• Drug of choicefor both type-I & type-II Iepra reactions: Steroids

 XII. ANTI VIRAL AND ANTI FUNGAL AGENTS

ANTI – RETRO VIRAL DRUGS

Reverse transcriptase inhibitors (RTI's) Protease inhibitors Entry inhibitor Integrase

inhibitor
Nucleoside RTI's Nucleotide Non nucleoside RTI's Saquinavir, Enfuvirtide Raltegravir
RTI's (NNRTI) Ritonavir, Indinavir, Maraviroc (first Elvitegravir
Nelfinavir, CCR5
Zidovudine, Tenofovir Efavirenz,
Amprenavir, antagonist)
Stavudine, Etravirine,
Fosamprenavir,
Lamivudine, Nevi rapine,
Lopinavir,
Zalcitabine, Delavirdine
Atazanavir,
Didanosine,
Darunavir, Tipranavir
Emtricitabine,
ABACAVIR

REVERSE TRANSCRIPTASE INHIBITORS

• HIV is a retrovirus that forms its DNA from RNA with the help of the enzyme RNA with the help of the reverse
transcriptase.
• Drugs may inhibit this enzyme either competitively (anti-metabolites) or non-competitively.
• The competitive inhibitors may be nucleoside reverse transcriptase inhibitors (NRTIs) or nucleotide reverse
transcriptase inhibitors.
• The non-competitive inhibitors are also known as non-nucleoside\non-nucleotide reverse transcriptase
inhibitors (NNRTIs).

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs):

Most of these are prodrugs and competitively inhibit reverse transcriptase and also act as chain terminators by
incorporation into the DNA chain. Resistance to these drugs emerges rapidly if used alone.
• Zidovudine is frequently used NRTI in the treatment of HIV infections. It can also be used for the prophylaxis
of needle stick injury patients and for the prevention of vertical transmission of HIV from mother to fetus.
• Major adverse effect of zidovudine is bone marrow suppression leading to megaloblastic anemia and
thrombocytopenia. It can also cause myopathy. Rifampicin increases the clearance of this drug.
• Didanosine is another NRTI. Its oral bioavailability is reduced by food. It can lead to dose limiting pancreatitis
(maximum chances), hyperuricemia, optic neuritis and also peripheral neuropathy.
• Stavudine causes dose limiting peripheral neuropathy. It has maximum chances of causing lactic acidosis.
• Zidovudine and stavudine: associated with a syndrome of hyperlipidemia, glucose intolerance/insulin
resistance and fat redistribution often referred to as lipodystrophy syndrome.
• Probenecid, Fluconazole, atovaquone, and valproic acid may increase plasma concentrations of zidovudine
probably through inhibition of glucuronosyl transferase.
• Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin,
methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass
metabolism or through decreased clearance.
• Zalcitabine: unique toxicity to cause oral ulceration. It is the least effective NRTI.
• Abacavir: increases the risk of myocardial infarction, in patients with HLA-B: 5701.
• Lamivudine and emtricitabine are best tolerated NRTIs. These are not associated with peripheral
neuropathy or pancreatitis.
• All NRTIs are excreted by the kidney (require dose adjustment in renal failure) except abacavir which gets
metabolized by alcohol dehydrogenase. Hypersensitivity is the major adverse reaction of abacavir.
• All NRTIs may cause lactic acidosis, hepatomegaly and steatosis by inhibiting mammalian mitochondrial DNA
polymerase. Risk factors are obesity and pre-existing liver dysfunction.

NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR:

• Tenofovir is a nucleotide and does not require bioactivation by kinases. It is excreted mainly by the kidney.
• Also effective against hepatitis-B
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
• These drugs inhibit reverse transcriptase by acting at a site (allosteric site) different from that of NRTIs.
• Resistance to these drugs develops very rapidly. Do not cause lipodystrophy.
• Skin rash is an adverse effect of all these drugs and nevirapine can cause Steven Johnson syndrome and
toxic epidermal necrolysis.
• Delavirdine and efavirenz should be avoided in pregnancy.
• Nevirapine is used in pregnancy to prevent vertical transmission (single oral dose to mother during labour
and single oral dose to neonate within 3 days after birth).
• Etravirine: the first identified 2nd generation NNRT1 effective against HIV resistant to other NNRTIs.
• HIV strains with the commonn K103N resistance mutation to the first generation of NNRTI's are fully
susceptible to entravirine.
• Nevirapine & Efavirenz are CYP 450 enzyme inducers a delaviridine is enzyme inhibitor.

PROTEASE INHIBITORS
Protease helps in the maturation of infectious virions and inhibitors of this enzyme can be used in the treatment of
HIV infections (by inhibiting the post-translational modification of viral proteins).
• Oral bioavailability of Indinavir is decreased by food. It can cause thrombocytopenia and kidney stones. To
prevent renal damage, good hydration must be maintained.
• This group of drugs inhibits the metabolism of several drugs by inhibiting CYP3A4. Ritonavir in low doses is
always used with other protease inhibitors to increase their plasma concentration. Lopinavir is used only in
combination with ritonavir.
• Tipranavir is the only non peptide protease inhibitor, used in resistant HIV infections. Can cause liver
damage & intra cranial hemorrhage.
• Of all of the HIV protease inhibitors, saquinavir inhibits CYP3A4 least potently.
• Amprenavir can cause Steven Johnson syndrome.
• All protease inhibitors are metabolized by liver and all can cause lipodystrophy characterized by
hyperglycemia, hyperlipidemia, insulin resistance and altered fat distribution.
• Atazanavir is an exception to cause lipodystrophy.

FUSION INHIBITOR
• Enfuvirtide is a drug that binds to Gp 41 subunit of HIV envelope protein and inhibits the fusion of viral and
host cell membranes. This prevents the entry of the virus in the host cells.
• Maraviroc: first CCR5 co receptor antagonist, active only against CCR-5 tropic virus.

INTEGRASE INHIBITOR
• Raltegavir is metabolized by UGT1A1 mediated glucuronidation, not influenced by cyt enzymes.
• Used in treatment of experienced patients on treatment with other anti viral agents, with evidence of viral
replication.

SIDE EFFECTS OF ANTI RETRO VIRAL DRUGS

Nucleoside Reverse Transcriptase inhibitor:
Zidovudine Anemia, granulocytopenia, nausea, malaise, headache, insomnia, myopathy, tactic acidosis,
hepatomegaly with steatosis.
Didanosine Pancreatitis, peripheral neuropathy, dry mouth, hepatitis.
Zalcitabine Peripheral neuropathy, pancreatitis, lactic acidosis, hepatomegaly, steatosis, oral ulcer (aphthous).
Stavudine Peripheral neuropathy, pancreatitis hepatitis & lactic acidosis
Lamivudine Rash, peripheral neuropathy.
Abacavir Rash, fever, hypersensitivity (can be fatal), Nausea, vomiting, malaise, loss of appetite.

• Stavudine: HIV lipodystrophy syndrome, especially lipoatrophy.

• Of all nucleoside analogs, stavudine use is associated most strongly with fat wasting.

Non-nucleoside nucleoside reverse transcriptase:

 Nevirapine Skin rash, abnormal liver function test
Delavirdine Skin rash, abnormal LFT
Efavirenz Rash dysphoria, elevated LFT

• Efavirenz is the only antiretrovirat drug that is unequivocally teratogenic

Nucleotide reverse transcriptase inhibitors

Tenofovir Gastrointestinal distress

Protease Inhibitors
Saquinavir Diarrhea, nausea, headache, hyperglycemia, fat redistribution, lipid abnormalities
Ritonavir Nausea, abdominal pain hyperglycemia fat redistribution
Indinavir Nephrolithiasis, Indirect Hyperbilirubinemia, hyperglycemia
Nelfinavir Diarrhea, hyperglycemia, fat redistribution.
Amprenavir NW, rash, oral paraesthesia, hyperglycemia
Lopinavir Diarrhea, hyperglycemia, fat redistribution

Fusion inhibitor
Enfuvirtide Hypersensitivity reactions, ↑rate of bacterial pneumonia

HIGHLY ACTIVE ANTI-RETROVIRALTHERAPY (HAART)

• Treatment of HIV under HAART includes use of 3 or more drugs, of which one or two are NRTIs.
• The combinations may be 2NRTIs+1P1 (protease inhibitor) or 1 NRTI+1 NNRTI+1 Pl.
• For prophylaxis zidovudine alone or along with other anti-HIV drugs like lamivudine may be used.
PREFERRED THERAPY: Emtricitabine + Tenofovir + Efavirenz

Anti-HIV drug combinations that should not be used:

• Zidovudine + stavudine: pharmacological antagonism
• Atazanavir + Indinavir: Additive unconjugated hyperbiirubinemia
• Didanosine/ stavudine: additive peripheral neuropathy
• Lamivudine + Zalcitabine: in vitro antagonism.

First - line antiretroviral regimens

Preferred regimen: Lamivudine + Zidovudine + Nevirapine
Alternative regimens:
1. Lamivudine + Zidovudine + Efavirenz
2. Lamivudine + Stavudine + Efavirenz
3. Lamivudine + Stavudine + Nevirapine
Other options
1. Lamivudine + Tenofovir + Nevirapine
2. Lamivudine + Tenofovir + Efavirenz
3. Lamivudine + Zidovudine + Tenofovir

Post - exposure prophylaxis of HIV

Basic (2 drug) regimen (for low risk)
Zidovudine 300 mg + Lamivudine 150 mg - Twice daily for 4 weeks
Expended (3 drug) regimen (for high risk)
Zidovudine 300 mg + Lamivudine 150 mg - Twice daily+ Indinavir 800 mg (or another PI) Thrice daily All for 4 weeks.

ANTI HERPETIC DRUGS

Most are anti metabolites & inhibit viral DNA polymerase after bio activation by kinase.
ACYCLOVIR AND ITS • Active against herpes simplex (HSV-1 and 2) & varicella zoster virus (VZV).
CONGENERS • Not active against CMV infections
• Can be used topically, orally or intravenously & primarily excreted by kidneys
 • Seizures, hypotension and nephrotoxicity but it does not cause bone marrow
suppression.
• Essential to maintain hydration while the patient is on acyclovir therapy because
dehydration increases its nephrotoxic potential (crystallinenephropathy or
interstitial nephritis)
• Famciclovir is a prodrug that gets converted to penciclovir.
• In HSV encephalitis, acyclovir (10 mg/ kg every 8 hours for at least 10 days)
reduces mortality by >50% and improves neurological outcome
GANCICLOVIR • Given as IV, active against CMV and HSV and acts by inhibiting DNA polymerase
• DOC for CMV infections including retinitis
• 100 times more potent than acyclovir. Valganciclovir: good oral absorption.
• Dose limiting adverse effect is myelosuppression
CIDOFOVIR Active against HSV, CMV, pox, polyoma, adeno and papilloma viruses. Nephrotoxic &
Carcinogenic.
FOSCARNET Used in CMV infections. Given as IV inacyclovir-resistant mucocutaneous H.
simplex type-II and varicella-zoster infections in AIDS patients.
Can cause Nephrotoxicity (in 30%), hypocalcemia & CNS problems.
OTHER DRUGS Vidarabine, idoxuridine, trifluridine, fomivirsen and docosanol: herpes infections
Fomivirsen: first antisense oligonucleotide, active against CMV retinitis by intravitreal
route
Idoxuridine: used topically for keratoconjunctivitis by HSV.
Docosanol: used topically (as a cream) for herpes tabialis

ANTI INFLUENZA DRUGS

AMANTADINE Prevent uncoating of influenza A virus • Also used in Parkinsonism. adverse effects:
(not influenza B). livedo reticularis and ankle edema
RIMANTADINE • Longer acting than amantadine
OSELTAMIVIR AND Neuraminidase inhibitors & prevent • Effective against both influenza A and
ZANAMIVIR the virion release by causing clumping influenza B (Bird flu is caused by influenza B).
of mature virions • Oseltamivir is an oral prodrug (can cause
nausea and vomiting) whereas zanamavir
(low bioavailability) is administered
intranasally (bronchospasm is an important
adverse effect).

Oseltamivir marketed as TAMIFLU is the DOC for SWINE FLU (epidemic caused by H1N1) & bird flu (H5N1)

Anti viral drugs under trial:

• Resiquimod (topical immuno modulator): treatment of HSV
• Plecoranil (capsid binder): treatment of rhinovirus
• Maribavir (DNA synthesis inhibitor): treatment of CMV

TREATMENT OF VIRAL HEPATITIS

Acute hepatitis HBV Symptomatic treatment, no antivirals

HCV Peg-interferon-alpha-2b & Ribavarin
Chronic hepatitis HBV Oral Lamivudine, Adefovir, Tenofovir, Telbivudine
DOC: Entecavir Subcutaneous Peg-interferon-alpha-2a & Interferon-alpha-2b
HCV Treatment of choice is Peg-interferon-alpha, Viramidine (under trial) &
Ribavarin

INTERFERONS
• Interferons (α, β, γ) have antiviral & important immunomodulatory activities.
 • Mechanism: Bind to specific cell-surface receptors that initiate a series of intracellular events: induction of
certain enzymes, inhibition of cell proliferation, and enhancement of immune activities, including increased
phagocytosis by macrophages and augmentation of specific cytotoxicity by T lymphocytes.

Recombinant interferon alfa-2b

• Obtained by recombinant expression in E. coll.
• Indicated in the treatment of a variety of tumors, including hairy cell leukemia, malignant melanoma,
follicular lymphoma, and AIDS-related Kaposi's sarcoma.
• Also is indicated for chronic hepatitis B infection, condylomata acuminata, in combination with
• ribavirin for treatment of chronic hepatitis C in patients with compensated liver function not
• treated previously with interferon alfa-2b or who have relapsed after interferon alfa-2b therapy.

Interferon beta-la & interferon beta-1b:

• Approved for the treatment of relapsing and relapsing-remitting multiple sclerosis.

Interferon gamma-1b:
• Recombinant polypeptide that activates phagocytes and induces their generation of oxygen metabolites that
is toxic to a number of microorganisms.
• Indicated to reduce the frequency and severity of serious infections associated with chronic granulomatous
disease.

INTERFERON-α Chronic hepatitis B & C, Genital warts caused by papilloma virus, Hairy cell leukemia, chronic
myelogenous leukemia, Kaposi sarcoma
INTERFERON-β Relapsing remitting multiple sclerosis
INTERFERON-γ Chronic granulomatous disease

ANTI-FUNGAL AGENTS

Drug altering membrane
permeability
Drug blocking DNA synthesis
Drugs disrupting mitosis /
microtubule function
Drugs inhibiting cell wall
synthesis
Azoles Triazoles e.g. Fluconazole, itraconazoie, voriconazole, terconazole,
posaconazole
Imidazoles e.g. Ketoconazole, miconazole, clotrimazole,
econazole,butoconazole,oxiconazole, sertaconazole,
sulconazote
Terbinafine, butenafine & naftifine
Polyenes e.g. Amphotericin-B, Nystatin, Hamycin, Natamycin.
Flucytosine
Griseofulvin
Caspofungin, nikkomycin

• Clotrimazole, miconazole, nystatin, flucanozole & Econazole: can be used topically.

• Griseofulvin, Ketoconozole, itraconazole: only oral route

DRUGS FOR SYSTEMIC FUNGAL INFECTIONS

• Amphotericin B, Triazoles, Ketoconazole, flucytosine & echinocandins.

AMPHOTERICIN B
• Widely distributed except in the CNS.
• DOC for most systematic fungal infection including aspergillosis, candidaemia etc.
• Can be used intrathecally in fungal meningitis and locally for corner ulcers and keratitis.
• Toxicity can be reduced by giving as liposomal formulations.
• Adverse effects: Nephrotoxicity (renal tubular acidosis), HYPOKALEMIA, hypomagnesemia & anemia.
• Intrathecal administration may cause seizure and neurological damage.
 • IV infusion of amphotericin B can cause fever, chills, rigors, and hypotension, the so called "shake and bake"
adverse reactions.

AZOLES
These drugs act by inhibiting 14 a demethylase, (converts lanosterol to ergosterol.)

Drugs Pharmacology Uses

Ketoconazole Inhibits cytochrome CYP3A4 enzyme  narrow Useful in both dermatophytosis and deep
spectrum Decreases the formation of adrenal and mycosis.
gonadal steroids.
Fluconazole Maximum oral bioavailability and CNS penetration Candidiasis, coccidiodal and
cryptococcal meningitis.
Itraconazole entry in the CNS is limited  not used for CNS DOC in blastomycosis (non-meningeal),
fungal infections histoplasmosis, coccidiodomycosis,
paracoccidioidomycosis and
sporotrichosis
Voriconazole Widest spectrum Recent DOC in invasive aspergillosis
Adverse reactions: hepatotoxicity, visual
disturbances like blurred vision, altered colour
perception and photophobia, prolongs QT interval
Posaconazole Only drug active against mucormycosis
• Candida kruseiand the agents of mucormycosis are resistant to azotes.

FLUCYTOSINE
• Used against Cryptococcus and Candida. Has synergistic activity with Amphotericin-B.
• Adverse effects: bone marrow suppression, alopecia and liver dysfunction.

NYSTATIN
• Obtained from S. noursei, it is similar to Amphotericin-B in antifungal action.
• Used only locally because of higher systemic toxicity.
• Given orally, it is not absorbed; can be used for moniliat diarrhoea (due to superinfection).
• Nausea and bad taste in mouth are the only side effects.
• Combined with tetracyclines for the prevention of superinfection (due to Candida) diarrhoea.
• It is effective (but less than azoles) in Monilial vaginitis.
• Corticosteroid aerosols (e.g. beclomethasone) can cause oral candidiasis: nystatin is effective in preventing
as well as treating it.
• Used for corneal, conjunctival and cutaneous candidiasis in the form of an ointment.
• It is ineffective in dermatophytosis.

ECHINOCANDINS: (Caspofungin, micafungin and antidulafungin)

• Act by inhibiting the synthesis of β1, 3 glycan, a component of fungal cell wall.
• Caspofungin is approved only for invasive aspergillosis not responding for Amphotericin or voriconazole.

NIKKOMYCINS: act by inhibiting chitin synthesis.

'SYSTEMIC DRUGS FOR SUPERFICIAL FUNGAL INFECTIONS'

Griseofulvin
• Distributed in stratum corneum & acts by interfering with microtubule function in dermatophytes.
• Used for dermatophytoses of skin and hair (tinea infections) because it gets concentrated in keratin.
• It causes gastrointestinal disturbances, photosensitivity and liver dysfunction.
• It can also cause disulfiram like reaction with alcohol. its metabolism is induced by phenobarbitone.

Allylamines (terbinafine, naftifine and butenafine)

• Acts by inhibiting squalene epoxidase resulting in decreased ergosterol synthesis.
• Accumulation of squalene (toxic to the fungus).
Azoles: Ketoconazole, Fluconazole and itraconazole

TOPICAL DRUGS FOR SUPERFICIAL FUNGAL INFECTIONS

• Polyenes e.g. nystatin (used topically for local candida infections and orally for gastrointestinal fungi),
• Imidazoles
• Allylamines
• Ciclopirox olamine
• Benzoic acid with salicylic acid (Whitfield's ointment)
• Tolnaftate
• Undecylenic acid
• Haloprogin

CHOICE OF DRUGS FOR SYSTEMIC MYCOSES

Disease First choice Alternative
Oral/vaginal/cutaneous candidiasis Fluconazole/ Nystatin/ Clotrimazole Itraconazole
Disseminated candidiasis Amphotericin B/ Voriconazole Fluconazole
Cryptococcosis Amphotericin B + Flucytosine Fluconazole
Histoplasmosis Itraconazole/ Amphotericin B Fluconazole
Coccidioidomycosis Amphotericin B/ Fluconazole Itraconazole/ Ketoconazole
Blastomycosis Itraconazole! Amphotericin B Ketoconazole/ Fluconazole
Sporotrichosis (disseminated) Amphotericin B Itraconazole
Paracoccidioidomycosis Itraconazole Amphotericin B
Aspergillosis Amphotericin B/ Voriconazole Itraconazole
Mucormycosis Amphotericin B -
Chromomycosis Itraconazole Ketoconazole /Flucytosine
 XIII. ANTI MALARIALS AND OTHER ANTI – PARASITIC AGENTS

ANTI MALARIALS

CLASSIFICATION
• 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine.
• Quinoline-methanol: Mefloquine.
• Cinchona alkaloid Quinine, Quinidine
• Biguanides Proguanil (Chloroguanide) Chlorproguanil
• Diaminopyrimidines Pyrimethamine
• B-Aminoquinoline Primaquine, Bulaquine
• Sulfonamides and sulfone: Sulfadoxine, Sulfamethopyrazine, Dapsone
• Tetracyclines: Tetracycline,Doxycycline
• Sesquiterpine lactones: Artesunate, Artemether, Arteether
• Amino alcohols: Halofantrine, Lumefantrine
• Mannich base: Pyronaridine
• Na htho uinone: Atova uone

Primary tissue Erythrocytic schizonticides Exo-erythrocytic Sporonticides or

schizonticides schizonticides gametocides
• Kill schizonts in • Kill schizonts in the blood • Kill the exo- • Kilt the gametes
the liver (pre- • Used for the treatment of acute erythrocytic • Prevent transmission
erythrocytic) attacks a suppressive forms of malaria.
• Used for causal prophylaxis, not for prophylaxis • Used for radical
prophylaxis Fast acting: chloroquine, cure e.g.
• Gametes of P.Vivax:
e.g. proguanil, mepacrine, artemisinin , quinine Primaquine
chloroquine,
primaquine and derivatives, mefloquine,
mepacrine, quinine
tetracyclines halofantrine, atovaquone
• Gametes of P.vivax
Slow acting: proguanil,
and P.falciparum:
Pyrimethamine, sulfonamides,
proguanil,
tetracyclines
pyrimethamine,
artemesin

• Chloroquine, mepacrine & quinine: kill the gametes of P. vivax.

• Mepacrine: concentrated in liver
• Proguanil, pyrimethamine, primaquine & artemisinin derivatives: kill the gametes of both P. vivax & P.
falciparum.

CHLOROQUINE
• Drug possessing largest volume of distribution (>1300L).
• Well absorbed from the Gl tract and rapidly from intramuscular and subcutaneous sites.
• Binds moderately (60%) to plasma proteins
• Biotransformation via hepatic CYPs to metabolites, desethylchioroquine & bisdesethylchloroquine.
• Specifically binds to heme  preventing its polymerization to hemozoin  increased pH and the
accumulation of heme  oxidative damage to the membranes  leading to lysis of both the parasite and
the RBC.
• It is an erythrocytic schizonticide and has no effect on exo-erythrocytic stages.

Indication Adverse effects

 • Treatment and prophylaxis of non-falciparum & • Lichenoid eruptions
chloroquine sensitive P.falciparum malaria(DOC) • Peripheral neuropathy,
• DOC for treatment of malaria in pregnant women • Hypotension, myocardial depression (T
• Rheumatoid arthritis wave changes in ECG),
• Extra intestinal amoebiasis • Auditory impairment and toxic psychosis.
• Discoid lupus erythematosus,Lepra reaction • Prolonged use leads to liver damage &
• Infectious mononucleosis blindness due to retinal damage (Bull's eye
• Photogenic reactions maculopathy).
• Malaria • Precipitates porphyria, psoriasis and
• Giardiasis seizures.

QUININE
• DOC in chloroquine resistant malaria.
• Its d-isomer, quinidine can be used i.v. for severe P.falciparum infections.
• Can be used for the treatment of chloroquine resistant malaria in pregnancy
• Adverse effects:
o Hypoglycemia (always given in 5% D solution), manifested by palpitations, sweating and tachycardia.
o Cinchonism: gastrointestinal distress, vertigo, blurred vision, headache and tinnitus.
o Cardiac conduction abnormalities and hemolysis in G-6-PD deficient patients.

PRIMAQUINE
• It is a tissue (pre as well as exo-erythrocytic) schizonticide and gametocide.
• it is always used along with blood schizonticides for radical cure of malaria.
• It can cause methemoglobinemia and hemolysis in G-6-PD deficient patients. Contraindicated in pregnancy.
• It has no role in P.falciparum malaria because it has no exo-erythrocytic stage

MEFLOQUINE
• Used for treatment & prophylaxis of chloroquine resistant P.falciparum (Quinine should not be used).
• Administration with halofantrine or quinine is contraindicated as it causes prolongation of QT interval.
• It is effective as a single dose treatment of malaria.

ANTIFOLATE DRUGS
• These include Pyrimethamine, proguanil, sulfadoxine and dapsone.
• Proguanil is a prodrug and is activated to form cycloguanil.
• Pyrimethamine and cycloguanil act by inhibiting DHFRase.
• These are slow acting blood schizonticides that are active against chloroquine resistant P.falciparum
infections.

ATOVAQUONE
• It is a rapidly acting blood schizonticide that acts by collapsing the parasite's membrane.
• Proguanil potentiates its antimalarial action.
• It can also be used for pneumocystis jiroveci pneumonia and Toxoplasma gondii infections.

ARTEMISININ DERIVATIVES (Artemisinin, dihydroartemisinin, artesunate, artemether and arteether)

• Obtained from a Chinese herb Artemisia annua.
• These drugs generate highly active free radicals that damage parasite membranes.
• Fastest acting drugs against malaria. Artesunate has a very short half life.
• Used in multidrug resistant malaria & cerebral malaria.
• Artemisinin derivatives are not indicated for chemoprophylaxis of malaria.

HALOFANTRINE AND LUMEFANTRINE

• Halofantrine can cause potentially serious cardiotoxicity (even more if combined with mefloquine).
• Used for treatment of multidrug resistant malaria.
• Lumefantrine is a new drug similar to halofantrine and is always used along with artemether.
 MANAGEMENT OF MALARIA
Type of malaria DOC
Treatment Prophylaxis
P.vivax and chloroquine sensitive Chloroquine (in pregnancy also) Chloroquine
P.falciparum
Chloroquine resistant Quinine Mefloquinine
Quinine resistant Mefloquine Mefloquine
Mefloquine resistant Quinine + Doxycycline Sulfadoxine-
Proguanil + Atovaquone Pyrimethamine

• Fosmidomycin inhibits 1- deoxy-D-xylutose-5-phosphate isomerase & inhibits in vitro growth of P

falciparum.

DEGREE OF RESISTANCE- WHO

• Analyzed by studying the parasitemia for 28 days by doing smears on day 2, 7 & 28.
• In a normal response, parasite count falls to 25% of pre treatment value by 48 hours a smear should be ne
ative by 7 days.

R1 resistance Asexual parasitemia falls to<25% of pre treatment value, but reappears b/w 2-4 weeks
R 2 resistance Marked fall in Asexual parasitemia (decrease>25% but < 75%) in 48hrs, without complete
clearance in 7days
R3 resistance Minimal fall in Asexual parasitemia, decrease < 25% or an increase in parasitemia after 48 hours

TREATMENT OF PARASITIC INFESTATIONS

• All nematode infestations including cutaneous & visceral larva migrans, neurocysticercosis: Albendazole.
• Strongyloides, Onchocerca volvulus: -Ivermectin
• Enterobius: mebendazole (Pyrantel pamoate & albendazole equally effective)
• Dracunculus: metronidazole
• Chagas disease : Nifurtimox /beznidazole
• Wucheria brancofti, Brugia malayi, Loa loa: -Diethyl carbamazine
• Early stage of African trypanosomiasis(Sleeping sickness ): Suramin
• Late stage (CNS involvement) of African trypanosomiasis: Melarsoprol/ Melarsen oxide (Inhibitor of
trypanothione reductase).
• Visceral leishmaniasis: Liposomal Amphotericin-B
• All other forms of Kala azar & M/c used drug in kala azar: sodium stibogluconate (pentavalent ammonium
compound), given parenterally & can cause QT prolongation.
• Babesia species - Clindamycin + Quinine
• Balantidiurn coil - Tetracycline
• Cryptosporidium - Paromomycin
• Cyclospora cayetanensis / Isospora belli /Pneumocystis jiroveci - Trimethoprim-sutfamethoxazole
• Dientamoeba fragilis- lodoquinol
• Giardia lamblia- Metronidazole or Tinidazole
• Microsporidia -Albendazole
• Toxoplasma gondii:
o Acute, congenital, immunocompromised: Pyrimethamine + dindamycin + folinic acid
o Pregnancy: Spiramycin, 3 g daily until delivery.
• Trichomonas va inalis: Metronidazole

Trematodes Cestodes
o All except Fasciota hepatica - o All except Echinococcus granulosus - Praziquental
Praziquental o Echinococcus granulosus & Neurocysticercosis -
o Fasciola hepatica -Bithionol Albendazole

Antihelminthics:
 • Ganglionic nicotinic acetylcholine agonists: levamisole, pyrantel pamoate, oxantel pamoate and
bephenium.
• Direct or indirect GABA agonists: piperazine
• Acting on the chloride ion channel: milbemycins and avermectins.

Metrifonate
• Organophosphorus compound used as an insecticide and then as an anthelmintic, especially for S.
haematobium.
• Metrifonate is a prodrug that is converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethyl
phosphate, DDVP), a potent cholinesterase inhibitor.

Drugs used in the treatment of leishmaniasis

• Antimonial: Sodium stibogluconate (SSG)
• Diamidine: Pentamidine
• Antifungal drugs: Amphotericin B (AMB), Ketoconazole (KTZ)
• Others: Miltefosine, Paromomycin, Altopurinol.

Liposomal amphotericin B
• Highly effective for visceral leishmaniasis, and is currently the drug of choice for antimony-resistant disease.
• Not useful against cutaneous or mucosal leishmaniasis.

TISSUE AMOEBICIDES LUMINAL AMOEBICIDES

For both intestinal & extra For extra intestinal Amide 8- hydroxyquinolines Antibiotics
intestinal amoebiasis amoebiasis only
Nitro imidazoles: Chloroquine Ditoxanide Quinidochlor(lodoch Tetracyclines
Metronidazoles, Tinidazole, furoate, torohydroxyquin,
Secnidazole, Ornidazole, Nitazoxanide Clioquinol)
Satranidazole Diiodohydroxyquin
Alkaloids:
Emetine, Dehydroemetine
For asymptomatic carriers: iodoquinol/paramomycin

NITROIMIDAZOLES
Metronidazole:
• DOC for intestinal wall diseases and amoebiasis. Usually combined with a luminal amoebicide.
• Also the DOC for trichomoniasis, giardiasis, bacterial vaginosis and pseudomembranous colitis by Cl. difficile
and in infections caused by anaerobic bacteria like bacteroides and clostridium, and in combination therapy
for H.pylori.
• Nausea, metallic taste and abdominal cramps are the most common adverse effects.
• It can cause disulfiram like reaction if used patients taking alcohol.
• Metronidazole can potentiate the anticoagulant effects coumarins.
Secnidazole: longest half life
Satranidazole: devoid of metallic taste, neurological side effects & disulfiram like reaction.

OTHERS
• DILOXANIDE FUROATE: DOC in asymptomatic intestinal amoebiasis & carriers.
• EMETINE & DIHYDROEMETINE: used in severe hepatic amoebiasis.
• IODOQUINOL QUINODOCHLOR: luminal amoebicide. High doses  subacute rnyelooptic neuropathy.
• PARAMOMYCIN: aminoglycoside used as luminal amoebicide. Has some activity against cryptosporidiosis in
AIDS & approved for treatment in Kala azar.
• NITAZOXANIDE: approved only for treatment of giardiasis & cryptosporidiosis.
XIV. CHEMOTHERAPY, MONOCLONAL ANTIBODIES, IMMUNOSUPPRESSANTS &
IMMUNOSTIMULANTS

ANTI NEOPLASTIC DRUGS

• Divided on the basis of stage of cell cycle at which they act into two groups- cell cycle specific (CCS) and cycle
non- specific (CCNS).
Phase CCS drugs CCNS drugs
Kills only actively dividing cells. Kill resting as well as dividing
Toxicity is generally expressed in S phase cells
G1 Vinblastine Platinum compounds,
S Antimetabolites, Doxorubicin, Daunorubicin, Podophyllotoxins & Alkylating agents,
Camptothecins Anthracyclines, Dactinomycin,
G2 Bleomycin, Etoposide Mitomycin
M Vinca alkaloids, Taxanes

• Cytotoxic drugs act with first order kinetics i.e. a constant proportion of cells are killed with a given dose
rather than constant number of cells. This is called 'log kill hypotheses".

CLASSIFICATION OF ANTI CANCER DRUGS:

Alkylating Nitrogen mustards Mechlorethamine, cyclophosphamide, ifosfamide, melphalan,
agents chlorambucil
Ethylenimines Thio-TEPA, hexamethylmelamine (altretamine)
Alkyl sulfonates Busulphan
Nitroso ureas Carmustine, lomustine, streptozocin
Triazines Procarbazine, dacarbazine, temozolomide
Platinum Cisplatin, carboplatin, oxaliplatin
compounds
Anti- Pyrimidine analogs 5-FU, cytarabine, gemcitabine
metabolites Purine analogs 6-MP, 6-thiogunanine, pentostatin, cladribine
Folic acid analogs Methotrexate, pemetrexed
Natural Vinca alkaloids Vincristine, vinblastine, vinorelbine
products Taxanes Paclitaxel, docetaxel
Epipodophyltotoxins Etoposide, teniposide
(Topoisomerase-2
inhibitors)
Cam ptothecins Topotecan, irinotecan
{Topoisomerase-1
inhibitors)
Antitumor antibiotics Anthracyclines (daunorubicin, doxorubicin, epirubicin,
idarubicin, mitoxantrone), bleomycin, dactinomycin, mitomycin-
C
Enzymes L-Asparaginase
Hormones and Corticosteroids Prednisolone, prednisone
related agents Antiestrogens SERMS & Aromatase inhibitors E.g: Tamoxifen,
Aminoglutethimide, formestane, exemestane, anastrozole, vorozole,
letrozole etc...
Progestins Medroxyprogesterone acetate
Estrogen Diethylstilbestrol, ethinyl estradiol
Androgens Testosterone
Antiandrogens Flutamide
GnRH analogs Leuprolide, goserelin, nafareline, busureline, histerelin, triptorelin
GnRH antagonists Cetorelix, ganirelix, abarelix
Miscellaneo Biological response Recombinant IL-2 (aldesleukin), GM-CSF, G-CSF, monoclonal
modifiers antibodies
 us agents Substituted urea Hydroxyurea
Adrenal cortex suppressant Mitotane
Retinoids Isotretinoin
Arsenic compounds As2 O3
Adenosine deaminase Pentostatin
inhibitor
Targeted Tyrosine protein kinase Imatinib, Nilotinib
drugs inhibitors
EGF receptor inhibitors Gefitinib, Erlotinib Cetuximab
Angiogenesis inhibitors Bevacizumab, Sunitinib
Proteasome inhibitor Bortezomib
Unarmed monoclonal Rituximab, Trastuzumab
antibody

• Interleukin-2 (IL-2) is a cytokine biological agent that itself has antitumour property by amplifying killer T-cell
response.
• Other unarmed antitumour MAbs are: Trastuzumab, Bevacizumab, Alemtuzumab, Cetuximab
• Toxin-linked MAbs : Ozogamicin, Gemtuzumab
• Radioisotope carrying MAbs : Ibritumomab (90Y), Tositumomab (131I)

ANTIMETABOLITES
• Act in the S- phase of cell cycle (CCS drugs),  only dividing cells are responsive.
• These drugs also have immunosuppressive properties.

FOLIC ACID ANALOGS:

• Methotrexate & pemetrexed: inhibitors of dihydrofolate reductase (DHFRase) & thymidylate synthase.
• In rheumatic diseases inhibits aminoimidazolecarboxamide (AICAR) transformylase, with secondary effects
on polymorphonuclear chemotaxis.
• Methotrexate's concentration is increased in the presence of hydroxychloroquine.
• DOC: Choriocarcinoma, acute leukemias, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, breast
cancer, rheumatoid arthritis, Psoriasis and ectopic pregnancy.
• Other indications: juvenile chronic arthritis, psoriatic arthritis, polymyositis, dermatomyositis,
Wegener's granulomatosis, giant cell arteritis, subacute lupus erythematosus, and vasculitis.
• Adverse effects: Nausea and mucosal ulcers (M/C), progressive dose-related hepatotoxicity in the form of
enzyme elevation occurs frequently, but cirrhosis is rare (< 1%), Bone marrow suppression, pulmonary
infiltrates and fibrosis.
• Liver toxicity is not related to methotrexate concentrations, and liver biopsy follow-up is only
recommended every 5 years.
• Methotrexate crystallizes in renal tubules.
• Toxicity is reduced by N10 formyl- tetrahydrofolic acid (folinic acid or leucovorin). (Leucovorin rescue).
• In extreme cases, toxicity can be treated by dialysis or administration of GLUCARPIDASE, a methotrexate
cleaving enzyme.
• NSAIDs like aspirin, penicillins and cephalosporins may decrease the renal excretion of methotrexate and
result in toxicity.
• Pralatrexate is a similar drug indicated for peripheral T-cell lymphoma.

PURINE ANALOGS: {6-mercaptopurine (6-MP), fludarabine phosphate, cladribine and 6-thioguanine (6-TG))
• Activated by hypoxanthine- guanine phosphoribosyl transferase (HGPRTase).
• Mainly for the treatment of leukemias (both acute leukemias and CML).
• Dose limiting toxicity is bone marrow suppression ahepatotoxicity.
• Cladribine: DOC in hairy cell leukemia and chronic lymphocytic leukemia (CLL).

PYRIMIDINE ANALOGS: (cytarabine (cytosine arabinoside), 5-fluorouracil (5-FU), capecitabine, decitabine &
gemcitabine).
• Cytarabine is activated by kinase to form arabinoside CTP that is an inhibitor of DNA polymerase.
 • High dose of cytarabine can lead to neurotoxicity (ataxia and peripheral neuropathy).
• 5 FU cause single strand breaks and thus affects both DNA & RNA.
• Gemcitabineis a potent radiosensitizer andis the DOC for pancreatic cancer.
• Capecitabine and 5-FU can cause hand and foot syndrome (a form of erythro-metalgia manifested as
tingling, numbness, pain, erythema, swelling and increased pigmentation).
• Leucovorin augments the action of 5-FU.
• 5' -Azacytidine acts by DNA hypomethylation and is approved for treatment of myelodysplasia.

PLATINUM COMPOUNDS
• Platinum coordination complexes act analogously to alkylatingagents.
• They bind to DNA atnucleophilic sites of guanine producing alterations in DNA structure and inhibition of
DNA synthesis.
• Cross-linking of platinum between adjacent guanines on the same DNA strand is primarily responsible for the
cytotoxicity.
• They do not possess phase specific action in cell cycle.
• Oxliplatinin addition, blocks DNA replication and transcription
• Uses of cisplatin- Testicular, ovarian, bladder, lung, prostate, head and neck cancer.
• Cisplatin is associated with Predominant large-fibersensory neuronopathy

Adverse effects
• Nephrotoxicity, nausea, vomiting, hearing loss, anaemia, allergic reactions.
• Highest emetogenic, Ototoxic, Neurotoxic, Hypokalemia, Hypomagnesemia, Hypocalcemia,
Hypophosphatemia.
• Monitoring of seum magnesium levels is indicated.
• Development of secondary cancer- AML usually after4 or 5 years (Etoposide- acute non lymphocytic
leukemiawithin 1 to 3 yrs).

NATURAL PRODUCTS
VINCA ALKALOIDS:
• Vincristine, vinblastine and vinorelbine: inhibits polymerization of microtubules.
• Binds specifically to the microtubule protein tubulin & results in mitotic arrest at metaphase.
• Effective in M-phase of cell cycle.
• Vinblastine causes bone marrow suppression whereas vincristine is 'marrow sparing' but is neurotoxic

TAXANES:
• Paclitaxel and docetaxel interfere with mitotic spindle formation by preventing disassembly of microtubules.
• Cisplatin decreases paclitaxel clearance and paclitaxel can decrease doxorubicin.
• Cabazitaxel is a microtubule inhibitor indicated in combination with prednisone for hormone refractory
metastatic prostate cancer.
• Adverse effects: bone marrow suppression, neurotoxicity & hypersensitivity reactions (not docetaxel)

EPIPODOPHYLLOTOXINS:
• Etoposide and teniposide act by inhibiting topoisomerase II resulting in DNA damage
• Act at the junction of late S and early G2 phase of cell cycle.
• Adverse effects: gastrointestinal distress and myelosuppression.

CAMPTOTHECINS:
• Irinotecan and topotecan are obtained from Camptotheca acuminata tree & inhibits topoisomerase I.
• Irinotecan is bioactivated by carboxylesterases to the potent topoisomerase inhibitor SN-38.
• Gilbert's syndrome alters patient responses to irinotecan.
• Topotecan: used in advanced ovarian carcinoma.
• Irinotecan is used for the treatment of advanced colorectal carcinoma.
• Main adverse effect: myelosuppression and diarrhea.

ANTITUMOR ANTIBIOTICS
This group includes anthracycline antibiotics, mitoxantrone, bleomycin, dactinomycin and mitomycin. Except
bleomycin (acts in G2 phase), all other drugs are CCNS drugs.
• Anthracycline antibiotics act by inhibiting topoisomerase II.
• Generate semiquinone free radicals are responsible for cardiotoxicity (manifested in the form of
cardiomyopathy and congestive heart failure).
• This adverse effect can be reduced by using dexrazoxane (a free radical scavenger).
• Can cause "radiation recall reaction" (erythema and desquamation of skin at the site of radiation exposure).
• Mitoxantrone is least cardiotoxic.
• Dactinomycin (Actinomycin -D) acts by inhibiting DNA dependent RNA synthesis whereas mitomycin acts as
an alkylating agent after metabolism in the liver.
• Bleomycin acts in the G2 phase by causing DNA strand breakage and free radical formation.
• Hemolytic uremic syndrome represents the most dangerous toxic manifestation of mitomycin

TYROSINE KINASE INHIBITORS

• All tyrosine kinase inhibitors are metabolized by CYP 3A4 enzymes. Thus, these have the potential of drug
interactions.
• All tyrosine kinase inhibitors can be administered orally.
• Imatinib acts by inhibiting tyrosine kinase activated due to abl-bcr fusion (t 9, 22; Philadelphia
chromosome).
o Orally used for chronic phase of CML.
o Dasatinib and nilotinib are similar drugs used in case of imatinib resistance.
o Imatinib is the drug of choice for CML and gastro-intestinal stromal tumor (GIST).
o Imatinib shows remarkable therapeutic benefit in patients with:
 CML (BCR-ABL)
 GIST (KIT mutation positive)
 HES (hypereosinophilic syndrome)
 Dermatofibrosarcoma protuberans.

Drug Inhibits tyrosine kinase activated by Indication

Axitinib VEGFR-1,2,3 Advanced renal cell carcinoma
Bosutinib Abl-bcr,scr CML
Crizotinib c-MET,ALK Non-small cell lung carcinoma
Cabozantinib c-MET, VEGFR-2 Medullary carcinoma thyroid
Dasatinib Abl-bcr CML
Erlotinib EGFR Non-small cell lung carcinoma
Pancreatic carcinoma
Geftinib EGFR Non-small cell lung carcinoma
Imatinib Abl-bcr, c-KIT, PDGF CML GIST
Lapatinib Her-2/neu, erb-B2 Breast carcinoma
Nilotinib Abl-bcr CML
Pazopanib VEGFR-1,2,3 PDGFR α, β c-KIT Advanced renal cell carcinoma
Ponatinib Abl-bcr CML Philadelphia positive ALL
Regorafenib VDGFR2, TIE2 Colorectal carcinoma GIST
Ruxolitinib JAK 1,2 Myelofibrosis
Sorafenib VEGFR, PDGFR RAF Renal cell carcinoma, HCC
Sunitinib VEGFR, PDGFR c-KIT, FLT -3 Renal cell carcinoma
RET Pancreatic neuroendocrine tumors
GIST
Tofacitinib JAK Rheumatoid arthritis
Vandetanib VEGFR,EGFR Medullary carcinoma thyroid
Vemurafenib BRAF Malignant melaonma
 • Geftinib and Erlotinib are inhibitors of tyrosine kinase associated with epidermal growth factor receptor
(EGFR).
o Indicated for non-small cell lung cancer.
o Erlotinib is effective in cases affecting women, nonsmokers, and persons of Asian ethnicity as well as
cases involving adenocarcinoma and bronchioalveolar carcinoma histology.
o Erlotinib is also indicated for pancreatic carcinoma with gemcitabine.
o Patients with EGFR mutations respond to Erlotinib at significantly high rates, but patients with K-ras
mutations do not respond.
• Sorafenib and sunitinib inhibit multiple tyrosine kinases & used for renal cell cancer.
o Sorafenib is indicated for hepatocellular cancer.
o Sunitinib for GIST.
o These can cause hypertension as an adverse effect.
• Lapatinib is indicated for breast carcinoma. It inhibits tyrosine kinase associated with EGFR and her-2 /neu
receptors.
• Pazopanib is to from multi targeted tyrosine kinase inhibitor against VEGF receptors, PDGF receptor and c-
kit. It is approved for treatment of advanced renal cell carcinoma.

ENZYMES
• L-Asparaginase is an enzyme used for the treatment of leukemias and lymphomas.
• These tumorsrequire exogenous asparagine for growth.
• L-Asparaginase acts by depleting this amino acid in the serum.
• Given i.v. route & may cause severe hypersensitivity reactions, acute pancreatitis and cortical vein
thrombosis.

NEWER DRUGS
• Ixabepilone:
o It is a new drug approved for treatment of advanced breast carcinoma resistant to anthracyclines and
taxanes.
o It is given in combination with capecitabine.
o It acts by binding to tubulin and promoting microtubule stabilization, thereby arresting cells in the G2 -M
phase of cell cycle.
• Erbulin Mesylate: It is a microtubule inhibitor recently approved for treatment of patients with metastatic
breast cancer.
• Estramustine:
o It is a combination of estrogen and mechlorethamine (nitrogen mustard) and is used for the treatment
of prostatic carcinoma.
o It acts as anti-mitotic drug by binding to tubulin.
o It can produce estrogenic side effects (gynaecomastia and impotence).
• Bortezomib:
o It acts by inhibiting proteasome resulting in down regulation of NF-KB (involved in cell survival).
o It has been approved for treatment of resistant multiple myeloma.
• Zolendronic Acid: bisphosphonate indicated for the treatment of bony metastases and multiple myeloma.
• Vorinostat and romidepsin
o These are histone deacetylase inhibitors approved for cutaneous T-cell lymphoma.
• Mitotane
o It is indicated for the palliation of inoperable adrenocortical carcinoma. Concomitant spironolactone
interferes with adrenal suppression produced by mitotane.
• Aldesleukin
o It is recombinant IL-2 and can be used for the management of renal cell carcinoma and malignant
melanoma.
o Aldesleukin: Indicated for metastatic renal cell carcinoma and melanoma.
o Administration of aldesleukin has been associated with serious cardiovascular toxicity resulting from
capillary leak syndrome, which involves loss of vascular tone and leak of plasma proteins and fluid into the
extravascutar space.
o Hypotension, reduced organ perfusion, and death may occur. An increased risk of disseminated
infection due to impaired neutrophil function also has been associated with aldesleukin treatment.
 • Denileukin deftitox
o It is a combination of IL-2 with diphtheria toxin and is used for cutaneous T cell lymphoma. Adjuvant
chemotherapy is administered after surgery or radiotherapy while neoadjuvant chemotherapy means
administered of anti-cancer drugs before surgery or radiotherapy.
o Neoadjuvant chemotherapy is used for cancers of
 Bladder
 Breast
 Colorectal
 Esophagus
 Stomach
 Lung (non-small cell)

SIDE EFFECTS
Distinctive toxicities of alkylating agents Distinctive toxicities of antimetabolites
Cyclophospha Alopecia, hemorrhagic cystitis 6-MP and 6TG Hepatotoxicity
mide Methotrexate Mucositis, hepatotoxicity
Ifosfamide Hemorrhagic cystitis 5-FU Hand and foot syndrome, neurotoxicity
Busulphan Pulmonary fibrosis, hyper Capecitabine Hand and foot syndrome
pigmentation. Adrenal insufficiency
Procarbazine Secondary leukemias, disulfiram Cytarabine Cerebellar ataxia
like reactions
Cisplatin Emesis, Nephrotoxicity, ototoxicity, Fludarabine Arthralgia
peripheral sensory neuropathy Gemcitabine Diarrhea

 All alkylating agents are myelo suppressive & cause veno occlusive disease of liver (treatment: defibrotide)
 They can cause sterility and secondary leukemias.
 All antineoplastic antimetabolites can cause bone marrow suppression

Toxicities of natural anticancer drugs Toxicities of hormonal agents

Bleomycin Pulmonary fibrosis Flutamide Hot flushes, liver dysfunction
(marrow sparing)
Anthracyclines Cardiotoxicity SERMs Menopausal symptoms, fluid retention,
thromboembolism, Ca.
Endometriuni
Paclitaxel Peripheral neuropathy, Progestins Fluid retention
Hypersensitivity
Docetaxel Peripheral neuropathy, Steroids Fluid retention, hypertension,
Fluid retention diabetes
Irinotecan Diarrhea GnRH agonists Impotence, Gynecomastia, osteoporosis
Vincristine Peripheral neuropathy Aminoglutethimide Adrenal insufficiency, myelosuppression,
(marrow sparing) rash

All natural anticancer products can cause bone marrow suppression except bleomycin and vincristine

Side effects Drug

Pulmonary fibrosis
No pulmonary fibrosis
Vomiting/ nausea
Maximum immunosuppression
Minimum bone marrow toxicity
Bleomycin, Busulphan, Cyclophosphamide, melphalan, methotrexate,
Methysergide, Amiodarone, acyclovir, nitrofurantoin
Doxorubicin, Methyldopa
Mithramycin, Actinomycin-D, dacarbazine, Cyclophosphamide
Methotrexate
Cisplatin

Maximum alopecia Cyclophosphamide, Dactinomycin

Skin pigmentation Arsenic, busulphan, Clofazimine, Chlorpromazine, Cyclophosphamide, Dapsone

MALIGNANCIES RESPONSIVE TO CHEMOTHERAPY

Diagnosis Hairy cell leukemia Current treatment of choice Cladribine

AML Cytarabine + daunorubicin/Idarubicin
CML Imatinib
CLL FCR or fludarabine
ALL Induction:Vincristine + Prednisolone + Daunorubicin + Asparaginase +
intrathecal Methotrexate
Consolidation: Hyper-CVAD alternated with Cytarabine + Methotrexate
Hodgkin disease ABVD
Non-Hodgkin Lymphoma CHOP-R
Multiple Myeloma Bortezomib + Dexamethasone + Lenalidomide
Waldenstrom Macroglobulinemia Fludarabine + Cyclophosphamide + Rituximab
Polycythemia vera Hydroxyurea
Non small cell lung Ca Cisplatin + Vinorelbine + Bevacizumab
Small cell lung Ca Cisplatin + Etoposide
Mesothelioma Cisplatin + Pemetrexed
Ca. head and neck Cisplatin + 5-FU
Ca.of oesophagus Cisplatin + 5-FU
Uterine Ca Progestins/ Tamoxifen/ Aromatase inhibitors
Carcinoma of ovary Cisplatin +carboplatin
Cisplatin/ Doxorubicinplus
+ Paclitaxel
Paclitaxel
Carcinoma or cervix Cisplatin plus Paclitaxel
Choriocaranoma Methotrexate/dactinomycin
Carcinoma of testis Combination chemotherapy : Cisplatin, bleomycin, and Etoposide
Ca. Kidney Sunitinib
Ca. Bladder Gemcitabine + Cisplatin
Ca. Prostate GnRH agonist + Anti androgens
Astrocytoma/ GBM Temozolomide
Neuroblastoma Cyclophosphamide + Doxorubicin + Cisplatin + Etoposide
Carcinoma of thyroid Radioiodine / Sorafenib
Carcinoma of stomach 5-Fluorouracil + Cisplatin + Epirubicin
Ca. Pancreas Gemcitabine
Colon Ca. Folinic Acid + 5-Fluoro uracit + oxaliplatin + Bevacizumab
Folinic Acid + 5-Fluoro uracil + irinotecan + Bevacizumab
Rectal Ca. Radiotherapy + 5-FU
Anal Ca. Radiotherapy + 5-FU
Multiple myeloma Melphalan plus prednisone or multi agent combination chemotherapy
Macroglobutinemia Chlorambucil or fludarabine
Carcinoma of adrenal gland Mitotane
Osteosarcoma Doxorubicin/ Cisplatin/ Ifosfamide/ high dose methotrexate
Soft tissue sarcoma Mesna + Adriamycin + Ifosfamide +Dacarbazine
Melanoma Dacarbazine
Hepatocellular Ca. Sorafenib
Kaposi sarcoma Liposomal doxorubicin /Daunorubicin
Wilms' tumor Vincristine plus dactinomycin after surgery and radiotherapy.
Carcinoid Doxorubicin plus cyclophosphamide, fluorouracil, octreotide.
Insulinoma Streptozocin +interferon.
Streptozocin, 5-FU
Refractory cases of TTP Vincristine
 Hyper eosinophitic syndrome Hydroxyureas.
Refractory cases of nephrotic Cyclophosphamide
syndrome
Sickle cell anemia or thalassemia Hydroxyurea.

Acronyms in cancer therapy:

• ABVD: Doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine
• CHOP: Cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin), prednisone
• CMF: Cyclophosphamide, methotrexate, fluorouracil
• COP: Cyclophosphamide, vincristine (oncovin), prednisone
• FAC: Fluorouracil, doxorubicin (adriamycin), cyclophosphamide
• FEC: Ftuorouracil, epirubicin, cyclophosphamide
• IFL: Irinotecan, fluorouracil, leucovorin
• MP: Melphatan, prednisone
• MOPP: Mechtorethamine, vincristine (oncovin), procarbazine, prednisone
• PCV: Procarbazine, lomustine, vincristine
• PEB: Cisplatin (platinum), etoposide, bleomycin
• VAD: Vincristine, doxorubicin (adriamycin), dexamethasone

Drug avoided in Ca. Breast with MI & CCF Anthracyclines.

Chemotherapeutic drugs can cause Necrosis and apoptosis.
M/C side effect of chemotherapy administration is Nausea.
Peripheral neuropathy can occur with the use of Vincristin, Cisplatin, procarbazine.
Pulmonary fibrosis is the most common complication of Bleomycin.
Hemorrhagic cystitis is caused by Cyclophosphamide
The primary target of chemotherapeutic drugs is Tumor stem cells.
Chemotherapeutic agents work by First order kinetics.
Anti folate agent that inhibits the dihydrofolate reductase Methotrexate
Anticancer drugs which inhibits mitosis Vinca alkaloids
Most common side effect of vincristine Peripheral sensory neuropathy
Most widely used alkylating agent Cyclophosphamide
Enzyme ineffective in solid tumors & used as anticancer agent L-asparaginase.
Drugs causing delayed bone marrow toxicity Nitrosoureas and mytomicin C.
Anticancer drug having prethrombotic potential L-asparagmase.
Most common dermatatologic side effect of anticancer Alopecia
drugs
Most nephrotoxic anticancer drug Cisplatin.
Anticancer drug causing blue urine Mitoxantrone
Anticancer agent causing renal tubular toxicity Cisplatin
M/C secondary malignancy due to anti neoplastic agents Acute non-lymphocytic leukemia.
Anti invasion agent used to reduce the cellularity of tumor mass Batibastat.
Used in Hodgkin's disease & a powerful vesicant Mechlorethamine

ADJUNCTS TO CHEMOTHERAPHY:
Drugs Mechanism Indication
Allopunnol Inhibit Xanthine Oxidase Prevent hyperuricemia due to tumor lysis syndrome
Rasburicase Recombinant Xanthine oxidase
Mesna Neutralizing agent Prevent hemorrhagic cystitis due to ifosfamide &
cyclophosphamide
Leucovorin Replete tetrahydrofolic acid Rescue after high dose methotrexate
Amifostine Prevent radiation induced xerostomia & cisplatin
induced nephrotoxicity
Dexrazoxane Iron chelators Prevent cardiotoxicity due to Anthracyclines
Palifermin Keratinocyte growth factor Prevent mucositis due to chemotherapy
Pilocarpine Cholinergic agonist Radiation induced xerostomia
Pamidronate & Bisphosphonates Hypercalcemia of malignancy
Zoledronate
Epoetin-alpha and Erythropoietin Anemia
Darbopoetin-alpha
Filgrastim, Peg- G-CSF and Febrile neutropenia prophylaxis
Filgrastim GM-CSF
Sargramostim
Oprelvekin IL-11 Thrombocytopenia
Ondansetron, 5-HT3 antagonist Nausea and vomiting
Granisetron,
Palonosetron
Aprepitant NK-1 antagonist Cisplatin-induced delayed vomiting

CO-STIMULATION INHIBITOR
• Abatacept acts by inhibiting CD 80 and CD 86 molecules present on APC.
• It is used for the treatment of severe rheumatoid arthritis resistant to DMARDs.
IL-1 INHIBITOR: Anakinra is an inhibitor of IL-I used in septic shock and RA.
• It can be used alone or in combination with anti- TNF agents such as etanercept, infliximab, or adalimumab.
• Indicated in neonatal-onset inflammatory disease, Muckle-Wells syndrome, and familial cold urticaria, as
well as systemic juvenile-onset inflammatory arthritis and adult-onset Still's disease.
• Canakinumab is an IL-1β monoclonal antibody approved for Cryoprin-associated periodic syndromes (CAPS),
a group of rare inherited inflammatory diseases associated with overproduction of IL-1 that includes Familial
Cold Autoinflammatory and Muckle-Wells Syndromes.
• Patients should not take other anti-TNF drugs or anakinra while taking abatacept.
• Canakinumab is also being evaluated for use in chronic obstructive pulmonary disease.
• Rilonacept (IL-1 TRAP) is another IL-1 blocker (a fusion protein that binds IL-1) that is now being evaluatedin
a phase 3 study for gout.

Emetogenic potential of cytotoxic drugs

High Moderate Mild
Cisplatin Carboplatin Bleomycin
Mustine Cytarabine Chlorambucil , Busulfan
Cyclophosphamide Procarbazine Fluorouracil
Actinomycin D Vinblastine 6-Thioguanine
Dacarbazine Doxorubicin Hydroxyurea
Lomustine Daunorubicin Vincristine, Methotrexate
Ifosfamide Etoposide
6-Mercapto- purine L-Asparaginase

IMMUNOSUPPRESSANTS
GLUCOCORTICOIDS: Most commonly used immunosuppressant drugs.
Mechanisms of action uses
• Inhibiting the production of prostaglandins, First line immunosuppressive drugs for:
teukotrienes, histamine, bradykinin and PAF. • Solid organ transplant
• Diminishing the chemotactic activity of • Hematological stem cell transplant treatment of
neutrophils and monocytes. graft rejection
• Causing sequestration of lymphocytes in • Graft versus host diseases (GVHD) treatment of
lymphoid tissue resulting in lymphopenia. ITP
• Inhibiting IL-1 production, decrease in 1L-2 and • Rheumatoid arthritis
IFNy production. • Bronchial asthma
• Continuous administration of Glucocorticoids
can increase the catabolism of lgG.
CALCINEURIN INHIBITORS:
• Cyclosporine and tacrolimus (FK 506) inhibits the activation of NFAT by binding to immunophilins
(cyclosporine binds to cyclophilin and tacrolimus binds to FKBP).
• Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis.
• Cyclosporine and tacrolimus inhibits gene transcription of IL-2.
• Used as immunosuppressive agents for organ transplantation, GVHD and some autoimmune diseases like
rheumatoid arthritis and psoriasis.
• Can cause nephrotoxicity, hypertension, Hyperkalemia, hyperglycemia, hirsutism and neurotoxicity.
• Incidence of hyperglycemia and neurotoxicity are more with tacrolimus than cyclosporine.
o Tacrolimus is more potent than cyclosporine.
o Tacrolimus is a macrolide antibiotic.

INHIBITORS OF mTOR
Sirolimus (rapamycin) binds to mTOR & inhibits the action of IL-2 without affecting transcription.
• Used as immunosuppressive agent in organ transplantation and GVHD.
• Incorporated in cardiac stents to decrease the chances of reocclusion.
• Adverse effects: thrombocytopenia. Everolimus is useful in cardiac transplantation.

PURINE SYNTHESIS INHIBITOR

• Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase after conversion to its active
metabolite mycophenolic acid.
• This enzyme is necessary for synthesis of purines.
• It is used as immunosuppressant in patients who are refractory to steroids
• GI disturbances and myelosuppression are major adverse effects of this drug.

ANTIMETABOLITES
• Azathioprine is the only antimetabolite that is used as immunosuppressant but not as an anticancer drug.
• It is a prodrug and is activated in the body to 6-mercaptopurine (anticancer drug).
• It lacks anticancer properties because conversion to active metabolite occurs only in lymphoid cells.
• Its major metabolite, 6-Thioguanine suppresses inosinic acid synthesis, B cell and T cell function,
immunoglobulin production, and IL-2 secretion.
• Major toxic effect is bone marrow suppression.

OTHER CYTOTOXIC AGENTS

Cyclophosphamide and methotrexate are other anticancer drugs that can be used as immuno suppressants.

LEFLUNOMIDE
• Active metabolite of this prodrug inhibits Dihydro-orotate dehydrogenase  inhibition of pyrimidine
synthesis.
• Liver and kidney damage are major toxicities.
• Also used in the treatment of polyomavirus nephropathy seen in immunosuppressed renal transplant
recipients.

THALIDOMIDE
• It is a sedative drug that was withdrawn due to teratogenic (phocomelia) effects.
• Reintroduced for its anti angiogenic, immunomodulatory and anti-inflammatory effects.
• Currently, it is being used for multiple myeloma, erythema nodosum leprosum and skin manifestations of
SLE.
• Important adverse effects of thalidomide include tetratogenicity, peripheral neuropathy, sedation,
constipation, hypothyroidism and increased risk of thrombosis particularly DVT.
• Immunomodulatory, derivatives of thalidomide are termed IMiDs. Lenalidomide is an IMiD approved for
myelodysplastic syndrome and multiple myeloma.
• Another group of thalidomide analogs, SelCIDs (SELective Cytokin Inhibitory Drugs) are phosphodiesterase-4
(PDE 4) inhibitors with potent anti-TNFa activity.
GENE THERAPY
Gene therapy refers to the introduction of functional genetic material into target cells to replace or supplement
defective genes, or to modify target cells so as to achieve therapeutic goals.

Approaches in gene therapy Applications of gene therapy

• Gene modification • Cystic fibrosis, Severe combined immuno deficiency
• Gene insertion • Growth hormone deficiency, Familial hypercholesterolemia
• Gene transfer • Lesch-Nyhan syndrome, Parkinsonism, Alzheimer's,
• Gene deletion • Gaucher's disease.
• Multiple Sclerosis, DMD, Cancer, HIV

FDA APPROVED MONOCLONAL ANTIBODIES & TARGETED THERAPIES

Antibody Type Target Approved for treatment of
Abciximab Chimeric Inhibition of glycoprotein High risk angioplasty
Ilb/Illa
Adalimumab Human Inhibition of TNF-α signaling Inflammatory disease-mostly autoimmune
disorder like rheumatoid arthritis, psoriatic
arthritis
Alemtuzumab Humanized CD52 Chronic lymphocytic leukemia, T-cell
lymphoma
Basiliximab Chimeric IL-2Rα receptor (CD25) Transplant rejection
Bevacizumab Humanized Vascular endothelial growth Metastatic colorectal cancer, non-small cell
factor (VEGF) lung cancer, metastatic breast cancer
Cetuximab Chimeric Epidermal growth factor Colorectal cancer, head and neck cancer
receptor (EGFR)
Certolizumab Humanized Inhibition of TNF-α signaling Crohn's disease, rheumatoid arthritis
pegol
Daclizumab Humanized IL-2Ra receptor (CD25) Transplant rejection

Dasatinib Targeted Bcr-abl, scr family, c- CML, ph+ ALL

kit,EPHA2,PDGFR-B
Erlotinib Targeted EGFR Non-small cell lung cancer

Eculizumab Humanized Complement system protein C5 Paroxysmal nocturnal hemoglobirturia

Efalizumab Humanized CD11a Psoriasis

Gemtuzumab Humanized CD33 Acute myelogenous leukemia (with

calicheamicin)
Golimumab Humanized TNFa Rheumatoid a psoriatic arthritis, active
ankylosing spondylitis
Imatinib Targeted c-kit,bcr-abl,PDGFR CML, GIST

Ibritumomab Murine CD20 Non-Hodgkin lymphoma, (with yttrium-90

tiuxetan or indium-111)
Infliximab Chimeric Inhibition of TNF-a signaling Several autoimmune disorders like Crohn's
disease
Lapatinib Targeted EGFR and HER2 Breast cancer

Muromonab- Murine T cell CD3 Receptor Transplant rejection

CD3
Natalizumab Humanized Alpha-4 (α4) integrin Multiple sclerosis and Crohn's disease

Omalizumab Humanized Immunoglobulin E (IgE) Mainly allergy-related asthma

 Palivizumab Humanized An epitope of the RSV Fusion Respiratory syncytial virus
protein
Panitumumab Human Epidermal growth factor Metastatic colorectal carcinoma
receptor
Ranibizumab Humanized Vascular endothelial growth Macular degeneration
factor A (VEGF-A)
Rituximab Chimeric CD20 Non-Hodgkin lymphoma, CLL

Sunitinib Targeted Second-generation receptor RCC, Imatinib resistant GIST, Progressive

tyrosine kinase inhibitors GIST, progressive well-differentiated
Sorafenib Targeted Raf, PDGF, VEGFR, c-kit pancreatic
RCC neuroendocrine tumors (pNET)

Temsirolimus Targeted m-TOR RCC

Tositumomab Murine CD20 Non-Hodgkin lymphoma

Trastuzumab Humanized erbB2/HER2-neu Breast cancer

(Herceptin)

Monoclonal Antibody Target Indication

Etanercept TNF α RA
Alefacept LFA-3 Plaque psoriasis
Donesumab RANK ligand Osteoporosis

IMMUNOST/MULANTS
• Levamisole
o It is used along with 5-FU for treatment of Dukes' stage C colon cancerafter surgery.
o Agranulocytosis is major adverse effect.
o It is also used for the treatment of pediculosis.
o It was also used as an antihelminthic drug via stimulation of ganglionic nicotinic receptors.
• BCG
o Bacillus Calmette Guerin is a viable stain of Mycobacterium bovis and is useful as intravesical therapy of
superficial bladder cancer.
o Cytokines
o These include interferons, colony stimulating factors (CSF) and various interleukins.
o Recombinant form of IL-2 (Aldesleukin) is useful in malignant melanoma and renal cell carcinoma.
o Filgrastim (recombinant G-CSF) and sargramostim (recombinant GM-CSF) are useful for chemotherapy
induced myelosuppression.
• Thalidomide: It is indicated for the treatment of ENL and multiple myeloma.

Imiquimod:
• It is an immune response modifier shown to be effective against external genital and pen-anal warts (i.e.
condyloma acuminata) by topical route.
• It act by releasing IFN α and cytokines like IL-1, IL-6 and TNF α etc.
• It has also been approved for basal cell carcinoma and actinic keratosis of the face and scalp.
• Off-label applications include the treatment of nongenital warts, molluscum contagiosum, extramammary
Paget's disease and Bowen's disease.
 XV. SPECIAL TOPICS

DRUGS DURING PREGNANCY

Risk Category of Drugs during Pregnancy
Category Examples
A No risk Adequate studies in pregnant women have failed to Magnesium sulfate,
demonstrate a risk to the foetus thyroxine
B No evidence Adequate human studies are lacking, but animal studies have Penicillin V, erythromycin,
of risk in failed to demonstrate a risk to the foetus OR Adequate paracetamol, cefaclor,
humans studies in pregnant women have failed to demonstrate a risk lignocaine, amoxicillin
to the foetus, but animal studies have shown an adverse
effect on the foetus
C Risk cannot No adequate studies in pregnant women and animal studies Morphine, codeine,
be ruled out are lacking OR have shown and adverse effect on foetus, but atropine, corticosteroids,
potential benefit may warrant use of the drug in pregnant adrenaline, thiopentone,
women despite potential risk bupivacaine
D Benefit may There is evidence of human foetal risk, but the potential Aspirin, phenytoin,
outweigh benefits from use of the drug may be acceptable despite Carbamazepine, valproate,
potential risk the potential risk lorazepam, methotrexate
X Contraindicate Studies in animals or humans have demonstrated foetal Estrogens, isotretinoin,
d abnormalities, and potential risk clearly outweighs possible ergometrine, thalidomide
benefit

Choice of drugs for common problems during pregnancy

Drug class (condition) Safety uncertain/unsafe Safer alternative

Anti-emetics (morning
sickness, other types of
vomiting)
Drugs for peptic ulcer and
GERD
Laxatives (constipation)
Antidiarrhoeals
Analgesics (headache, body
ache, joint pain, visceral pain)
Cold-cough remedies
Anti-allergics
Antibacterials (systemic
bacterial infections)
Anti-tubercular
Anti-amoebic
Domperidone (X)
Ondansetron
Cimetidine, Lansoprazole Cisapride (X),
Mosapride
Senna, Bisacodyl, Docusates
Saline purgatives
Diphenoxylate-atropine, Loperamide
Aspirin, Metamizol, NSAIDs COX-2
inhibitors, Codeine Dextropropoxyphene,
Morphine (X) Pethidine, Tramadol
Codeine, Dextromethorphan
Bromhexine, Expectorants
Cetirizine, Loratadine
Fexofenadine, Astemizole (X)
Cotrimoxazole, Fluoroquinolones (X),
Tetracycline (X), Doxycycline (X),
Chloramphenicol (X), Gentamicin,
Streptomycin (X), Kanamycin (X),
Tobramycin (X), Clarithromycin,
Azithromycin, Clindamycin, Vancomycin,
Nitrofurantoin
Pyrazinamide, Streptomycin (X)
Metronidazole, Tinidazole
Quiniodochlor
Promethazine, Doxylamine
Dicyclomine, Prochlorperazine
Metoclopramide
Ranitidine, Famotidine
Omeprazole, Pantoprazole,
Dietary fibre, Ispaghula
Lactulose
Oral rehydration salts
Paracetamol Ibuprofen (low does)
Xylometazoline,Oxymetazoline,
Budesonide (Nasal drops)
Chtorpheniramine
Promethazine
Penicillin G, Ampicillin
Amoxiciltin-clavutanate
Cloxacillin, Piperacillin
Cephalosporins
Erythromycin
Isoniazid, Rifampicin, Ethambutol
Diloxanide furoate, Paromomycin
Antimalarial
Anthelmintic
Antifungal (superficial
and deep mycosis)
Antiretroviral (HIV-AIDS)
Antiviral (other than HIV)
Anti-hypertensives
Artemether, Artesunate
Primaquine (X)
Albendazole (X), Mebendazole (X)
Ivermectin, Pyrantel pamoate,
Diethylcarbamazine (X)
Amphotericin B (X), Fluconazole
Itraconazole (X), Ketoconazole (X)
Griseofulvin (X), Terbinafine
Didanosine, Abacavir,Indinavir
Ritonavir, Efavirenz
Acyclovir, Ganciclovir (X)
Foscarnet (X), Amantadine (X)
Vidarabine (X), a-interferon (X)
ACE inhibitors (X), Angiotensin
antagonists (X), Thiazide diuretics,
Furosemide, Propranolol Nitroprusside
Chloroquine, Mefloquine,
Proguanil Quinine (only in l't
trimester), Pyrimethamine +
Sulfadoxine (only single dose)
Piperazine
Niclosamide
Praziquantal
Clotrimazote,
Nystatin,
Tolnaftate (Topical)
Zidovudine, Lamivudine,
Nevirapine, Nelfinavir, Saquinavir
-
Methyldopa, Hydralazine,
Atenolol, Metoprolol, Pindolol,
Nifedipine Prazosin, Clonidine

Antianaemic - Iron salts (oral), Iron dextran (i.m.)

Folic acid, Vit B12
Anti-diabetics Sulfonylureas (X), Metformin (X) Insulin (preferably human insulin)
Pioglitazone, Repaglinide, Nateglinide,
Acarbose (X)
Corticosteroids Betamethasone, Dexamethasone Inhaled corticosteroids
(high does and prolonged use) Topical corticosteroids
Prednisolone oral (low does)
Thyroid hormone - Thyroxine
(hypothyroidism)
Anti-thyroid drugs Carbimazole, Radioactive iodine (X) Propylthiouracil
(thyrotoxicosis) Iodine
Antipsychotic Chlorpromazine, Fluphenazine (X) Haloperidol
(schizophrenia) Clozapine, Olanzapine, Risperidone Trifluoperazine
Anti-maniac (bipolar illness) Lithium carbonate, Valproate -
Carbamazepine
Anti-depressants Trimipramine (X), Dothiepin (X) Amitriptyline, Imipramine,
Sertratine, Paroxetine, Citalopram Fluoxetine
Trazodone, Venlafaxine Moclobemide
Anti-coagulants Warfarin (X), Acenocoumarol Phenindine Heparin (unfractionated)
(thromboembotism) (X) Heparin (LMW)
Anti-asthmatic Theophylline, Ketotifen (X) Montelukast, Salbutamol/Salmeterol,
Zafirlukast Ipratropium bromide
Systemic corticosteroids Beclomethasone/
Budesonide
Sod. Cromoglycate-Inhaled

DRUGS OF CHOICE IN PREGNANCY:

• Muscle relaxant- d-Tubo curarine
• Anti-convulsant-Pheno barbital
• Eclampsia-Magnesium sulphate
• Hypertensive crisis: labetalol, hydralazine, NTG
• UTI- Nitrofurantoin, Ampicillin, Cephalosporins
• Chlamydia: Azithromycin/ erythromycin
 • DMARD: hydroxychloroquine
• Ventricular arrhythmia: IV lidocaine> Quinidine
• Supraventricutar tachycardia: Adenosine
Vertical transmission:
• HIV- Zidovudine, Nevirapine
• Toxoplasma- Spiramycin

CATEGORY-X DRUGS
• ANTIEMETIC: Domperidone
• ANALGESIC : Morphine
• ANTIBIOTICS : Fluoroquinolones, Tetracycline, Doxycyctine, chloramphenicol, Streptomycin, Kanamycin,
Tobramycin
• ANTITUBERCULAR : Streptomycin
• ANTIAMOEBIC : Tinidazote
• ANTIMALARIAL : Quinine, Sulfadoxine, Primaquine
• ANTIHELMINTHIC : Mebendazole, DEC
• ANTIFUNGAL : Amphotericin - B, Itraconazole, Ketoconazole, Griesofulvin
• ANTIVIRAL : Gancickovir, Foscarnet, Amantadine, a-interferon
• ANTIHYPERTENSIVE : ACE inhibitors, Angiotensin antagonist
• ANTIDIABETIC : Sulfonylurea, Acarbose, Metformin
• ANTICOAGULANT : Warfarin
• OTHERS : Thalidomide, Alcohol, Radioactive iodine, Isotretinoin, Cytotoxic drugs

CHELATING AGENTS
Agent Used for Contraindication Specific points
Dimercaprol (BAL) All heavy metals. Specific for Iron and cadmium As adjuvant to EDTA in lead
mercury. Others: Au, Bi, Sb poisoning poisoning & Penicillamine in
Cu poisoning
Desferrioxamine Iron chelator Acute iron poisoning, Transfusion
Deferiprone Siderosis, Iron toad in liver
Cirrhosis
Dexrazoxane Iron Doxorubicin induced
cardiomyopathy
Calcium disodium Specific for lead poisoning Hg poisoning
edetate EDTA Also in, Cd, Mn, Cu, Fe,
Poisoning
Penicillamine Specific for Cull-Ig poisoning Adjuvant to EDTA
Wilson disease: now II DOC to zinc

Trientine Cu poisoning disease Wilson disease

Zinc acetate Wilson disease

SPECIFIC ADVERSE EFFECTS OF DRUGS

Colour vision alteration Glaucoma Ototoxicity (vestibular) Ototoxicity (Auditory)
Sulfonamides Mydriatics Aminoglycosides NSAIDs, vancomycin,
Thiazides TCAs Mustine ethacrynic acid,
Barbiturates Corticosteroids Quinidine aminoglycosides
Digitalis Sympathomimetics Quinine, Chloroquine
Ethambutol Vancomycin
Quinine Furosemide
Streptomycin Ethacrynic acid
Salicylates (high dose)

Megaloblastic anemia Aplastic anemia Hemolytic anemia in G-6-PD deficiency

 Pentamidine Chloramphenicol Primaquine, furazolidone, chloramphenicol,
Methotrexate Phenytoin dapsone, aspirin, quinidine, procainamide,
Trimethoprim Gold salt nalidixic acid, quinine, cotrimoxazole,
Cotrimoxazole Carbamazepine nitrofurantoin, sulfonamides,
N2O Phenylbutazone phenazopyridine (urinary analgesic used in
Oral Contraceptives Sulfonamides cystitis)
Metformin Zidovudine
Primidone Colchicines
Phenobarbitone Carbimazole
Phenytoin Quinacrine
Triamterene Felbamate
Cytotoxics
Thioamides
Trimethadione

Decreased libido/ impotence Hyperprolactinemia

β- blockers, antipsychotics, lithium, clonidine, Phenothiazines, butyrophenones, TCAs, reserpine,
diuretics, methyl dopa, oral contraceptives, methyldopa, Metoclopramide, domperidone
sedatives, TCAs

Extra pyramidal reactions Seizures

Metoclopramide INH TCA
Methyldopa Nalidixic acid Vincristine
Phenothiazines Amphetamines Bupropion
Reserpine Imipenem Clozapine
Amitriptyline Local Anesthetics Physostigmine (IV)
L-dopa Pethidine Quinolones
Butyrophenones e.g., Haloperidol Penicillins Theophylline
Phenothiazines

Pulmonary fibrosis Pulmonary Eosinophilia

Bleomycin, mitomycin, amiodarone, busulfan,
chlorambucit, Cyclophosphamide, methysergide,
vinblastine, methotrexate
Amiodarone, Bleomycin, Captoprit, Gold salts, GM-
CSF, Nitrofurantoin, Contrast media, L-tryptophan,
Phenytoin, Iodine, Carbamazepine, Aspirin,
Sulfasalazine, Nilutamide, Propytthiouracit,
Penicitlamine, Methotrexate, Minocycline.

First dose phenomenon Prolonged QTc interval

Prazosin, murumonab CD3, sargramostim, ACE Terfenadine, Astemizole, cisapride, sparfloxacin,
inhibitors esp. captopril gatifloxacin, grepafloxacin, amiodarone, bretylium,
disopyramide, procainamide, quinidine, sotalol,
mefloquine, pentamidine, thioridazine, ziprasidone

Hypertension
Cocaine, MAO inhibitors, cyclosporine, Glucocorticoids,
oral contraceptives, TCAs, rofecoxib, valdecoxib,
clonidine withdrawal, Sympathomimetics
Hypotension
Theophylline, adenosine, morphine, quinidine,
fosphenytoin (l.V), amiodarone, IL-2, levo-dopa, alpha
blockers, guanethidine, bretylium, β- blockers (I.V), glyceryl
trinitrate, chlorpromazine, diuretics, clonidine, calcium
channel blockers

Hypoglycemia Hyperglycemia
Oral hypoglycemics, quinine, β- blockers, insulin, Thiazides, furosemide, Glucocorticoids, oral
ethanol, octreotide, salicylates (late in over dose), contraceptives, diazoxide, L-Asparaginase, glucagon,
pentamidine (early in therapy) cyclosporine, phenytoin, propranolol, tacrolimus, protease
 inhibitors, niacin, encainide, pentamidine (late in therapy)

Interstitial nephritis Hyperuricemia

Cephalosporins, ciproftoxacin, Allopurinol, furosemide, Cyclosporine, diuretics, pyrazinamide, low dose salicylates,
NSAIDs, methicillin, phenindione, rifampicin, sulfonamides, nicotinic acid, cytotoxics
thiazides

Disulfiram -like reaction Myopathy

Metronidazole, cefamandole, cefotetan, cefoperazone, Statins, clofibrate, daptomycin, amphotericin B,
moxalactam, chforpropamide, procarbazine Carbenoloxone, chtoroquine, cimetidine, oral
contraceptives, corticosteroids

Pancreatitis Cardiomyopathy
Asparaginase, Didanosine, Stavudine, Zalcitabine, Daunorubicin, emetine, lithium, phenothiazines,
Azathioprine, Ethacrynic acid, sulfonamides, furosemide, Sympathomimetics, trastuzumab, doxorubicin
corticosteroids, opioids, thiazides, estrogens,
mercaptopurine, pentamidine, valproic acid, oral
contraceptives

Hypercalcemia Osteoporosis Hypocalcemia

Cholecalciferol, thiazides, calcium Glucocorticoids, heparin, thyroxine Calcitonin, bisphosphonates,
(IV). plicamycin, Phenytoin, gallium
nitrate

Contraceptive failure
• Enzyme inducers: phenytoin, phenobarbitone, carbamazepine, rifampicin.
• Suppression of intestinal microflora: tetracyclines, Ampicillin

Gynecomastia Cholestatic jaundice

• Calcium antagonists • Erythromycin estolate
• Cirnetidine • Acetohexamide
• Clomiphene • Anabolic steroids
• Cyproterone acetate • Androgens
• Digitalis • Chlorpropamide
• Estrogens • Phenothiazines
• Ethionamide • Nitrofurantoin
• Flutamide • Gold salts
• Goserelin • Oral contraceptives
• Griseofulvin, INH, Ketoconazole • Flucloxacillin
• Methyldopa • Cyclosporine
• Phenytoin • Methimazole
• Reserpine • Co-amoxyclav
• Spironolactone
• Testosterone

Erythema multiforme/ Stevens-Johnson Pseudo tumor cerebri (Raised ICT)

syndrome/ Toxic epidermal necrolysis
Sulphones, Allopurinol, cephalosporins, Sympathomimetics, nalidixic acid, OCPs, tetracyclines,
chlorpropamide, codeine, ethosuximide, hypervitaminosis A, Glucocorticoids, amiodarone
lamotrigine, nalidixic acid, phenyl butazone,
Piroxicam, quinolones, tocainide, valproic acid,
penicillins, tetracyclines, salicylates, barbiturates,
carbamazepine, Phenytoin, thiazides
 Skeletal muscle tremors Lactic acidosis Gingival hyperplasia
β2-agonists, zaleplon Phenformin, metformin, zidovudine, Phenytoin, Lamotrigine, Calcium
zalcitabine, spironolactone, antagonists, Cyclosporine, Sirolimus
acetazolamide, salicylates

Nephrogenic DI Syndrome of inappropriate ADH

Lithium Vinca alkaloids
Demectocycline Cyclophosphamide
Methoxyflurane Desmopressin
Oxytocin

Hypothyroidism Hyperthyroidism
Lithium Amiodarone
Iodides Iodides
Sulfonamides
Amiodarone
rifampin, carbamazepine, phenylbutazone, carbimazole,
acetazolamide, Phenytoin

Peripheral Neuropathy SLE- like syndrome

• Chloramphenicot • Sulfonamides • Hydralazine
• Colchicine • Thiouracil • Acebutolol
• Dapsone • Methyldopa • Asparaginase
• Disulfiram • Phenytoin • Barbiturates
• Ethambutol • INH • Bleomycin
• Ethionamide • Quinine • Cephalosporins
• Isoniazid • Procainamide • Iodides
• Metronidazole
• Misonidazole
• Nitrofurantoin

Pseudoporphyria Hirsutism
• Antibiotics: tetracyclines, Nalidixic acid, quinolones, ampicillin - sulbactam, • Anabolic steroids
cefepime • Minoxidil
• Diuretics: chlorthalidone, bumetanide, furosemide, hydrochlorthiazide, • Cyclosporine
triamterene • Phenytoin
• Retinoids: isotretinoin, etretinate, acitretin
• Oral contraceptives
• NSAIDS especially Naproxen, Nabumetone, diflunisal, ketoprofen,
oxaprozin, mefenamic acid, rofecoxib
• Antifungals- voriconazole
• Anti arrythmics: amiodarone
• Chemotherapy: 5-fluorouracil
• Immunosuppresants: cyclosporine
• Dapsone
• Muscle relaxants: carisoprodol/aspirin
• Non steroidal anti androgens: flutamide
• Hemodialysis, narrow band UV-B phototherapy

Causes of Raynaud's disease

• Bleomycin
• Cisplatin
• Amphetamines
• Beta blockers
 • Ergot derivatives
• Methysergide
• Vinblastine

SPECIFIC MANAGEMENT OF POISONINGS

MANAGEMENT POISONING
Acetylcysteine (Mucomyst) Acetaminophen
Atropine Antichotinesterases: organophosphates, carbamates
Amyl nitrite Hydrogen Sulfide
Sodium Bicarbonate Membrane-depressant cardiotoxic drugs (TCAs, quinidine)
Calcium Fluoride; calcium channel Blockers
Desferoxamine Iron
Digoxin antibodies Digoxin and related cardiac glycosides
Esmolol Theophylline, caffeine, metaproterenol
Ethanol , Fomepizole Methanol, ethylene glycol
Flumazenil Benzodiazepines, Zolpidem
Glucagon and calcium β-blockers
Naloxone Narcotic drugs, other opioid derivatives
Oxygen Carbon monoxide
Physostigmine Suggested for antimuscarinic anticholinergic agents; not for TCAs
Pralidoxime Organophosphate cholinesterase inhibitors
Nitroprusside Ergot Alkaloids
O2 + amyl nitrite + sodium thiosulphate Cyanide
Hyperbaric oxygen Carbon monoxide
High dose O2 + Methylene Blue Methemoglobinemia
Alkaline diuresis with sodium bicarbonate Salicylates
Pyridoxine Isoniazid
Hemodialysis Lithium
Cyproheptadine or chlorpromazine Serotonin syndrome
Prazosin Scorpion sting

DRUGS ACTING ON SKIN AND MUCOUS MEMBRANE

ANTISEPTICS AND DISINFECTANTS

• Potency of a germicide is generally expressed by its phenol coefficient or Rideal Walker coefficient, which is
the ratio of the minimum concentration of test drug required to kill a 24 hour culture of B. typhosa in 7.5
minute at 37.5° C to that of phenol under similar conditions.
• Therapeutic index of an antiseptic is defined by comparing the concentration at which it acts on
microorganisms with that which produces local irritation, tissue damage or interference with healing.

CLASSIFICATION
• Phenol derivatives: Phenol, Cresol, Hexylresorcinol, Chloroxylenol, Hexachlorophene.
• Oxidizing agents: Pot. Permanganate, Hydrogen peroxide, Benzoyl peroxide.
• Halogens: Iodine, lodophores, Chlorine, Chtorophores.
• Biguanide: Chlorhexidine.
• Quaternary ammonium (Cationic): Cetrimide, Benzalkonium chloride, Dequalinium chloride.
• Soaps: of Sod. And Pot.
• Alcohols: Ethanol, Isopropanol.
• Aldehydes: Formaldehyde, Glutaraldehyde.
• Acids: Boric acid, Acetic acid.
• Metallic salts: Silver nitrate, Silver sulfadiazine, Mild silver protein, Zinc sulfate, Calamine, Zinc oxide.
• Dyes: Gentian violet, Acriflavine, Proflavine.
• Furan derivative: Nitrofurazone.
Demulcents Sooth the inflamed/ denuded Glycyrrhiza, methylcellulose, propylene glycol,
area by preventing contact with glycerine
air/ surroundings
Emollients Bland oily agents which sooth and Olive oil, arachis oil, sesame oil, cocoa butter, liquid
soft the skin paraffin, wool fat, bees wax, spermaceti
Adsorbants & Finely powdered, inert agents Magnesium/zinc stearate, talc, calamine (zinc oxide),
protective binds with noxious & irritant starch, boric acid, aloe vera gel, polyvinyl polymer,
substances feracrylum, dimethicone, sucralfate
Astringents Precipitate protein, do not penetrate Tannic acid, tannins, alcohol, mineral stringents
cells, affects the superficial layer
Irritants & Stimulate sensory endings & Volatile oils: turpentine oils, clove oil, eucalyptus oil,
counter induce inflammation at the site of camphor, thymol, menthol
irritants application, Mustard seeds, capsicum, canthridin, oil of wintergreen
(methyl salicylate), alcohol
Caustics and Local tissue destruction & Podophyllum resin, silver nitrate, phenol, trichloroacetic
escharotics sloughing acid, glacial acetic acid
Keratolytics Dissolve the intercellular substance Salicylic acid, resorcinol, urea
in the horny Layer of skin. Used on
hyperkeratotic lesions like corns,
warts, psoriasis, chronic dermatitis,
ring worm, athletes foot
Anti seborrheics Effective in seborrheic dermatitis Selenium sulphide, zinc pyrithione, steroids, imidazole
antifungals, sulfur, resorcinol, coaltar, ammoniated
mercury, salicylic acid
Melanizing agents Increase sensitivity to solar radiation Psoralen, methoxsalen, trioxsalen
& promote repigmentation
Drugs for psoriasis Calcipotriol, tazarotene, coaltar, PUVA, Acitretin,
etanercept
Demelanizing Lighten hyperpigmented patches on Hydroquinone, monobenzone, azelaic acid
agent skin