BP602T Unit 1-3

Respiratory stimulants
(Analeptics)
Mr. Rakesh Kumar (27441)
Asst. Professor
Dept. Pharmacology
School of Pharmaceutical Sciences
LPU, Phagwara, 144411, Punjab, India
Y2931: BP602T: Pharmacology III

Definition
 It is defined as "the drug
or chemical agent which is
used to stimulate the
respiratory system or restore
the normal respiration.
 When lungs are unable to
eliminate sufficient amount
of carbon dioxide and
unable to take sufficient
amount of oxygen molecule.

It includes the class of those drug which is used to
stimulate the CNS i.e. central nervous system of the
body, hence it is known as CNS stimulator.
•It also stimulates the chemo receptor and vasomotor
centre (regulates blood vessel diameter ) of the body.
•As the drug act as a irritating agent therefore it irritate
the epithelial layer of the air passage such as bronchi,
trachea and lungs which leads to respiratory stimulation.

In human the respiratory system
goes through a critical task.
a. To regulate and respond to oxygen
demand.
b. Maintaining a constant oxygen and
carbon dioxide in the blood. Hence,
regulation of respiration is critically
important for homeostasis.

Respiratory stimulants
Examples
1. Methylxanthines
 Caffeine
 Theophylline
 Theobromine
2. Respiratory CNS stimulants
 Doxapram
 Nikethamide

1. Methylxanthines
 Theophylline and its derivatives are most commonly used for
the treatment of COPD and asthma.
 Caffeine, theophylline and theobromine are naturally occurring
xanthine alkaloids which have qualitatively similar actions.
 Mechanism of action
Three distinct mechanisms:
i. Release of Ca2+ from sarcoplasmic reticulum, especially in
skeletal and cardiac muscle.
ii. Inhibition of phosphodiesterase (PDE) which degrades
cyclic nucleotides intracellularly.
 The concentration of cyclic nucleotides is increased.
bronchodilatation, cardiac stimulation and vasodilatation
occur when cAMP level rises in the concerned cells.

iii. Blockade of adenosine receptors: adenosine acts as a local
mediator in CNS, CVS and other organs especially bronchial;
dilates cerebral blood vessels, depresses cardiac pacemaker and
inhibits gastric secretion. “Methylxanthines produce opposite
effects”.
Raised cAMP levels in inflammatory cells may attenuate
mediator release and promote eosinophil apoptosis adding to the
therapeutic effect of theophylline in asthma.
Adenosine A1 receptor antagonism is considered responsible for
cardiac arrhythmias and seizures occurring in theophylline
toxicity.
Methylxanthines
Mechanism of action:
Fig. Schematic diagram showing mechanism of action of theophylline

Pharmacological action
CNS: Stimulant; affects higher center
 Caffeine 150-200 mg produce a sense of wellbeing,
alertness, beats boredom, sleep disturbances and improve
performance and increase the motor activity.
Caffeine is more active than theophylline in producing
these effects.
Higher dose cause nervousness, restlessness, panic,
insomnia and excitements.
High dose: Vomiting and gastric irritation and CTZ
stimulation.
Stimulates medullary vagal, respiratory and vasomotor
centers.

 CVS :
Stimulates the heart and increase force of contraction. Increase the heart
rate (direct action) but decrease it by vagal stimulation- net effect is variable.
Tachycardia; increased cardiac output; increased cardiac work .
 High dose: cardiac arrhythmias
 Effect on blood pressure is variable and unpredictable. Usually a rise in
systolic and fall in diastolic BP is observed.
• Vasomotor center and direct cardiac stimulation- tends to raise BP
• Vagal stimulation and direct vasodilatation- tends to lower BP.
 Smooth muscles:
Relaxation
 Theophylline is more potent and slow, sustained dose related
bronchodilatation.
 Increase vital capacity
 Direct action due to adrenergic stimulation
 Biliary spasm is relived, but the effects on intestines and urinary tract is
negligible.
Theophylline is more potent; caffeine has minimal actions.

 Kidneys:
 Mild diuretics
 Inhibiting tubular reabsorption of Na+ and water
 Increasing vascular blood flow and g.f.r.
 Theophylline is more potent; caffeine has minimal actions.
 Skeletal muscles:
 Caffeine enhance contractile power. In high dose it increases release of Ca+
from sarcoplasmic reticulum by direct action.
 Twitch response at low doses.
 Caffeine facilitates neuromuscular transmission by increasing Ach release.
 Stomach:
 Enhance secretion of acid and pepsin
 Gastric irritation (more with theophylline).
 Metabolism:
 Increase BMR.
 Plasma free fatty acid levels are increased.
 Mast cells and inflammatory cells:
 Theophylline inhibits the release of histamine and other mediators form mast
cells and active inflammatory cells.

Fig.: An overview of pharmacological actions of methylxanthines Y2931: BP602T: Pharmacology III
1. Methylxanthines- Theophylline
Pharmacokinetics
Absorption: Absorbed orally; rectal absorption form suppositories
is erratic.
Distribution: All tissues; crosses placenta and is secreted in milk;
50% plasma protein bound.
Metabolism: Metabolized in liver (CYPP1A2) by demethylation and
oxidation.
Excretion: Excreted in urine; 10 % of total administration excreted
unchanged form.
Adult t1/2 is around 7-12 h.
Children elimination is much faster (t1/2 3-5 h);
In premature infants has prolonged t1/2 (24-36 h).
 In higher dose pharmacokinetics changes form first order to zero
order.

Adverse effects
 Narrow margin safety
 CVS and CNS stimulant
 GIT distress
 Children are more liable to developed CNS toxicity
 Rapid i.v injection cause precordial pain, syncope and sudden death
bronchodilatation
Fig. Relationship between efficacy and toxicity of theophylline with its plasma concentration.
 Interactions
Theophylline metabolism decreased by smoking, phenytoin,
rifampicin, phenobarbitone and charcoal boiled meat meal., which
increases the parenthesis.
 Erythromycin, ciprofloxacin, cimetidine, oral contraceptives,
allopurinol inhibits CYP1A2 and increasing the theophylline
plasma concentraction.
 Theophylline reduce the effects of phenytoin, lithium.
 Theophylline enhance the effects of furosemide,
sympathomimetics, digitalis, oral anticoagulants and
hypoglycemics.
 Indications
Primarily used to treat chronic obstructive lung disorders (COPD)
and asthma.

Marketed preparations

2. Respiratory CNS stimulants
Doxapram is a respiratory CNS stimulant which is used to treat the respiratory
depression caused by the over dose of the drug, pre & post anaesthesia
respiratory depression and COPD.
Mechanism of Action
Doxapram
↓
Stimulate
↓
Peripheral carotid chemo receptors
↓
Centre of respiration medulla oblongata
stimulation
↓
Enhance the respiratory depth and rate of
respiration

 Pharmacokinetics
 Onset of action: 20-40 sec
 Duration: 5-12 min (single IV injection)
 Peak Plasma Time: 1-2 min
 Half-life: 3.4 hr (2.4 - 4.1 hr).
 Marketed preparation
 Dopram (Doxapram hydrochloride, USP)
Ref. https://www.rxlist.com/dopram-drug.htm#clinpharm
Adverse effect
Adverse reactions reported coincident with the administration of
DOPRAM (doxapram hydrochloride, USP) include:
 Central and autonomic nervous systems
 Pyrexia, flushing, sweating; pruritus, paresthesia, disorientation,
pupillary dilatation, hallucinations, headache,
dizziness, hyperactivity, involuntary movements, muscle spasticity,
muscle fasciculations, increased deep tendon reflexes,
clonus, bilateral Babinski, and convulsions.
Respiratory
 Dyspnoea, cough, hyperventilation, tachypnoea, laryngospasm,
bronchospasm, hiccough, and rebound hypoventilation.

 Cardiovascular
 Phlebitis, variations in heart rate, lowered T-waves, arrhythmias
(including ventricular tachycardia and ventricular fibrillation), chest
pain, tightness in chest.
 A mild to moderate increase in blood pressure is commonly noted
and may be of concern in patients with severe cardiovascular diseases.
 Gastrointestinal
Nausea, vomiting, diarrhea, desire to defecate.
 Genitourinary
 Stimulation of urinary bladder with spontaneous voiding; urinary
retention. Elevation of albuminuria.
 Hemic and Lymphatic
 Hemolysis with rapid infusion.
A decrease in hemoglobin, hematocrit, or red blood cell count has
been observed in postoperative patients.
In the presence of pre-existing leukopenia,
 Further decrease in WBC has been observed following anesthesia
and treatment with doxapram hydrochloride.
Drug interactions
 Administration of doxapram to patients who are receiving
sympathomimetic or monoamine oxidase inhibiting drugs may
result in an additive pressure effect.
 In patients who have received neuromuscular blocking agents,
doxapram may temporarily mask the residual effects of these drugs.
In patients who have received general anesthesia utilizing a volatile
agent known to sensitize the myocardium to catecholamines,
administration of doxapram should be delayed until the volatile
agent has been excreted in order to lessen the potential for
arrhythmias, including ventricular tachycardia and
ventricular fibrillation.
There may be an interaction between doxapram and aminophylline
and between doxapram and theophylline manifested by
increased skeletal muscle activity, agitation, and hyperactivity.
Indications
 Post anaesthesia
 When the possibility of airway obstruction and/or hypoxia have been eliminated,
doxapram may be used to stimulate respiration in patients with drug-induced
postanaesthesia respiratory depression or apnea other than that due to muscle
relaxant drugs.
To pharmacologically stimulate deep breathing in the postoperative patient.
(A quantitative method of assessing oxygenation, such as pulse oximetry, is
recommended.)
 Drug-induced central nervous system depression
Exercising care to prevent vomiting and aspiration, doxapram may be used to
stimulate respiration, hasten arousal, and to encourage the return of
laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS
depression due to drug overdosage.
 Chronic pulmonary disease associated with acute hypercapnia
Doxapram is indicated as a temporary measure in hospitalized patients with acute
respiratory insufficiency superimposed on chronic obstructive pulmonary disease.
Contraindications
Doxapram is contraindicated in patients with known hypersensitivity
to the drug or any of the injection components.
Doxapram should not be used in patients with epilepsy or other
convulsive disorders.
Doxapram is contraindicated in patients with pulmonary embolism.
Doxapram is contraindicated in patients with mechanical disorders
of ventilation such as mechanical obstruction,
muscle paresis (including neuromuscular blockade), flail
chest, pneumothorax, acute bronchial asthma, pulmonary fibrosis, or
other conditions resulting in restriction of the chest wall, muscles
of respiration, or alveolar expansion.
Doxapram is contraindicated in patients with evidence of head
injury, cerebral vascular accident, or cerebral edema, and in those with
significant cardiovascular impairment, uncompensated heart failure,
severe coronary artery disease, or severe hypertension, including that
associated with hyperthyroidism or pheochromocytoma.
Text Books:
1. Essentials of medical pharmacology by K.D.Tripathi,
Jaypee brothers medical publishers Pvt. Ltd.
References:
1. Lippincott illustrated reviews: pharmacology by Karen
Whalen, Lippincott Williams & Wilkins, Wolters Kluwer.
2. Goodman & Gilman's the pharmacological basis of
therapeutics by Laurence Brunton, Bruce Chabner, Bjorn
Knollman, McGraw Hill Professional.

NASAL DECONGESTANTS

Asst. Professor
Dept. Pharmacology
Nasal spray

Nasal congestion:
 It refers to obstructed (blocked) breathing
through the nose.
 Nasal congestion or "stuffy nose" occurs
when nasal and adjacent tissues and blood
vessels become swollen with excess fluid,
causing a "stuffy" plugged feeling.
 Nasal congestion may or may not include a
nasal discharge or "runny nose."

Nasal Decongestants:
 Definition: Nasal decongestants are the drugs that reduce congestion of
nasal passages, which in turn open clogged nasal passages and enhances
drainages of the sinuses.
 Nasal decongestants are prescribed in patients with allergic or vasomotor
rhinitis and in acute rhinitis in patients with upper respiratory infections.
 Major limitation with chronic nasal decongestants therapy or withdrawal
of therapy is loss of efficacy, “rebound” hyperaemia, and worsening of
symptoms may due to receptor desensitization and damage to the
mucosa.
 “These are α agonists which on topical application as dilute solution
(0.05–0.1%) produce local vasoconstriction.”
Classification Of Nasal Decongestant :
A. Depends upon duration of action;
1. Short acting decongestants (upto 4 hr):
 Phenylephrine
 Phenylpropanolamine
2. Intermediate acting decongestants (upto 6 hr):
 Ephedrine,
 Pseudoephedrine
 Naphazoline
 Tetrahydrozoline
3. Long acting decongestants (upto 12 hr).
 Xylometazoline
 Oxymetazoline
B. Depends upon α receptor agonists/ sympathomimetic decongestants :
1. α1adrenoceptor agonist:
Phenylephrine,
2. α2 adrenoceptors agonists / Imidazoline compounds :
Clonidine
Naphazoline,
oxymetazoline

A. α1 agonist:
Definition:
 “These drugs probably decrease resistance to airflow by decreasing
the volume of the nasal mucosa;
 This may occur by activation of α-receptors in venous capacitance
vessels in nasal tissues that have erectile characteristics”
 Example: Phenylephrine.
 At high concentration it has negligible β action.
 These are less likely to induce mucosal damage but on i.v. infusion
causes marked arterial vasoconstriction causes raises BP.

Phenylephrine & epinephrine:
 Chemically, phenylephrine differs from epinephrine only in lacking a hydroxyl group at
position 4 on the benzene ring.
 Pseudoephedrine is less potent than ephedrine in producing tachycardia, increased blood
pressure, and CNS stimulation.
 Uses: Used as nasal decongestant in acute rhinitis.
 Topically used as mydriatic when cycloplegia is not required.
 It reduces intraocular tension by constricting ciliary body blood vessels.

B. α2 receptors agonists/ Imidazoline compounds:
 Examples- Clonidine, naphazoline, xylometazoline and oxymetazoline.
 α2 receptors may mediate contraction of arterioles that supply nutrition
to the nasal mucosa but intense constriction may cause structural
damage to the mucosa.
 They may cause initial stinging sensation (specially naphazoline).
 Regular use of these agents for long periods should be avoided because
mucosal ciliary function is impaired.
 Atrophic rhinitis and anosmia can occur due to persistent
vasoconstriction.
 They can be absorbed from the nose and produce systemic effects,
mainly CNS depression and rise in BP.
 These drugs should be used cautiously in hypertensives and in those
receiving MAO inhibitors.
Clonidine:
 It is an imidazoline derivatives.
 It was originally tested as a vasoconstrictor acting at peripheral α2 receptors.
 During clinical trials as a topical nasal decongestant, clonidine was found to cause
hypotension, sedation, and bradycardia.
 Pharmacological Effects: It changes in blood pressure and heart rate.
 Intravenous infusion of clonidine causes an acute rise in blood pressure.
 For example: They have a longer duration of action (12 hours) than ephedrine.

Mechanism of nasal decongestants
Fig.: Nasal decongestants act on alpha-1 receptor located in nasal blood vessel. It activate Phosphotidyl inositol (PI) system by releasing two
secondary messengers Inositol triphosphate and Diacyl glycerol which increase calcium level intracellularly, resulting in vasoconstriction.
Side effects:
 Common side-effects include:
 Sleeplessness
 Dryness
 High blood pressure
 Fast heartbeat
Tremors
 Stinging
 Sneezing
 Anxiety
 Dizziness
 Excitability
 Nervousness

Contraindications:
 These agents are contraindicated in patients with hypertension.
 These agents are contraindicated in patients who are taking MAO (Monoamine oxidase)
inhibitors such as Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam) and
Tranylcypromine (Parnate).
 The effects are not limited to the nose, and these medicines may cause hypertension (high
blood pressure) through vasoconstriction, it is for this reason that people with hypertension
are advised to avoid them.
 Long-term use is not recommended, since these agents lose effectiveness after a few days.
References:
 Tripathi K.D.: Essentials of Medical Pharmacology, Jaypee Brothers, Medical
Publishers, New Delhi.
 Rang H.P. and Dale M.M.: Pharmacology, Churchill Livingstone, Edinbergh.
 Katzung B.G.: Basic and Clinical Pharmacology, Lange Medical Publications,
California.
 P.N Bennett & M J Brown: Clinical Pharmacology, Churchill Livingstone,
Edinburgh.
Digestants, Carminatives and
Gallstone
Asst. Professor
Dept. Pharmacology

Digestive system:
DIGESTANTS
 These are substances intended to promote digestion of food.
 A number of proteolytic (e.g. papain), amylolytic (e.g. Diastase and Takadiastase) and
lipolytic enzymes.
 They are marketed in combination formulations.
 They are vigorously promoted for dyspeptic symptoms, and as appetite stimulants or health
tonics.
 They are occasionally beneficial, only when elaboration of enzymes in g.i.t. is deficient.
 Their routine use in tonics and appetite improving mixtures is irrational.
1. Pepsin:
 It may be used along with HCl in gastric achylia due to atrophic gastritis, gastric
carcinoma, pernicious anaemia, etc.
2. Papain:
 It is a proteolytic enzyme obtained from raw papaya.
 Its efficacy after oral ingestion is doubtful.
3. Diastase and Takadiastase:
 These are amylolytic enzymes obtained from the fungus
Aspergillus oryzae.
 They have been used in pancreatic insufficiency, but efficacy is
equivocal.
4. Pancreatin:
 It is a mixture of pancreatic enzymes obtained from hog and pig pancreas.
 It contains amylase, trypsin and lipase.
 It is indicated in chronic pancreatitis or other exocrine pancreatic deficiency
states.
 Fat and nitrogen content of stools may be reduced and diarrhoea/steatorrhoea
may be prevented.
 It has to be used as enteric coated tablets or capsules to protect the enzymes
from being themselves digested in stomach by pepsin.
 Nausea, diarrhoea and hyperuricaemia are the occasional side effects.
Preparations
ARISTOZYME:
 Fungal diastase 50 mg, pepsin 10 mg, simethicone 50
mg cap and per 5 ml liquid.
DIGEPLEX:
 Diastase 62.5 mg, pepsin 20 mg per 10 ml after
dissolving the tablet in sorbitol base provided.
ENTOZYME:
 Fungal diastase 50 mg, pepsin 10 mg per 5 ml syr.
VITAZYME:
 Fungal diastase 40 mg, cinnamon oil 0.25 mg,
caraway oil 0.5 mg, cardamom oil 0.5 mg per 10 ml
liq.
LUPIZYME:
 Pepsin 125 mg, fungal diastase 18.75 mg,
thiamine 2 mg, riboflavine 1 mg, pyridoxine
1.5 mg, vit B12 1 microg, nicotinamide 15
mg per cap and per 5 ml syr.
PANZYNORM:
 Pancreatine 100 mg, bile ext. 40 mg, dry
stomach ext. 110 mg tab.
UNIENZYME:
 Fungal diastase 20 mg, papain 30 mg,
simethicone 50 mg, nicotinamide 25 mg,
activated charcoal 75 mg tab.
Methyl polysiloxane:
 (Dimethyl polysiloxane, Simethicone, Dimethicone) It is a silicone polymer, a viscous
amphiphilic liquid—reduces surface tension and collapses froth, ‘antifoaming agent’.
 It is not absorbed from g.i.t.
 It is pharmacologically inert.
 Added to antacid, digestant and antireflux preparations.
 It is briskly promoted as a remedy for ‘gas’, a verycommon gastric complaint.
 It is also claimed to coat and protect ulcer surface, to aid dispersion of antacids in gastric
contents, and to prevent gastroesophageal reflux.
 However clinical efficacy is equivocal.
Dose: 40–120 mg 3 to 4 times a day.
DIMOL 40 mg tab. (single ingredient).
Carminatives:
Definition: “These are the agents which Promotes
expulsion of gases from the Gastro intestinal tract and
give a feeling of warmth and comfort in the
epigastrium”.
 Various drugs used for the purpose are as
• Sodium bicarbonate,
• Oil peppermint,
• Cardamom oil,
• Cadamom oil,
• Oil of dil,
Herbal carminatives
• Tincture ginger.
Uses of Digestants and carminative:
• Dyspepsia
• Discomfort in the upper abdomen
• Gas formation
• Feeling of fullness
• Burning sensation
Gallstones:
These are hardened deposits of bile that can form in your gallbladder. Bile is a
digestive fluid produced in your liver and stored in your gallbladder. When you eat, your
gallbladder contracts and empties bile into your small intestine (duodenum).
Gallstones causes:
GALLSTONE DISSOLVING DRUGS:
 Cholesterol (CH) remains dissolved in bile with the help of bile salts (salts of cholic acid and
chenodeoxycholic acid conjugated with glycine and taurine) because bile salts are highly
amphiphilic.
 A high CH : bile salt ratio favours crystallization of CH in bile; these crystals act as nidi for
stone formation.
 Chenodeoxycholic acid (Chenodiol) and
 Ursodeoxycholic acid (Ursodiol) decrease CH content of bile, enabling solubilization of CH
from stone surface.
CHENODIOL
 Acts primarily by inhibiting CH synthesis liver.
 Does not reduce intestinal CH absorption.
 Raises plasma LDL-CH by reducing LDL receptors in liver.
 Reduces CH secretion in bile after prolonged administration.
 Generates a more litho-lytic bile acid pool.
 Promotes micellar solubilization of CH.
URSODIOL
 Little inhibition of hepatic in CH synthesis.
 Acts primarily by inhibiting intestinal CH absorption.
 Does not raise plasma LDL-CH level.
 Promptly reduces CH secretion in bile.
 Itself lowers CH saturation index of bile.
 Promotes solubilization by liquid crystal formation.
Chenodiol:
 Administered daily.
 It has been found to partially or completely dissolve CH gallstones
in about 40% patients over 1/2 to 2 years.
 However, only 1/3 of these had complete dissolution.
 Diarrhoea is common.
 Aminotransferase level may rise, but overt liver damage occurs in
only 3% patients.
 Gastric and esophageal mucosal resistance to acid is impaired
favouring ulceration.
Ursodiol:
 It is a hydroxy epimer of chenodiol, is more effective and
needs to be used at lower doses.
 Complete dissolution of CH stones has been achieved in
upto 50% cases.
 It is also much better tolerated.
 Diarrhoea and hypertransaminaemia are infrequent, but
effect on mucosal resistance is similar to chenodiol.
 Calcification of some gall stones may be induced.
Dose: 450 – 600 mg daily in 2–3 divided doses after meals;
UDCA, UDIHEP 150 mg tab.
 Dissolution of gallstones is a very slow process: patient compliance is often
poor.
 However, medical treatment is now possible in selected patients.
 Once treatment is discontinued after stone dissolution, recurrences are
common, because bile returns to its CH supersaturated state.
 Repeat courses may have to be given.
 Because of these problems the pros and cons of medical therapy must be
weighed against cholecystectomy.
References:
California.
Emetics and Anti-emetics
Asst. Professor
Dept. Pharmacology

Emesis:
 Vomiting occur due to stimulation of the emetic centre situated in medulla
oblongata.
Pathways involved in vomiting:
1. Chemoreceptor trigger zone (CTZ)
2. Nucleus tactus solitarius (NTS)
Emetic:
 Any agent or drugs that produces nausea and vomiting.
1. Drug act on CTZ such as Apomorphine
2. Act reflexly and on CTZ such as Ipecacuanha
Apomorphine :
 It act as a dopaminergic agonist on CTZ.
 Apomorphine acts directly on the chemoreceptor trigger zone to
induce emesis. Apomorphine is generally the emetic of choice
because of its rapid onset and the ability to reverse its action.
 Apomorphine is given at a dose of 0.02 to 0.04 mg/kg i.v. or
i.m. or 6mg dose injected i.m./s.c.
 It can also be administered by placing it directly behind the
eyelid in the subconjunctival sac.
 It induce the vomiting in 5 minutes.
 It is used as emetic.
Adverse side effects:
 CNS depression
 Respiratory depression
 Excessive vomiting
 Occasionally CNS stimulation
Contraindication:
 Apomorphine may also be contraindicated when further CNS depression will
significantly alter the patient's condition.
Ipecacuanha:
 It is obtained from the dried roots of
the Cephaelis ipecacuanha which
contain emetine.
 It acts as emetic.
 It act by irritating gastric mucosa as
well as through the CTZ.
Uses:
 In adult 15 – 30 mL,
 Children 10 – 15 mL,
 Infants 5 mL
Fig. Major central and visceral structures involved in emesis and neurohumoral receptors mediating the emetic response.
Anti-emetics:
 Agents or drugs which are used to prevent or suppress vomiting.
Classification of anti-emetics:
, hyoscine, dicyclomine
ANTICHOLINERGICS:
Hyoscine:
 It is the most effective drug for motion sickness.
 However, it has a brief duration of action.
 Antiemetic action is exerted probably by blocking conduction of nerve impulses across a
cholinergic link in the pathway leading from the vestibular apparatus to the vomiting centre.
 It has poor efficacy in vomiting of other etiologies.
Dose: 0.2–0.4 mg oral, i.m.
Side effects:
 produces sedation,
dry mouth
Dicyclomine:
It has been used for prophylaxis of motion sickness and for morning sickness.
It has been cleared of teratogenic potential.
Dose:10–20 mg oral
H1 ANTIHISTAMINICS:
Some antihistaminics are antiemetic.
They are useful mainly in motion sickness and to a lesser extent in morning sickness,
postoperative and some other forms of vomiting.
Their antiemetic effect appears to be based on anticholinergic, antihistaminic, weak
antidopaminergic and sedative properties.
Promethazine, diphenhydramine, dimenhydrinate:
 These drugs afford protection of motion sickness for 4–6 hours, but
produce sedation and dryness of mouth.
Due to its central anticholinergic action, block the extrapyramidal
side effects of metoclopramide while supplementing its antiemetic
action.
Promethazine is a phenothiazine, has weak central antidopaminergic
action as well.
Their combination has been used in chemotherapy induced nausea
and vomiting.
Promethazine theoclate: AVOMINE 25 mg tab.
 This salt of promethazine has been specially promoted as an
antiemetic, but the action does not appear to be significantly different
from promethazine HCl.
Doxylamine:
 It is a sedative H1 antihistaminic with prominent anticholinergic activity.
Marketed in combination with pyridoxine.
 It is specifically promoted in India for ‘morning sickness’ “vomiting of early pregnancy”.
Pharmacokinetics:
 Oral absorption of doxylamine is slow,
 t½ is 10 hr.
Side effects: drowsiness, dry mouth, vertigo and abdominal
upset.
Dose: 10–20 mg at bed time; if needed additional doses may be
given in morning and afternoon.
Marketed brand: DOXINATE, GRAVIDOX, VOMNEX,
NOSIC 10 mg with pyridoxine 10 mg tab.
Meclozine (meclizine):
 It is less sedative and longer-acting; protects against sea sickness for nearly 24 hours.
 DILIGAN: meclozine 12.5 mg + nicotinic acid 50 mg tab;
PREGNIDOXIN: meclozine 25 mg + caffeine 20 mg tab.
Cinnarizine:
 It is an antivertigo drug having antimotion sickness property.
It probably acts by inhibiting influx of Ca2+ from endolymph into the vestibular sensory
cells which mediates labyrinthine reflexes.
Motion sickness:
 Antiemetics with anticholinergic- antihistaminic property are the first choice drugs for motion sickness.
 Antidopaminergic and anti-HT3 drugs are less effective.
 All antimotion sickness drugs act better when taken ½–1 hour before commencing journey.
 Once sickness has started, it is more difficult to control; higher doses/ parenteral administration may be
needed.
Morning sickness:
 The antihistaminics are suspected to have teratogenic potential, but there is no conclusive proof.
 Nevertheless, it is better to avoid them for morning sickness.
 Most cases of morning sickness can be managed by reassurance and dietary adjustment.
 If an antiemetic has to be used, dicyclomine, promethazine, prochlorperazine or metoclopramide may
be prescribed in low doses.
NEUROLEPTICS:
The older neuroleptics such as “phenothiazines, haloperidol”.
These are potent antiemetics; act by blocking D2 receptors in the CTZ; antagonize
apomorphine induced vomiting and have additional antimuscarinic as well as H1 antihistaminic
property.
Broad spectrum antiemetic action effective in:
i. Drug induced and postoperative nausea and vomiting (PONV).
ii. Disease induced vomiting: gastroenteritis, uraemia, liver disease, migraine, etc.
iii. Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting.
iv. Radiation sickness vomiting (less effective).
v. Morning sickness: should not be used except in hyperemesis gravidarum.
Prochlorperazine:
 This D2 blocking phenothiazine is a labyrinthine suppressant.
It has selective antivertigo and antiemetic actions.
 It is highly effective when given by injection in vertigo associated
vomiting.
 Prochlorperazine is used as an antiemetic, but not as antipsychotic.
Side effects:
Muscle dystonia
 Extrapyramidal
Dose: 5–10 mg BD/TDS oral, 12.5–25 mg, i.m.
Marketed brand: STEMETIL 5 mg tabs., 12.5 mg/ml inj, 1 ml amp,
VOMTIL 5 mg tab.
PROKINETIC DRUGS:
 These are drugs which promote gastrointestinal transit and speed gastric emptying by
enhancing coordinated propulsive motility.
This excludes traditional cholinomimetics and anti-ChEs which produce tonic and largely
uncoordinated contraction.
Metoclopramide:
 Metoclopramide, a substituted benzamide, is chemically related to procainamide.
 It has no pharmacological similarity.
 Introduced in early 1970s as a ‘gastric hurrying’ agent.
 It is a commonly used antiemetic.
Fig. Structure depiction of seronergic (5 – HT) regulation of peristalsis reflexes and site of action of prokinetic drugs
Pharmacological actions:
GIT:
 Metoclopramide has more prominent effect on upper g.i.t.
 Increases gastric peristalsis while relaxing the pylorus and the first part of duodenum →
speeds gastric emptying, especially if it was slow.
 This action is independent of vagal innervation, but is stronger when vagus is intact.
 Lower esophageal sphincter (LES) tone is increased and gastroesophageal reflux is opposed.
 It also increases intestinal peristalsis to some extent, but has no significant action on colonic
motility and gastric secretion.
CNS:
 Metoclopramide is an effective antiemetic; acting on the CTZ, blocks apomorphine
induced vomiting.
 The gastrokinetic action may contribute to the antiemetic effect.
 However, it has no chlorpromazine (CPZ) like antipsychotic property, though it does
share the extrapyramidal and prolactin secretion augmenting action of CPZ.
5-HT3 ANTAGONISTS:
Ondansetron:
 It is the prototype of a distinct class of antiemetic drugs developed to control cancer
chemotherapy/radiotherapy induced vomiting, and later found to be highly effective in
PONV and disease/drug associated vomiting as well.
 It blocks the depolarizing action of 5-HT exerted through 5-HT3 receptors on vagal
afferents in the g.i.t. as well as in NTS and CTZ.
 Cytotoxic drugs/radiation produce nausea and vomiting by causing cellular damage →
release of mediators including 5-HT from intestinal mucosa → activation of vagal afferents
in the gut → emetogenic impulses to the NTS and CTZ.
 Ondansetron blocks emetogenic impulses both at their peripheral origin and their central
relay.
Pharmacokinetics:
 Oral bioavailability of ondansetron is 60–70% due to first pass metabolism.
 It is hydroxylated by CYP1A2, 2D6 and 3A, followed by glucuronide and sulfate
conjugation.
 It is eliminated in urine and faeces, mostly as metabolites;
 t½ is 3–5 hrs,
 Duration of action is 8–12 hrs (longer at higher doses).
Marketed brands:
 EMESET, VOMIZ, OSETRON, EMSETRON 4,8 mg tabs,
2 mg/ml inj in 2 ml and 4 ml amps. ONDY, EMESET 2 mg/5
ml syrup.
Side effects:
 Ondansetron is generally well tolerated:
 The common side effects are such as:
• Headache
•Dizziness
•Mild constipation
•Abdominal discomfort occur in few patients.
•Hypotension,
•Bradycardia,
•Chest pain
•Allergic reactions are reported, especially after i.v. injection.
Granisetron:
 It is 10 times more potent than ondansetron and probably more effective during the repeat cycle of
chemotherapy.
The weak 5-HT4 blockade seen in ondansetron has not been detected in granisetron.
 Its plasma t½ is longer (8–12 hrs) and it needs to be given only twice on the day of chemotherapy.
Dose:
1–3 mg diluted in 20–50 ml saline and infused i.v. over 5 min before chemotherapy, repeated after 12 hr.
 For less emetogenic regimen 2 mg oral 1 hr before chemotherapy or 1 mg before and 1 mg 12 hr after it.
 For PONV 1 mg diluted in 5 ml and injected i.v. over 30 sec before starting anaesthesia or 1 mg orally every
12 hours.
Marketed preparations:
GRANICIP, GRANISET 1 mg, 2 mg tabs; 1 mg/ml inj. (1,3 ml amps).
Palonosetron:
 It is longest acting 5-HT3 blocker having the highest affinity for the 5-HT3 receptor.
Efficacy is comparable to ondansetron, but it is more effective in suppressing delayed
vomiting occurring between 2nd to 5th days, probably because of its longer duration of
action.
Elimination t½ is 40 hours.
It is the only drug of its class approved by USFDA.
Antiemetic efficacy is maintained during repeat cycles of chemotherapy.
Palonosetron is metabolized in liver as well as in kidney, mainly by CYP2D6, but also by
CYP3A4 and CYP1A2.
Side effects:
Headache, fatigue, dizziness, abdominal pain.
Additive Q-T prolongation can occur when given with moxifloxacin, erythromycin,
anti-psychotics, antidepressants, etc. Rapid i.v. injection has caused blurring of vision.
Dose:
250 μg by slow i.v. injection 30 min before chemotherapy. Do not repeat before 7
days.
For PONV 75 μg i.v. as a single injection just before induction.
Marketed preparations:
PALONOX 0.25 mg/ml inj, PALZEN 0.25 mg/50 ml inj.
NK1 RECEPTOR ANTAGONISTS:
Realizing that activation of neurokinin (NK1) receptor in CTZ and NTS by substance P
released due to emetogenic chemotherapy and other stimuli plays a role in the causation of
vomiting, selective antagonists of this receptor have been produced, and are being used as
antiemetic.
Aprepitant:
 It is a recently introduced selective, high affinity NK1 receptor antagonist that blocks the
emetic action of substance, with little effect on 5 HT3 and D2 or other receptors.
Gastrointestinal motility is not affected.
Dose: Oral aprepitant (125 mg + 80 mg + 80 mg over 3 days).
It is combined with standard i.v. ondansetron + dexamethasone regimen significantly
enhanced the antiemetic efficacy against high emetogenic cisplatin based chemotherapy.
ADJUVANT ANTIEMETICS:
Corticosteroids, e.g. dexamethasone 8–20 mg i.v.:
It can partly alleviate nausea and vomiting due to moderately emetogenic chemotherapy.
But they are more often employed to augment the efficacy of other primary antiemetic
drugs like metoclopramide and ondansetron against highly emetogenic regimens.
Corticosteroids benefit both acute and delayed emesis.
The basis of the effect appears to be their anti-inflammatory action.
They also serve to reduce certain side effects of the primary antiemetic.
Benzodiazepines:
 The weak antiemetic property of BZDs is primarily based on the sedative action.
 Used as adjuvant to metoclopramide/ondansetron, diazepam/lorazepam (oral/ i.v.) help by
relieving the psychogenic component, anticipatory vomiting and produce amnesia for the
unpleasant procedure.
They also suppress dystonic side effects of metoclopramide.
Cannabinoids:
 Δ9 Tetrahydrocannabinol (Δ9 THC) is the active principle of the hallucinogen
Cannabis indica that possesses antiemetic activity against moderately emetogenic
chemotherapy.
It probably acts through the CB1 subtype of cannabinoid receptors located on
neurones in the CTZ and/
or the vomiting centre itself.
Dronabinol is pure Δ9THC produced synthetically or extracted from Cannabis.
In a dose of 5–10 mg/m2 BSA orally (repeated as required).
it can be used as an alternative antiemetic for moderately emetogenic
chemotherapy in patients who cannot tolerate other antiemetics or are
unresponsive to them.
The hallucinogenic, disorienting and other central sympathomimetic effects are
produced, and some subjects may experience a ‘high’, that may lead to addiction.
The CNS actions limit the use of dronabinol to few nonresponsive patients.
Its antiemetic action can be supplemented by dexamethasone. Dronabinol is an
appetite stimulant as well; has been used in lower doses to improve feeding in
cachectic/AIDS.
Text Books:
1. Essentials of medical pharmacology by K.D.Tripathi, Jaypee brothers medical
publishers Pvt. Ltd.
References:
1. Lippincott illustrated reviews: pharmacology by Karen Whalen, Lippincott
Williams & Wilkins, Wolters Kluwer.
2. Goodman & Gilman's the pharmacological basis of therapeutics by Laurence
Brunton, Bruce Chabner, Bjorn Knollman, McGraw Hill Professional.
General Principles of Chemotherapy
Asst. Professor
Dept. Pharmacology
LPU, Phagwara,144411, Punjab, India

β - Lactam antibiotic
(Cephalosporins)
Asst. Professor
Dept. Pharmacology,

Penicillins
Beta - Lactam
Antibiotics
Monobactams Cephalosporins
Carbapenems
Cephalosporins
CephalosporinC
• First isolated by Brotzu from Cephalosporium acremonium (a mold) from a

sewage outfall (and popular swimming spot) in Sardinia.
• He noticed the C. acremonium cultures inhibited the growth of Salmonella
enterica (typhi), a Gram- bug that produces a penicillinase
• M.O.A. same as penicillins, to inhibit synthesis and maintenance of bacterial
peptidoglycan
• Slightly different nucleus shape made them more resistant to penicillinases
Semi-synthetic cephalosporins
side chain(s)
affects activity, spectrum,etc.
R1 7-ACA
Cephalosporin C
R2
• Cephalosporin C had poor bioavailability, rapidly cleared

• Cleave off natural sidechain to yield 7-aminocephalosporanic acid (7-ACA)
core, which then could be synthetically substituted with other sidechains.
• Alter the spectrum, stability, bioavailability, resistance to beta-lactamases
• All cephalosporins in use are of the semi-synthetic variety, no equivalents to Pen
G and V in use.
Cephalosporins general features
๏ Generally broader spectrum coverage than penicillins

๏ Whereas original penicillins had primarily Gram+ coverage, most
cephalosporins also cover some Gram-
๏ Better resistance to beta-lactamases
๏ Cleared renally with ~5-30% metabolic breakdown, much
active drug excreted in urine
๏ Exceptions: cetriaxone, significant biliary elimination
๏ Low toxicity:
๏ Generally lower allergenicity than penicillins though still some due to beta-
lactam ring opening (10% cross-reactivity with penicillins)
๏ Diarrhea: the broader the spectrum, the more likely of disruption of gut
flora and diarrhea, which can lead to significant problems
Cephalosporins general features
๏ Other adverse drug reactions from cephalosporins containing N-MTT or N-MTD
moieties:
๏ Example: cefotetan has an N-methylthiotetrazole (N-MTT) moiety that is released as a

metabolic byproduct.This can cause hypoprothrombinemia, which manifests as bleeding due to
combination of effects: 1) altered vitamin K production, 2) direct interaction of N- MTT with
prothrombin, 3) platelet dysfunction. First noted with moxalactam (2-3% fatalities; off market);
much higher N-MTT levels than cefotetan.
๏ N-MTT also can inhibit aldehyde degydrogenase, giving rise to a disulfram-like reaction
following alcohol consumption. Intense hang-over feeling, hyper-sensitivity to alcohol.
Cefotetan
Cephalosporins classification
๏ Cephalosporin “generations”: generally get broader, more Gm- coverage with

later generations
๏ Generation 1: Generally had better Gram+ than Gram- activity; susceptible to
many Gram- beta-lactamases
๏ Examples: Cephalexin,Cefazolin
(Az ale)
๏ Generation 2: Better resilience to Gram- beta-lactamases, Gram- coverage
๏ Examples:Cefuroxime
๏ Generation 3: More potent, better Gram- beta-lactamase stability, better

penetration; pick up some anti-Pseudomonal activity, give up some Gram+ coverage
๏ Examples:Cefpodoxime,Cefdinir, Cefixime, Cefotaxime,Ceftriaxone, Ceftazidime,
๏ Generation 4: Very broad spectrum (Gm- and Gm+)

๏ Example:Cefepime
๏ Generation 5: MRSA and PRSPcoverage

๏ Example:Ceftaroline
Cephalosporins
๏ Some penetrate to the CNS:
๏ Cefuroxime
๏ Cefotaxime
๏ Ceftazidime
๏ Ceftriaxone
Some cephalosporins are prodrugs
๏ Examples: Cefpodoxime,Cefuroxime, Ceftizoxime, Cefditoren, Cefetamet
๏ Metabolized to active drug by intestinal mucosal tissue
๏ Sometimes aids in better absorption; e.g. crossingmembranes
๏ Sometimes aids in better solubility
cefpodoxime proxetil cefpodoxime

Cephalexin (Gen1, PO)
๏ Keflex ® (Eli Lilly), and generics

๏ Up to 90%excreted unmodified in urine.
๏ Indications:
๏ Skin infections: S.aureus(MSSAeven w/ penicillinase, not MRSA),S.pyogenes
๏ Respiratory infections: S.pneumoniae(not PRSP),S.pyogenes
๏ Otitis media: S.pneumoniae, H. influenzae, M.catarrhalis
๏ H. influenzae and M. catarrhalis may haveresistance due tobeta-lactamases
๏ Urogenital: E.coli, Klebsiellapneumoniae, Proteusmirabilis
๏ Bone: S.aureus, P.mirabilis
Cephalexin (Gen1, PO)
Indicated spectrum for cephalexin (Gen1, oral):
Aerobic gram-positive microorganisms:
Staphylococcusaureus (including penicillinase-producing strains)
Streptococcus pneumoniae (only penicillin-sensitive strains)
Streptococcus pyogenes
Resistant Gm+ bacteria, not covered:

MRSA
PRSP
Most strains of enterococci (E. faecalis) are resistant to cephalosporins, including Cephalexin.
Enterobacter spp.
Morganella morganii
Proteus vulgaris
Pseudomonas spp.
Acinetobacter calcoaceticus
Aerobic gram-negative microorganisms:

Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Cefazolin (Gen1, Parenteral IV/IM)
N-MTD
(N-methylthiodiazole)
๏ Ancef ® (GSKB), and generics

๏ Up to 80% excreted unmodified in urine.
๏ For Gm+ Staphylococciincluding Staph. aureus (not MRSA), Streptococci including Strep.
pyogenes, Strep. pneumoniae (not PRSP)
๏ Respiratory tract infections (Staph., Strep.)
๏ Uncomplicated skin infections
๏ Osteomyelitis: bone and joint
๏ Some Gram- coverage: E.coli, H. influenzae (some resistance), P.mirabilis,
๏ Urogenitial
๏ Like N-MTT, N-MTD sidechain, potential for bleeding and disulfram-like alcohol sideeffects
๏ Co-administration with parenteral vitamin K may counter bleeding
Cefazolin (Gen1, Parenteral IV/IM)
Indicated spectrum for cefazolin (Gen1, parenteral):

Staphylococcusaureus (including penicillinase-producing strains; notMRSA)
Staph.epidermidis
Strep. pneumoniae (only penicillin-sensitive strains; not PRSP)
Strep. pyogenes
Strep.agalactiae
Resistant Gm+ bacteria, not covered:

MRSA
PRSP
Enterococci (E.faecalis)

Escherichia coli
Proteus mirabilis
Cefuroxime axetil (Gen2, PO)
cefuroxime axetil cefuroxime

๏ Ceftin ® (GSKB) and generics
๏ Prodrug: cefuroxime axetil converted to cefuroxime (also IV, not as prodrug)
๏ Indications:
๏ Pharyngitis,Tonsollitis,Otitis media,sinusitis,bronchitis (H. flu, S.pneumo,M. cat)
๏ Skin infections (S. pyogenes, MSSA)
๏ UTI (E. coli,Klebsiella)
๏ N. gonorrhoeae includingpenicillinase-producing
๏ Early Lyme disease Borrelia Burgdorferi (amoxicillin, doxycycline also)
๏ Penetrates to CNS: meningitis (N. meningitidis, H. influenzae,S.pneumoniae)
Cefpodoxime proxetil (Gen3, PO)
๏ Vantin ® (Pharmacia), and generics
๏ Prodrug
๏ Good Gram- and Gram+ coverage cefpodoxime proxetil
๏ not Pseudomonas,Enterococci, B.fragilis
๏ Indications: big for otitis media, pharyngitis,sinusitis
๏ Community Acquired Pneumonia (CAP):
๏ S.pneumoniae,H. influenzae, M.catarrhalis
๏ H. influenzae and M. catarrhalis may have resistance due to
beta-lactamases
๏ N. gonorrhoeae: single 200mg dose
๏ UTI
๏ Otitis media:
cefpodoxime
๏ S.pneumoniae,H. influenzae, M.catarrhalis
๏ Uncomplicated skin infections: S.aureus (not MRSA), S.pyogenes
Cefdinir (Gen3, PO)
๏ Omnicef ® (Abbot) and generics

๏ Similar coverage to cefpodoxime, but tastes better (important for children)
๏ Best selling cephalosporin, often prescribed for AOM (acute otitis media) if
infection not responding to amoxicillin
Cefotaxime (Gen3, Parenteral IV/IM)
๏ Claforan® (SanofiAventis)
๏ Cefotaxime becomes deacetylated, resulting desacetylcefotaxime also active
๏ Broad spectrum; Gram-,Gram+
๏ Activity against PRSP,but used in combination with other antimicrobials
๏ Notable Gm+ exceptions: Enterococci
๏ Notable Gm- exceptions: Pseudomonas
๏ Lower respiratory tract infections, bone and joints, skin, urogenital infection,septicemia
๏ Intra-abdominal including use aspre-surgery prophylaxis
๏ Penetrates to CNS: meningitis
Ceftriaxone (Gen3, Parenteral IV/IM)
๏ Rocephin ® (Hoffman-La Roche)

๏ Broad spectrum; Gram-, Gram+
๏ Can be used for Penicillin-resistant Strep. Pneumoniae (PRSP)
๏ Highly active against N. gonorrhoeae: 250mg single IMdose
๏ Some activity against Pseudomonasaeruginosa, but not the mostpotent
๏ Very long half-life ~6-8h (vs e.g. 1h for cefotaxime); less frequent dosing
๏ Penetrates the CNS
๏ Often used in combination w/ aminoglycoside or macrolide
๏ E.g. w/ azithromycin for Chlamydia tracomatis
๏ Do not co-administer or dilute with calcium-containing compounds/solutions
๏ Ceftriaxone precipitates with calcium

Ceftriaxone (Gen3, Parenteral IV/IM)
Acinetobactercalcoaceticus
Enterobacteraerogenes Enterobacter
cloacae Escherichia coli
Haemophilusinfluenzae (including ampicillin-resistant and beta-lactamase producingstrains)
Haemophilusparainfluenzae Klebsiella
oxytoca
Klebsiellapneumoniae
Moraxella catarrhalis (including beta-lactamase producing strains)
Morganella morganii
Neisseriagonorrhoeae (including penicillinase-and nonpenicillinase-producing strains)
Neisseriameningitidis Proteus
mirabilis Proteusvulgaris
Serratiamarcescens
Pseudomonasaeruginosa
Staphylococcusaureus(including penicillinase-producing strains, notMRSA)
Staphylococcusepidermidis
Streptococcuspneumoniae (active for PRSP)
Streptococcuspyogenes Viridans
group streptococci
NOTE: MRSAresistant to most cephalosporins, including ceftriaxone. Most strains of Group D streptococci and enterococci, eg, Enterococcus faecalis,
are resistant.
Anaerobic microorganisms:
Bacteroides fragilis
Clostridium species (NOTE: Most strains of Clostridium difficile are resistant)
Peptostreptococcus species
Ceftazidime (Gen3, Parenteral IV/IM)
๏ Tazidime ® (Eli Lilly), Fortum ® (GSK)

๏ Broad spectrum; Gram-, weak Gram+
๏ Activity against Pseudomonasaeruginosa, ~85-90% sensitive (only ~68% for CFpatients)
๏ Poorer against Gm+, not generallyused
๏ CNS penetration in meningitis
Cefepime (Gen4, Parenteral IV/IM)
๏ Maxipime ® (Elan)
๏ Even more resistant to beta-lactamases binds tightly to PBPs
๏ Better penetration of Gram- outer membranes
๏ Broad spectrum: Gram- and Gram+
๏ Activity against PRSP
๏ Pseudomonas aeruginosa coverage (90% sensitive for non-CF patients, only 50% forCF)
๏ Enterobacteriaceae
๏ Not anaerobes
๏ Empiric therapy: used to suppress infection, then switch to another cephalosporin
๏ Does not induce the expression of chromosomal beta-lactamases;
๏ FDA precaution for neurotoxicity (encephalopathy, myoclonus, seizures)
Ceftaroline fosamil (Gen5, Parenteral IV/IM)
๏ Teflaro® (Cerexa, Forest Labs); FDA approved fall, 2010.
๏ Ceftaroline fosamil prodrug becomes dephosphonated in the blood to ceftaroline
๏ Similar spectrum to ceftriaxone, but gain increased Gram+ coverage including MRSA andPRSPdue to
increased affinity for MRSA’s PBP2aand pen. resistant S.pneumoniae’s PBP2x, which confers resistance
to most beta-lactams.
๏ MRSAand VRSAPRSP
๏ H.influenzae
๏ M.catarrhalis
๏ S.pyogenes
๏ S.viridans group
๏ E.faecalis
๏ K.pneumoniae
๏ Shigella
๏ NOT for P.aeruginosa, beta-lactamase (ESBL,AmpC)
๏ producing Enterobacteriaceae, Bacteriodes, C.difficile
๏ Indicated uses
๏ Complicated skin infection
๏ Community associated pneumonia (CAP)
Cephalosporins Summary
๏ MOA
• Bind to PBPs(transpeptidase enzymes), disrupting cell wall synthesis
• Bactericidal
• Time-dependent, concentration-independent activity: maintain [drug]>MIC, maximal killing
~4-5xMIC
๏Spectrum of activity
• Gen1: Mostly Gram+, less against Gram-
• Gen2,3: generations: More Gram- activity, give up some Gram+ coverage
• Gen4: Broad spectrum, Gram+ and Gram-activity
• Early generation oral drugs: used for less serious community-acquired infections
• Later generation IV/IM drugs: used for hospital-acquired infections, serious infections
๏ Resistance
• Beta-lactamases
• Altered PBPbinding site
• Decreased drug penetration
๏ Distribution
• Generally good distribution throughout
• Only some have penetration to CSF
• Generally elimination through kidneys
Cephalosporins Summary
๏Adverse reactions
• Hypersensitivity
• <10% cross-reactivity of penicillin-allergic patients with cephalosporins
• If patient has had an immediate, serious reaction to penicillin, would not give ceph
• If patient had adelayed, less serious reaction to penicillin, could try ceph with caution;
early generations more cross-reactivity, later generations less so
• Those containing N-MTT or N-MTD: bleeding reaction, disulfram-like alcohol
hypersensitivity
• Rash
• Diarrhea: broader spectrum, bigger issue
References:
California.
Thanks
β - Lactam antibiotic
(Penicillin)
Asst. Professor
Dept. Pharmacology,

Penicillins
Beta - Lactam
Antibiotics
Monobactams Cephalosporins
Carbapenems
2. Fungus
Penicillium
notatum and
Penicillium
chrysogenum
4.
First antibiotic β-Lactam
used clinically antibiotic: β-
1. lactam ring
in 1941 Penicillin
3.
Alexander
Fleming: Scottish
physician and
microbiologist,
Nobel prize 1945
Classification of Penicillin
Mechanism
action of
Penicillin
β-Lactam
(penicillin)
resistant
bacteria
Uses:
 Streptococcal Infections:
Pharyngitis,
Otitis Media,
Scarlet Fever
Rheumatic Fever Pharyngitis Otitis Media
Subacute Bacterial Endocarditis

 Pneumococcal Infections:
 Lobar Pneumonia
 Meningococcal Infections:
Meningitis
Lobar Pneumonia
 Gonococcal Infections:
 Ophthalmia Neonatorum
 Syphilis
 Leptospirosis
Syphilis
 Diphtheria
 Tetanus
 Anthrax
 Actinomycosis
 Rat bite fever
 Prophylaxis
 Rheumatic Fever
 Bacterial Endocarditis
 Agranulocytosis
Agranulocytosis
Uses:
Penicillin G- DRUG OF CHOICE IN:
 Subacute Bacterial Endocarditis
Sodium PnG 10-20 MU i.v daily + Gentamicin for 2-6 weeks
 Ophthalmia Neonatorum
 Saline irrigation
 Sodium PnG 10,000-20,000 U/mL
 1 drop in each eye every 1-3hours
 Syphilis
• Early/Latent Syphilis
Procaine Pn 1.2 MU i.m. daily for 10 days OR
Benzathine Pn 2.4 MU i.m. weekly for 4 weeks
Syphilis
• Late Syphilis
Benzathine Pn 2.4 MU weekly for 4 weeks
• Cardiovascular/Neurosyphilis
Sodium PnG 5 MU i.m. 6 hourly for 2 weeks
 Leptospirosis
Sodium PnG 1.5 MU i.v. 6 hourly for 7 days Leptospirosis
 Diphtheria
 Tetanus and Gas gangrene
 Anthrax
 Actinomycosis
 Rat bite fever
 Prophylaxis
• Rheumatic Fever
 Benzathine Pn 1.2 MU every 4 weeks until 18 years of age or 5 years
after attack.
Adverse Effects:
 Hypersensitivity
 rash,
 itching,
 urticaria,
 fever
 wheezing,
 angioneurotic edema,
 serum sickness,
 exfoliative dermatitis (less common)
 Anaphylaxis (rare, but fatal)
*Commonly seen after PARENTERAL administration
*Incidence highest with PROCAINE pn
Intradermal Test
*History of penicillin allergy should be elicited
*Scratch test or Intradermal Test dose - negative test does not rule
out delayed hypersensitivity reactions!
 Superinfections
 Rare with PnG
 Bowel,
 respiratory and cutaneous microflora can undergo changes
 Jarisch- Herxheimer Reaction Myalgia
 Shivering,
 fever,
 myalgia,
 exacerbation of lesions,
 vascular collapse
 Seen in syphilitic patients injected with Penicillin
 Due to sudden release of spirochetal lytic product
 Symptomatic treatment with aspirin and sedation
 Local irritation
Neurotoxicity
 Pain at injection site
 Thrombophlebitis
 Neurotoxicity
 Mental confusion,
 muscular twitching,
 convulsions,
 coma
 Bleeding
 Due to interference of platelet function
 Intrathecal PnG injections (not recommended)
 Arachnoiditis,
 Degenerative changes in spinal cord
 Accidental IV procaine penicillin injection
 CNS stimulation, hallucinations, convulsions
References:
California.
Thanks
Sulfonamides and Cotrimoxazole
Asst. Professor
Dept. Pharmacology,

SULFONAMIDES
 Sulfonamides were the first antimicrobial agents (AMAs)
effective against pyogenic bacterial infections.
 It’s structural analogue of Paraamino benzoic acid (PABA).
 Sulfonamido - chrysoidine (Prontosil Red) dyes.
 Domagk to treat experimental streptococcal infection in
mice and found it to be highly effective.
 Subsequently an infant was cured of staphylococcal
septicaemia (which was 100% fatal at that time) by
prontosil.
Classification of Sulfonamides based on the clinical interest:
1. Short acting (4–8 hr): Sulfadiazine
2. Intermediate acting (8–12 hr): Sulfamethoxazole
3. Long acting (~7 days): Sulfadoxine, Sulfamethopyrazine
4. Special purpose sulfonamides: Sulfacetamide sod.

Mafenide, Silver sulfadiazine, Sulfasalazine
Antibacterial Spectrum
Pharmacological action: Sulfonamides act as
bacteriostatic.
Antimicrobial spectrum: Sulfonamides have broad
spectrum activity against gram-positive and gram-
negative bacteria.
 Gram positive:
 Cocci: Staphylococci, gonococci, meningococci,
pneumococci, streptococci etc.
 Bacilli: Calymmatobacterium, clostridium etc.
 Gram negative: Escherichia coli, Salmonella etc.
The bactericidal concentrations may be attained in
urine.
Sensitivity patterns among microorganisms have
changed from time-to-time and place-to-place.
Those still sensitive are: many Strepto. pyogenes,
Haemophilus influenzae, H. ducreyi,
Calymmatobacterium granulomatis, Vibrio cholerae.
Only a few Staph. aureus, gonococci, meningococci,
pneumococci, Escherichia coli, Salmonella.
 Shigella respond, but majority are resistant.
Anaerobic bacteria are notsusceptible.
 Many bacteria synthesize their own folic acid (FA)
of which para aminobenzoic acid (PABA) is a
constituent.
 Step -1: PABA is utilized by bacteria to form
Dihydrofolic acid in presence of dihydropteroate
synthetase enzyme.
 Step – 2: DHF acid converted into Tetrahydrofolic acid
in presence of dihydrofolate reductase enzyme, then
form to purines which are essential for synthesis of
nucleic acids (DNA) of bacteria cell.
 Therefore, in absence of DNA molecules, the bacterial
cell cannot divide.
 Sulfonamides competitively inhibit
the union of PABA with pteridine
residue to form Dihydropteroic acid
Which conjugates with glutamic
acid to produce Dihydrofolic acid.
Resistance to sulfonamides:
 Most bacteria are developing resistance to sulfonamides such as:
 Gonococci,
 Pneumococci,
 Staph. aureus,
 Meningococci,
 E. coli,
 The resistant mutants either:
a. produce increased amounts of PABA, or
b. their folate synthase enzyme has low affinity for sulfonamides,
or
c. adopt an alternative pathway in folate metabolism.
Pharmacokinetics:
 Sulfonamides are rapidly and nearly completely
absorbed from g.i.t.
 Extent of plasma protein binding differs
considerably (10–95%) among different members.
 The highly protein bound members are longer
acting.
 Sulfonamides are widely distributed in the body
enter serous cavities easily.
 The free form of sulfadiazine attains the same
concentration in CSF as in plasma.
 They cross placenta freely.
Adverse effects:
• Nausea, vomiting and epigastric pain.
• Crystalluria (can be minimized by taking plenty of fluids and by alkalinizing
agents).
• Hypersensitivity reactions (rashes, urticaria and drug fever) occur in 2–5%
patients.
Urticaria
• Photosensitization
• Hepatitis, unrelated to dose, occurs in 0.1%patients.
•Sulfonamides cause haemolysis in a dose dependent manner in individuals with
G- 6PD deficiency.
Hepatitis
•Kernicterus may be precipitated in the newborn, especially premature, by
displacement of bilirubin from plasma protein binding sites and more permeable
blood-brain barrier.
Interactions
 Sulfonamides inhibit the metabolism:
 Phenytoin,
 Tolbutamide and
 warfarin - enhance theiraction.
 They displace methotrexate from binding
and decrease its renal excretion-toxicity can
occur.
Uses:
 In chronic urinary tractinfection (UTI).
UTI
 In streptococcal pharyngitis and gum infection.
 Combined with trimethoprim (as cotrimoxazole)
sulfamethoxazole is used for many bacterial infections, P. jiroveci.
 A long with pyrimethamine, certain sulfonamides are
used for malaria and toxoplasmosis.
 Ocular sulfacetamide sod. (10–30%) is a
cheap alternative in trachoma/inclusion conjunctivitis, Pharyngitis
 Topical silver sulfadiazine or mafenide are used for preventing

infection on burn surfaces.
Gum infection
COTRIMOXAZOLE
 The fixed dose combination of trimethoprim
and sulfamethoxazole is called cotrimoxazole.
 Trimethoprim is a diaminopyrimidine related
to the antimalarial drug pyrimethamine which
selectively inhibits bacterial dihydrofolate
reductase (DHFRase).
 Cotrimoxazole introduced in 1969 causes
sequential block of folate metabolism.
 Trimethoprim is >50,000times more active against bacterial
DHFRase than against the mammalian enzyme.
 T hus, human folate metabolism is not interfered at
antibacterial concentrations of trimethoprim.
 Individually, both sulfonamide and trimethoprim are
bacteriostatic, but the combination becomes cidal against many
organisms.
 Sulfamethoxazole was selected for combining with trimethoprim because both
have nearly the samet½(~ 10hr).
Spectrum of action
 Antibacterial spectra of trimethoprim and
sulfonamides overlap considerably.
 Additional organisms covered by the combination
are, Salmonella typhi, Serratia, Klebsiella,
Enterobacter, Yersinia enterocolitica, Pneumocystis
Salmonella typhi
jiroveci and many sulfonamide resistant strains of
Staph. aureus, Strep. pyogenes, Shigella,
enteropathogenic E. coli, H.influenzae, gonococci and
meningococci.
H. influenzae
Adverse effects:
• Nausea, vomiting, stomatitis, headache and rashes are the usual
manifestations.
•Folate deficiency (megaloblastic anaemia) is infrequent, occurs only
in patients with marginal folate levels.
• Blood dyscrasias, teratogenic risk, Neonatal haemolysis.
• Patients with renal disease may develop uremia.
•A high incidence (upto 50%) of fever, rash and bone marrow
hypoplasia due to cotrimoxazole.
• The elderly are also at greater risk of bone marrow toxicity from
cotrimoxazole.
Bone marrow toxicity
Uses:
 Urinary tractinfections
 Respiratory tract infections
 Typhoid
 Bacterial diarrhoeas and dysentery
 Pneumocystis jiroveci
 Chancroid
 Effective alternative topenicillin
 Forprotecting agranulocytosis patients and treating
 Respiratory
 Other infections
References:
California.
Thanks

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Respiratory stimulants

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Fig. Schematic diagram showing mechanism of action of theophylline

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Mr. Rakesh Kumar (27441)

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

Y2931: BP602T: Pharmacology III

• First isolated by Brotzu from Cephalosporium acremonium (a mold) from a

• Cephalosporin C had poor bioavailability, rapidly cleared

๏ Generally broader spectrum coverage than penicillins

๏ Example: cefotetan has an N-methylthiotetrazole (N-MTT) moiety that is released as a

๏ Cephalosporin “generations”: generally get broader, more Gm- coverage with

๏ Generation 3: More potent, better Gram- beta-lactamase stability, better

๏ Generation 4: Very broad spectrum (Gm- and Gm+)

๏ Generation 5: MRSA and PRSPcoverage

cefpodoxime proxetil cefpodoxime

๏ Keflex ® (Eli Lilly), and generics

Resistant Gm+ bacteria, not covered:

Aerobic gram-negative microorganisms:

๏ Ancef ® (GSKB), and generics

Indicated spectrum for cefazolin (Gen1, parenteral):

Aerobic gram-positive microorganisms:

Resistant Gm+ bacteria, not covered:

Aerobic gram-negative microorganisms:

cefuroxime axetil cefuroxime

๏ Omnicef ® (Abbot) and generics

๏ Rocephin ® (Hoffman-La Roche)

๏ Ceftriaxone precipitates with calcium

๏ Tazidime ® (Eli Lilly), Fortum ® (GSK)

Y2931: BP602T: Pharmacology III

Subacute Bacterial Endocarditis

Y2931: BP602T: Pharmacology III

1. Short acting (4–8 hr): Sulfadiazine

2. Intermediate acting (8–12 hr): Sulfamethoxazole

3. Long acting (~7 days): Sulfadoxine, Sulfamethopyrazine

4. Special purpose sulfonamides: Sulfacetamide sod.

 Topical silver sulfadiazine or mafenide are used for preventing