‫بسم هللا الرحمن الرحيم‬

‫جامعة الرباط الوطني ‪ -‬كلية الصيدلة‬

‫دبلوم فنيي صيدلة السنة الثانية ‪ -‬الفصل الدراسي الرابع‬
‫قسم العالجيات‬

‫علم االدوية – ‪Pharmacology-2‬‬

‫‪17.10.2019‬‬ ‫‪1‬‬
 Course content
: 2- ‫محتويات مقرر علم االدوية‬

Drugs acting in CNS ‫• ادوية الجهاز العصبي المركزي‬

Drugs acting on endocrine system ‫ ادوية الغدد الصماء‬

Antimicrobials ‫• االدوية المضادة للميكروبات‬

-----------------------------------
• Reference: Lippincott’s illustrated reviews: Pharmacology (by:
Richard D. Howland – Mary J. Mycek), 5th edition

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 ‫بسم هللا الرحمن الرحيم‬

Drugs Acting On The CNS

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• The CNS consists of brain and spinal cord.
• Transmission of impulses in the CNS is by
- chemical transmitters, e.g. glycine,GABA
- electerical transmission, e.g voltage-gated
sodium or calcium ion channels.
• Most drugs acting on CNS alter some steps in
the neurotransmission process.
• Drugs affecting CNS may act presynaptically to
influence production, storage, release or
termination of action of neurotransmitters.
• Other agents may activate or block post
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synaptic receptors
17.10.2019 5
 Neurotransmission in the CNS:
• The basic functioning of neurons in CNS is similar to
ANS
• eg transmission of impulses in CNS and ANS involves
release of neurotransmitters that diffuse across
synaptic space and bind to receptors on postsynaptic
neuron
• In both systems binding of transmitter to its receptor
triggers intracellular changes.
• But several differences exist between the two systems
• eg the circuitry of the CNS is more complex than in
ANS and the number of synapses is greater.
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• The CNS contains powerful networks of
inhibitory neurons that are constantly active in
modulating the rate of neuronal transmission.

• Also the CNS communicates through the use

of more that 10 (or perhaps more than 50)
different neurotransmitters , while the PNS
uses primarily Ach and norepinephrine as
neurotransmitters.

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 Synaptic potentials
• In CNS, receptors at most synapses are coupled to
ion channels.
• Binding of neurotransmitter to receptor results in rapid
but transient opening of ion channel, which allows
specific ions in and outside the membrane to flow
down their concentration gradients
• The resulting change in ionic composition across
membrane of neuron alters the postsynaptic potential,
producing either depolarization or repolarization of the
postsynaptic membrane depending on the ions that
move and their direction of movement.
• Neurotransmitters are calassified either as excitatory
inhibitory,depending on nature of action they elicit8
17.10.2019
or
• Excitatory Pathways:

• Their stimulation causes movement of ions that

cause depolarization of postsynaptic membrane.

• These EPSP are generated by:

-stimulation of an excitatory neuron causes release
of neurotransmitters such as glutamate or Ach that
bind to receptors on postsynaptic membrane, this
causes a transient increase in permeability of
sodium(Na+) ions through sodium ion channels.

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 influx of Na+ causes a weak depolarization,
or EPSP that moves the postsynaptic
potential towards its firing threshold.

 if the number of stimulated excitatory

postsynaptic neurons increases, more
transmitter is released.This ultemately
causes the EPSP depolarization of
postsynaptic cells to pass a threshold
thus generating an all- or- none action
potential
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• Inhibitory pathways:
• Stimulation of inhibitory neurons causes movement of
ions that result in hyperpolarization of postsynaptic
membranes
• These IPSP are generated by the following:
-stimulation of inhibitory neurons releases
neurotransmitters such as GABA or glycine which bind
to receptor on postsynaptic membranes, this causes a
transient increase in permeability of ions such as
potassium(K+), and chloride(Cl-) ions.
- the influx of Cl- and eflux of K+ causes a weak
hyperpolarization,or IPSP that moves the postsynaptic
potential away from the firing threshold.This
11
diminishes
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the generation of action potentials
17.10.2019 12
• Combined effects of the EPSP and IPSP:
• Most neurons in the CNS receive both EPSP and
IPSP inputs.
• Thus several different types of neurotransmitters may
act on the same neuron, but each binds to its specific
receptor.
• The overall result action is the summation of the
individual actions of the various neurotransmitters on
the neuron.
• The neurotransmitters are not uniformly distributed in
the CNS but are localized in specific clusters of
neurons, the axons of which may synapse with
specific regions of the brain
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 Transmitter Anatomy Receptor & Recetor Mechanism
preffered antagonist
agonist
Ach Cell bodies at all Muscarinic,m1 Atropine, Excitatory ,
levels muscarine pirenzepine

Ach Muscarinic m2 Atropine, inhibitory

muscarine, methoctramine
bethanechol

Ach Metoneuron- Nicotinic: Excitatory

Renshaw cell nicotine
synapse

Dopamine Cell bodies at all D1 Phenothiazines Inhibitory

levels

Dopamine D2 bromocriptine Phenothiazines, Inhibitory

buterophenones

GABA Supra- spinal and GABAA Bicuculline , Inhibitory

spinal inter-neurons muscimol: pirotoxin
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involved in pre- and 14
postsynaptic
inhibition
Transmitter Anatomy Receptor & Receptor Mechanisms
preferred agonist antagonist
GABA GABAB baclofen 2-OH saclofen Inhibitory

Glutamate Relay neurons at N-methyl-D- dizocilpine Excitatory

all levels aspartate
(NMDA)
Glycine Relay neurons at Taurine, β- Strychnine Inhibitory
all levels& some alanine
interneurons
Serotonin(5-HT Cell bodies in 5-HT1A: LSD meterogoline inhibitory
midbrain &pon
projections
Serotonin 5-HT2A: LSD Ketanserin Excitatory
5-HT3: 2-methyl-
5-TH Ondansetron Excitatory
Norepinephrine Cell bodies in α1: Prazocin Excitatory
pons&brain stem phenylepherine
projection at all α2: clonidine yohimbine excitatory
levels β1:dobutamine atenolol inhibitory
β2:albuterol butoxamine inhibitory
17.10.2019 Cells in ventral
Histamine H1 :2(m- mepyramine Excitatory
posterior flurophenyl)
 Drugs acting on the CNS

• Anxiolytic and Hypnotic drugs

• Anti-epileptics
• Anti-Parkinsonian drugs
• Narcotic analgesics (opiates)
• General anesthetics
• Antipsychotic drugs
• Antidepressants

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Quiz No.(1) 15/3/2015
Which of the following is an excitatory
neurotransmitter in the CNS?
A-dopamine acting on D1-receptors
B- Ach acting on muscarinic m2 receptors
C-Ach acting on nicotinic receptors
D-GABA acting on GABAA receptors
E-norepinephrine acting on α1-receptors

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 ‫بسم هللا الرحمن الرحيم‬

Anxiolytic and Hypnotic drugs

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• A sedative(anxiolytic) agents reduce anxiety &
exert a calming effect.
• Degree of CNS depression is minimum.

• A hypnotic drug produces drowsiness &

encourages onset & maintenance of sleep.
• The degree of CNS depression is more than
that produced by sedatives.

• Graded dose-dependent depression of CNS is

a characteristic of sedative-hypnotic drugs
(fig. 1).
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 Dose-response curve for two sedative-
hypnotics

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• Drug A is typical of older sedative-
hypnotics such as barbiturates & alcohols.

• Increasing doses of such drugs may lead

to anesthesia, and still higher doses cause
medullary depression and death.

• Drug B achieves CNS depression but not

to death, eg benzodiazepines

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 Anxiolytic and hypnotic drugs
Classes of anxiolytic and hypnotic
Drugs:
• Benzodiazepines (BNZ), the most important
class, are used for treating both anxiety
states and insomnia.
•
• They include:diazepam(valium).
chlordiazepoxide(libium),flurazepam(dal-
amane), lorazepam(ativan), nitrazepam
(mogadon),triazolam and alprazolam (xanax)
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 • Novel drugs that differ structurally
from benzodiazepines are recently
introduced to treat sleep disorders,
these include zolpidum, zaleplon
and eszopiclone.
• They share same mechanism of
action as benzodiazepines.
• Ramelteon,a melatonin receptor
agonist is a new hypnotic drug.
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• Buspirone is a nonbenzodiazepine
anxiolytic drug.
- is a partial agonist at 5-HT1A receptors
- relieves anxiety without causing marked
sedative hypnotic or euphoric effects.
- unlike BZs, it has no anticonvulsant or
muscle relaxant effects

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 • Barbiturates are now largely obsolete as
anxiolytic/ sedative agents, eg
phenobarbital,secobarbital
• Also antipsychotics eg chlorpromazine &
antidepressants eg imipramine
• Certain antihistamines such as
promethazine
• Miscellaneous agents such as chloral
hydrate and alcohols(ethanol).
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• Benzodiazepines (BNZ):
– Act by enhancing the inhibitory effect of
GABA at GABAA receptors in neuronal
membranes in CNS, by increasing frequency
of chloride ion(Cl-) channel opening.
– BZs cause:
• Reduction of anxiety
• Hypnosis, anesthesia
• Muscle relaxation,
• Suppression of convulsions (antiepileptic
effect)
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– Some are used IV, e.g. diazepam in status
epilepticus
– BNZs are relatively safe in overdose
– Their main disadvantages are the
development of dependence and
withdrawal symptoms
– The actions of benzodiazepine may be
antagonized by flumazenil.It blocks actions
of BZs,eszopiclone,zaleplon, and zolpidum
but does not block actions of barbiturates.
– examples of BZs used clinically include
diazepam,lorazepam, nitrazepam
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• Barbiturates:
Phenobarbitone,Thiopentone,secobarbital,
pentobarbital
-They are dangerous in overdose.
-Mechanism of action:
• -act by enhancing action of GABA at GABAA
by increase duration of chloride ion channel
opening
• -They also depress actions of the excitatory
neurotransmitter glutamic acid by binding to
AMPA (amino-methoxy-propionic acid) receptor
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 -They also exert nonsynaptic membrane
effects
-Thus they may induce full surgical
anesthesia,& more pronounced CNS
depression, have low margin of safety
-Barbiturates are mainly used in
anesthesia(eg thiopental) and treatment of
epilepsy(eg. phenobarbital)
-Use as sedative/hypnotic agents is no
longer recommended
- Tolerance and dependence may occur
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• Often classified according to their rate of onset
or duration of action:
– Long- acting barbiturates e.g.
Phenobarbitone
– Short- acting e.g. pentobarbitone
– Ultra short- acting e.g. thiopentone
• Non-barbiturate sedatives:
– Chloral hydrate
– Antihistamines: e.g
diphenhydramine,promethazine(phenergan)
– Ethanol
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 Clinical uses of sedative -hypnotics
• Treatment of anexity states as in
preanesthetic cases.
• Relief of insomnia.
• For sedation and amnesia before and
during medical and surgical
procedures(endoscopy,bronchoscopy)
• Treatment of epilepsy and seizure states
• As a component of balanced
anesthesia(IV)
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• For control of ethanol and other sedative-
hypnotic withdrawal states
• For muscle relaxation in specific
neuromuscular disorders
• As diagnostic aids or for treatment in
psychiatry( eg initial management of
mania)
• ---------------------------------------------------------
---------------------------------------------------------
---------28/2/2016----------------------
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 ‫بسم هللا الرحمن الرحيم‬

Antiepileptic(Antiseiuzre) Drugs
(AEDs)

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• Epilepsy is a chronic disorder characterized by
recurrent seizures that have in common the
sudden, excessive and disorderly discharge of
central neurons.
• Causes of seizures include the full range of
neurologic disease, from infection to neoplasm
and head injury.Also some cases are inheretid.
• Some antiseizure drugs are also used for
nonepileptic seizures, as febrile seizures or
seizures of acute illness, as in meningitis or
hypoglycemic seizures.
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 Classification of epileptic seizures
• GENERALIZED SEIZURES,are subdivided into:
-generalized tonic-clonic(grand mal seizures)
-absence(petit mal) seizures,(brief abrupt loss of
consciousness that lasts for 3 to 5 minutes).
-tonic seizures
-atonic seizures
-clonic and myoclonic seizures
• PARTIAL SEIZURES, are subdivided into:
-simple partial seizures
-complex partial seizures
-Partial seizures secondarily generalized
-infantile spasms
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Mechanisms of action of antiepileptic
drugs:
 Elecrophysiologic: inhibit excessive discharge ,
inhibit spread of discharges
 Molecular:
-potentiate GABA neuronal function
-diminish excitatory (glutamatergic)
transmission
-inactivation of voltage-gated Na ion channels
-modulating Ca, K, and Cl ion channel function

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Drugs used in Partial Seizures and
Generalized tonic- clonic seizures
The classic drugs include: phenytoin(Epanutin),
carbamazepine(Tegretol),valproate(Depakine),
and barbiturates

The newer agents include:

lamotrigene,levetiracetam,gabapentin,
oxcarbazepine, pregabalin, topiramate,
vigabatrin,lacosamide and zonisamide

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Phenytoin (diphenylhydantoin)
The oldest nonsedative antiseizure.Fosphenytoin
is a more soluble prodrug that is administerd
parentrally.
Mechanism of action: it blocks sustained, high
frequency repetitive firing of action potentials
by blocking Na+ ion conductance.
This action is due to prolongation of the
inactivated state of Na+ ion channels
This action is shared by carbamazepine ,
lamotrigene, & valproate
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• Used for:
-partial seizures(simple and complex)
-grand mal epilepsy( tonic-clonic )seizures.
-trigeminal neuralgia
-antiarrythmic
• Not used for absence seizures.
• Adverse effects:
– Nystagmus,and loss of smooth extraoccular
pursuit movements
– Diplopia and ataxia are dose related
– Sedation at high doses
– Gingival hyperplasia (reversible),hirsutism
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– Coarsening of facial features.
 2. Carbamazepine
• Structurally resembles imipramine and was
used to treat bipolar depression and trigeminal
neuralgia.
• As antiepileptic it resembles actions of
phenytoin, with low incidence of unwanted
effects(blocks sodium ion channels in
neuronal cells).
• Is a drug of choice for both partial seizures
and generalized tonic-clonic seizures.
• Is used for trigiminal neuralgia
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 Drugs used in generalized seizures
1. Valproic Acid & sodium
valproate(depakene)
• It is fully ionized at physiological pH,thus the
active form may be the valproate ion.
• It blocks high frequency repetitive firing of
neurons due to blockade of sodium ion
currents.Blockade of NMDA receptor-
mediated excitation may also be involved.
• It Potentiates GABA effects by increasing
GABA synthesis
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• Second choice for absence seizures and if
generalized tonic-clonic seizures are also
present
• It is also used in bipolar disorder and
migraine prophylaxis
• it is well absorbed orally,food may delay
absorption
• It may cause hepatotxicity
• May cause spina bifeda(a defect in the
spinal column, through which the spinal
membranes with or without spinal tissue
may protrude).
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 2- Ethosuximide(zarontin)
• Was introduced as a pure petit mal drug
• It acts by reducing T-type calcium ion
currents in thalamic neurons responsible
for generating discharges of absence
attacks.
• It is used for absence seizures

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• Adverse effects:
– hepatotoxicity
– Birth defects (spina bifida)

6 - Vigabatrin
• It is an irreversible inhibitor of GABA
aminotransferase(GABA-T),the enzyme that
degrades GABA.It produces a sustained
increase in extracellular GABA concentration.
• It is useful in treatment of partial seizures and
West’s syndrome
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 Lamotrigene:
• Like phenytoin it suppresses sustained
rapid firing of neurons and produces a
voltage –and use-dependent inactivation
of sodium ion channels.It may also inhibits
voltage gated Ca++ channels
• Used for partial seizures and absence and
myoclonic seizures in children
• It is also used for bipolar disorders
-----------------------------------------------------------
--------------------------------------15/3/2015
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 Quiz 2 22/3/2015
• Which of the following
anticonvulsants causes gingival
hyperplasia?
• A- Carbamazepine
• B- Diazepam
• C- Phenytoin
• D- Gabapentin
• E- valproate
17.10.2019 46
 Neurodegenerative Diseases

• These include Parkinson disease, Alzheimer

disease, Multiple sclerosis(MS) and Amyotropic
lateral sclerosis(ALS)
• These diseases are characterized by
progressive loss of selected neurons in discrete
brain areas, resulting in characteristic disorders
of movement,cognition or both

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• Alzheimer disease is due to loss of
cholinergic neurons in the nucleus basalis
of Mynert.Affects cognition and knowledge.
• Parkinson’s disease is due to loss of
dopaminergic neurons in the substantia
nigra and excess Ach.Affects movement.
• Multiple sclerosis is an autoimmune
inflammatory demyelination of the CNS
neurons that leads to disabling.

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 Anti-Parkinsonian drugs

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 Schematic representation of the sequence
of neurons involved in parkinsonism

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 Parkinson’s Disease: (PD)
(Parkinsonism=Paralysis Agitans)
• Pd is a progressive neurodegenerative
disorder of CNS that usually impair
motion skills of muscle movement
characterized by tremors, muscle
rigidity, bradykinesia and postoral and
gait abnormalities.
• Occurs as a result of deficiency of
dopamine or excess of Ach in
substantia nigra
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Drugs for Parkinson’s Disease
(Anti-Parkinsonian drugs) = Anti- PD Drugs

• Available drugs offer temporary relief of

symptoms,but do not arrest or reverse
neuronal degenerative.
• Strategy of treatment is aimed at restoring
dopamine in basal ganglia and
antagonizing the excitatory effect of
cholinergic neuron, thus restablishing
DA/ACh balance
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 Anti- Parkinsonism Drugs
• Amantadine(antiviral)
• Apomorphine
• Benztropine, trihexyphenydyl (antimuscarinics)
• Biperiden
• Bromocriptine,pergolide,pramipexole,ropinirole,
rotigotine(dopamine receptor agonists)
• Levodopa/with carbidopa(sinemet)
• Entecapone,tolcapone
• Procyclidine
• Seligline,rasagiline(MAO-B
17.10.2019
inhibitors) 53
 1. Drugs that are precursors of dopamine:
e.g. Levodopa (L-DOPA)
• L-DOPA, a precursor of DA, can be rapidly
absorbed in intestine,
• Dopamine does not cross BBB,but levodopa can,
and is converted in CNS to dopamine.
• Levodopa is rapidly metabolised in peripheral
tissues (the major cause of adverse effects).
• Only 1% of L-DOPA enters the brain to increase
the DA contents.Thus large doses are required
which increases incidence of adverse effects.
• Carbidopa diminishes peripheral metabolism of
L-dopa thus increases its availability to CNS.
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• Action:it decreases rigidity and tremors of PD.
 Fate of oral levodopa and the effect of carbidopa

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• Adverse effects of levodopa include nausea,
vomiting, postural hypotension and cardiac
arrhythmias
• The peripheral side effects can be reduced by co-
administration of dopa decarboxylase inhibitors
(e.g. carbidopa); to reduce peripheral synthesis of
DA
• Carbidopa does not cross the blood-brain barrier
• Dyskinesia on prolong use and is also dose-
dependent
• Behavioral effects such as depression, anxiety,
agitation, insomnia,confusions, delusions,
hallucinations, neightmares, euphoria and other
mood changes
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 2-Dopamine Receptor agonists
• Bromocriptine, pergolide are ergot alkaloids,
• Pramipexole, ropinirole and rotigotine, apomorphine
are nonergot dopamine receptor agonists:
– They all act as D2 agonists in subistantia nigra
– Adverse effects similar to those of levodopa
3-Muscarinic antagonists
• In the corpus striatum, ACh has an excitatory effect
opposite to that of DA
• Blockage of cholinergic transmission produces effects
similar to augmentation of dopaminergic transmission
• As adjunct therapy
• E.g: Benztropine,trihexyphenidyl,orphenandrine,
biperiden and procyclidine
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4-Monoamine oxidase inhibitors(MAOI):
-selegline and rasagiline are selective MAO-B
inhibitors in low doses(MAO-A metabolizes
norepinephrine & serotonin whereas MAO-B
metabolizes dopamine at low doses).
-they retard breakdown of dopamine & enhances its
effects
5-Catechol-O -methyltransferase inhibitors:
-tolcapone and entecapone.They enhance action of
levodopa by inhibiting its peripheral metabolism
6-Amantadine is an antiviral useful in parkinsonism,
acts by increasing dopamine release,blocking
cholinergic receptors and inhibiting NMDA
receptors
17.10.2019 58
 Drugs used in Alzeheimer
Disease
• Treatment is only palliative.These drugs do not
alter the underlying neurodegenerative
processes.
• A- AchE inhibitors:
• Donepezil
• Galantamine
• Rivastigmine
• Tacrine
-They
17.10.2019 reduce in rate of loss of cognitive function
59
 2-NMDA-receptor antagonists:
• Stimulation of glutamate receptors in CNS
is critical in formation of certain memories,
but overstimulation of these receptors
(mainly NMDA-type) may result in
excitotoxic effects on neurons and their
apoptosis(programmed cell death).
• Memantine is an NMDA-receptor
antagonist that prtotects apoptosis of
neurons following ischemic and other
injuries 6/3/2016
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 ‫بسم هللا الرحمن الرحيم‬

Opioid analgesics
(Narcotic analgesics)

These drugs are used to control severe

visceral pain and cancer pain

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• Pain is defined as an unpleasant sensation that can
be either acute or chronic, and is a consequence of
complex neurochemical processes in peripheral and
CNS systems.It is usually subjective.
• Its alleviation depends on its specific type, either
nociceptive or neurogenic.
• Nociceptive pain(as moderate arthritic pain) is
releived by NSAIDs.
• Neurogenic pain responds best to anticonvulsants(
eg pregabalin),tricyclic antdepressants(eg
amitriptylline)or serotonin/norepinephrine reuptake
inhibitors(eg duloxetine).
• But for severe or chronic malignant or nonmalignant
62
pain, opioids are the drugs of choice.
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 Opioid analgesics
(Narcotic analgesics)
• Opioids are natural or synthetic compounds that
produce morphine- like effects.
• The term opiate denotes the natural products,
morphine and codeine.
• Natural: e.g. morphine, codeine.
• Semi-synthetic: e.g. Heroin.

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• Synthetic:e.g.meperidine(pethidine),metha
done, tramadol(blocks serotonin
reuptake).
• These drugs act by binding to opioid
receptors in CNS, to produce effects that
mimic actions of the endogenous
peptides(endorphins, enkephalins &
dynorphins).
• They are major drugs of abuse for their
euphoric properties
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 Opioid receptors
• Three types of opioid receptors, termed mu(µ),delta
(δ) and kapa (κ), mediate the main effects of
opioids
• Opioids:
– promote the opening of potassium ion channels
– inhibit the opening of voltage-gated calcium
channels.
• Thus inhibiting neural firing and transmitter release
• Opioids relieve pain by:
– raising the pain threshold at the spinal cord level
– altering the brain’s perception of pain.
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 Actions of morphine
-analgesia mediated through mu receptors
-euphoria mediated through mu receptors
Sedation medaiated through mu receptors
-respiratory depression mediated through mu
receptors
-cough suppression mediated through mu
receptors
-miosis,tolerance does not develop to this action
Truncal rigidity
-Nausea
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and vomiting 66
 Opioid agonists and antagonists

• Strong agonists:
-morphine, heroin, methadone,
-pethidine

• Moderate agonists: codeine

• Antagonists: naloxone, naltrexone

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 Analgesic activity
• The most important pharmacological effect
of these drugs is their ability to relieve pain

• Used clinically to relieve pain associated

with tissue injury, inflammation and cancer

• The clinical use of narcotic analgesics is

limited due to their ability to induce
tolerance and dependence (both physical
and psychological)
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 Morphine
• The prototype – strong agonist
• Has high affinity for µ receptors
• It acts on µ receptors in the substantia
gelatinosa of the spinal cord and decreases
the release of substance P

• Therapeutic uses:
– Analgesia:
• morphine is effective in most kinds of
acute and chronic pain associated with
tissue injury, inflammation and tumour
69
growth and cancer
17.10.2019
 – Treatment of diarrhea
– Relief of cough: codeine and
dextromethorphan have greater antitussive
action than morphine.
– Administered parentrally (IM, SC, IV).
– Oral absorption is slow and erratic

• Methadone :

– Given orally
– Causes milder withdrawal syndrome
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• Pethidine:
– Not useful in diarrhea or cough

• Codeine:
– Relieves mild to moderate pain
– Shows good antitussive activity

• Naloxone:
– Is a competitve antagonist at at µ receptors
– Is used (i.v. ) to reverse coma and respirotary
depression of opioid overdose 22/3/2015
===============================
17.10.2019 71
 Quiz 3
• Which of the following drugs is a MAOI
that is used in parkinssonism?
• (a) beztropine
• (b) carbidopa
• (c) selegline
• (d) bromocriptine
• (e) entecapone

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 ‫بسم هللا الرحمن الرحيم‬

General Anesthetic Drugs

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 Anesthesia
• General anesthesia is a state of reversible
absence of sensation and loss of
consciousness for the purpose of carrying out
surgery.
• The physiological state produced by general
anesthetics includes analgesia, amnesia, loss
of consciousness, inhibition of sensory &
autonomic reflexes & skeletal muscle relaxation

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 Types of anesthesia are:
(A) IV which include(1) barbiturates(thiopental)
(2) benzodiazepines (diazepam midazolam)
(3) porpofol,(4)ketamine,(5)opioid analgesics
(morphine,fentanyl)
(6)miscellaneous sedative-hypnotics(etomidate)

(B)inhalational(isoflurane,desflurane,sevoflurane).

(C) balanced anesthesia: this is the use of both IV

anesthetics for induction and inhaled
anesthetics
17.10.2019
for maintenance of anesthesia 75
 Stages of anesthesia
– Stage I :analgesia without amnesia initially
then both lately
– Stage II:excitement: delirium-combative
behaviour,irregular respiration in volume and
rate,retching and vomiting
– Stage III: surgical anesthesia begins with
recurrence of regular respiration and extends
to complete sesation of respiration
– Stage IV:medullary paralysis, thus
respiratory and circulatory sport is imprtant or
17.10.2019 76
death will ensue.
 General Anesthetics
• General Anesthetics have small margin of safety
• General Anesthetics are divided into two classes:
– Inhaled Anesthetics
– Intravenous Anesthetics
1. Inhaled Anesthetics
Mechanism of Action of Inhaled Anesthetics
-depression of spontaneous and evoked CNS activity.
-modification of ion currents by direct interaction with
specific nerve cell membrane components
-A primary molecular target for general anesthetics is
the inhibitory GABAA receptor chloride ion channel.
-They facilitate synaptic transmission at GABAA 77
17.10.2019
receptor
 Rate at which therapeutic concentration
of inhaled anesthetic is achieved in CNS
depends on:
• Solubility properties of the anesthetic
• Its concentration in the inspired air
• Volume of pulmonary ventilation
• Pulmonary blood flow
• Arteriovenous concentration gradient

17.10.2019 78
 Advantages & Disadvantages of Selected Inhaled
Anesthetics
• These include nitrous oxide,desflurane,sevoflurane,
isoflurane,enflurane,halothane and methoxyflurane.
• Nitrous Oxide: (N2O = laughing gas)
– Low blood solubility (quick recovery)
– Low potency
– Needs other agents for surgical anesthesia
• Halothane
– Potent inhaled anesthetic
– Can cause cardiac arrhythmias and hypotension
– Used for maintenance of anesthesia
– Cause hepatotoxicity and malignant hyperthermia
17.10.2019 79
• Isoflurane:
– Arrhythmias are uncommon
– Minimally metabolized and no reports of heptato- or
nephrotoxicity
– most widely used agent
• Methoxyflurane,enflurane, and sevoflurane may
cause nephrotoxicity since they are metabolized to
fluoride ions which are nephrotoxic
2-Intravenous Anesthetics
• Primarily used for induction of general anesthesia in
balanced anesthesia
• These include:thiopental, etomidate,propofol,ketamine
(ketalar),morphine,
17.10.2019 fentanyl,diazepam and midazolam80
 Thiopentone(Pentothal)
• A potent IV anesthetic
• Ultra-short acting barbiturate
• most commonly used to induce anesthesia
• Has rapid onset of action and recovery
Propofol
• Its rate of onset of action is similar to IV barbiturates
but recovery is rapid, and pts are able to ambulate
earlier after general anesthesia also pts feel better
postoperatively due to reduction in postoperative nausea
and vomiting and a sense of well being , thus is more
popular
ketamine: produces dissociative anesthesia
characterized by catatonia,amnesia,& analgesia with or
without loss of consciousness
17.10.2019 81

=====================13/3/2016
 ‫بسم هللا الرحمن الرحيم‬

‫‪Antipsychotic Drugs‬‬

‫‪17.10.2019‬‬ ‫‪82‬‬
• These drugs reduce psychotic symptoms in a variety
of conditions including: schizophrenia, bipolar
disorder, psychotic depression, senile psychosis and
drug- induced psychosis.
• They can also reduce mood and anxiety and sleep
disturbances.They are called neuroleptics.
• A neuroleptic drug is an antipsychotic drug that
produces a high incidence of extrapyramidal side
effects(EPS) at clinically effective doses.
• Typical(conventional) antipsychotic drugs act by
blocking dopamine receptors in CNS, thus producing
EPS eg chlorpromazine.
• Atypical antipsychotics do not produce EPS eg
clozapine.They
17.10.2019
act by blocking 5-HT2A receptors 83
 Nature of Psychosis and Schizophrenia:
• Psychosis is a variety of mental disorders including
delusions(false beliefs), hallucinations (auditory or
visual),but sometimes tactile(touch) or olfactory &
disorganized thinking.
• Schizophrenia is a kind of psychosis characterized
by a clear sensorium but a marked thinking
disturbance.
• It is a neurodevelopmental disorder, ie structural
and functional changes in the brain are present,
even in utero in some patients, or they develop
during childhood or adolescence.
• It is a genetic disorder with high heritability
17.10.2019 84
The Serotonin Hypothesis of Schizophrenia
• 5-HT2A receptor stimulation causes hallucination.
• 5-HT2A receptor blockade is the mechanism of action
of atypical antipsychotics such as clozapine and
quetiapine.
• The Dopamine Hypothesis of Schizophrenia
• Many antipsychotics block dopamine D2 receptors in
the CNS eg aripiprazol & bifeprunox.
• Dopaminergic agonists such as bromocriptine either
aggravate schizophrenia or produce psychosis.
• High density of dopamine receptors was found in the
brains of psychotics postmortally.
17.10.2019 85
 Schizophrenia:
• A group of mental illnesses characterized by
disorganization of the patient's personality:
– Positive symptoms – hallucination, delusion
(false beliefs), disordered thinking, agitation ‫هياج‬
etc.
– Negative symptoms – emotional withdrawal, lack
of motivation, poor self-care etc.
• Conventional(typical) antipsychotic agents relieve
positive symptoms better.
• Atypical antispychotic agents relieve both positive
and negative symptoms.
17.10.2019 86
Antipsychotic Drugs
• Antipsychotic drugs = Antischizophrenic drugs=
Major tranquillizers= Neuroleptics
• Classified into groups:
-phenothiazines (chlorpromazine, thioridazine,)
-thioxanthines(eg thiothixine)
-butyrophenones (eg haloperidol -Serenase)
-miscellaneous typical agents(pimozide,
molindone)
-atypical agents (loxapine, clozapine,
olanzapine.etc)
17.10.2019 87
• Antipsychotic drugs are not curative, but
permit the psychotic patient to function in a
supportive environment.
• Antipsychotic drugs are classified into:
– Typical(conventional) antipsychotic
drugs
– Atypical antipsychotic drugs

17.10.2019 88
• Distinction between typical and atypical groups is
according to:
– Incidence of extrapyramidal side-effects (EPS)

 Typical antipsychotic agents:

• e.g. chlopromazine (CPZ largactil), haloperidol
– Block dopamine D2 receptors for therapeutic
effects (probably)
– Block dopamine, acetylcholine, histamine, and
norepinephrine ,adverse effects

– Used to treat acute (not chronic) schizophrenia

17.10.2019 89
 – Adverse Effects of Typical Antipsychotic
Drugs :
extrapyramidal symptoms (EPS): Movement
disorders; probably from Dopamine blockade

• Butyrophenones: e.g. haloperidol

Atypical antipsychotic agents:

– E.g. clozapine, sulpiride
– Few EPS symptoms

17.10.2019 90
• Unwanted effects of antipsychotic drugs:
– Extrapyramidal motor disturbances
– Sedation
– Dry mouth

• Chlorpromazine (CPZ , Largactil);

– The first phenothiazine used and is widely used.

– Produces more side effects than newer drugs

– Very sedative (useful for violent patients)

17.10.2019 91
• Haloperidol(Serenase):
– Less sedative & hypotensive than CPZ
– Little anticholinergic effects.
– High incidence of movement disorders
• Clozapine:
– Restricted to patients refractory to other
neuroleptics
• Sulpiride:
– A very specific D2-blocker
– Widely used because it has a low liability for
EPS and tolerated sedation 29/3/2015
==========================
17.10.2019 92
 Quiz 4
• Which stage of general anesthesia is
characterized by irregular respiration,
retching and vomiting?
• (a) stage 1
• (b) stage 2
• (c) stage 3
• (d) stage 4

17.10.2019 93
 ‫بسم هللا الرحمن الرحيم‬

Antidepressant Drugs

17.10.2019 94
• Major depressive disorder(MDD) is
characterized by depressed mood most of
the time for at least 2 weeks, and/or loss
of interest or pleasure in most activities.
• Depression is also characterized by
disturbances in sleep and appetite ,as well
as deficits in cognition and energy.
• Thoughts of guilt, worthlessness and
suicide are common.
• Coronary artery disease, diabetes and
stroke are common in depressed patients
17.10.2019 95
• What are the possible mechanisms of
depression?
• Deficiency of monoamine neurotransmitters is a
major cause(the monoamine hypothesis).
• Also neurotrophic and endocrine factors play
important role(neurotrophic hypothesis).
– Reserpine, which depletes the brain of
norepinephrine(NE) and 5-HT, often causes
depression
– Most clinically useful antidepressant drugs
potentiate, either directly or indirectly, the
actions of NE and /or 5-HT in the brain
17.10.2019 96
 Antidepressant Drugs
• Can be classified according to their modes of
action into several groups:

1. Tricyclic antidepressants (TCAs)

2. Monoamine oxidase inhibitors (MAOIs)

3. Selective Serotonin Reuptake Inhibitors

(SSRIs)
17.10.2019 97
• Clinical indications of antidepressant
drugs:
– Major Depressive Disorder(MDD)
– Obsessive-compulsive disorder(OCD)
‫وسواس قهري‬
– Panic disorder
– Generalized anxiety disorder(GAD)
– Post-traumatic stress disorder(PTSD)
– Enuresis (bed-wetting in children)

17.10.2019 98
 1. Tricyclic antidepressants (TCAs)
• E.g. Imipramine (prototype), Amitriptyline,
nortriptyline,desipramine,clomipramine
• Are valuable for patients who do not respond to
SSRIs
• Drugs with sedative actions such as amitriptyline
are more suitable for agitated ‫ هائج‬and anxious
patients
• Mechanisms of action:
– Block non-selectively reuptake of NE and
serotonin
– TCAs also block α-adrenergic, histaminic and
17.10.2019
muscarinic receptors 99
• Adverse effects:
– Anticholinergic effects(eg dry mouth)
– Postural hypotension ( due to a1-blocking activity)
– Sedation
– TCAs have a narrow therapeutic index
2. Monoamine Oxidase Inhibitors (MAOIs)
• Monoamine Oxidase:
– Metabolize noradrenaline, dopamine or 5-HT.
– Two types are known:
– MAO-A metablizes norepinephrine and 5-HT
– MAO-B metabolizes dopamine,blocked by
selegline
17.10.2019 100
• Monoamine Oxidase Inhibitors (MAOI's):
– Last choice for treatment
– Examples: phenelzine, selegline,
isocarboxazid, Tranylcypromine

• MAOIs interact with tyramine-containing

foods and cause hypertensive crisis
(‘cheese reaction’)

17.10.2019 101
 3. Selective serotonin reuptake inhibitors
(SSRIs)
• E.g. fluoxetine, fluvoxamine
• Selectively inhibit reuptake of 5-HT
• Fluoxetine :
– Most commonly prescribed antidepressant.
– Uses : depression, Obsessive-compulsive
disorder.
– Advantages:
• lacks cardiovascular and anticholinergic
side effects.
• no ‘cheese’ reaction
• safer (low risk of overdose)
102
17.10.2019
================20/3/2016
 ‫بسم هللا الرحمن الرحيم‬

Drugs acting on the Endocrine

System

17.10.2019 103
 Drugs acting on the Endocrine system

1. Hypothalamic and pituitary hormones &

Drugs
2. Thyroid hormones & Drugs
3. Insulin & oral hypoglycemic drugs
4. Adrenal corticosteroids
5. Oestrogens & progestins

17.10.2019 104
 Endocrine Glands

17.10.2019 105
 Hypothalamic and pituitary hormones &
Drugs
• Each hypothalamic regulatory hormone
controls the release of a specific hormone
from the anterior pituitary

• The hormones of the anterior pituitary are

regulated by the following neuropeptides:
– releasing factors (or hormones)
– inhibiting factors (or hormones)

17.10.2019 106
• The hypothalamic releasing hormones are
primarily used for diagnostic purposes (that is,
to determine pituitary insufficiency)
• The hypothalamus also synthesizes the
hormones oxytocin and vasopressin, which
are transported to the posterior pituitary
where they are stored until released
• Hormones of the anterior and posterior
pituitary are administered either IM, SC or
intranasally but not orally, because they are
peptides,thus may be destroyed by
proteolytic enzymes
17.10.2019 107
i. Hypothalamic and anterior pituitary
hormones & Drugs:
A. Hypothalamic hormones & Drugs:
• Corticotropin-releasing hormone (CRH)
• Thyrotropin-releasing hormone (TRH)
• Growth hormone-releasing factor
(GHRF), somatorelin,
• Growth hormone-inhibiting factor
(somatostatin, octreotide):
• Gonadotropin-releasing hormone
17.10.2019 (GnRH):leuprolide, goserelin 108
 Vasopressin(ADH)
• Is structurally related to oxytocin
• Has both antidiuretic and vasopressor effects

• The major use of vasopressin is to treat

diabetes insipidus

• Adverse effects: water intoxication,

hyponatremia, headache,
==============

17.10.2019 117
 quiz
• Oxytocin and vasopressin are synthesized
in posterior pituitary gland( )
• Somatostatin is agrowth hormone-relesing
hormone( )
• Leuprolide is a growth hormone-inhibiting
hormone( )
• Octreotide is used to treat acromegally( )
• Vasopressin is used to treat diabetus
insipidus( )
17.10.2019 118
 ‫بسم هللا الرحمن الرحيم‬

Thyroid & Antithyroid Drugs

17.10.2019 119
 Thyroid Gland
 Found at the base of the throat
 Butterfly shaped
 Produces two hormones:
1)Thyroid hormone control
metabolism
2) Calcitonin control
calcium levels in blood
17.10.2019 120
 Regulation of thyroid hormones synthesis &
release

17.10.2019 121
 Thyroid & Antithyroid Drugs
• The thyroid gland facilitates normal growth and
maturation by maintaining the level of
metabolism in the tissues that is optimal for their
normal function
• The thyroid hormones are T3 = triiodothyronine
(the most active form), and T4 (thyroxine =
tetraiodothyronine, levothyroxine)
• inadequate secretion of thyroid hormones
(hypothyroidism) results in poor growth,
bradycardia, poor resistance to cold, mental and
physical slowing, (in children this can cause
mental retardation and dwarfism).
17.10.2019 122
• If, however, an excess of thyroid
hormones is secreted (hyperthyroidism),
tachycardia, arrhythmias, body wasting,
nervousness, tremor and excess heat
production can occur. The upper eyelids
are retracted, causing a wide stare,
exophthalmia
• Thyroid function is controlled by TSH
(thyrotropin), synthesized by the anterior
pituitary which inturn is controlled by
thyrotropin releasing hormone (TRH) from
hypothalamus
17.10.2019 123
 Treatment of hypothyroidism:
• hypothyroidism is treated with
levothyroxine (T4). It is the drug of choice
for replacement therapy

• The drug is given once daily because of its

long half-life
• Toxicity is directly related to thyroxine
levels and manifests itself as nervousness,
heart palpitation, intolerance to heat and
unexplained weight loss
17.10.2019 124
 Treatment of hyperthyroidism (thyrotoxicosis):
• Excessive amounts of thyroid hormones in the
circulation are associated with a number of
disease state, including Graves’ disease (an
autoimmune disease), toxic adenoma, goiter
and thyroiditis
• The goal of therapy is to decrease synthesis and
∕or decrease release of additional hormone:
– This can be accomplished by removing part or
all of the thyroid gland, by
• inhibiting synthesis of the hormones,
• or by blocking release of the hormones
from the follicle:
17.10.2019 125
 1. Removal of part or all of the thyroid:
This can be accomplished either
surgically or by destruction of the gland
by beta particles emitted by radioactive
iodine (131I), which is selectively taken
up by the thyroid follicular cells

2. Inhibition of thyroid hormone synthesis:

• propylthiouracil (PTU), carbimazole
and methimazole, inhibit synthesis of
T3 and T4.
17.10.2019 126
 • All the antithyroid drugs are administered
orally and are accumulated in the thyroid
gland

• Their onset of action is delayed until the

preformed hormones are depleted, a
process that may take 3-4 weeks

1. Carbimazole:
• is rapidly converted to methimazole in vivo.
• For treatment of hyperthyroidism
• Contraindicated in pregnancy
17.10.2019 127
2. Propylthiouracil (PTU):
• is usually reserved for patients
intolerant to carbimazole

 L-thyroxine:
– As a replacement therapy in
hypothyroidism, myxoedema, simple
goitre
– L-thyroxine increases the basal and
metabolic rate, and activates all
cellular biochemical reactions
– Side effects; tachycardia, headache,
sweating, insomnia, fever
17.10.2019 128
Propranolol:
• β-blockers are effective in blunting the
widespread sympathetic stimulatn that
occurs in hyperthyroidism
=========27/3/2016

17.10.2019 129
 quiz
• Thyroid hormone decreases metabolic
rate( )
• Hypothyroidism in children leads to mental
retardation and dwarfism( )
• Hyperthyroidism leads to braycardia and
low heat production( )
• The drug of choice for treatment of
hypothyoidism is liothyronine( )
•17.10.2019
Carbimazole thyroid hormone release( )130
 ‫بسم هللا الرحمن الرحيم‬

Anti-Diabetic Drugs
(Insulin & Oral Hypoglycemic Drugs)

17.10.2019 131
 Diabetes mellitus:
• Diabetes mellitus (DM) is a chronic metabolic
disorder of glucose metabolism in which there is
hyperglycemia ( increased levels of blood glucose)
due to lack of insulin with polydipsia and polyurea.
• There are two main types:
- Type 1(insulin-dependent diabetes mellitus, IDDM),
with an absolute deficiency of insulin due to β cells
destruction.
- Type 2 (non-insulin-dependent diabetes mellitus,
NIDDM) diabetes, in which there is resistance to
insulin action, or insufficient amounts of insulin.
17.10.2019 132
A. Type 1 diabetes (IDDM):
• It most commonly afflicts juveniles(less
than 25 years).
• There is loss of β-cell function which is
usually due to the actions of autoimmune
antibodies directed against the β-cells.

• Chronic DM can lead to development and

progression of neuropathy, nephropathy,
atherosclerosis, retinopathy and
decreased rate of wound healing
17.10.2019 133
B. Type II diabetes (NIDDM):
• Genetic and environmental factors rather
than autoimmune antibodies are
apparently the cause of NIDDM.

• Long-term clinical consequences can be

devastating ‫( تخريبي‬e.g. vascular
complications and subsequent infection
can lead to amputation of the lower
limbs)
17.10.2019 134
• Treatment of Type II diabetes:
• Weight reduction, exercise and dietary
modification decrease insulin resistance and
correct the hyperglycemia of Type II diabetes
in some patients

• However, most are dependent on oral

hypoglycemic agents or even insulin in
resistant cases.

• Treatment of type I diabetes:

– Patients with type I diabetes require long-

term maintenance treatment with insulin 135
17.10.2019
 – Soluble insulin is used IV in emergency (e.g.
ketoacidosis)
– Many patients with type 2 diabetes ultimately
require insulin treatment
– During pregnancy, for gestational diabetes
not controlled by diet alone.

• Clinical uses of oral hypoglycemic drugs:

– Type 2 diabetes mellitus requires oral
hypoglycemic drugs as a supplement to diet
and exercise
17.10.2019 136
 Drugs in diabetes: insulin and oral
hypoglycemic drugs
 Insulin:
– Insulin secretion is most commonly triggered
by high blood glucose
• Sources of insulin:
– is isolated from beef and pork pancreas.
However, human insulin produced by DNA
technology is replacing the animal hormone
for therapy
• For routine use it is given SC (or by IV infusion
in emergencies)
17.10.2019 137
 Insulin preparations:
 Insulin is produced in many pharmaceutical formulations to
control the onset and duration of action
1. Rapid actining insulin preparations
• Insulin lispro,aspart and glulisine are human analogs of
soluble insulin provided in 100 units
2. short-acting preparations
-regular (soluble) insulin is a short acting insulin that acts
within 30 minuntes peaks in 2-3hrs and lasts for 5-8hrs
3. Intermediate action insulin prepns:
A. Isophane insulin suspension:
• This insulin preparation, (sometimes called protamine
Hagedorn, NPH), is a suspension of crystalline zinc
insulin combined at neutral pH with the polypeptide,
protamine
17.10.2019 138
 • Onset of action 2- 5hrs and duration 4 -12
hrs
• Its usally mixed with regular ,lispro or aspart.

• The NPH should only be given SC (never

IV)

B. Lente insulin:
• This insulin is a mixture of 30% semilente
insulin (prompt acting) and 70% ultralente
insulin (prolonged acting)

17.10.2019 139
3. Longed -acting insulin prepns:
– Ultralente insulin is a suspension zinc insulin
crystals composed of large particles which
are slow to dissolve, producing a slow onset
of action and a long-lasting hypoglycemic
effect
– Insulin galargine
– Insulin detemir
• Adverse reactions to insulin:
– Hypoglycemia
– lipodystrophy and allergic reactions
17.10.2019 140
 Oral hypoglycemic drugs:
• These are used in type 2 diabetes, who cannot be
managed by diet alone

 Insulin secretagogues:
A. Sulfonylureas:
• Are only effective if B-cells are functional
• Block potassium channels in B-cells:
– Stimulation of insulin release
• The primary drugs used today are tolbutamide, and the
second generation derivatives glyburide (glibenclamide),
and glipizide
B Repaglinide and nateglinide
17.10.2019 141
• NIDDM women should be treated with insulin
• Can cause hypoglycemia (which stimulates
appetite and leads to weight gain)

 Insulin sensitizers:
A. Biguanides:
• e.g. Metformin
• The risk of hypoglycemia is less than with
sulfonylurea agents, because it does not
increase insulin release

• Biguanides increase glucose uptake in striated

muscle and inhibit hepatic glucose output

17.10.2019 142
• Cause anorexia and weight loss
• Metformin is preferred for obese patients
• Adverse effects:
– Rarely, potentially fatal lactic acidosis
 Agents that decrease insulin resistance
-pioglitazone and rosiglitazone decrease
resistance at receptor site and increase
glucose uptake
 Agents that decrease blood sugar
- acarbose and meglitol inhibit pancreatic
digestive enzymes that decrease glucose
absorption from GIT
17.10.2019 143
 ‫بسم هللا الرحمن الرحيم‬

Adrenal corticosteroids

17.10.2019 144
 Adrenal corticosteroids
• The adrenal cortex is divided into three zones,
that synthesize various steroids from cholesterol
and secrete them: e.g mineralocorticoids,
glucocorticoids
• Abrupt withdrawal of pharmacologic doses of
glucocorticoids which have been given for more
than 5 - 7 days causes acute, life-threatening
insufficiency
• Pharmacologic doses of systemic
glucocorticoids must be reduced slowly

17.10.2019 145
 Actions of glucocorticoids:
• They favor gluconeogenesis
• They stimulate protein catabolism and lipolysis

• eosinophils, basophils, monocytes and lymphocytes, by

redistributing them to lymphoid tissues from the
circulation
• Gucocorticoids cause a decrease in circulating
lymphocytes and macrophages which compromise the
body’s ability to fight infections

• Anti-inflammatory action:
– The mechanism involves the inhibition of PLA2
17.10.2019 146
 Drug Anti-inflam Na+ Duratn
retaining

Hydrocortisone 1 1 Short

Cortisone 0.8 0.8 Short

Prednisolone 4 0.8 Short

Dexamethasone 30 Minimal Long

17.10.2019 147
 Actions of mineralocorticoids:
• Aldosterone acts on kidney tubule cells, causing a
reabsorption of sodium, and water
• Hyperaldosteronism is treated with spironolactone

 Therapeutic uses of the adrenal corticoids;

1. Replacement therapy for primary adrenocortical
insufficiency (Addison’s disease):
• Hydrocortisone is given to correct the deficiency: two
thirds of the dose is given in the morning and one
third in the afternoon

17.10.2019 148
2. Relief of inflammatory symptoms:
• Glucocorticoids dramatically reduce the manifestations
of inflammations

3. Treatment of allergies:
• Glucocorticoids are useful in the treatment of the
symptoms bronchial asthma, and allergic rhinitis

• These drugs are not, however, curative

• Inhaled glucocorticoids (e.g. beclomethasone

dipropionate), minimizes systemic effects

17.10.2019 149
4. Other uses:
– Preventing rejection following tissue transplantation
(immunosuppression):

– To suppress certain leukemias and lymphomas

• Hydrocortisone: is used:
– Orally for replacement therapy
– IV in shock and status asthmaticus
– Topically (e.g. ointment in eczema, enemas in
ulcerative colitis)

17.10.2019 150
• Prednisolone is the most widely used drug given orally in
inflam and allergic diseases
• Beclometasone dipropionate passes membranes poorly
and is more active topically

 The common adverse effects of long-term corticosteroid

therapy:
• Osteoporosis, increased risk of infection, hypertension,
edema, peptic ulcers
• Withdrawal from the drugs can be a serious problem
============3/4/2016

17.10.2019 151
 quiz
• Adverse effects of corticosteroids include
all the following except:
• Hypoglycemia
• Oral cndidiasis
• Osteoporosis
• Gastric ulceration
• Cataract

17.10.2019 152
 ‫بسم هللا الرحمن الرحيم‬

Oestrogens & progestins

17.10.2019 153
 Estrogens & progestin hormones and drugs
• Sex hormones produced by the gonads & adrenals
are necessary for conception, embryonic maturation &
development of primary & secondary sexual
characteristics at puberty.
• The gonadal hormones are used therapeutically in
replacement therapy & in the case of estrogen, for
contraception & osteoporosis.
• Sex hormones are released by gonadotropin releasing
hormone(GnRH) from hypothalamus,that stimulates
anterior pituitary to secrete leuteinzing hormone(LH)&
follicle stimulating hormone(FSH)
• FSH & LH stimulate the gonads(ovary and testes) to
secrete sex hormones (testosterone in men, estrogen
17.10.2019 154
& progesterone in women).
 Estrogens:
• Natural estrogens produced in women include:
estradiol(E2),estrone(E1) and estriol(E3).
• Synthetic estrogens,such as ethinyl estradiol,
undergo less first-pass metabolism and thus
are effective when administered orally at lower
doses
 Mechanism of action:
– Steroid hormones bind to nuclear-receptors,
produce proteins that cause estrogen-
induced changes in various target organs
17.10.2019 155
 Therapeutic uses of estrogens:
• The most frequent uses of estrogens are
for contraception, postmenopausal
hormone therapy, and osteoporosis

1. Postmenopausal hormone therapy:

• In the past, estrogen therapy was
reserved for postmenopausal women
that experience “hot flashes”, atrophic
vaginitis and women wishing to reduce
the risk of osteoporosis
17.10.2019 156
• A progestin is usually included with the
estrogen therapy, since the combination
reduces the risk of endometrial
carcinoma associated with estrogen
treatment alone

2. Primary hypogonadism:
• Estrogen therapy usually in combination
with progestins is instituted to stimulate
development of secondary sex
characteristics in young women (11 – 13
years) with hypogonadism
17.10.2019 157
 Adverse effects:
• Nausea and vomiting , edema, headache,
hypertension

 Antiestrogens:
• include clomiphene and tamoxifen

• They act as competitive antagonists

17.10.2019 158
– Clomiphene:
• By interfering with the negative feedback
inhibitory effect of estrogens on the
hypothalamus and pituitary, clomiphene
increases the secretion of gonadotropin-
releasing hormone (GnRH) and
gonadotropins, leading to a stimulation of
ovulation.

• The drug has been used successfully to

treat infertility associated with anovulatory
cycles
17.10.2019 159
 – Tamoxifen:
• is currently used in the treatment of
breast cancer in postmenopausal
women.

 Progestins:
• In females, progestrone promotes the
development of a secretory endometrium
that can accommodate implantation of a
newly forming embryo
17.10.2019 160
• Therapeutic uses of progestins:
– The major clinical use of synthetic
progestins is in contraception, in which
they are generally used with estrogens,
either in combination or in a sequential
manner.

– These synthetic progestins include

norethindrone, and norgestrel.

• Adverse effects:
– Edema
17.10.2019
and depression. 161
 Oral and implantable contraceptives
• Interference with ovulation is the most common
pharmacologic intervention for preventing pregnancy

 Major classes of oral contraceptives:

1. Combination pills:
• products containing a combination of estrogen
and a progestins are the most common type of
oral contraceptives.

• The estrogen component suppresses ovulation

while the progestin prevents implantation in the
endometrium and makes the cervical mucus
impenetrable to sperm.
17.10.2019 162
 • The pills are taken for 21 days followed by a 7-day
withdrawal period to induce menses

2. Progestin only pills:

– Products containing progestin only, usually
norethindrone or norgestrel (called a “mini-pill”),
are taken daily on a continuous schedule.

• Adverse effects:
1. Major adverse effects: breast fullness,
depression, dizziness, edema, headache,
nausea, break through bleeding and vomiting
17.10.2019 163
 2. Cardiovascular: the most serious: include
thromboembolism, thrombophlebitis,
hypertension

• Contraindications:
– Oral contraceptives are contraindicated in
the presence of cerebrovascular and
thromboembolic disease, estrogen-
dependent neoplasms, liver disease, and
migraine headache
========================

17.10.2019 164
 quiz
• Which of the following drugs is a growth
hormone inhibitor used in acromegally?
• (a) mecasermin
• (b) pegvisomant
• (c) bromocriptine
• (d) octeriotide

17.10.2019 165
 ‫بسم هللا الرحمن الرحيم‬

Basic principles of chemotherapy

17.10.2019 166
 Chemotherapeutic Drugs
Basic principles of chemotherapy
• Chemotherapeutic Drugs include:
– Anti-infective drugs:
• Antimicrobial drugs:
Antibacterial drugs
Antifungal drugs
Antiviral drugs
• Antiparasitic drugs:
Antiprotozoal
Anthelminthics
– Anticancer drugs
17.10.2019 167
 Sites of action of antimicrobials

17.10.2019 168
 Basic principles of chemotherapy
• Ideally, the antimicrobial agent used to
treat an infection is selected after the
organism has been identified and its drug
sensitivity established. However, in the
critically ill patient, empiric therapy is
indicated.

• Empiric therapy with a combination of

antibiotics or a single drug covering
infections by both gram-positive and gram-
negative microorganisms may be started
initially
17.10.2019 169
• Elimination of infecting organism from the
body depends on intact immune system.
• Antibacterial drugs decrease the microbial
population (bactericidal), or inhibit further
bacterial growth (bacteriostatic), but the
host defense system must eliminate the
invading organism.
• Antibiotics are chemicals isolated from
microorganisms(eg bacteria,fungi) or
produced synthetically, that inhibit growth
of other microrganisms
17.10.2019 170
• All antibiotics cross the placenta:
– Adverse effects to the fetus are rare, except
for tooth discolouration and inhibition of bone
growth encountered with the tetracyclines
– Some anthelmintics are embryotoxic and
teratogenic
– Aminoglycosides induce ototoxic effect in the
fetus.
• Renal and hepatic eliminatn are poorly
developed in newborns, making neonates
vulnerable to toxic effects of chloramphenicol
and sulfonamides.
• Fluoroquinolones interfere with cartilage growth
in children
17.10.2019 171
• Most of the antibiotics, such as the penicillins,
are among the least toxic of all drugs. Other
antimicrobial agents (e.g. chloramphenicol) are
less specific and are reserved for life-threatening
infections

• The chemotherapeutic spectrum of a drug refers

to the species of organisms affected by that
drug:
– Chemotherapeutic agents acting only on a
single or a limited group of microorganisms
are said to have a narrow spectrum of action.
For example, isoniazid is active only against
Mycobacterium tuberculosis.
17.10.2019 172
 – Extended spectrum is the term applied
to antibiotics that are effective against
gram-positive organisms and also
against a significant number of gram-
negative bacteria (e.g. ampicillin)

– Drugs such as tetracycline and

chloramphenicol affect a wide variety of
microbial species and are referred to as
broad spectrum antibiotics:
• Administration of these antibiotics can
17.10.2019
precipitate a superinfection 173
• It is advisable to treat with the single agent
that is most specific for the infecting
organism. This strategy reduces
superinfection, emergence of resistance
and minimizes toxicity.

• Antibiotic use, promotes the emergence of

drug-resistant microbes ( especially the
use of broad-spectrum antibiotics).
• The more the use, the greater the chance.
17.10.2019 174
• Delaying the emergence of resistance
– Prescribed only when needed
– Narrow-spectrum
– Limit use of newer drugs

17.10.2019 175
• Multidrug resistance:
– Many pathogenic bacteria have developed
resistance to the commonly used antibiotics;
some examples are:
• Some strains of staphylococci and enterococci
are resistant to virtually all current antibiotics,;
these organisms can cause seriuos and
virtually untreatable nosocomial infections.

• Some strains of Mycbacterium tuberculosis

have become resistant to most antituberculus
agents.
====================7/5/2014
17.10.2019 176
 ‫بسم هللا الرحمن الرحيم‬

‫‪Sulfonamides‬‬

‫‪17.10.2019‬‬ ‫‪177‬‬
 Antibacterial Drugs
• Folate inhibitors, these include:
– Sulfonamides, Trimethoprim,Pyrimethamine and Co-
trimoxazole

• Inhibitors of cell wall synthesis:

– β-Lactam antibiotics:
• Penicillins, Cephalosporins

• Antimicrobial agents affecting bacterial protein synthesis:

– Tetracyclines,
– Chloramphenicol,

17.10.2019 178
 – Aminoglycosides
– Macrolides

• Antimicrobial agents affecting DNA topoisomerase II:

– Fluoroquinolones

• Antituberculosis drugs:
– Isoniazid
– Rifampicin
– Streptomycin
– Ethambutol
– Pyrazinamide

17.10.2019 179
 Folate inhibitors

A/ Sulfonamides
• Sulfonamides (Sulfa drugs) are synthetic structural
analogs of p-aminobenzoic acid (PABA)
• They are inhibitors of bacterial folic acid synthesis

• The sulfonamides, including co-trimoxazole

(sulfamethoxazole + trimethoprim) are bacteriostatic
• Are active against selected enterobacteria, chlamydia

17.10.2019 180
 Mechanism of action

17.10.2019 181
• Adverse effects:
– Most commonlly are fever,skin rashes,exfoliative
dermatits,photosensituvity urticaria
– Crystalluria due to precipitation in acidic or neutral urine.
This treated by urine alkalinization
– Hemolytic anemia,granulocytopenia,thrombocytopenia.
– Hemolytic anemia in patients with glucose-6-phosphate
dehydrogenase deficiency

– Kernicterus: may occur in newborns because

sulfonamides displace bilirubin from binding sites on
serum albumin. The bilirubin is then free to pass into the
CNS

17.10.2019 182
 B/ Trimethoprim and Pyrimethamine
• Potent inhibitors of bacterial DHF reductase
• Trimethoprim is 20 to 50 times more potent than the
sulfonamide
• Trimethoprim may be used alone in acute urinary tract
infections
• Trimethprim can produce folate deficiency, that is,
megaloblastic anemia
• Trimethoprim or pyrimethamine in combination with a
sulfonamide(eg sulfamethoxazole) block sequential
steps in folate synthesis resulting in marked
enhancement(synergistic effect).The combination is
often bactericidal rather than bacteriostatic

17.10.2019 183
 C/ Co-trimoxazole
• It is a combination of sulfamethoxazole and trimethoprim
• It shows greater and broader antimicrobial activity

• Adverse effects:
– Dermatologic rxs are very common
– Nausea, vomiting

– Hemolytic anemia in G-6-PDH deficiency patients

(due to the sulfamethoxazole)

17.10.2019 184
 Clinical use:
• Oral trimethoprim 100mg is usedin urinary
tract infections
• Oral pyrimethamin+aulfadiazine is used to
treat leishmaniasis or toxoplasmosis
• Oral pyrimethamine+sulfadoxine is used to
treat malaria
• Oral
trimethoprim+sulfamethoxazole(septrin) is
effective in treatment of a wide variety of
bacterial infections 17/4/2016
17.10.2019 185
 ‫بسم هللا الرحمن الرحيم‬

Inhibitors of cell wall synthesis

(β-Lactam antibiotics)

17.10.2019 186
 Inhibitors of cell wall synthesis
• Include and vancomycin:
– β-Lactam antibiotics:
• Penicillins, Cephalosporins,carbapenems(eg
imipenem),monobactams( eg aztreonam)
• The most important members of the group are the β-
lactam antibiotics
• These agents require actively proliferating
microorganisms
• Beta-lactam antibiotics:
– Are bactericidal by interference with peptidoglycan
synthesis, thus preventing bacterial cell wall
synthesis
– The β-lactam ring is essential for activity
17.10.2019 187
 Penicillins
• The penicillins interfere with the last step in bacterial
cell wall synthesis (peptidoglycan synthesis) binding
to PBPs
• Cell lysis can then occur, and these drugs are
therefore bactericidal
• They are inactive against organisms devoid of this
structure, such as mycobacteria (e.g., G+ve rods: M.
TB, M. leprae), protozoa, fungi, and virus

17.10.2019 188
• Penicillins are poorly lipid soluble thus do not cross
BBB unless meninges are inflammed.
• Are excreted unchanged in urine.some are acid labile.
• Cross allergy is foun between β-lactam group except
aztreonam
• Resistance may occur due to:
- β-lactamase production by bacteria
-Modification of target PBPs
-Impaired penetration to target PBPs
-Trapping by β-lactamase
- shortage of autolytic enzymes
- presence of an efflux pump
17.10.2019 189
• Antibacterial spectrum:
• Example of natural penicillins
• Penicillin G (benzylpenicillin):
• Is acid labile(given by injection),β-lactamase
sensitive
– Has relatively narrow spectrum coveing:
– Streptococcus pyogens, S.pneumonia,
Neisseria gonorrhea, treponemes, listeria,
Actinomycetes and closteridia
– Many staphyloccoci are now resistant to
penicillin G
17.10.2019 190
• Semisynthetic penicillins:
• Produced by substitution on the R group
• Have broader activity against both G+ve
and G-ve organisms,but some are
susceptible to penicillinase, include:
• Phenoxymethylpenicillin (penicillin V), is
acid stable,given orally for minor infections
• Penicillinase resistant(oxacillin)
• Extended spectrum antipseudomonal
(ampicillin,amoxicillin)
•17.10.2019
Antistaphyllococcal(nafcillin) 191
• Extended spectrum penicillins:
– Ampicillin and amoxicillin have antibacterial
spectrum similar to that of penicillin G, but
are more effective against Gram-negative
bacilli

– Formulations with a β-lactamase inhibitor,

such as clavulanic acid, protects amoxicillin
or ampicillin, from enzymatic hydrolysis, and
extends their antimicrobial spectrum
17.10.2019 192
• Procaine penicillin G is administered IM and
serves as depot form.Is slowly absorbed into
the circulation over a long period
• Most of penicillins are incompletely absorbed
after oral administration. Amoxicillin is almost
completely absorbed
• Clinical uses of the penicillins:
– Bacterial meningitis, pneumonia: amoxicillin
– Urinary tract infections (e.g. with E. coli)

17.10.2019 193
• Metabolism of these drugs by the host is
usually insignificant
• The primary route of excretion is through the
organic acid (tubular) secretory system of the
kidney, as well as by glomerular filtration.
• Probenecid competes with peniciilin for this
secretory system and prolongs duration of
action of penicillins.

• β-lactam inhibitors: clavulanic acid, sulbactam

and tazobactam inhibit β-lacamase thus protecting
the β-lactam ring
17.10.2019 194
• Adverse reactions: penicillins are among the
safest drugs:
– Hypersensitivity:
• Approximately 5% of patients have some
kind of rx, ranging from maculopapular
(raised palpable spots) rash to angioedema
(marked swelling of lips, tongue) and
anaphylaxis
• Cross-allergic rxs do occur among β-lactam
antibiotics
– Diarrhea: occurs to a greater extent with
those agents that are incompletely absorbed
and have an extended antibacterial spectrum
============================14/5/2014
17.10.2019 195
 ‫بسم هللا الرحمن الرحيم‬

‫‪Cephalosprins‬‬

‫‪17.10.2019‬‬ ‫‪196‬‬
• The cephalosporins are semisynthetic antibiotics
derived from products of various microorganisms,
including Cephalosporium
• As with the penicillins, the β-lactam ring in
cephalosporin is essential for antibacterial activity.
• Cephalosporins are more stable to many bacterial β-
lactamases, thus have a broader specrum of activity.
However some strains of E coli and Klebsiella
produce extended spectrum β-lactamases that can
hydrolyse most cephalosporins.
• Cephalosporins are not active against enterococci and
L. monocytogens

17.10.2019 197
• Cephalosoprins can be classified into four groups or
generations according to antibacterial spectrum:
• First generation include: cefazolin,cefadroxil,
cephalexin,cephalothin,cephapirin & cephradine.Are
active against G+ve cocci,such as
pneumococci,streptococci,and staphylococci,but little
activity against G-ve bacteria and are β-lactamase
stable.
• Second generations include cefaclor, cefuroxime,
cefotetan and others.Are active against both G+ve
and G-ve bacteria and are β-lactamase stable.
• Third generations include: ceftriaxone, cefixime,
cefotaxime and others.are active against both G+ve
and G-ve bacteria and are β-lactamase stable.
17.10.2019 198
• Antibacterial Spectrum:
– The cephalosporins are classified into
generations according to their antibacterial
spectrum and stability to β–lactamases:
– The first-generation cephalosporins: e.g.
cephalexin

– The second-generation cephalosporins have

greater stability against β-lactamase
inactivation and possess a broader spectrum
of activity that include gram-positive cocci,
gram-negative organisms, and anaerobes

17.10.2019 199
 – Among the second-generation cefoxitin

– Third -generation cephalosporins (e.g.

cefoperazone) possess a high degree of in
vitro potency and β-lactamase stability and a
broader spectrum of action against many
common gram-negative bacteria and
anaerobes while retaining good activity
against streptococci

– Most parenteral cephalosporins have good

bioavailability after intramuscular injection,
and a few members of each cephalosporin
200
generation have good oral bioavailability
17.10.2019
• Fourth generation cephalosporins include:
• Cefepime which is resistant to hydrolysis
by β-lcatamases(eg produced by
enterobacter),but may be hydrolysed by
extended spectrum β-lactamases
• Cefepime has good activity against
P.aerugenosa, staphylococcus aureus,
enterobacteriaceae and S.pneumonia

17.10.2019 201
• Adverse Effects
– The cephalosporins have good safety
profiles.

– Because of cross-reactions between

cephalosporins and penicillins, caution
should be used when prescribing
cephalosporins to patients with penicillin
allergy

17.10.2019 202
 Other β-lactam Drugs
1-Monobactams:they have a monocyclic
bactam ring
• Spectrum of activity is limited to G-ve rods
including pesudomonas.
• Unlike other β-lactam they have no activity
against G+ve bacteria or anaerobes
• Aztrenoam is an example of these agents
• Penicillin-sensitive pts tolerate aztreonam
without reaction
17.10.2019 203
2-Β-lactamase inhibitors(clavulanic acid, sulbactam&
tazobactam)
-they resemble β-lactam antibiotics structurally but have
little antibacterial activity.Instead they inhibit some β-
lactamases
3- Carbapenems: have structural resembelance to β-
lactams
-include:imipenem,meropenem,doripenem & ertapenem
-imepenem is active against G-ve rods including
P.aerugenosa ,G+ve organisms & anaerobes
-is resistant to most β-lactamases but not to metallo-β-
lactamases
---------------------------------------------------------------------------
17.10.2019 204
--------------------------------------------------------------------
 ‫بسم هللا الرحمن الرحيم‬

Antimicrobial agents affecting

bacterial protein synthesis

17.10.2019 205
 Tetracyclines

• Tetracyclines bind to the bacterial 30S ribosome

leading to inhibition of protein synthesis.

• Resistance is due to increased efflux of the drug

• Antibacterial Spectrum:
• The tetracyclines display broad-spectrum activity
and are effective against both gram-positive and
gram-negative bacteria, including Rickettsia,
Mycoplasma, and Chlamydia spp.
17.10.2019 206
• Tetracyclines include:
-chlortetracycline
-oxytetracycline
-demeclocycline
-methacycline
-doxycycline
-tigecycline(the newest, is a semisynthetic
derivative of minocycline)
• Tetracyclines chelate divalent cations, which
interferes with their absorption and activity
• They are bacteriostatic antibiotics that inhibit
bacterial protein synthesis
17.10.2019 207
• Spectrum of action of tetracyclines include:
G+ve,G-ve bacteria including anaerobes,
rickettsiae,chlamediae,mycoplasms,also against
some protozoa(amebas)
• Minocycline,doxycycline and tigecycline are
more active since they are not susceptible to
efflux mechanism of resistance.
• Food impairs absorption of all tetracyclines
except doxycycline and minocycline
• Since the tetracyclines form insoluble chelates
with calcium, their simultaneous administration
with milk and antacids, will interfere with
absorption
17.10.2019 208
• Clinical Uses:
• The tetracyclines are still the drugs of choice for
treatment of cholera, the chlamydial diseases
(trachoma,)
• Tetracyclines are clinically effective in acne

• Adverse Effects:
• Staining of teeth and retardation of bone growth
can occur if tetracyclines are administered after
the fourth month of gestation or if they are given
to children less than 8 years of age.
• Superinfection may result in oral, and intestinal
Candida albicans infections
17.10.2019 209
 Chloramphenicol
• Chloramphenicol inhibits bacterial protein synthesis by
binding to the 50S ribosomal subunit affects protein
synthesis
• Antibacterial Spectrum:
• Chloramphenicol is a broad-spectrum bacteriostatic
antibiotic that is effective against aerobic and anaerobic
gram-positive and gram-negative bacteria, including
Rickettsia, Mycoplasma, but not Chlamydia spp.
• Haemophelus influenzae and Neisseria meningitidis are
highly susceptible and for them chloramphenicol may be
bactericidal
• Resistance may develop due to production of
chloramphenicol acetyltranferase that inactivates the
17.10.2019 210
drug
• Clinical Uses:
• The potentially fatal nature of chloramphenicol induced
bone marrow suppression restricts its use to a few life-
threatening infections in which the benefits outweigh the
risks.
• Chloramphenicol is no longer recognized as the
treatment of choice for any bacterial infection except for
bacteria meningitidis.
• In almost all instances, other effective antimicrobial
agents are available
• Chloramphenicol is mainly indicated for bacterial
meningitis.
• Chloramphenicol also is widely used for the topical
treatment of eye infections.

17.10.2019 211
• Adverse Effects
• In newborn infants, it can cause a potentially fatal toxic
reaction called gray baby syndrome (characterized by
cyanosis, hypothermia, and vasomotor collapse)
• Bone marrow depression which causes dose-related
suppression of RBCs production.
• It may also cause aplastic anemia, which is not dose-
related
• Interaction with other drugs since it inhibits hepatic
microsomal enzymes that metabolize several
drugs.T1/2 are prolonged and serum concentrations of
phenytoin, tolbutamide, chlorpropamide and warfarin
are increased.24/4/2016
17.10.2019 212
 MACROLIDE ANTIBIOTICS
• The macrolide antibiotics are those that contain a
large macrolide lactone ring to which deoxy sugars are
attached
• Antibiotics in this group include erythromycin,
clarithromycin, azithromycin
• The prototype erythomycin is obtained from
Streptomyces erythreus , clarithromycin and
azithromycin are semisynthetic derivatives of
erythromycin
• Mechanism of Action:
• Macrolides bind to the 50S ribosomal subunit of
bacteria: inhibit protein synthesis
17.10.2019 213
• Antibacterial Spectrum:
• The macrolides are effective against a number
of organisms, including Mycoplasma spp., H.
influenzae, Streptococcus spp.

• The half-life of azithromycin approaches 68

hours.

• Clinical Uses:
• Erythromycin is a suitable alternative drug for
the penicillin-hypersensitive individual.

17.10.2019 214
• Adverse Effects:
• The incidence of side effects associated with
erythromycin therapy is very low.

• Hepatitis has been associated with the estolate

salt of erythromycin but not with other
formulations.
==========================

17.10.2019 215
 Aminoglycoside Antibiotics
• The major clinically important aminoglycosides are
gentamicin, neomycin, streptomycin

• The antibacterial actions of the aminoglycosides involve

disrupting membrane integrity, and also disrupt the
initiation of protein synthesis.

• The systemic bioavailability of the aminoglycosides is

low: For example, more than 95% of an oral dose of
neomycin is excreted unchanged in the feces.

17.10.2019 216
• CLINICAL USES
• Gentamicin is the aminoglycoside antibiotic most
commonly used to treat serious infections due to gram
negative aerobic bacilli, such as Escherichia coli and
Klebsiella Pneumoniae

• Neomycin is often combined with other antibiotics, such

as polymyxin B, and applied as an ointment to prevent
any infection of minor skin abrasions, burns, and cuts.

17.10.2019 217
• For tuberculosis: with other TB drugs

• Adverse rxs:
– Aminoglycosides cause nephrotoxicity,
– Can cause ototoxicity, which can be irreversible.
====================

17.10.2019 218
 Fluoroquinolones
• The principal member of this group is ciprofloxacin,
which has the widest clinical application

• This class of antibiotics has wide antibacterial spectrum,

and relative lack of adverse rxs

• Unfortunately, their overuse has already led to the

emergence of resistant strains

17.10.2019 219
• The older drug, nalidixic acid, is a non-fluorinated
quinolone, and is not effective against systemic
infections

• Its use in the treatment of urinary tract infections (UTIs)

is limited due to the rapid emergence of resistant strains

• Fluoroquinolones interfere with the action of DNA gyrase

(topoisomerase II) during bacterial growth and
reproduction

17.10.2019 220
• All of the fluoroquinolones are bactericidal

• In general, they are effective against gram-negative

organisms

• Ciprofloxacin:
• This is the most potent of the fluoroquinolones

• Effective against many systemic infections

• Ciprofloxacin is particularly useful in treating infections
caused by many Enterobacteriaceae and other gram-
negative bacilli

17.10.2019 221
• Ofloxacin:
• is primarily used in the treatment of prostatitis due to E.
coli

• Adverse rxs:
• The most prominent side effects are nausea, headache
and dizziness

• Contraindications: fluoroquinolones should be avoided in

pregnancy, in nursing mothers and in children under 18
years of age, since articular cartilage erosion occurs in
immature experimental animals

17.10.2019 222
 Antimycobacterial drugs
• Mycobacterium tuberculosis, can lead to serious
infections of the lungs, the genitourinary tract, skeleton,
and meninges

• Treating TB presents therapeutic problems: the

organism grows slowly, and thus the disease may have
to be treated for up to 2 years

• Multiple drug therapy is employed to delay or prevent

resistance

17.10.2019 223
• Isoniazid, rifampin, ethambutol, streptomycin and
pyrazinamide are the first line drugs because of their
efficacy and acceptable degree of toxicity

• Some bacteria are resistant to as many as seven

antitubercular agents

• Treatment regimens always include a minimum of two

drugs, preferably both (cidal)

• The regimen is continued well beyond the

disappearance of clinical disease so as to eradicate any
persistent organisms: e.g., isoniazid, rifampin and
pyrazinamide for 2 months, and isoniazid and rifampin
for the next 4 months
17.10.2019
============10/5/2015 224
 ‫بسم هللا الرحمن الرحيم‬

‫‪Antifungal Drugs‬‬

‫‪17.10.2019‬‬ ‫‪225‬‬
 Antifungal antibiotics
• These drugs are used in the treatment of
subcutaneous and systemic mycoses.
• They include amphotericin B, and the azoles,
(ketoconazole, fluconazole, itraconazole) and
the echinocandins(caspofungin,micafungin&
anidulafungin) which are the newest antifungals.
Amphotericin B:
• It is an antifungal antibiotic produced by
Streptomyces nodosus
• In spite of toxic potential, it is the drug of choice
used in the treatment of most systemic mycoses.
• Binds to ergosterol present in cell membranes of
sensitive fungal cells. This disrupts membrane
function, resulting in cell death.It is fungicidal.
• Amphotericin B has a low therapeutic index
17.10.2019 226
• The commonest and most serious unwanted
effect is renal toxicity

• Azoles:
• Are synthetic antifungal agents

• Are fungistatic with a broad spectrum of activity.

•
• The main drugs available are ketoconazole,
fluconazole and itraconazole

• The azoles inhibit conversion of lanosterol to

ergosterol, the main sterol in the fungal cell
membrane,by inhibiting fungal cytochrome P450
enzyme system.
17.10.2019 227
• Ketoconazole:
• Although active against the same fungi as
amphotericin B, it is most useful in the treatment
of histoplasmosis
• No resistance has been observed
• Ketoconazole is only administered orally

• Adverse effects are primarily gastrointestinal

• Low incidence of hepatic dysfunction

17.10.2019 228
 Drugs for superficial mycotic infections
• Fungi that cause superficial skin infections are
called dermatophytes

• Griseofulvin:
• It is fungistatic and it acts by interacting with
microtubules and inhibit mitosis

• It is given orally
• The drug is ineffective topically
• It may cause hepatotoxicity
17.10.2019 229
• Nystatin:
• Is similar in structure to amphotericin B and with
the same mechanism of action and resistance

• Its use is restricted to topical treatment of

Candida infections because of systemic toxicity

• The drug is negligibly absorbed from the GIT,

and is never used parenterally
• It is administered as an oral agent for treatment
of oral candidiasis
===================
17.10.2019 230
 ‫بسم هللا الرحمن الرحيم‬
Antiparasitic drugs:
• Antiprotozoal Drugs:
– Antimalarial Drugs
– Drugs used in amoebiasis
– Drugs used in Giardiasis
– Drugs used in African trypanosomiasis
– Drugs used in leishmaniasis

• Anthelmintic Drugs:
– Drugs for treament of nematodes
– Drugs for the treatment of trematodes
– Drugs for the treatment of cestodes
17.10.2019 231
 Antimalarial Drugs
• Protozoal infections
• Are common among people in under developed
tropical and subtropical countries

• Protozoal diseases include malaria, amebiasis,

leishmaniasis, trypanosomiasis, and giardiasis

• Most antiprotozoal agents have not proved safe

for pregnant patients.

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 Malaria
• Malaria is caused by various species of plasmodia.
The female anopheline mosquito injects sporozoites
(the asexual form of the parasites) into blood,
circulating sporozoites rapidly invade liver cells and
exoerythrocytic stage tissue schizonts mature in the
liver.
– Schizonts (the liver stage),then liberate merozoites
in blood which infect RBCs causing the clinical
illness in many cycles
– Sexual stage gametocytes also develop in
erythocytes before being taken by mosquitoes
where they develop into infective sporozoites
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 – In P. falciparum and malariae only one
cycle of liver cell invasion occurs.
– In P.vivax and ovale a dormant liver
stage,the hypnozoite is not eradicated,
thus relapses can occur after treatment
-Eradication of both erythrocytic and
hepatic parasites is required to cure
these infections

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• The main malarial parasites causing
‘tertian’ malaria (by definition fever ‘every
third day), though various patterns are
seen) are:
– P. vivax, which causes benign tertian
malaria
– P. falciparum, which causes malignant
tertian malaria; unlike P. vivax and
P.Ovale , this plasmodium and P.
malariae have no dormant
exoerythrocytic stage in liver
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 Classification of antimalaral drugs
• Tissue schizonticides eliminate developing or
dormant liver forms
• Blood schizonticides eliminate erythrocyte stages
• Gametocides kill sexual stages and prevent
transmission to mosquitoes
• Causal prophylactics prevent erythrocytic
infection
• No drug can cause radical cure,i.e. eliminate both
hepatic and erythrocytic stages.

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• Antimalarial therapy and the parasite life cycle:
– Drugs used to treat the acute attack of malaria (i.e.
for suppressive or clinical cure) act on the parasites
in the blood; they can cure infections with parasites
(e.g. P. falciparum ) that have no exoerythrocytic
stage. These are called blood schizonticides.
– Drugs used for prophylaxis (i.e. to prevent malarial
attacks when in a malarious area) act on
merozoites emerging from liver cells. These are
called causal prophylactic.
– Drugs used for radical cure are active against
parasites in the liver.
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 Antimalarial drugs
• Chloroquine:
• Effective blood schizonticde.Also moderately effective
gametocide against P.vivx, P.malariae, P. ovale but
not agaist P.falciparum
• Used for treatment of sensitive strains of malaria
• Chloroquine is the drug of choice in treatment of
erythrocytic falciparum malaria, except in resistant
strains
• It is a blood schizonticide that acts by concentrating in
prasite food vacuoles, preventing the biocrystallization
of heme into hemozine causing toxicity to parasite due
to buildup of heme.
• Is17.10.2019
also used in treatment of amebic liver abscess 238
• Quinine
• Is an alkaloid obtained from Cinchona bark
• Its mechanism of action is similar to chloroquine
• Is reserved for malaria strains resistant to other drugs
• When a chloroquine-resistant organism is
encountered, therapy usually consists of a
combination of quinine and Fansidar®; (is a
combination of pyrimethamine and sulfadoxine)
• Quinine is fetotoxic,hypoglycemic & ototoxic
• Primaquine:
• It eradicates primary exoerythrocytic forms of P. ovale
and P. vivax
• Hemolysis is produced in individuals with genetic
deficiency
17.10.2019
of erythrocyte glucose-6-phosphate 239
dehydrogenase
• Artemisinin and related compounds:
• Include artemisinin, artesunate, artemether

• They are fast-acting blood schizonticidal agents

that are effective against both P. falciparum and
P. vivax.

• There have been few unwanted effects reported

• No reported cases of resistance
=========

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 Drugs used in amoebiasis:
• Amoebiasis (also called amebic dysentery) is
caused by infection with Entamoeba histolytica,
which causes dysentery associated with
invasion of the intestinal wall and, rarely, of the
liver.

• Metronidazole:
• It is effective against E. histolytica, Giardia
lamblia and Trichomonas vaginalis

• Also effective against anaerobic cocci and

anaerobic gram-negative bacilli
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• Diloxanide:
• Is useful in the treatment of asymptomatic
passers of cysts.
• Usually combined with metronidazole

Chemotherapy of Giardiasis
• Giardia lamblia is an intestinal parasite

• Ingestion, usually from contaminated drinking

water, leads to infection
• Severe diarrhea can occur
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• The treatment is usually either quinacrine or
metronidazole

• Quinacrine:
• Is primarily used in the treatment of giardiasis,
but is also effective against tapeworm, malaria,
and topically against leishmaniasis
===========================25/4/2016

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 ‫بسم هللا الرحمن الرحيم‬

‫‪Anthelmintic Drugs‬‬

‫‪17.10.2019‬‬ ‫‪244‬‬
Anthelmintics include:
(A) Round worms(nematodes)that include:
• Ascaris lumbricoides(round worm)
• Trichuris trichura(whipe worm)
• Nicator americanus(hook worm)
• Ancylostoma duodenale (hook worm)
• Strongyloides stercuralis (thread worm)
• Enterobious vermicularis (pinworm)
• Wuchereria bancrofti (filariasis)
• Onchocerca volvulus (onchocerciasis)
245
• Dracunculus medinensis(guinea worm)
17.10.2019
 (B) Flukes (trematodes) include:
• Schistosoma haematobium(bilharziasis)
• Schistosoma mansoni
• Schistosoma japonicum
• Clonorchis sinensis(liver fluke)
• Paragonimus westermani(lung fluke)
• Fasciola hepatica(sheep liver fluke)
• Fasciolopsis buski(large intestinal fluke)
• Heterophytes hetrophytes( small intestinal
fluke)
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(C) Tape worms include:
• Taenia saginata(beef tape worm)
• Taenia solium(pork tape worm)
• Diphyllobotherium latum(fish tape worm)
• Cysticercosis (pork tape worm larval
stage)
• Hymenolepis nana(dwarf tape worm
• Echinoccus graulosus(hydated disease)
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Drugs for treament of Nematodes
• They cause infections of the intestine as well as the
blood and tissues

• Mebendazole:
• Is effective against a wide spectrum of nematodes
• Affected parasites are expelled with feces

• Pyrantel pamoate:
• is effective (along with mebendazole) in treatment of
infections caused by common round worm, pin worms
and hook worms
• Is poorly absorbed orally and exerts its effect in
intestinal tract
• The paralysed worm is then expelled from intestine248
17.10.2019
• Thiabendazole:
• Is effective against threadworm

• Ivermectin:
• Used to treat onchocirciasis(first choice), ascariasis
and trichuriasis and filariasis (as second choice) drug.
• Ivermectin targets the parasite’s γ-aminobutyric acid
(GABA) receptors common round worms

• Diethylcarbamazine used to treat filariasis.It

immobilizes microfilariae,alters their surface
strcuture,dispace them from tissue making the more
susceptible for distruction by host defense
mechanisms
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 Drugs for the treatment of Trematodes
• Trematodes (flukes) are leaf-shaped flatworms
• They are generally characterized by the tissues
they infect (e.g., liver, lung, intestinal or blood
flukes)
• Schistosomiasis (bilharziasis) is infection with
flukes of the genus Schistosoma:
• These flukes affect the bladder and urinary tract
(S. haematobium) or intestine (S. mansoni, S.
japonicum)
• The secondary host is an aquatic snail that
releases cercariae into the water
• Praziquantel:
• Trematodes infections are generally treated with
praziquantel as a first choice drug.
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 Drugs for the treatment of Cestodes
• The cestodes, or tapeworms typically have a
flat, segmented body and attach to the host’s
intestine
• Like the trematodes, the tapeworms lack a
mouth and a digestive tract throughout their life
cycle
• Taenia saginata and T. solium infections occur
after eating undercooked infected beef or pork,
respectively
• Praziquantel and niclosamide are the drug of
choice for most cestodes
• Albendazole is a drug of choice for
cysticercosis (pork tape worm laval stage) and
Echinococcus
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granulosus (hydated disease)251
• A laxative is administered prior to oral
administration of niclosamide.

• This is done to purge the bowel of all dead

segments in order to preclude digestion
and liberation of the ova, which may lead
to cysticercosis
=====================17/5/2015

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