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ةيودلاا ملع - Pharmacology-2
ةيودلاا ملع - Pharmacology-2
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Course content
: 2- محتويات مقرر علم االدوية
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بسم هللا الرحمن الرحيم
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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
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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.
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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
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or
• Excitatory Pathways:
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influx of Na+ causes a weak depolarization,
or EPSP that moves the postsynaptic
potential towards its firing threshold.
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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
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• A sedative(anxiolytic) agents reduce anxiety &
exert a calming effect.
• Degree of CNS depression is minimum.
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• Drug A is typical of older sedative-
hypnotics such as barbiturates & alcohols.
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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)
• ---------------------------------------------------------
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---------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
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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
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Neurodegenerative Diseases
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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
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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
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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)
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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
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Analgesic activity
• The most important pharmacological effect
of these drugs is their ability to relieve pain
• 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
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– 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
===============================
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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
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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).
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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
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• 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,
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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
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=====================13/3/2016
بسم هللا الرحمن الرحيم
Antipsychotic Drugs
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• 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
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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
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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.
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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.
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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)
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• 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
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• Distinction between typical and atypical groups is
according to:
– Incidence of extrapyramidal side-effects (EPS)
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• Unwanted effects of antipsychotic drugs:
– Extrapyramidal motor disturbances
– Sedation
– Dry mouth
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• 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
==========================
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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
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بسم هللا الرحمن الرحيم
Antidepressant Drugs
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• 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
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• 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
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Antidepressant Drugs
• Can be classified according to their modes of
action into several groups:
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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
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• Monoamine Oxidase Inhibitors (MAOI's):
– Last choice for treatment
– Examples: phenelzine, selegline,
isocarboxazid, Tranylcypromine
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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
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================20/3/2016
بسم هللا الرحمن الرحيم
17.10.2019 103
Drugs acting on the Endocrine system
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
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
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
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
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.
B. Lente insulin:
• This insulin is a mixture of 30% semilente
insulin (prompt acting) and 70% ultralente
insulin (prolonged acting)
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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
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
• Anti-inflammatory action:
– The mechanism involves the inhibition of PLA2
17.10.2019 146
Drug Anti-inflam Na+ Duratn
retaining
Hydrocortisone 1 1 Short
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
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
17.10.2019 149
4. Other uses:
– Preventing rejection following tissue transplantation
(immunosuppression):
• 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
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
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
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
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.
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.
• 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
• 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
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.
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.
Sulfonamides
17.10.2019 177
Antibacterial Drugs
• Folate inhibitors, these include:
– Sulfonamides, Trimethoprim,Pyrimethamine and Co-
trimoxazole
17.10.2019 178
– Aminoglycosides
– Macrolides
• 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
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
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
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
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
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.
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
17.10.2019 199
– Among the second-generation cefoxitin
17.10.2019 201
• Adverse Effects
– The cephalosporins have good safety
profiles.
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
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بسم هللا الرحمن الرحيم
17.10.2019 205
Tetracyclines
• 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.
• 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.
17.10.2019 215
Aminoglycoside Antibiotics
• The major clinically important aminoglycosides are
gentamicin, neomycin, streptomycin
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
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
17.10.2019 219
• The older drug, nalidixic acid, is a non-fluorinated
quinolone, and is not effective against systemic
infections
17.10.2019 220
• All of the fluoroquinolones are bactericidal
• Ciprofloxacin:
• This is the most potent of the fluoroquinolones
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
17.10.2019 222
Antimycobacterial drugs
• Mycobacterium tuberculosis, can lead to serious
infections of the lungs, the genitourinary tract, skeleton,
and meninges
17.10.2019 223
• Isoniazid, rifampin, ethambutol, streptomycin and
pyrazinamide are the first line drugs because of their
efficacy and acceptable degree of toxicity
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
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
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• Nystatin:
• Is similar in structure to amphotericin B and with
the same mechanism of action and resistance
• Anthelmintic Drugs:
– Drugs for treament of nematodes
– Drugs for the treatment of trematodes
– Drugs for the treatment of cestodes
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Antimalarial Drugs
• Protozoal infections
• Are common among people in under developed
tropical and subtropical countries
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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
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of erythrocyte glucose-6-phosphate 239
dehydrogenase
• Artemisinin and related compounds:
• Include artemisinin, artesunate, artemether
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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
Chemotherapy of Giardiasis
• Giardia lamblia is an intestinal parasite
• 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
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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)
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(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
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• 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
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