CNS pharmacology

Objectives
Explain about receptors and neurotransmitters in CNS.
Explain about the steps of neurotransmission.
• Discuss the MOA, indication, drug interaction and adverse effect
of antiparkinson's, sedetive-hypnotics, antipsychotics, antide-
pressants, anti-epileptics,general anaesthetics, NSAIDs and opi-
oid analgesics.
• Reading assignment
Drug treatment of alzheimer.
Introduction
 CNS
• CNS- brain and the spinal cord
• Semi-liquid structure at body temperature
• Excitable tissues and glial cells
• Brain is sensitive structure and protected by Blood Brain
Barrier (BBB)
BBB composed of
• Tight endothelial junction
• Astrocytes
 Highly polar compounds do not enter CNS
 Creates a more stable, nearly pathogen-free environment
 Oxygen, glucose, and other small non-polar are molecules
that cross the barrier
 BBB is the major challenge for drug delivery to brain
 Receptors in the CNS
– Kinase linked receptors:
Eg. Cytokine, insulin Rs
– Nuclear receptors
Eg. Steroid R
– Channels
Voltage gated channels
Eg. Muscarnic Ach R
Ligand gated channels
Eg. Nicotinic Ach, GABAA Rs
Ion channels
• Proteins form water filled pore
• Switch b/n open and closed state
 Conti…
• Selective either for cations or anions
• Cation selective channels (for Na+,Ca++ or K+ or may be
permeable to all)
• Anionic channels mainly permeable to Cl-
• Drugs and endogenous mediators that act on ion channels
produce either excitatory or inhibitory effect
• The level of electrical activities determine the state of
the patient - seizure, anxiety, depression
 NTs in the CNS
• Inhibitory : GABA, Glycine
• Excitatory : Glutamate, Aspartate
• Others
- Monoamines: DA, NE and 5-HT
- Ach
-neuropeptides (e.g. sub-P,enkephalins)
-Purine nucleotides (adenosine, ATP)
GABA
• Major inhibitory AA in the mammalian CNS
• Reduced function/amount of GABA will cause excessive
stimulation
– Seizure
• Synthesized from glutamate by the action of glutamic acid
decarboxylase
• linked to chloride channel opening
• Hyperpolarization
 Conti…
Glycine
• Inhibitory AA
• Linked to Cl- ion channels
• Mainly limited to the spinal chord
• Blockade of Glycine receptors cause seizure
Glutamate
• Excitatory NT with different receptors
• Excessive stimulation may lead to Seizure
Dopamine (DA):NT and a precursor for NA
 Common brain function disorders related with DA
• Parkinson's disease,psychosis/ schizophrenia, Drug depen-
dence, Attention deficit disorder and Certain endocrine disor-
ders
•Two types of receptors:-D1 family (D1 & D5) and D2 family
(D2, D3 & D4)
Norepinephrine
• β hydroxylation of dopamine
• Important to remain awake
 also play role in attention, control of mood and feeding
• its reduction will contribute to occurrence of depression
Serotonine (5-HT)
• Can exert inhibitory or excitatory effects on individual
neuron acting either pre or postsynapticaly
•Main receptor subtypes in CNS: 5-HT1A, 5-HT1B, 5-
HT1D,5-HT2 and 5-HT3
• Involved in feeding behavior, behavioral responses, con-
trol of mood and emotion, sensory pathways, body T and
vomiting
 Acetylcholine (Ach)
• Widely distributed in CNS
• Involved in different activities including in arousal, learn-
ing, short-term memory and movement coordination
• Parkinsonism- relatively excessive Ach function
Benzatropine (Muscarnic Ach antagonist)
• Alzheimer - profound cholinergic neuron loss
Revastigmine(cholinesterase inhibitor)
Principles of Chemical Neurotransmission
 Neurotransmitters are the chemical messengers that en-
able neuron to neuron communication.
 Neurotransmitters are released from a pre-synaptic termi-
nal and interact with pre- and post-synaptic receptors.
Steps in Synaptic transmission
1. Action potential in pre-synaptic fiber propagates to
synaptic terminal and activates voltage-sensitive calcium
channels
2. Calcium enters terminal and causes the fusion of synap-
tic vesicles with the terminal membrane
3. Neurotransmitters stored in the synaptic vesicle are re-
leased into the synaptic cleft and diffuse.
4. Neurotransmitters bind to receptors on the post-synaptic
membrane.
5. Binding of the neurotransmitter causes a brief change in
ion conductance in the post-synaptic cell.
Sites of Drug Action
• Virtually all of the drugs that act in the CNS produce their
effects by modifying some step in chemical synaptic
transmission.
• Steps in chemical synaptic transmission include: Neuro-
transmitter synthesis, storage and release ; Neurotrans-
mitter reuptake and degradation; Receptor activation or
blockade.
Antiparkinsonian drugs
Parkinson’s disease (PD)
• PD is disorder of extra pyramidal system, a complex
neuronal network that helps to regulate movement.
• Underlying cause: loss of dopaminergic neuron in the
substantia nigra.
Characterized by a combination of : rigidity,bradykinesia,
tremor & postural instability
• In severe disease, bradykinesia may progress to akine-
sia-complete absence of movement. Patients frequently
experience psychological disturbances, including demen-
tia, depression and impaired memory.
• Occurs for a variety of possible reasons
-Exposure to certain toxins (manganese dust, car-
bondisulfide, alpha-synclein, etc)
Conti…
-Drug induced Parkinsonism: reserpine, chlorpromazine,
haloperidol & other antipsychotic that block D2.
-Post encephalitic parkinsonism : after viral infection
- Idiopathic parkinsonism : unknown cause
Pathophysiology of PD
• Extensive destruction of the dopaminergic neurons of
the substantia nigra
-DA deficency
• DA level in the brain’s substantia nigra normally fall with
ageing.
Classification of drugs for Parkinson's disease
 Drugs affecting brain dopaminergic system
• Dopamine precursors: levodopa
• Peripheral decarboxylase inhibitors: carbidopa
• Dopaminergic agonists: bromocriptine, lisuride, per-
golide, ropinirole,cabergoline & pramipexole
• MAO-B inhibitors : selgiline
• COMT inhibitors: Entacapone,tolcopone
• Dopamine facilitator : Amantidine
 Dopaminergic approach
- Release of dopamine
- [Dopamine]
- Dopamine breakdown
Conti…
 Drugs affecting brain cholinergic system
• Anticholinergcs: Benzotropine, Trihexyphenidyl (ben-
zhexol), Procyclidine, biperiden
 Cholinergic approach
- Amount of ACh released
-Directly block ACh receptor
Levodopa
• Levodopa (L-DOPA) is the immediate metabolic precur-
sor of dopamine
-Prodrug for DA
-Levodopa can cross BBB while DA does not.
Pharmacokinetics
• Levodopa is rapidly absorbed from the small intestine
• Food delays absorption of the drug
- should be taken 30–60 minutes before meals
• More than 95% of oral dose is decarbxylated in periph-
ery tissue mainly in gut & liver
-DA in periphery thus acts on peripheral organs &
may cause unwanted effects. It also acts on CTZ.
• Therefore, peripheral dopa decarboxylase inhibitor (car-
bodopa) reduce Levodopa metabolism in periphery.
Pharmacodynamics
 Undergoes conversion to DA in the brain and then acti-
vates dopamine receptors.
 The benefits of levodopa treatment begin to diminish af-
ter about 3 or 4 years of therapy regardless of the initial
therapeutic response.
• Initial effective doses may fail to produce therapeutic
benefit & responsiveness to levodopa may be lost com-
pletely. Possibly due to
-The disappearance of dopaminergic nigrostriatal
nerve or
- Some pathologic process directly involving the stri-
atal dopamine receptors
• Early initiation lowers mortality rate but does not stop the
progression.
• Long term therapy associated with number of adverse ef-
fects.
• The most appropriate time to introduce levodopa therapy
must be determined individually
 Adverse effects
• Dyskinesia (involuntary writhing movements)
• On / off phenomenon
-Fluctuations in clinical response with increasing fre-
quency as treatment continues
-patient's motor state may fluctuate dramatically with
each dose of levodopa
 The possible reason for on/off effect
As the disease advances
 The ability of neurons to store dopamine is lost
 Continuous supply of levodoapa is required otherwise the
on/off phenomenon will occur
 Conti…
 ↑dose & frequency of administration can improve the
on/off effect ;however, this will associate with the devel-
opment of dyskinesias, excessive & abnormal involun-
tary movements
• Nausea & vomiting
• Postural hypotension, cardiac arrthymias & exacerbation
of angina
- Due to β adrenergic action of peripherally formed DA
-More sever for patients with pre existing heart dis-
eases
• Psychological effects: schizophrenia-like syndrome
-C/I to psychotic patients
Drug Interactions
• Pharmacologic doses of vit B6 enhance extracerebral
metabolism of levodopa as pyridoxin (vit B6) is cofactor
for dopa decarboxylase
• Phenothiazines, butyrophenones & metoclopramide
block DA receptors. Hence decrease therapeutic effects
of levodopa.
• Nonselective MAO inhibitors prevent degradation of pe-
ripherally synthesized DA & NE --- hypertensive crisis
can occur.
Carbidopa.
• Carbidopa inhibits decarboxylation of levodopa in the in-
testine and peripheral tissues, thereby making more lev-
odopa available to CNS.
• Carbidopa does not prevent the conversion of levodopa
to dopamine by decarboxylation with in the brain. Be-
cause it is unable to cross the BBB.
Advantages of carbidopa
• Increase the fraction of levodopa available for actions in
the brain.
• By reducing production of dopamine in the periphery,
carbidopa reduces CV responses to levodopa and also
reduces nausea and vomiting.
• By causing direct inhibition of decarboxylase,carbidopa
obviates stimulation of decarboxylase by pyridoxine
Dopamine receptor agonists
 Act directly on postsynaptic DA receptor types (primarily
D2).
 Effective as monotherapy or as adjuncts to carbidopa /
levodopa therapy.
 Used for patients who have largely lost the capacity to
synthesis, store & release dopamine from levodopa.
 Have longer duration of action than that of levodopa.
 When used long-term, dopamine agonists have a lower
incidence of response failures and less likely to cause
disabling dyskinesias.
 Lower incidence of on /off phenomenon.
Bromocriptine (Ergot derivative)
 Potent D2 agonist & partial D1 agonist /antagonist.
 It is excreted in the bile and feces.
 Also used for treatment of hyperprolactinemia (reduce
prolactine release) in lower doses than for PD
Pergolide
 Ergot derivative
 Agonist of both classes (D1 & D2)
 More effective than bromocriptine in relieving the symp-
toms & signs of PD
 Allow the levodopa dose to be reduced
Pramipexole
 Nonergoline derivative.
 Selective activity at D2 class (D2 & D3 receptors)
 Effective when used as monotherapy for mild PD.
 Also helpful in patients with advanced disease
 Conti…
Ropinirole
 Nonergoline derivative.
 Relatively pure D2 receptor agonist.
 Metabolized by CYP1A2
 drugs metabolized by CYP1A2 may significantly reduce
clearance of ropinirole
 Can harm developing fetus.
Adverse effects of DA agonists
GIT effects
• Anorexia , nausea & vomiting : can be minimized by tak-
ing the medication with meals
• Constipation, dyspepsia, & symptoms of reflux esophagi-
tis may also occur
CVS effects
• Postural hypotension at the initiation of therapy
• Cardiac arrhythmias an indication for discontinuing
treatment
• Cardiac valvulopathy may occur with pergolide
Dyskinesias
• Abnormal movements similar to those produced by lev-
odopa
• Can be reversed by reducing the total dose of the drug
 Conti…
Mental disturbances
• Confusion, hallucinations, delusions & other psychiatric
reactions
• More common & severe with DA receptor agonists than
with levodopa
• They clear on withdrawal of the medication
Contraindications
• DA agonists are C/I in patients with
-History of psychotic illness
-Recent myocardial infarction
-Active peptic ulceration
• Patients with peripheral vascular disease should avoid
taking ergot-derived agonists
MAO-B inhibitors
MAO-B: The predominant form of MAO in the striatum &
responsible for most of oxidative metabolism of DA in the
brain
Selegiline (deprenyl)
• It is selective & irreversible MAO-B inhibitor, the enzyme
that inactivates dopamine in the striatum.
• Suppresses destruction of dopamine derived from lev-
adopa.
• Delays the progression of PD.
• Used as adjunctive therapy for patients with declining or
fluctuating response to levodopa
• Rapidly absorbed following oral administration and read-
ily penetrates the BBB.
• Undergoes hepatic metabolism followed by renal excre-
tion.
• Metabolites of selegiline (amphetamine & metham-
phetamine) may cause anxiety & insomnia
Drug interactions
Levodopa:when used with selegiline,intensify adverse ef-
fects to levodopa –derived dopamine.
Meperidine:cause stupor,rigidity,agitation and hyperther-
mia.
Fluoxetine: withdraw it at least 14 days before giving se-
legiline.
 COMT inhibitors
-Tolcapone & entacapone
• Inhibition of dopa decarboxylase associated with activa-
tion of other levodopa metabolism pathways by COMT.
• prolong the action of levodopa by diminishing its periph-
eral metabolism.
• The pharmacologic effects of tolcapone and entacapone
are similar, and both are rapidly absorbed, bound to
plasma proteins, and metabolized prior to excretion.
Tolcapone
• Has long duration of action
• Inhibit both central & peripheral COMT
• is slightly more potent than Entacapone.
• Associated with hepatotoxicity
 Conti…
Entacapone
• Has short duration of action.
• Act peripherally.
Adverse effects of the COMT inhibitors.
• Relate in part to increased levodopa exposure and in-
clude dyskinesias, nausea, and confusion.
• Diarrhea, abdominal pain, orthostatic hypotension, sleep
disturbances, and an orange discoloration of the urine.
Drug interaction
• Increase levels of drugs metabolized by COMT, lev-
odopa, methyldopa, dobutamine and isoproterenol
 Conti…
Amantadine
• Antiviral agent with several pharmacological effects
• MoA for its anti PD activity is not clear, possibly by
-Facilitating synthesis, release or reuptake of DA in the
striatum
-Its anticholinergic properties
Adverse Effects
• CNS effects:restlessness, depression, irritability, insom-
nia, agitation, excitement, hallucinations, and confusion
• Peripheral effects:blurred vision, urinary retention, dry
mouth, constipation.
 Muscarinic receptor antagonists
• Reduce the unbalanced cholinergic activity in striatum.
• These agents may improve the tremor and rigidity of
parkinsonism but have little effect on bradykinesia.
• Antimuscarnic agents include: Benztropine, Biperiden,
orphenadrine, procyclidine, and rihexyphenidyl.
• Side effect profile is similar to atropine:
-Dryness of mouth, nausea, constipation, palpitation,
cardiac arthymias, confusion, agitation, restlessness,
mydriasis, increased intraocular pressure, defective ac-
commodation
Sedative- Hypnotics
• Are used to treat anxiety and insomnia.
• Agents that relieve anxiety are called antianxiety agents
or anxiolytics. They are also called mild tranquilizers.
• Agents given to promote sleep are known as hypnotics.
Anxiety
• Anxiety is uncomfortable state that has both psychologi-
cal (fear, apprehension, dread and uneasiness) and
physical (tachycardia, palpitations,t rembling,dry mouth,
sweating, weakness, fatigue and shortness of breath)
components.
 Conti…
Insomnia is difficulty in falling asleep or maintaining
sleep, premature awakening and/or lacking refresh-
ment from sleep
• Non-pharmacologic therapies for sleep problems
– proper diet and exercise
– avoiding stimulants before bed time
– ensuring a comfortable sleeping environment
– retiring at a regular time each night
 key:
A= Barbiturates
B= BZD
Classification of sedative-hypnotics
• Barbiturates
• Benzodiazepines
• New sedative/hypnotics
• Older sedative/hypnotics
• Other drugs
1.Barbiturates
– MOA: bind to the GABA –receptor chloride channel
complex
– Enhance the inhibitory actions of GABA.
– At high concentrations, the barbiturates may also be
GABA-mimetic and inhibit excitatory neurotransmis-
sion .
Classification based on duration of action
• Long acting: Phenobarbitone
• Short acting: butobarbitone and pentobarbitone
• Ultrashort: Thiopental.
Conti…
• All have CNS depressant activity.
• Produce dose dependent effects.
• Large doses result in death b/c of respiratory & CVS de-
pression.
• Cause tolerance and dependence, have high abuse po-
tential and are subject to multiple drug interactions.
• Their use as sedative hypnotics has declined.
• Mainly used in anesthesia & treatment of epilepsy.
Pharmacokinetics: lipid soluble.
Pharmacological effects:
• CNS: cause depression.
• CV: decrease BP & HR.
• Induction of hepatic drug metabolizing enzymes.
Therapeutic use
• Insomnia
• Induction of anesthesia
• Seizure disorder
• To treat acute manic state and delirium.
• To decrease excessive excitation from CNS
stimulants(amphetamine)
• For emergency treatment of convulsions caused by
tetanus, eclampsia and epilepsy.
Adverse effects
• Respiratory depression, abuse, hangover, paradoxical
excitement, hyperalgesia
• Use in pregnancy: readily crosses the placenta and can
injure the developing fetus. On the third trimester, it can
cause drug dependence on the children.
 Drug interaction
• CNS depressant: intensify depressant effects of ben-
zodizepines,alcohol,opioid and anthistamines.
• Interaction from induction of drug metabolizing en-
zymes: warfarin,OCP,phenytoin.
• Abrupt withdrawal results weakness, restlessness, in-
somnia,hyperthermia,orthostatic hypotension, confusion
and disorientation.
 2.Benzodiazepines (BZDs)
MOA: potentiate the action of GABA(amplify the action of
GABA, but doesn’t mimic).
Pharmacokinetics: well absorbed following oral adminis-
tration, high – lipid soluble, so that cross BBB.
Pharmacological effect
• CNS: has depressant effect; reduce anxiety; promote
sleep and induce muscle relaxation.
• CV: Oral –no effect on heart and blood vessels. IV-pro-
duces hypotension and cardiac arrest.
Therapeutic use: anxiety, insomnia, seizure disorder.
• BDZs can cause tolerance and physical dependence.
• There is cross – tolerance to barbiturates, alcohol and
other general CNS depressants.
• Flumazenil is an antidote for BDZs.
Adverse effect
well tolerated.
• CNS: drowziness,lightheadedness,incoordination and dif-
ficulty in concentration.
• Anterograde amnesia: impaired recall of events that
take place after dosing.
• Paradoxical effect:
insomnia,excitation,euphoria,heightened anxiety.
• Respiratory depression: weak.
• Abuse: lower potential than barbiturates.
 Drug interaction
• CNS depressants: intensify depressant effects of alco-
hol, barbiturates, opioids.
Use in pregnancy and lactation
• They cross placenta.during first trimester cause conjeni-
tal malformation; cleft lip,inguinal hernia and cardiac
anomalis.
• Use in near term can cause CNS depression in neonate.
• BDZs enter breast milk with ease and may accumulate
to toxic levels in the breast – fed infant. So that avoid
their use by nursing mother
 3. Newer sedative hypnotics
• Non- BZD sedatives: agonist for a subtype of BZD re-
ceptor
*Zopicolone ,Zolpidem & Zalepon
• Preferred for treating insomnia, not indicated for anxiety.
• Have low potential for tolerance, dependence or abuse.
Buspirone ( potent agonist for 5-HTA receptor)
-Also binds to brain dopamine receptor (D2)
-Relief anxiety without causing marked sedative, hypnotic,
or euphoric effects
-No rebound anxiety/withdrawal signs on abrupt discontin-
uance.
Side effects of Buspirone
• dizziness, nausea, headache
4. Older sedative hypnotics
*Alcohol, Chloral hydrates
5. Other drugs that induce sedation
• Antihistaminics (promethazine, diphenhydramaine)
• Neuroleptics / antidepressant (chlorpromazine, amitripty-
line).
• Opoids (morphine, pethidine)
• They have significant sedation effect but not reliable for
treatment of insominia.
 Conti…
• β-adrenoceptor antagonists (e.g. propranolol) to treat
some forms of anxiety (for physical symptoms such as
sweating, tremor and tachycardia)
– block of peripheral sympathetic responses
– ‘ ….actors and musicians to reduce the symptoms of
stage fright’
Antipsychotics
• Psychoses are sever psychiatric illness with se-
rious distortion of thought, behaviour, capacity to
recognize reality and of perception(delusions
and hallucinations).
• Types
• - Acute and chronic organic brain syn-
dromes(cognitive disorders)
• - Functional disorders
• Schizophrenia
• Paranoid states
• -Mood(affective) disorders
• Mania
Deression
 Anti psychotics
• Antipsychotic drugs are not curative and do not eliminate
the chronic disorder, but they often decrease the inten-
sity of hallucination and delusions
• Also called
– Psychopharmacological agents
– Psychotropic drugs
– Neuroleptics
– Major tranquillizers
Classification of antipsychotic drugs
Two major groups:
1. Conventional antipsychotics: block receptors for
dopamine in the mesolimbic area of brain.
• Phenothiazines:chlorpromazine,thioridazine,fluphenazine
• Butyrophenones :Haloperidole, trifluperidole
• Thioxanthenes: Chlorprothixene, flupenthixol
2. Atypical antipsychotics: produce only moderate blockade
of receptors for dopamine and much stronger blockade of
receptors for serotonin.
E.g. Clozapine, Risperidone, Olanzapine
Therapeutic uses: schizophrenia, bipolar disorder (manic-de-
pressive illness), emesis (except thioridazine).
Pharmacokinetics
• Most are readily but incompletely absorbed.
• Most are highly lipid-soluble and protein-bound (92–99%)
• They tend to have large VD (usually > 7 L/kg).
• Most antipsychotic drugs are almost completely metabolized.
 Typical antipsychotic drugs Adverse effect
• Anticholinergic effects
• Some of antipsychotics, particularly thioridazine, chlor-
promazine, clozapine, and olanzapine, produce anti-
cholinergic effects.
• These effects include blurred vision, dry mouth, confu-
sion, and inhibition of gastrointestinal and constipation
and urinary retention.
Extrapyramidal effects
• The inhibitory effects of dopaminergic neurons are normally
balanced by the excitatory actions of cholinergic neurons in the
striatum.
• Blocking dopamine receptors alters this balance, causing a rel-
ative excess of cholinergic influence, which results in ex-
trapyramidal motor effects
• .The appearance of the movement disorders is generally time-
and dose dependent
 Cont…..EPS
• The following are most common EPS side effect of
first generation anti psychotics
 Dystonia (sustained contraction of muscles leading
to twisting, distorted postures)

 Parkinson-like symptoms

 akathisia (motor restlessness)

 Cont…..EPS
Tardive dyskinesia (TD)
Defn. hyperkinetic mov’t disorder that appears with
delayed onset after prolonged use of dopamine
receptor blocking agents, mainly the antipsychotic
• Can interfere with chewing, swallowing and
speaking
• Symptoms are usually irreversible
 The disorder consisting of abnormal involuntary
irregular mov’t of the muscle of the head,limbs
and trunk
 tardive dyskinesia is irreversible and persists after
discontinuation of therapy
Cont.…..TD

Management
• Gradual drug withdrawal (to avoid dyskinesia)
• Use lowest effective dose
• Use 2nd generation antipsychotic drugs
• Clozapine for severe, distressing TD
Adrenergic effect

• Alpha 1 adrenergic blockade – orthostatic hy-

potension
Orthostatic Hypotension
Is mediated by adrenergic blockade
Most common with low-potency drugs, particu-
larly chlorpromazine, thioridazine, and chlor-
prothixene
• Alpha 2 adrenergic blockade
Neuroleptic malignant syndrome (NMS)
• This potentially fatal reaction to antipsychotic drugs is
characterized by ;
 muscle rigidity
 fever
 altered mental status
 stupor
 unstable blood pressure
Cont…
Management of NMS

– Discontinue antipsychotic
– Paracetamol for hyperthermia
– IV fluids for hydration
– Benzodiazepines for anxiety
– Dantrolene for rigidity and hy-
perthermia
– Bromocriptine for CNS toxicity
Other Adverse effects
 Prolactinemia
• In the pituitary, antipsychotics that block D2
receptors may cause an increase in pro-
lactin release Resulting in galactorrhea,
amenorrhea, loss of libido
– Managed with bromocriptine
 Sedation occurs with those drugs that are po-
tent antagonists of the H1-histamine receptor,
including chlorpromazine, olanzapine, queti-
apine, and clozapine
• Administer once daily at bedtime

By group 4
Atypical antipsychotic adverse effect

• Also known as “Serotonin-dopamine antagonists”

• The most common atypical antipsychotic are
Amisulpiride
Risperidone
Olanzapine
Clozapine
Quetiapine
Ziprasidone
Aripiprazole
 Adverse Effects
Treatment with atypical(second-
generation )antipsychotics can contribute to:
• weight gain and, subsequently, metabolic
syndrome with high blood sugar, hyperten-
sion, abnormal cholesterol, and triglyceride
concentrations, posing a patient at risk for
stroke, myocardial disease, and diabetes mel-
litus
 Cont….
Weight Gain
 High –Clozapine, Olanzap-
ine
 Moderate -Chlorpro-
mazine,
-Risperidone
 Low-Haloperidol,
-Trifluoperazine
Dyslipidaemia
Clozapine
Olanzapine
Hypertension
 Clozapine, Olanzapine
and Risperidone most
likely to cause hyperten-
sion.
04/21/2024
 Cont…..
DIABETES
 Insulin resistance (body does
not use insulin efficiently to lower glucose
and triglyceride levels) DM
 Risk of diabetes is increased
rapid weight gain and a rise in
plasma triglycerides
(during treatment).
High risk=> Clozapine, olanzapine
Moderate risk=> Quetiapine, risperidone, phe-
nothiazines
Low risk =>High potency FGAs (e.g. haloperidol)
 Cardiac effect
Some antipsychotics block cardiac potassium
channels and prolong
cardiac QT interval =>ventricular arrhythmia
torsade de pointes, which is often fatal.
 Low –Fluphenazine, Clozapine,

Olanzapine,Risperidone
 Moderate- Chlorpromazine
-Haloperidol
 High- Thioridazine, Mesori-
dazine, Pimozide, and
-High dose intravenous
haloperidol
-Any IV antipsychotic
-Doses exceeding rec-
ommended maximum
Drug interaction
• Neuroleptics potentaite all CNS depresant
• Hypnotics, anxiolytics, alcohol, opioids, antihis-
tamines & analgesics
• Neuroleptics block the action of levodopa & DA ago-
nists in parkinsonism
• Neuroleptics potentaite anticholinergic drugs.
• They are poor enzyme inducers
Antidepressant drugs
• Antidepressant is drugs used for the treatment of de-
pression and other related psychiatric disorders
• Most antidepressant drugs potentiate, either directly or
indirectly, the actions of norepinephrine and/or serotonin
(5-HT) in the brain
Etiology and pathogenesis
• Genetic causes
• Environmental factors
• Biochemical factors
– Deficiency of NT amines in certain part of the brain
(NA, 5-HT & DA)
• Endocrine factors
– ↑ plasma cortisol level in depressed patients
• Monoamine theory
– The theory states that depression is caused by a func-
tional deficit of monoamine transmitters (NA &/or 5-HT)
at certain sites in the brain, while mania results from a
functional excess
Classification of antidepressants

• Tricyclic antidepressants (TCAs)

• Selective serotonin reuptake inhibitors (SSRIs)
• Monoamine oxidase inhibitors (MAOIs)
• Miscellaneous ('atypical') antidepressants
Tricyclic antidepressants(TCAs)
• Drugs: imipramine, amitriptyline, clomipramine.
• MOA: Block reuptake of norepinephrine & serotonin.
TCAs also block serotonergic, α-adrenergic, histaminic, and mus-
carinic receptors.
• It is not known if any of these actions produce
the therapeutic benefit of the TCAs.
• However, actions at these receptors are likely
responsible for many of their adverse effects.
• Amoxapine also blocks 5-HT2 and dopamine
D2 receptors
PHARMACOKINETICS:
• TCAs are incompletely absorbed and undergo signif-
icant first-pass metabolism.
• TCAs are widely distributed
• TCAs are oxidized by hepatic microsomal enzymes,
followed by conjugation with glucuronic acid.
• TCAs are excreted in the urine.
Adverse effects TCA
• Anticholinergic side effects include dry mouth, con-
stipation, urinary retention, blurred vision, confusion,
and delirium.
• The TCAs also block α-adrenergic receptors, causing
orthostatic hypotension, dizziness, and reflex tachy-
cardia.
• Sedation is the most common side effect of tricyclic
antidepressants and is a result of anticholinergic and
anti-histaminergic effects
• Weight gain is a common adverse effect of the TCAs.
• Sexual dysfunction occurs in a minority of patients.
• Tremor & insomnia
Drug interactions
• The combination of a TCA with MAOI can lead to hy-
pertensive crisis.
• Tricyclics potentiate responses to direct- acting sym-
pathomimetics.
• TCAs intensify the effects of anticholinergic agents.
II. Selective serotonin reuptake inhibitors (SSRIs)
• Include: fluoxetine, fluvoxamine, paroxetine,
citalopram and sertraline.
• MOA: selectively inhibit serotonin reuptake.
Adverse effects
• If SSRI is combined with MAOI it will result Sero-
tonin syndrome(e.g. agitation, fever, confusion, anx-
iety, poor concentration, in coordination, sweating,
tremor, hallucination)
• Gastrointestinal symptoms
• Weight gain
Adverse effects......
Teratogenic potential with paroxetine
Sexual dysfunction is the most common side effect of
all serotonin reuptake inhibitors
Anorexia early in the treatment and weight gain later
Nausea, vomiting, and diarrhea.
Sedation or insomnia
Serotonin syndrome
Constipation and dry mouth
III. Monoamine oxidase inhibitors (MAOIs)
• MAO-A is primarily responsible for NE, 5-HT & tyramine
metabolism
• MAO-B is more selective for DA
• Non-selective MAOIs or selective MAO-A inhibitors have
antidepressant effect
• Older non selective MAOIs :Tranylcypromine, phenelzine
& isocarboazid
– Irreversible, long-acting & non-selective
• Moclobemide (MAO-A inhibitor)
– Reversible, short acting & selective
 Monoamine oxidase inhibitors
• The four MAOIs currently available for the treatment
of depression include phenelzine tranylcypromine,
isocarboxazid and selegiline
• Monoamine oxidase inhibitors are very effective an-
tidepressants, but dietary restrictions and the risk of
hypertensive crises limit their use
• Severe and often unpredictable side effects, due to
drug–food and drug–drug interactions, limit the
widespread use of MAOIs.
• For example, tyramine, which is contained in foods,
such as aged cheeses and meats, liver, pickled or
smoked fish, and red wines, is normally inactivated
by MAO in the gut
• Tyramine causes the release of large amounts of
stored catecholamines from nerve terminals, result-
ing in a hypertensive crisis,
Side effect of MAOIs
• Orthostatic hypotension, the most frequent side
effect, is secondary to alpha-1 adrenergic blockad
• Hypertensive crises are usually induced by con-
suming food rich in tyramine or by medications
with sympathomimetic activity.
• Other possible adverse effects of treatment with
MAOIs include drowsiness, blurred vision, dry
mouth, and constipation.
• SSRIs should not be administered with MAOIs
due to the risk of serotonin syndrome.
Adverse effect.....
Headache,Drowsiness,Dry mouth,Weight gain,
Sexual disturbances
• Therapeutic use: depression,obsessive-com-
pulsive disorder
Drug interactions
• Indirect –acting sympathomimetics: these
drugs produce hypertensive crisis in patients
taking MAOI
• TCA + MAOI= hypertensive crisis
• SSRIs + MAOI =serotoin syndrome.
V. Miscellaneous ('atypical') antidepressants
• Buspirone
– Inhibit DA & NA uptake
– Has excitant effect.
– Adverse effect: headache, dry mouth, weight loss, GI up-
set, tremor, insomnia
 Epilepsy and Antiepileptic drugs
Epilepsy
• Epilepsy refers to a group of disorders character-
ized by excessive excitability of neurons in the
CNS.
• Starts as a local abnormal discharge may then
spread to other areas of the brain.
• Site of the primary discharge and extent of its
spread determine symptoms that are produced.
Types of epilepsy
A. Generalized seizures
– Generalized tonic-clonic (grand mal) seizures
– Absence (petit mal) seizures
– Atonic seizures
– Clonic and myoclonic seizures
B. Partial seizures
– Simple partial seizures
– Complex partial seizures
– Partial seizures secondarily generalized
Generalized seizures(GS)
• Involves the whole brain
• Abnormal electrical activity throughout both hemi-
spheres
• Immediate loss of consciousness
1. Generalized tonic-clonic seizures (grand mal)
• Tonic phase (< 1 min)
– Sudden loss of consciousness
– Patient become rigid and falls to ground , respiration ar-
rested
• Clonic phase (2mins):-Jerking of the body musculature
• Clonic phase followed by prolonged sleep and depression
of all CNS functions
• micturition and salivation often occur
• Immediately after the seizure the patient may
– recover consciousness
– drift in to sleep
– have further convulsion (status epilepticus or serial
seizure)
• Convulsion with out recovery of consciousness
(Status epilepticus)- May lead to brain damage and
death
• Further convulsion, after recovering consciousness (serial
seizure)
2. Absence (petit mal) seizures– minor epilepsy
• Prevalent in child and cease at the age of 20
• Momentary loss of consciousness, patient freezes and
stares in one direction
• Onset and termination of attacks are abrupt
• Patient abruptly ceases whatever he/she was doing
• Many seizures each day may occur as compared to
GTCS
3. Atonic seizures (akinetic epilepsy)
• Unconsciousness with relaxation of all muscles due to
excessive inhibitory discharges
4. Clonic and myoclonic seizures
• Shock like momentary movement, contraction of mus-
cles of a limb or whole body that last just for one sec-
ond.
 B. Partial seizure
• The discharge begins locally and often remains localized
• Symptoms depend on the brain region/regions involved.
• The EEG (electroencephalograph) discharge in this type
of epilepsy is normally confined to one hemisphere
1. Simple partial seizures (cortical focal epilepsy)
• Lasts 0.5 – 1 min
• Convolutions are confined to a group of muscles or local-
ized sensory disturbance.
• With out loss of consciousness
2. Complex partial seizures (temporal lobe epilepsy,
psychomotor)
– Confused behaviors, purposeless movements, emo-
tional changes
– Seizure focus is located in temporal lobe
3. Simple or complex partial seizures secondarily gen-
eralized
• Partial seizures occurs followed by GTCS with loss of
consciousness
Possible causes of seizures
• primary (idiopathic) – most of the cases
• secondary to trauma/ surgery on head, intracranial
tumor, tuberculoma,cerebral ischemia, etc
Mechanism of action of antiepileptic drugs
1. Enhancement of GABA action
– Barbiturates & BZDs
– Vigabartrin and valproat (GABA transaminase inhibitor)-
increase synaptic GABA conc.
– Gabapentin (increase GABA release)
– Tiagabine (inhibit GABA reuptake to presynaptic neuron)
– All these facilitate GABA mediated Cl- channel opening
and end up with inhibitory effect
2. Inhibition of Na+ channel function
– Drugs: Phenytoin, Carbamazepine, Valproic acid,
Lamotrigine, Topiramate, Zonisamid Prolong
Na+channel inactivation state
3. Inhibition of Ca 2+ channel function
– Drugs: Ethosuximide, Trimethadione, Valproate
Phenytoin (diphenylhydantoin)
• Oldest nonsedative antiseizure drug
• Used against partial seizures and primary generalized tonic-
clonic seizures
Mechanism of action
• Prolonging inactive state of voltage sensitive Na+ channel.
Adverse effects
• Gum hypertrophy/ gingival hyperplasia (20%)
• Skin rash
• Megaloblastic anemia
Drug interaction
– 90% plasma proteins binding
• Hypoalbuminemia and drugs which displace phenytoin
from plasma proteins alter total plasma conc. of the
drug.
– Phenytoin induce microsomal enzymes
• Enhance metabolism of drugs(e.g.
OCP,warfarin,glucocorticoides)
Phenobarbitone
– Effective against GTC,SP and CP seizures
– Ineffective in absence seizure
Mechanism of action
• Exact mechanism of action is unknown
– Probably through enhancement of inhibitory processes
and diminution of excitatory transmission
Drug interaction
• Additive effect with CNS depressants.
• Induce metabolism of many drugs (warfarin,oral contracep-
tives,chloramphinicol,theophyline,griseofulvin)
• It decreases GIT absorption of griseofulvin.
• Plasma conc. increased by sodium valproat.
Carbamazepine
• Delays recovery of sodium channels from their inactivation
state.
• Antidiuretic effect / enhance ADH action
• Effective in most forms of epilepsy (except absence
seizures).
Valproic acid (sodium valproate)
• Effective against GTCS, partial seizures as well as ab-
sence seizures.
• Valproate is used in mixed absence seizures and GTCS.
Mechanism of action
• Prolongation of Na+ channel inactivation
• Inhibit Ca 2+ influx.
• Effect on GABA metabolism (degradation & uptake inhibi-
tion, increase synthesis from glutamic acid)
Drug interaction
– Inhibit phenobarbitone metabolism.
– Displaces phenytoin plasma protein binding and
decrease metabolism (phenytoin toxicity).
Ethosuximide
• Drug used to treat absence seizures and may exac-
erbate other forms
Mechanism of actions: inhibit calcium influx.
Oxacarbazepine
• Derivative of carbamazepine
MOA: block sodium channels.
• It is used for monotherapy and adjunctive therapy of
partial seizures in adults and children.
 General Anesthetics (GA)

Coma

Anesthetia

Hypnosis

sedation

Amnesia

Awake
Mechanism of action of GA
 Most anesthetics enhance activity of inhibitory GABAA re-
ceptors, and inhibit activation of excitatory receptors.
Types of GAs.
 Inhaled anesthetics (gases or volatile liquids)
– Desflurane
– Sevoflurane
– Isoflurane
– Enflurane
– Halothane
– Ethoxyflurane
– Nitrous oxide
– Diethyl ether
– Xenon
Individual inhalation anaesthetics
 Halothane (widely used)
• potent, non-explosive and non-irritant and hypotensive
• risk of liver damage if used repeatedly
 Nitrous oxide
• low potency, it is used in cobination with other agents
• rapid induction and recovery
• good analgesic properties
• risk of bone marrow depression with prolonged admn.
 Enflurane
• halogenated anaesthetic similar to halothane
• faster induction and recovery than halothane (less accumu-
lation in fat)
2. Intravenous anesthetics
• Barbiturates (eg, thiopental, methohexital)
• Propofol
• Ketamine
• Etomidate
 I.V. anaesthetics have faster onset of action.
• Used for induction of general anesthesia
• Rapid recovery (but not propofol) and used for short
ambulatory (outpatient) surgical procedures
Thiopental
(Barbiturate)
 high lipid solubility
 Rapid action due to rapid transfer across BBB
 Short duration due to redistribution
Etomidate
 Similar to thiopental but more quickly metabolised
 Causes minimal cardiovascular and respiratory depres-
sion(compared to other i.v.anesthetics)
ketamine
 The only i.v anesthetic with analgesic & dose-related car-
diovascular stimulation effects
 Increases cerebral blood flow, oxygen consumption, & in-
tracranial pressure
 Propofol
(Michael Jackson's Killer)
Is rapidly acting, has a short recovery
time.
Propofol anesthesia very popular as an
induction agent for outpatient anesthesia
- Rapid recovery and its antiemetic
properties
Considered safe for use in pregnant
women
Pharmacology of pain medication
 Inflammation
• Inflammation is a complex protective response of the organism
to injury caused by damaging agents.

Signs of inflammation

• Redness:

• Hotness:

• Swelling:

• Pain:
Inflammatory mediators:

– histamine
– 5-HT (serotonin)
– Bradykinin Main
– Prostaglandins (e.g PGE2) inflammatory
– Interleukines mediator
– Substance P
– Nitrous oxide
 The role of some prostaglandins in the body

• PGE2 – vasodilation, bronchodilation, inhibition of gas-

tric acid secretion, stimulation of gastric mucus secre-
tion, sensitization of pain receptors to chemical and
mechanical stimuli, promotion of anterior pituitary
hormones release;
• PGF2α - uterus contraction, bronchoconstriction, de-
crease in intraocular tension;
• TXA2 (thromboxane), produced by platelets, - induc-
tion of platelet aggregation, vasoconstriction;
• PGI2 - inhibition of platelet aggregation, potent vasodi-
lation;
 Analgesics
• Analgesics are drugs that relieve pain without caus-
ing loss of consciousness.
• Analgesics fall into two categories:
– Narcotics
– Non-narcotics
• Aspirin
• Pyrazolone derivatives
• Propionic acid derivatives
• Indol acetic acid derivatives
• Meclofenamic acid
 Opiates(Narcotics)

• Full agonists: morphine, codeine, pethidine.

• Partial agonists : pentazocine, buprenorphine
• Antagonists: naloxone
Mechanism of action of opiates
• Opioids produce analgesia by binding to specific receptors lo-
cated in brain & spinal cord regions involved in the transmission
& modulation of pain.
• Reduce neuronal excitability
– b/c of the ↑ K+ conductance causes
– hyperpolarisation of the membrane.
• Reduce transmitter release due to inhibition of Ca 2+ entry
Clinical use of opiates
1.Analgesic effect
• Selective relief of pain at doses which do not produce hypno-
sis or impair sensation
• Opioids are mainly used for severe & constant pain.
• Opioid analgesics are used during obstetric labor
• As opioids cross the placental barrier, care must be
taken to minimize neonatal depression.
• If it occurs, immediate injection of the antagonist
naloxone will reverse the depression.
2. Cough Suppression / antitussives
• Depression of cough centers in the medulla (possibly in the
periphery too).e.g. dextromethorphan.
Clinical use of opiates
3. Diarrhea
• Opioids cause constipation beneficial for treatment of diar-
rhea.
• Synthetic drugs (diphenoxylate & loperamide) with selective
effect on GIT.
4. Applications in anesthesia
– Used in cardiovascular surgery b/c of low cardiac depres-
sant effects
• Opioids can be used
– Preoperatively b/c of their sedative, anxiolytic & analgesic
properties
– Intraoperatively as adjuncts to other anesthetic agents &
as a primary component of the anesthetic regimen
– Postoperatively as analgesics
Side effects
• Respiratory depression (reduces sensitivity of
respiratory centers in brain stem to CO2).
• Euphoria, sedation, hypothermia, constipations.
• Tolerance & dependence.
• Bronchoconstriction (histamine release stimulated).
 Anti-inflammatory
Drugs

Steroidal Non-steroidal
- Cortisone - Acetaminophen
- Hydrocortisone - Aspirin
Steroids (SAIDs)
- Containing steroid moiety in their structure

Glucocorticoids
(GC)

Cortisone
 Glucocorticoids (GC)

Natural Synthetic
produced by the adrenal glands

- Cortisone Fluorinated - Betamethasone

Glucocorticoids - Dexamethasone
- Hydrocortisone
- Predinsone
Liver enzymes

Prednisolone
 Glucocorticoids
• May be categorized as
– Short-acting
• Cortisone and hydrocortisone
– Intermediate-acting
• Prednisone, prednisolone, prednisolone sodium succinate,
methylprednisolone, methylprednisolone acetate, and triamci-
nolone
– Long-acting
• Dexamethasone, betamethasone, and fluocinolone
• May be given orally, parenterally, or topically
 Glucocorticoids (GC)
Mechanism of Action :

- They act by indirect inhibition of the enzyme phospholipase A2

which activate synthesis of arachidonic acid with subsequent
formation of prostaglandins.
They induce synthesis of a protein “lipocortin-1” which has the
- inhibitory effect on phospholipase A2.
GC inhibition
 Side Effects
• Immunosuppression
• Hyperglycemia due to increased gluconeogensis, insulin resistance.
• Steroid-induced osteoporosis: reduced bone density
• Redistribution of body fat: moon face, buffalo.
• Adrenal insufficiency
• Muscle breakdown (proteolysis), weakness; reduced muscle mass
and repair
• Growth failure
• Increased plasma amino acids, increased urea formation;
• Delay wound healing
• Increase risk of infection
• May cause GI ulceration and bleeding
Non-Steroidal Anti-inflammatory Drugs
(NSAIDs)
• They don’t contain steroid moiety

• They also have analgesic and antipyretic activity

 Cyclo-oxygenase (COX)
• Exists in the tissue as constitutive isoform (COX-1).

• At site of inflammation, cytokines stimulate the induction of the

2nd isoform (COX-2).

• Inhibition of COX-2 is thought to be due to the anti-inflammatory

actions of NSAIDs.

• Inhibition of COX-1 is responsible for their GIT toxicity.

• Most currently used NSAIDs are somewhat selective for COX-1,

but selective COX-2 inhibitors are available.
Non-Steroidal Anti-inflammatory Drugs
(NSAIDs)

Non-selective
selective COX2
COX inhibitors
inhibitors
- Aspirin - Celecoxib
- Ibuprofen - Rofecoxib
- Diclofenac
- Meloxicam
- Indomethacin
- Mephenamic acid
 Mechanism of action
1. Anti-inflammatory effect

a. The anti-inflammatory effect of NSAIDs is due to the inhibition of

the enzymes which converts arachidonic acid to
prostaglandins,TXA2 and prostacyclin.

b. Additional anti-inflammatory mechanisms may include

interference with the potentiative action to other mediators of
inflammation (bradykinin, histamine, serotonin)
 Mechanism of action
2. Analgesic effect
a.PGE2 and PGI2 are the most important prostaglandins
involved in pain. Inhibition of their synthesis is a primary
mechanism of NSAID-mediated analgesia.
(1)Prostaglandins sensitize pain receptors.
b. NSAIDs prevent the potentiating action of prostaglandins
on endogenous mediators of peripheral nerve stimulation
(e.g., bradykinin).
3. Antipyretic effect.
Blocks pyrogen-induced prostaglandin production in
thermoregulatory center (CNS)
 • Prostaglandins
Pyrogen
• pGE2

NSAIDs
thermoregulatory cen-
ter
• Antipyretic Mechanism
Block prostaglandins pro-
set point ↑ duction

heat production ↑ • Sites of action:Central

Heat dissipation ↓ Nervous System

Fever
 1. Aspirin
• Anti-inflammatory actions
• Analgesic action
Inhibits synthesis of Prostaglandin E2 (PGE2) “thought to sensitize
nerve endings to the action of bradykinin, histamine, and other
chemical mediators released locally by the inflammatory process”.
 Used for the management of pain of low to moderate intensity
arising from musculoskeletal disorders rather than that arising from
the viscera.
• Antipyretic action
The salicylates lower body temperature in patients with
fever by impeding PGE2 synthesis and release
Body effect
Gastrointestinal effects
 Epigastric distress, ulceration, haemorrhage, and iron-defi-
ciency anaemia due to inhibition of PGE2
 Misoprostol (PGE1-derivative) and the proton-pump
inhibitors(lansoprazole, omeprazole, pantoprazole) can also be
used for the treatment of NSAID-induced ulcer
Effect on platelets (anticoagulant effect)
Low doses of aspirin can irreversibly inhibit thromboxane (en-
hances platelet aggregation) production in platelets
Because platelets lack nuclei, they cannot synthesize new en-
zyme, and the lack of thromboxane persists for the lifetime of
the platelet (3-7 days).
 Actions on the kidney
 Cyclooxygenase inhibitors prevent the synthesis of PGE2 and PGI2 -
prostaglandins that are responsible for maintaining renal blood flow
 Decreased synthesis of prostaglandins can result in retention of
sodium and water and may cause edema and hyperkalemia in some
patients
Therapeutic indications
• Anti-inflammatory, antipyretic, and analgesic uses
 The salicylic acid derivatives are used in the treatment of rheumatic
fever, osteoarthritis, and rheumatoid arthritis
• External applications
 Salicylic acid is used topically to treat corns and warts.
• Cardiovascular applications
 Aspirin is used to inhibit platelet aggregation.
Drug interactions
 Adverse effects
• GIT
 epigastric distress, ulceration, haemorrhage nausea, and vomiting.
 Aspirin is an acid and at stomach pH, aspirin is uncharged; conse-
quently, it readily crosses into mucosal cells, where it ionizes (be-
comes negatively charged) and becomes trapped, thus potentially
causing direct damage to the cells.
Blood
 Inhibition of platelet aggregation and a prolonged bleeding time
 Aspirin should not be taken for at least 1 week prior to surgery
 Adverse effects…
• Reye's syndrome
 Aspirin and other salicylates given during viral infections has been
associated with an increased incidence of Reye's syndrome (which is
an often fatal, fulminating hepatitis with cerebral edema)
 This is especially encountered in children, who therefore should be
given acetaminophen or Ibuprofen
 2. Propionic acid derivatives
• Ibuprofen, naproxen, fenoprofen, ketoprofen, and oxaprozin

• All these drugs possess anti-inflammatory, analgesic, and

antipyretic activity; additionally, they can alter platelet function
and prolong bleeding time.

• They have gained wide acceptance in the chronic treatment of

RA and osteoarthritis.

• These drugs are reversible inhibitors of the cyclooxygenases

3. Acetic acid derivatives
• Indomethacin, sulindac, and etodolac
• All have anti-inflammatory, analgesic, and antipyretic activity
• They act by reversibly inhibiting cyclooxygenase
4. Oxicam derivatives
• Piroxicam and meloxicam are used to treat RA and
osteoarthritis.
• They have long half-lives, which permit once-daily
administration
5.Heteroaryl acetic acids
• Diclofenac and tolmetin are approved for long-term use in
the treatment of RA, osteoarthritis
• Diclofenac is more potent than indomethacin or naproxen.
 5.Heteroaryl acetic acids…
Celecoxib
• Celecoxib is significantly more selective for inhibition of
COX-2 than of COX-1
• Unlike Aspirin, celecoxib does not inhibit platelet aggregation
and does not increase bleeding time.
• Detection of serious cardiovascular events associated with
COX-2 inhibitors have led to withdrawal of rofecoxib and
valdecoxib from the market
6. Acetaminophen
• Acetaminophen inhibits prostaglandin synthesis in the CNS.
This explains its antipyretic and analgesic properties.
• Acetaminophen has less effect on cyclooxygenase in periph-
eral tissues, which accounts for its weak anti-inflammatory ac-
tivity.
• Acetaminophen does not affect platelet function.
Therapeutic indications
Acetaminophen is a suitable substitute for the analgesic and an-
tipyretic effects of Aspirin for those patients with:
gastric complaints,
Those in whom prolongation of bleeding time would be a dis-
advantage,
Those who do not require the anti-inflammatory action of As-
pirin.
Acetaminophen is the analgesic/antipyretic of choice for chil-
dren with viral infections or chickenpox (recall that aspirin in-
creases the risk of Reye's syndrome).
Acetaminophen does not antagonize the uricosuric agents
probenecid or sulfinpyrazone and, therefore, may be used in pa-
tients with gout who are taking these drugs.
Actions of non-steroidal anti inflammatory drugs (NSAIDs) and acetaminophen
 Adverse effects
• With normal therapeutic doses, acetaminophen is virtually
free of any significant adverse effects.
• With large doses of acetaminophen, the available
glutathione in the liver becomes depleted, and
N-acetyl-p-benzoiminoquinone reacts with the sulfhydryl
groups of hepatic proteins, forming covalent bonds, hepatic
necrosis, a very serious and potentially life-threatening
condition can result.
• N-acetylcysteine (Antidote)– MOA: a glutathione precursor.
• Beyond 8 hours, NAC efficacy progressively decreases.