Sedatives Hypnotics, Analgesics, Anti Gout, CNS Drugs

Tahir Muhammad
DEFINITION:
“Drugs that relieve pain are called analgesic.”
“A drug that selectively relieves pain by acting in the CNS or on
without significantly altering consciousness.”
The drugs that relieve pain by acting at some points in the body’s pain signaling mechanism
(peripheral, spinal, supraspinal) are called analgesics.
ALGESIA/PAIN:
“Characteristic
Pain is a warning signal, primarily protective in nature, but causes discomfort and suffering; may
even be unbearable and incapacitating.
It is the unpleasant sensory & emotional experience associated with actual t
Pain is also considered as a complex body response to a noxious stimulus followed by
emotional response.
Excessive pain may produce other effects like sinking sensation, apprehension, sweating,
nausea, palpitation, and rise or fall in BP, tac
TYPES OF PAIN:
• Chronic pain;
Pain is transitory, lasting only until the noxious stimulus is removed, eg, rheumatoid
arthritis, peripheral neuropathy, cancer, & idiopathic pain
Lasts ↑ than 1 month → Having long duration
• Acute pain;
The pain that resolve quickly is called acute pain.
Lasts less than 30 days
PAIN FIBERS:
Three main types of fiber,
A-fiber
• A-alpha fiber
ANALGESICS
OR
“A drug that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms,
(peripheral, spinal, supraspinal) are called analgesics.
“Characteristic sensation arise from a noxious sensation”
even be unbearable and incapacitating.
It is the unpleasant sensory & emotional experience associated with actual t
nausea, palpitation, and rise or fall in BP, tachypnoea etc.
arthritis, peripheral neuropathy, cancer, & idiopathic pain
↑ than 1 month → Having long duration
that resolve quickly is called acute pain.
Lasts less than 30 days → ↓ duration
1
peripheral pain mechanisms,
sensation arise from a noxious sensation”
It is the unpleasant sensory & emotional experience associated with actual tissue damage.

Tahir Muhammad
• A-beta fiber
• A-gamma fiber
• A-delta fiber
B-fiber
C-fiber → most imp
Pain pathway:
From periphery the pain through pain fibers is transmitted to the spinal cord and then higher centers
of brain.
Periphery
Neospinothalamic tract:
Fast pain travels via type Aδ fibers
they synapse on dendrites of the neospinothalamic tract. The
(decussate) through the anterior
fibers terminate on the ventrobasal complex
the somatosensory cortex.
Fast pain is felt within a tenth of a secon
prickling pain,& felt in response to mechanical and thermal stimulation.
It can be localized easily if Aδ fibers are stimulated together with tactile receptors.
Paleospinothalamic tract
through pain fibers is transmitted to the spinal cord and then higher centers
Periphery → spinal cord → higher centers of brains.
Aδ fibers to terminate in the dorsal horn of the spinal cord where
of the neospinothalamic tract. The axons of these
anterior and ascend contralaterally along the anterolateral columns
ventrobasal complex of the thalamus and synapse with the dendrites of
Fast pain is felt within a tenth of a second of application of the pain stimulus and is a sharp, acute,
prickling pain,& felt in response to mechanical and thermal stimulation.
Paleospinothalamic tract
2
through pain fibers is transmitted to the spinal cord and then higher centers
→ spinal cord → higher centers of brains.
of the spinal cord where
of these neurons cross the midline
anterolateral columns. These
of the thalamus and synapse with the dendrites of
d of application of the pain stimulus and is a sharp, acute,

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Slow pain is transmitted via slower type C fibers to laminae II and III of the dorsal horns, together
known as the substantia gelatinosa. Impulses are then transmitted to nerve fibers that terminate in
lamina-V, also in the dorsal horn, synapsing with neurons that join fibers from the fast pathway,
crossing to the opposite side via the anterior white commissure, and traveling upwards through the
anterolateral pathway. These neurons terminate throughout the brain stem, with one tenth of fibers
stopping in the thalamus and the rest stopping in the medulla, pons and periaqueductal grey of
the midbrain tectum.
Slow pain is stimulated by chemical stimulation, is poorly localized and is described as an aching,
throbbing or burning pain.
Putative sites of action of opioid analgesics (darker color). On the left, sites of action on the pain
transmission pathway from the periphery to the higher centers are shown. A: Direct action of opioids on
inflamed peripheral tissues. B: Inhibition occurs in the spinal cord. C: Possible site of action in the thalamus.
Different thalamic regions project to somatosensory (SS) or limbic (L) cortex. Parabrachial nuclei
(medulla/pons) projects to the amygdala. On the right, actions of opioids on pain-modulating neurons in
the midbrain (D) and medulla (E) indirectly control pain transmission pathways.

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TYPES OF ANALGESICS:
There are two main classes of analgesics which are;
A) CLASS-1 / STRONG / OPOIDS / NARCOTIC ANALGESICS:
• Morphine is prototype drug of this class.
• These drugs acts centrally at spinal or supraspinal level (brain).
• Used for severe pain → such as pain arising from burns, neoplasm, etc
• Strong analgesics (these ) are used, where there other analgesics can’t works properly.
• Having sedative & analgesic properties.
DISADVANTAGE
• The big disadvantage of this class is addiction, but still used as analgesic b/c some severe
pain can’t be controlled without this drug such as cancer pain.
B) CLASS-2 / WEAK ANALGESICS / NSAIDS:
• Here aspirin is prototype drug.
• Mostly used in musculoskeletal pain.
• They have also anti-inflammatory properties.
• Some have anti-pyretic activity also.
The imp neurotransmitters such as adrenalin and 5-OH-tryptamine also relieve pain in CNS.
Classification of Analgesics:
• Opioids (Type-1)→ narcotic, centrally acting & strong
• NSAIDS (Type-2) → non-narcotic peripherally acting, &weak
Definition:
“The term opioids applied to any substance whether endogenous or synthetic that act like morphine,
and its effects are antagonized by Naloxone.”
Introduction:
• Morphine, the prototypical opioid agonist, has long been known to relieve severe pain with
remarkable efficacy.
• The opium poppy is the source of crude opium from which Serturner in 1803 isolated
morphine, the pure alkaloid and named it after Morpheus, the Greek god of dreams.
• It remains the standard against all the drugs that have strong analgesic action.
Source:
• Obtained from the poppy → Papaver somniferum
1) Opioids Receptors:
Opioids interact stereospecifically with protein receptors on the membranes of certain cells in the
CNS, on nerve terminals in the periphery, and on cells of the gastrointestinal tract and other
anatomic regions.
OPIOIDS

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The major effects of the opioids are mediated by three major receptor families. These are
designated by the Greek letters
µ-Receptor
µ1
µ2
Delta Receptor
Delta1
Delta2
Kappa Receptor
K1
K2
K3
Each receptor family exhibits a different specificity for the drug(s) it binds.
The analgesic properties of the opioids are primarily mediated by the μ receptors.
However, other receptors also contribute. For example, butorphanol and nalbuphine primarily
owe their analgesic effect to K-receptor activation. The enkephalins interact more selectively with
the Delta receptors in the periphery.
All three opioid receptors are members of the G protein coupled receptor family and inhibit
adenylyl cyclase. They are also associated with ion channels, increasing postsynaptic K+ efflux
(hyperpolarization) or reducing presynaptic Ca2+ influx, thus impeding neuronal firing and
transmitter release
2) Endogenous Opioids:
• Discovered in 1975.
• These are pentapeptides involved in regulating nociception in the body.
• These are also called endogenous ligands or specifically endorphins.
• These are internally derived and binds to opioids receptors.
• Three families of endogenous opioid peptides have been described:
Pro-enkephalin → The pentapeptides
o Methionine-enkephalin (met-enkephalin) and
o leucine-enkephalin (leu-enkephalin)
Selctivity → Delta ↑ & µ receptors
The endorphins → Selectivity → both Delta & µ receptors
And the dynorphins → Selectivity → ↑ for Kappa receptor
• The three families of opioid receptors have overlapping affinities for these endogenous
peptides derived from three precursor proteins:
Prepro-opiomelanocortin (POMC)
Preproenkephalin (proenkephalin A)
And preprodynorphin (proenkephalin B)
• Selectivity of Endogenous towards opioids receptors:
Enkephalin
µ-receptor
++
Delta-receptor
+++
kappa-receptor

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Endorphin +++ +++
Dynorphin A ++ +++
Dynorphin B + + +++
3) Opioid classification:
1) STRONG AGONIST:
Naturally occurring:
Phenanthrene derivatives:
Morphine → 9-17%
Codeine → 0.3-4%
Thebaine → 0.2-8 %
Benzyl Iso-quinoline derivatives:
Papaverine → 1%
Noscapine → 6%
Semisynthetic:
Morphine derivatives:
Hydromorphone
Oxomorphone
Diacetylmorphine (Heroin)
Apomorphine
Codeine derivatives:
Hydrocodone
Oxycodone
Dihydrocodeine
Pholcodeine
Synthetic:
Phenyl pepiredine derivatives:
Fentanyl
Alfentanil
Sufentanil
Remifentanil
Pethidine (Meperidine)
Diphenoxylate → weakly agonist
Loperamide → weakly agonist
Phenyl-heptyl-amines:
Methadone
Propoxyphene
Morphinans:
Dextromethorphan
Levorphanol

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2) PARTIAL AGONIST:
Nalbuphine
Buprenorphine
Butorphanol
Pentazocine
Dezocine
Tramadol
3) ANTAGONIST:
Naloxone
Naltrexone
Nalorphine
Levallorphan
4) P-K:
Route:
Parentral → S/C, I/M,
P/O
Nasal
ABSORPTION:
• Most opioid analgesics are well absorbed
• However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to
be much higher than the parenteral dose to elicit a therapeutic effect.
• Certain analgesics such as codeine and oxycodone are effective orally because they have reduced
first-pass metabolism.
• Nasal insufflation of certain opioids can result in rapid therapeutic blood levels by avoiding first-
pass metabolism.
DISTRIBUTION:
• High
• Highest concentrations in tissues that are highly perfused such as the brain, lungs, liver, kidneys,
and spleen.
• Drug concentrations in skeletal muscle may be much lower
METABOLISM:
• The opioids are converted mostly to glucuronides.
• For example, morphine
→ morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties.
→ 10% of morphine to morphine-6-glucuronide (M6G), an active metabolite with analgesic
potency 4-6 six times that of its parent compound.
EXCRETION:
• Polar metabolites & Small amounts of unchanged → urine.
• Glucuronide conjugates also found in the bile
5) P-D:

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• ↓ Ca++ influx
• ↓ the release of neurotransmitters
• ↑ K+ efflux
Opioids exert their major effects by interacting with opioid receptors in the CNS and in other anatomic
structures, such as the gastrointestinal tract and the urinary bladder.
Opioids cause hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of
transmitter release.
Morphine acts at µ receptors in Lamina II and III of the dorsal horn of the spinal cord, and it decreases
the release of substance P, which modulates pain perception in the spinal cord.
Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals
carrying nociceptive (painful) stimuli.

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6) Site of Action:
Direct action the inflamed peripheral tissue
Act at spinal cord level and causes inhibition
Effects at supra-spinal level ( Thalamus is involved)
Spinal sites of opioid action.
7) Organ system effects:
o CNS effects
o Peripheral effects
A) CNS EFFECTS:
The principal effects of opioid analgesics with affinity for µ-receptors are on the CNS; the more
important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a
high degree of tolerance occurs to all of these effects.
1) Analgesia:
Pain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in
that they can reduce both aspects of the pain experience, especially the affective aspect.
2) Euphoria:
Patients or drug users → i/v morphine → experience a pleasant Oloating sensation with lessened
anxiety and distress.
3) Dysphoria:

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An unpleasant state characterized by restlessness and malaise, may sometimes occur.
4) Sedation:
Drowsiness and clouding of mentation are common concomitants of opioid action. There is little or
no amnesia. Sleep is induced by opioids more frequently in the elderly than in young, healthy
individuals.
5) Respiratory depression:
All of the opioid analgesics can produce significant respiratory depression by inhibiting brainstem
respiratory mechanisms. Alveolar CO2 may increase, but the most reliable indicator of this depression
is a depressed response to a carbon dioxide challenge. The respiratory depression is dose-related.
6) Cough suppression:
Suppression of the cough reflex is a well-recognized action of opioids. Codeine in particular has been
used in persons suffering from pathologic cough. However, cough suppression by opioids may allow
accumulation of secretions and thus lead to airway obstruction and atelectasis.
7) Miosis:
Constriction of the pupils is seen with virtually all opioid agonists. Miosis
is a pharmacologic action to which little or no tolerance develops, thus,
it is valuable in the diagnosis of opioid overdose. Even in highly tolerant
addicts, miosis is seen. This action, which can be blocked by opioid
antagonists, is mediated by parasympathetic pathways, which, in turn,
can be blocked by atropine.
8) Truncal rigidity:
An intensification of tone in the large trunk muscles has been noted with
a number of opioids. It results from an action at supraspinal levels. Truncal rigidity reduces thoracic
compliance and thus interferes with ventilation. The effect is most apparent when high doses of the
highly lipid-soluble opioids (eg, fentanyl, Sufentanil, Alfentanil, Remifentanil) are rapidly
administered intravenously.
9) Nausea and vomiting:
The opioid analgesics can activate the brainstem CTZ to produce nausea and vomiting.
10) Temperature:
µ-opioids such as Morphine administered to the anterior hypothalamus produces hyperthermia,
whereas administration of k-agonists induce hypothermia.
B) PERIPHERAL EFFECTS:
1) Cardiovascular system:
Most opioids have no significant direct effects on the heart and, other than bradycardia, no major
effects on cardiac rhythm. Meperidine is an exception → antimuscarinic action → result in
tachycardia.
Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular
system is stressed, in which case hypotension may occur. This hypotensive effect is probably due to
peripheral arterial and venous dilation, which is b/c central depression of vasomotor and release of
histamine.
No consistent effect on cardiac output is seen, caution should be exercised in patients with decreased
blood volume, because will lead to → hypotension.

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Increased CO2 level leads to cerebral vasodilation associated with a decrease in cerebral vascular
resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.
2) Gastrointestinal tract:
Constipation has long been recognized as an effect of opioids, an effect that does not diminish with
continued use; that is, tolerance does not develop to opioid-induced constipation.
Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the
opioids are mediated through an action on the enteric nervous system as well as the CNS.
Stomach Motility (rhythmic contraction and relaxation) may decrease but tone (persistent
contraction) may increase particularly in the central portion; gastric secretion of hydrochloric acid is
decreased.
Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive
contractions is markedly decreased.
Large intestine propulsive peristaltic waves are diminished and tone is increased; this delays
passage of the fecal mass and allows increased absorption of water, which leads to constipation.
The large bowel actions are the basis for the use of opioids in the management of diarrhea.
3) Biliary tract:
The opioids contract biliary smooth muscle, which can result in biliary colic. The sphincter of Oddi
may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase
and lipase levels.
4) Renal:
Renal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased
renal plasma flow. In addition, u-agonist opioids have been found to have an antidiuretic effect in
humans. Mechanisms may involve both the CNS and peripheral sites.
Opioids also enhance renal tubular sodium reabsorption. The role of opioid-induced changes in
antidiuretic hormone (ADH) release is controversial.
Ureteral and bladder tone ↑ by therapeutic doses of the opioid analgesics. Increased sphincter tone
may precipitate urinary retention, especially in postoperative patients.
5) Uterus:
The opioid analgesics may prolong labor. The mechanism for this action is unclear, but both
peripheral and central actions of the opioids can reduce uterine tone.
6) Endocrine:
Opioid analgesics stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of
luteinizing hormone. These effects suggest that endogenous opioid peptides, through effects in the
hypothalamus, regulate these systems.
7) Pruritis:
Therapeutic doses of the opioid analgesics produce flushing and warming of the skin accompanied
sometimes by sweating and itching; CNS effects and peripheral histamine release may be responsible
for these reactions.
8) Immune system:

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The opioids modulate the immune system by effects on lymphocyte proliferation, antibody
production, and chemotaxis. Natural killer cell cytolytic activity and lymphocyte proliferative
responses to mitogens are usually inhibited by opioids.
8) Uses:
A) ANALGESIA
Severe, constant pain is usually relieved with opioid analgesics with high intrinsic activity
whereas sharp, intermittent pain does not appear to be as effectively controlled.
Another type of pain control called patient-controlled analgesia (PCA) is now in widespread
use for the management of breakthrough pain. With PCA, the patient controls a parenteral
(usually intravenous) infusion device by depressing a button to deliver a preprogrammed dose of
the desired opioid analgesic.
B) ACUTE PULMONARY EDEMA
The relief produced by intravenous morphine in dyspnea from pulmonary edema associated with
left ventricular failure is remarkable. Proposed mechanisms include reduced anxiety (perception
of shortness of breath), and reduced cardiac preload (reduced venous tone) and afterload
(decreased peripheral resistance).
C) COUGH
Suppression of cough can be obtained at doses lower than those needed for analgesia. But now-a-
days synthetic cough suppressants are used.
D) DIARRHEA
Diarrhea from almost any cause can be controlled with the opioid analgesics, but if diarrhea is
associated with infection such use must not substitute for appropriate chemotherapy. Crude
opium preparations (eg, paregoric) were used in the past to control diarrhea, but now synthetic
surrogates with more selective gastrointestinal effects and few or no CNS effects, eg,
diphenoxylate, are used. Several preparations are available specifically for this purpose.
E) SHIVERING
Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to
have the most pronounced anti-shivering properties. It is interesting that meperidine apparently
blocks shivering through its action on subtypes of the a2 adrenoceptor.
F) APPLICATIONS IN ANESTHESIA
The opioids are frequently used as premedicant drugs before anesthesia and surgery because of
their sedative, anxiolytic, and analgesic properties. They are also used intraoperatively both as
adjuncts to other anesthetic agents and, in high doses (eg, 0.02-0.075 mg/kg of fentanyl), as a
primary component of the anesthetic regimen. Opioids are most commonly used in cardiovascular
surgery and other types of high-risk surgery in which a primary goal is to minimize
cardiovascular depression. In such situations, mechanical respiratory assistance must be
provided.
9) Toxicities:
• Behavior restlessness
• Dysphoria

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• Neuroexcitatory effects
• Seizures
• Constipation
• Postural hypotension
• Nausea & vomiting
• Itching around nose
• Urticaria
• Tolerance
• Dependence
→ Physical
→ Psychological
10)Contra-indications:
1) Use of pure agonists with weak partial agonists:
When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist
(eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal;
combining full agonist with partial agonist opioids should be avoided.
2) Use in patients with head injuries:
Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. In
patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.
3) Use during pregnancy:
In pregnant women who are chronically using opioids, the fetus may become physically
dependent in uterus and manifest withdrawal symptoms in the early postpartum period. A daily
dose as small as 6 mg of heroin (or equivalent) taken by the mother can result in a mild
withdrawal syndrome in the infant, and twice that much may result in severe signs and
symptoms, including irritability, shrill crying, or even seizures.
4) Use in patients with impaired pulmonary function:
In patients with borderline respiratory reserve, the depressant properties of the opioid analgesics
may lead to acute respiratory failure.
5) Use in patients with impaired hepatic or renal function:
Because morphine and its congeners are metabolized primarily in the liver, their use in patients
in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal
function, and morphine and its active glucuronide metabolite may accumulate; dosage can often
be reduced in such patients.
6) Use in patients with endocrine disease:
Patients with adrenal insufficiency (Addison's disease) and those with hypothyroidism
(myxedema) may have prolonged and exaggerated responses to opioids.
11) Drug-interactions:

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Drug Group Interaction with Opioids
Sedative-hypnotics
Increased central nervous system depression, particularly respiratory
depression.
Antipsychotic tranquilizers
Increased sedation. Variable effects on respiratory depression.
Accentuation of cardiovascular effects (antimuscarinic and a-blocking
actions).
MAO inhibitors
Relative contraindication to all opioid analgesics because of the high
incidence of hyperpyrexic coma; hypertension has also been reported.
NSAIDS
Properties:
Antipyretic
Analgesic
Anti-inflammatory
All of the NSAIDs act by inhibiting the synthesis of prostaglandins.
These properties of NSAIDS depends upon the inhibition of cyclo-oxygenase enzyme (COX)
There are 3 types of COX enzymes
• COX-1 (Cyclo-oxygenase-1)
These are also called prostaglandins synthetase 1, 2 & 3.
Synthesis of prostaglandins:
Arachidonic acid, a 20-carbon fatty acid, is the primary precursor of the prostaglandins and related
compounds. Arachidonic acid is present as a component of the phospholipids of cell membranes.
Cyclooxygenase pathway:
i. COX-1:
Cyclooxygenase-1 (COX-1) is responsible for the physiologic production of prostanoids, COX-1 is
described as a housekeeping enzyme that regulates normal cellular processes, such as gastric
cytoprotection, vascular homeostasis, platelet aggregation, and kidney function.
ii. COX-2:
Cyclooxygenase-2 (COX-2) causes the elevated production of prostanoids that occurs in sites of
disease and inflammation.

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COX-2 is continuously expressed in tissues
such as the brain, kidney, and bone. Its
expression at other sites is increased
during states of inflammation.
Lipoxygenase pathway:
Alternatively, several lipoxygenases can act on
arachidonic acid to form 5-HPETE, 12-HPETE, and
15-HPETE, which are unstable peroxidated
derivatives that are converted to the
corresponding hydroxylated derivatives (the
HETEs) or to leukotrienes or lipoxins, depending
on the tissues.
(Hydroperoxyeicosatetraenoic and
hydroxyeicosatetraenoic acids → HPETEs and
HETEs, respectively)

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Classification of NSAIDS:
1) Classification based on selectivity for COX enzyme
2) Chemical classification:
i. Salicylates:
o Salicylic acid
o Acetyl salicylic acid (Aspirin)
o Methyl salicylic acid
o Diflunisal
ii. Propionic acid (phenyl alkanoic acid)derivatives:
o Flurbiprofen
o Ibuprofen
o Fenoprofen
o Ketoprofen
o Naproxen

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o Oxaprozin
iii. Indole derivative:
o Indomethacin
iv. Pyrazolone derivatives:
o Phenyl beutazone
v. Phenyl acetic acid:
o Diclofenac
vi. Femanates derivatives:
o Mefenamic acid
o Flufenamic acid
o Meclofenamate
vii. Oxicam/ Enolic acid derivatives:
o Piroxicam
o Meloxicam
o Nabumetone
viii. Para-aminophenol derivatives:
o Acetaminophen
ASPIRIN
Introduction:
• Properties:
o Analgesic
o Anti-pyretic
o Anti-inflammatory:
• Aspirin is the prototype of traditional NSAIDs
• Officially approved by the FDA in 1939.
• It is the most commonly used and is the drug to which all other anti-inflammatory agents are
compared.
• It has been replaced by ibuprofen and naproxen, since
o they are effective,
o available over the counter,
o And have good-excellent safety records.
P-K:
Absorption:
• After oral administration, the un-ionized salicylates are passively absorbed well & rapidly
from stomach & upper part of GIT.
• Rectal absorption of the salicylates is slow and unreliable, but it is a useful route for
administration to vomiting children.
• Antacids → All types ↓ its absorption b/c they ↓ acidity of the stomach while aspirin is
absorbed in acidic environment.

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Distribution:
• Well
• Salicylates (except for Diflunisal) cross both the BBB and the placenta and are absorbed
through intact skin (especially methyl salicylate).
• PPC → 1-2 hours
• T1/2 → 3-5 hours
• Displace so many dugs from binding site of protein i.e. Tolbutamide, etc
Effect of dose on the half-life of aspirin.
Metabolism:
• Aspirin is metabolized to salicylate and acetic acid by esterases in tissues and blood.
• Then followed by Oxidation & Conjugation.
Excretion:

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• Being an organic acid, salicylate is excreted into the urine and can affect uric acid excretion
• At low doses of aspirin, uric acid secretion is decreased, whereas at high doses, uric acid
secretion is increased.
• Both hepatic and renal function should be monitored periodically in those receiving long-
term, high-dose aspirin therapy.
Dosage:
• Analgesic or antipyretic dose → less than the 0.6-0.65 gram oral dose.
• The anti-inflammatory dose → for adults is 45 mg/kg/d in divided doses (For children is 50-
75 mg/kg/d in divided doses)
• For those with RA or osteoarthritis → 3 grams/day
• Acute myocardial infarction, the dose is 162 to 325 mg of nonenteric coated
Pharmalogical Actions:
1) ANTI-INFLAMMATORY EFFECTS
Because aspirin inhibits cyclooxygenase activity, it diminishes the formation of prostaglandins and,
thus, modulates those aspects of inflammation in which prostaglandins act as mediators.
Aspirin inhibits inflammation in arthritis, but it neither arrests the progress of the disease nor
induces remission.
2) ANALGESIC EFFECTS:
Prostaglandin E2 (PGE2) is thought to sensitize nerve endings to the action of bradykinin, histamine,
and other chemical mediators released locally by the inflammatory process.
Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs repress the sensation of pain. The
salicylates are used mainly for the management of pain of low to moderate intensity arising from
musculoskeletal disorders rather than that arising from the viscera. Combinations of opioids and
NSAIDs are effective in treating pain caused by malignancy. Diflunisal is three- to four-fold more
potent than aspirin as an analgesic and an anti-inflammatory agent, but it has no antipyretic
properties.
3) ANTIPYRETIC EFFECTS:
Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated.
This can be caused by PGE2 synthesis, which is stimulated when an endogenous fever-producing
agent (pyrogen), such as a cytokine, is released from white cells that are activated by infection,
hypersensitivity, malignancy, or inflammation.
The salicylates lower body temperature in patients with fever by impeding PGE2 synthesis and
release. Aspirin resets the thermostat toward normal, and it rapidly lowers the body temperature of
febrile patients by increasing heat dissipation as a result of peripheral vasodilation and sweating.
Aspirin has no effect on normal body temperature. Diflunisal does not reduce fever, because it does
not cross the blood-brain barrier.
4) ANTI-PLATELET EFFECT:
Aspirin irreversibly inhibits platelet COX, so that aspirin's antiplatelet effect lasts 8-10 days.
Arachidonic acid

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Endoperoxides
Aspirin
Thromboxane-A2 Prostacyclin
Aggregation of platelets De-aggregation of platelets
& vasoconstriction
5) URICOSURIC EFFECT:
In ↓ doses → ↓ uric acid secretion & ↑ tubular absorption → leads to ↑ uric acid in the body.
This is mainly due to interference with uric acid secretory enzymes.
In ↑ doses (3-4gm/day) → ↑ uric acid secretion ↓ tubular absorption → leads to ↓ uric acid in the body
→ used in gout.
Even small doses of salicylate can block the effects of probenecid and other uricosuric agents that
decrease tubular reabsorption of uric acid.
Organ system effects:
1) Respiration:
Salicylates increase oxygen consumption and CO2 production (especially in skeletal muscle) at full
therapeutic doses; these effects are a result of uncoupling oxidative phosphorylation. The increased
production of CO2 stimulates respiration (mainly by an increase in depth of respiration with only a
slight increase in rate. The increased alveolar ventilation balances → the increased CO2 production,
and thus plasma CO2 tension (PCO2) does not change or may decrease slightly
2) Cardiovascular Effects:
Low doses of aspirin (<100 mg daily) are used widely for the cardioprotective effects. At high
therapeutic doses (>3 g daily), as might be given for acute rheumatic fever, salt and water retention
can lead to an increase (up to 20%) in circulating plasma volume and decreased hematocrit (via a
dilutional effect). There is a tendency for the peripheral vessels to dilate because of a direct effect on
vascular smooth muscle. Cardiac output and work are increased. Those with carditis or compromised
cardiac function may not have sufficient cardiac reserve to meet the increased demands, and
congestive cardiac failure and pulmonary edema can occur.
3) Gastrointestinal Effects:
The ingestion of salicylates may result in epigastric distress, nausea, and vomiting. Salicylates also
may cause gastric ulceration, exacerbation of peptic ulcer symptoms (heartburn, dyspepsia),
gastrointestinal hemorrhage, and erosive gastritis. These effects occur primarily with acetylated
salicylates (i.e., aspirin). Because nonacetylated salicylates lack the ability to acetylate
cyclooxygenase and thereby irreversibly inhibit its activity, they are weaker inhibitors than aspirin
4) Effects on the Blood:
Ingestion of aspirin by healthy individuals prolongs the bleeding time

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5) Hepatic Effects:
Salicylates can cause hepatic injury, usually in patients treated with high doses of salicylates that
result in plasma concentrations of more than 150 µg/ml. The injury is not an acute effect; rather, the
onset characteristically occurs after several months of treatment.
6) Actions on the kidney:
Cyclooxygenase inhibitors prevent the synthesis of PGE2 and PGI2 prostaglandins that are
responsible for maintaining renal blood flow, particularly in the presence of circulating
vasoconstrictors. Decreased synthesis of prostaglandins can result in retention of sodium and water
and may cause edema and hyperkalemia in some patients. Interstitial nephritis can also occur with
all NSAIDs except aspirin
Uses:
Anti-inflammatory
Antipyretic
analgesic uses
RA → in combo with other drugs.
Cardiovascular applications:
Aspirin is used to inhibit platelet aggregation. Low doses are used prophylactically to
• Reduce the risk of ischemic attacks and stroke or death
• Reduce the risk of death in those having an acute myocardial infarction or unstable angina
pectoris.
• Reduce the cardiovascular risk in patients undergoing certain revascularization procedures.
Side effects:
Gastrointestinal:
Epigastric distress, nausea, and vomiting. Microscopic GI bleeding is almost universal in patients
treated with salicylates.
Blood:
The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet TXA2, resulting in
inhibition of platelet aggregation and a prolonged bleeding time. For this reason, aspirin should not
be taken for at least 1 week prior to surgery. When salicylates are administered, anticoagulants may
have to be given in reduced dosage
Respiration:
In toxic doses, salicylates cause respiratory depression and a combination of uncompensated
respiratory and metabolic acidosis.
Metabolic processes:
Large doses of salicylates uncouple oxidative phosphorylation. The energy normally used for the
production of adenosine triphosphate is dissipated as heat, which explains the hyperthermia caused
by salicylates when taken in toxic quantities.
Hypersensitivity:
Approximately 15 percent of patients taking aspirin experience hypersensitivity reactions.
Symptoms of true allergy include urticaria, bronchoconstriction, or angioedema. Fatal anaphylactic
shock is rare.

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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 instead of aspirin when
such medication is required to reduce fever. Ibuprofen is
also appropriate.
Toxicity:
Salicylate intoxication is called Salicylism → may be mild or
severe
Mild cases:
Characterized by nausea, vomiting, marked
hyperventilation, headache, mental confusion, dizziness,
and tinnitus (ringing or roaring in the ears).
Treatment → measurement of serum salicylate
concentrations and of pH to determine the best form of
therapy. In mild cases, symptomatic treatment is usually
sufficient. Increasing the urinary pH enhances the
elimination of salicylate.
In serious cases:
When large doses of salicylate are administered, severe
salicylate intoxication may result.
The symptoms listed above are followed by restlessness,
delirium, hallucinations, convulsions, coma, respiratory and
metabolic acidosis, and death from respiratory failure
Treatment → Mandatory measures include the intravenous
administration of fluid, dialysis (hemodialysis or peritoneal
dialysis), and the frequent assessment and correction of
acid-base and electrolyte balances.
[Note: Diflunisal does not cause salicylism.]
Dose dependent effects of salicylate.
Drug Interactions:
The plasma concentration of salicylates generally is little affected by other drugs, but concurrent
administration of aspirin lowers the concentrations of indomethacin, naproxen, Ketoprofen, and
Fenoprofen, at least in part by displacement from plasma proteins.

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Aspirin could displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic
acid, resulting in higher free concentrations of the other agent → Lead to toxicity of these agents.
Other interactions of aspirin include the antagonism of spironolactone-induced natriuresis.
Blockade of the active transport of penicillin from CSF to blood.
Contra-Indications:
Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and category D
during Trimester 3.
Because salicylates are excreted in breast milk, aspirin should be avoided during pregnancy and
while breast-feeding
Aspirin Resistance
All forms of treatment failure with aspirin have been collectively
called "aspirin resistance."
Genetic variants of COX-1 that cosegregate with resistance have
been described, but the relation to clinical outcome is not clear.
PARACETAMOL
Introduction:
• Also called Acetaminophen/N-acetyl-p-aminophenol.
• It is the active metabolite of phenacetin / also called coal tar
analgesic.
• Acetaminophen is an effective alternative to aspirin as an
analgesic-antipyretic agent.
• however, its anti-inflammatory effects are much weaker
• Acetaminophen is well tolerated and has a low incidence of
gastrointestinal side effects.
• It is available without a prescription and is used as a
common household analgesic like aspirin.
• It was introduced into market in 1886 under the name
antifebrin by Cahn and Hepp, who had discovered its
antipyretic action accidentally.
P-K:
• Absorption:
Acetaminophen is administered orally.
Rapidly & well.
Absorption is related to the rate of gastric emptying.
• Distribution:
Uniformly distributed throughout most body fluids
PPC → 30-60 mins

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T1/2 → 2 hours
Acetaminophen is slightly bound to plasma proteins → less than other NSAIDs.
• Metabolism:
Partially metabolized by hepatic microsomal enzymes.
Hepatic conjugation with glucuronic acid (about 60%), sulfuric acid (about 35%), or cysteine
(about 3%).
Small proportion of acetaminophen undergoes N-hydroxylation to form N-acetyl-p-
benzoquinoneimine (NAPQI), a highly reactive intermediate. This metabolite normally reacts
with sulfhydryl groups in glutathione (GSH) and thereby is rendered harmless. However, after
ingestion of large doses of acetaminophen, the metabolite is formed in amounts sufficient to
deplete hepatic GSH and contributes significantly to the toxic effects of overdose.
• Excretion:
Renal pathway
Pharmalogical Actions:
• Acetaminophen has analgesic and antipyretic effects
similar to those of aspirin. However, it has only weak
anti-inflammatory effects and has been thought to have
a generally poor ability to inhibit COX in the presence of
high concentrations of peroxides as are found at sites of
inflammation.
• Daily dose, 1000 mg, results in roughly 50% inhibition
of both COX-1 and COX-2 in whole blood in healthy
volunteers.
• Recent evidence suggests that acetaminophen may
inhibit a third enzyme, COX-3, in the central nervous
system. COX-3 appears to be a splice variant product of
the COX-1 gene.
• No CNS, platelets, & uricosuric effects.
• No effects on acid-base balance
• ↓ GIT upset
Uses:
Although equivalent to aspirin as an effective analgesic and antipyretic agent, acetaminophen
differs in that it lacks anti-inflammatory properties.
• The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain, and
other circumstances in which aspirin is an effective analgesic.
• For mild analgesia, acetaminophen is the preferred drug in patients allergic to aspirin or when
salicylates are poorly tolerated.
• It is preferable to aspirin in patients with hemophilia or a history of peptic ulcer and in those in
whom bronchospasm is precipitated by aspirin.

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• Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents; it may be used
concomitantly with probenecid in the treatment of gout.
• It is preferred to aspirin in children with viral infections
Dosage:
Acute pain and fever may be effectively treated with 325-500 mg four times daily and
proportionately less for children.
Side effects:
• Mild doses:
In therapeutic doses, a mild increase in hepatic enzymes may occasionally occur in the absence of
jaundice; this is reversible when the drug is withdrawn.
• Larger doses:
CNS → dizziness, excitement, and disorientation are seen.
Hepatotoxicity → Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe
hepatotoxicity with centrilobular necrosis. Early symptoms of hepatic damage include nausea,
vomiting, diarrhea, and abdominal pain.
Nephrotoxicity → acute renal tubular necrosis → Cases of renal damage without hepatic damage
have occurred, even after usual doses of acetaminophen.
Blood → Hemolytic anemia and methemoglobinemia are very rare.
Contra-Indications:
• Alcoholism → Given with Cautions
• Any type of liver disease.
Overdose treatment:
• Antidote → N-acetylcysteine (NAC) which functions by detoxifying NAPQI. It is administered
orally within 8-10 hours after overdosing. NAC form complex with NAPQI (Contains sulfhydryl
group to which the toxic metabolite can bind) → excreted.
• Can also be removed from the body by hemodialysis or peritoneal dialysis.
• When damage occurred to the liver → Liver transplantation should be done.
GENERAL ANESTHESIA
Anesthesia is of two types;
• General
• Local
GENERAL ANESTHESIA:
“Induction of a state of unconsciousness with the absence of pain sensation over the entire body”.
So generally anesthesia having two main effects which are;
Unconsciousness
Inhibition of pain sensation
The physiologic states of general anesthesia typically includes analgesia, amnesia, loss of
consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation.
The extent to which any individual anesthetic drug can exert these effects depends upon,

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the drug
the dosage
& the clinical situation.
PURPOSE OF G.ANESTHESIA:
• To produce unconsciousness
• To relief pain → Analgesia
• Blocking of memory of the procedure → called amnesia.
• Inhibiting of the normal reflexes → to make the surgery safe.
• Relaxing the skeletal muscles.
PROPERTIES OF A GOOD ANESTHETIC:
• An ideal anesthetic drug would induce anesthesia smoothly and rapidly.
• Prompt/Quick recovery after its administration is discontinued.
• The drug would also possess a wide margin of safety and be devoid of adverse effects.
• Should produce complete relaxation of the skeletal muscles.
• Should be stable and non-inflammable.
No single anesthetic agent is capable of achieving all of these desirable effects without some
disadvantages when used alone, so thas why combo of inhaled & i/v anesthetics are used to obtain
these desirable properties.
STAGES OF ANESTHESIA:
There are mainly 4 stages of anesthesia, all of which can’t be seen because of proper selection and
combo of anesthetics.
• Stage-1:
Stage of analgesia
Patient feels initially analgesia which is followed by amnesia.
Starts from the beginning of anesthesia and lasts Upto the loss of consciousness.
Normal reflexes are there
Patient can conversant with the fellow and can hear.
Analgesic effects are produced b/c of inhibition sensory transmission in the spinothalamic
tract in the dorsal horn of spinal cord.
• Stage-2:
Stage of excitement and delirium
Onset of unconsciousness.
During this stage, the patient often appears to be delirious and excited but definitely is
amnesic.
Respiration is irregular both in volume and rate, and retching and vomiting may occur.
For these reasons, efforts are made to limit the duration and severity of this stage, which ends
with their establishment of regular breathing.
Cortical inhibitory centers are depressed before than the excitatory center i.e;
o Blockade of inhibitory
o Release of excitatory neurotransmitters
o The results will be;

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High reflexes of tone
High autonomic activities
More reflex vomiting
High respiratory pneumonia
High cardiac arrhythmia (vagal inhibition)
So thas why in modern anesthesia this stage is bypassed by the use short acting barbiturates.
• Stage-3:
Stage of surgical anesthesia
This stage begins with the recurrence of regular respiration and extends to complete
cessation of spontaneous respiration. Four planes of stage III have been described in terms of
changes in ocular movements, eye reflexes, and pupil size,& respiration, which under specified
conditions may represent signs of increasing depth of anesthesia.
o Plane-1:
Normal respiration
Constricted pupil
Roving/Pendular movement of the eyeball (b/c of effects on medulla)
Reflexes are abolished except corneal reflex
o Plane-2:
Respiration become shallow
Pupil size begin to dilate
Eyeballs become fixed
Loss of corneal reflex
No ocular movement
Skeletal muscles are relaxed
o Plane-3:
Respiration further depressed
Pupil size further dilated
Skeletal muscles are further relaxed
B.P decreased
All reflexes are absent
o Plane-4:
Medullary center begins to depress
Intercostal muscles paralyzed
Respiration shifted to abdominal muscles i.e further shallowed
B.P falls & H.R increase (reflex T.Cardia)
Pupil widely dilated
All reflexes are absent
Dangerous plane.
• Stage-4:
Stage of medullary depression.
This stage is never achieved otherwise will lead to death b/c of cessation of breathing and
failure of circulation.

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Medullary neurons are depressed b/c of high dose of anesthetic.
This stage occurs when center for breathing and other functions i.e Medulla cease to
function.
So this stage should never be reached and careful amount of anesthesia should be
administered to prevent this stage.
CLASSIFICATION OF GENERAL ANESTHETICS
Three types of drugs are used in general anesthesia which are;
Pre-anesthetic drugs
For induction
For maintenance
A) PRE-ANESTHETIC DRUGS:
1. Anti-cholinergic & H2 antagonists:
• For the prevention of secretions.
2. Benzodiazepines:
• For sedation and anxiolytic purpose.
3. Opioids:
• For pain.
4. Muscle relaxants:
• For muscle relaxation e.g Suxamethonium.
B) DRUGS FOR THE INDUCTION OF ANESTHESIA:
• Thiopental-Na
• Propofol
• paraldehyde
C) DRUGS FOR THE MAINTAINANCE OF ANESTHESIA:
For this purpose combo of inhalant & i/v anesthetics are used b/c none of this alone can
maintain well anesthesia.
1. Inhaled anesthetics:
a) Gases:
These are gases at room temp
• Nitrous oxide
• cyclopropane
b) Volatile liquids:
Halogenated agents;
• Halothane
• Isoflurane
• Enflurane
• Sevaflurane
• Desflurane
• Methoxyflurane
• Chloroform

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• Trichloroethylene
Ethers;
• Diethyl ether
• Divinyl ether
2. I/v anesthetics:
a) Barbiturates:
• Thiopental-Na
• Methohexital
b) BDZ:
• Diazepam
• Midazolam
• Lorazepam
c) Opioids:
• Opium
• Fentanyl
• Sofentanil
• Alfentanil
• Remifentanil
• Propofol
d) Miscellaneous:
• Ketamine
ANESTHETICS: HOW THEY WORK
Type Name(s) Administered Affect
General Halothane,
Enflurane
Isoflurane,
Ketamine,
Nitrous Oxide,
Thiopental
Intravenously,
Inhalation
Produces total
unconsciousness
affecting the entire
body
Regional Mepivacaine,
Chloroprocaine,
Lidocaine
Intravenously Temporarily inter-
rupts transmission
of nerve impulses
(temperature,
touch, pain) and
motor functions in
a large area to be
treated; does not

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P.k PROPERTIES OF INHALED ANESTHETICS:
These properties depend upon the following factors;
• Solubility or partition coefficient of anesthetic.
• Pulmonary ventilation rate.
• Pulmonary blood flow.
• Its concentration in the inspired air.
produce
unconsciousness
Local
Procaine,
Lidocaine,
Tetracaine,
Bupivacaine
Intravenously Temporarily blocks
transmission of
nerve impulses and
motor functions in
a specific area;
does not produce
unconsciousness
Topical Benzocaine
Lidocaine
Tetracaine
Demal
(Sprays,
Drope,
Ointments,
Creams, Gels)
Temporarily blocks
nerve endings in
skin and mucous
membranes; does
not produce
unconsciousness

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Tensions of three anesthetic gases in arterial blood as a function of time after beginning
inhalation. Nitrous oxide is relatively insoluble (blood: gas partition coefficient = 0.47);
methoxyflurane is much more soluble (coefficient = 12); and halothane is intermediate (2.3).
1) Solubility of anesthetic:
The blood-gas partition coefficient is a useful index of solubility and defines the relative affinity of
an anesthetic for the blood compared to air.
“Partition coefficient is the ratio of concentration of anesthetics in blood to the concentration in
gas”.
Partition coefficient = Anesthetic conc. in blood
Anesthetic conc. in gas
NO2 ↓ P.coefOicient ↓ solubility in blood ↑ P.Pressure ↑ induction.
Halothane ↑ P.coefOicient ↑ solubility in blood ↓ P.Pressure ↓ induction.
Methoxyflurane ↑↑ P.coefOicient ↑↑ solubility in blood ↓↓ P.Pressure ↓↓
induction.
The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in blood,
are extremely low. When an anesthetic with low blood solubility diffuses from the lung into the
arterial blood, relatively few molecules are required to raise its partial pressure, and therefore
the arterial tension rises rapidly.
There is inverse relation b/w Solubility(P.Coefficient) and P.Pressure
And Direct relation b/w P.Pressure & Induction.
Why induction of anesthesia is slower with more soluble anesthetic gases. In this schematic diagram,
solubility in blood is represented by the relative size of the blood compartment (the more soluble, the
larger the compartment). Relative partial pressures of the agents in the compartments are indicated by
the degree of filling of each compartment. For a given concentration or partial pressure of the two
anesthetic gases in the inspired air, it will take much longer for the blood partial pressure of the more
soluble gas (halothane) to rise to the same partial pressure as in the alveoli. Since the concentration of

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the anesthetic agent in the brain can rise no faster than the concentration in the blood, the onset of
anesthesia will be slower with halothane than with nitrous oxide.
2) Pulmonary ventilation rate:
The rate of rise of anesthetic gas tension in arterial blood is directly dependent on both the rate
and depth of ventilation (i.e, minute ventilation).
The magnitude of the effect varies according to the blood: gas partition coefficient.
An increase in pulmonary ventilation is accompanied by only a slight increase in arterial tension
of an anesthetic with low blood solubility or low coefficient but can significantly increase tension
of agents with moderate or high blood solubility (Figure below).
For example, a fourfold increase in ventilation rate almost doubles the arterial tension of
halothane during the first 10 minutes of anesthesia but increases the arterial tension of nitrous
oxide by only 15%.
Therefore, hyperventilation increases the speed of induction of anesthesia with inhaled
anesthetics that would normally have a slow onset.
Depression of respiration by opioid analgesics will slow the onset of anesthesia of some inhaled
anesthetics if ventilation is not assisted.
Ventilation rate and arterial anesthetic tensions. Increased ventilation (8 versus 2 L/min) has
a much greater effect on equilibration of halothane than nitrous oxide.
3) Pulmonary blood flow:
Changes in blood flow to and from the lungs influence transfer processes of the anesthetic gases.

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An increase in pulmonary blood flow (increased cardiac output) slows the rate of rise in arterial
tension, particularly for those anesthetics with moderate to high blood solubility. This is because
increased pulmonary blood flow exposes a larger volume of blood to the anesthetic; thus, blood
"capacity" increases and the anesthetic tension rises slowly.
A decrease in pulmonary blood flow has the opposite effect and increases the rate of rise of
arterial tension of inhaled anesthetics in a patient with circulatory shock, the combined effects of
decreased cardiac output (resulting in decreased pulmonary flow) and increased ventilation will
accelerate the induction of anesthesia with halothane and isoflurane. This is not likely to occur
with nitrous oxide, desflurane, or sevoflurane because of their low blood solubility.
4) Conc. in inspired air:
Increases in the inspired anesthetic concentration will increase the rate of induction of
anesthesia by increasing the rate of transfer into the blood according to Fick's law.
That is, simply if the concentration in the inspired air is more/ high then rapid will be the onset
of anesthesia and vice versa.
The concentration of an individual gas in a mixture of gases is proportionate to its partial
pressure or tension. These terms are often used interchangeably in discussing the various transfer
processes of anesthetic gases in the body. Achievement of a brain concentration of an inhaled
anesthetic adequate to cause anesthesia requires transfer of that anesthetic from the alveolar air
to blood and then to brain. The rate at which a given concentration of anesthetic in the brain is
reached depends on the solubility properties of the anesthetic, its concentration in the inspired
air, pulmonary ventilation rate, pulmonary blood flow, and the partial pressure gradient of the
anesthetic between arterial and mixed venous blood.
Similarly Cerebral blood flow ↑ → Quick onset & recovery.
Alveolar exchange ↑ → Quick onset & recovery, and vice versa.
5) Recovery:
The time to recovery from inhalation anesthesia depends on the rate of elimination of anesthetics
from the brain after the inspired concentration of anesthetic has been decreased.
Many of the processes of anesthetic transfer during recovery are similar to those that occur
during induction of anesthesia.
The blood: gas partition coefficient/ solubility of the anesthetic agent.
The pulmonary blood flow, the magnitude of ventilation.
Duration of administration of anesthesia also prolong the anesthesia.
Accumulation of anesthetics in skeletal muscles, brain, adipose tissues etc
If exposure is low, rapid will be the recovery and vice versa.
Alveolar exchange etc.
6) Elimination:
Inhaled anesthetics that are relatively insoluble in blood (low blood: gas partition coefficient) and
brain are eliminated at faster rates than more soluble anesthetics.
Clearance of inhaled anesthetics by the lungs into the expired air is the major route of their
elimination from the body. However, metabolism by enzymes of the liver and other tissues ma also
contribute to the elimination of volatile anesthetics. For example, the elimination of halothane

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during recovery is more rapid than that of enflurane, which
would not be predicted from their respective solubilities.
MECHANISM OF ACTION OF G.ANESTHETICS:
The inhaled anesthetics, and most of the intravenous agents
depress spontaneous and evoked activity of neurons in many
regions of the brain.
There are two types of mechanisms:
Cellular mechanism:
Molecular mechanism:
A) CELLULAR MECHANISM
• Older concepts of the mechanism of anesthesia, evoked by
nonspecific interactions of these agents with the lipid matrix
of the nerve membrane (the Meyer-Overton principle)
interactions that were thought to lead to secondary changes
in ion flux.
• Recently, evidence has accumulated, suggesting that the
modification of ion currents by anesthetics results from more
specific interactions with nerve membrane components. The
ionic mechanisms involved for different anesthetics may vary,
but at clinically relevant concentrations they appear to
involve interactions with members of the ligand-gated ion
channel family.
General anesthetics produce two important physiologic effects
at the cellular level.
First, the inhalational anesthetics can hyperpolarize neurons .
Second, at anesthetizing concentrations, both have
substantial effects on synaptic transmission and much smaller
effects on action-potential generation or propagation.
B) MOLECULAR MECHANISM:
• It is the more recent concept.
There is strong evidence that ligand-gated ion channels are
important targets for anesthetic action.
Chloride channels gated by the inhibitory GABAA receptors (GABAA receptor-chloride channel) are
sensitive to clinical concentrations of a wide variety of anesthetics.
Halogenated inhalational agents and many intravenous agents such a Propofol, barbiturates,
etomidate, and neurosteroids acts through this mechanism.
Anesthetic molecules do not interact directly with the GABA binding site but with specific sites in
the transmembrane domains of both αααα and ββββ subunits.
This causes a prolongation of the inhibitory chloride ion current after a pulse of GABA release.
Postsynaptic neuronal excitability is thus diminished.
C) OTHER MECHANISMS:

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Inhaled anesthetics have been reported to cause membrane hyperpolarization (an inhibitory
action) via their activation of ligand-gated potassium channels. These channels are ubiquitous in
the central nervous system and are linked to several neurotransmitters, including acetylcholine,
dopamine, norepinephrine, and serotonin.
Ketamine does not produce its effects via facilitation of GABAA receptor functions, but it may
function via antagonism of the action of the excitatory neurotransmitter, glutamic acid on the
NMDA receptor.
ORGAN SYSTEM EFFECTS:
1) CVS:
The most prominent physiological effect of anesthesia induction is a decrease in systemic arterial
blood pressure. The causes includes,
• Direct vasodilatation,
• Myocardial depression,
• A blunting of baroreceptor control,
• And a generalized decrease in central sympathetic tone.
Heart effects:
↓ H.R ↓ CO this is due to alteration of sinus node activity and blunting of baroreceptor
control.
With halothane and enflurane, the reduced arterial pressure appears to be caused by a reduction
in cardiac output……
Peripheral resistance:
This is due to shift of the autonomic balance, i.e ↑ p. sympathetic activity through vagal tone
shifting and ↓ sympathetic activity.
Isoflurane, desflurane, and sevoflurane have a depressant effect on arterial pressure as a result of
a decrease in systemic vascular resistance with minimal effect on cardiac output.
So in general Halothane and enflurane has got ↑ CVS depressant activity than isoflurane,
desflurane and sevoflurane etc.
Nitrous oxide also depresses CVS activity but upto a limited extent.
Certain factors influence the CVS effects are;
→ surgical stimulus
→ volume status
→ duration status
→ ventilating status
With the use of anesthetic CO2 level ↑ (called Hypercapnia) → causes ↑ release of the
catecholamines which in turn ↑ B.P.
Halothane upto a lesser extent sensitize the myocardial tissues towards catecholamine → ↑ effect
will there on the heart → ↑ B.P.
2) RESPIRATORY SYSTEM:
With the exception of nitrous oxide, all inhaled anesthetics in current use cause a dose dependent
decrease in tidal volume and an increase in respiratory rate. However, the increase in rate is
insufficient to compensate for the decrease in volume, resulting, a decrease in minute ventilation.

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All inhaled anesthetics are respiratory depressants, as indicated by a reduced response to
increased levels of carbon dioxide.
Inhaled anesthetics increase the apneic level for the CO2 below which apnea occurs (through lack
of CO2-driven respiratory stimulation) and decrease the ventilatory response to hypoxia.
Depression is vary depending on the volatile nature of the anesthetic. To prevent respiratory
depression, mechanical ventilation is used.
Inhaled anesthetics also depress mucociliary function in the airway. Thus, prolonged anesthesia
may lead to pooling of mucus and then result in atelectasis and postoperative respiratory
infections.
However, inhaled anesthetics tend to be bronchodilators, an effect of value in the treatment of
status asthmaticus. The bronchodilating action of halothane and sevoflurane makes them the
induction agents of choice in patients with underlying airway problems.
Airway irritation, which may provoke coughing or breath holding, is rarely a problem with most
inhaled anesthetics (especially with desflurane).
3) KIDNEY:
Inhaled anesthetics decrease glomerular filtration rate and effective renal plasma flow and
increase filtration fraction.
All anesthetics tend to increase renal vascular resistance.
4) LIVER:
All volatile anesthetics cause a decrease in hepatic blood flow, ranging from 15% to 45% of the
preanesthetic flow rate.
Halothane causes hepatotoxicity
5) BRAIN:
Inhaled anesthetics decrease the metabolic rate of the brain.
Nevertheless, most volatile agents increase cerebral blood flow because they decrease cerebral
vascular resistance. The increase in cerebral blood flow is often clinically undesirable. For
example, in patients who have an increased intracranial pressure because of a brain tumor or
head injury, administration of a volatile anesthetic may increase cerebral blood flow, which in
turn will increase cerebral blood volume and further increase intracranial pressure.
Of the inhaled anesthetics, nitrous oxide increases cerebral blood flow the least.
6) REPRODUCTIVE SYSTEM:
Causes abortion.
The risk of abortion is clearly higher following this experience. It is not obvious whether the
underlying disease, surgery, anesthesia, or a combination of these factors is the cause of the
increased risk
TOXICITY:
1) HEPATOTOXICITY:
Hepatotoxicity mainly occurs with halothane.
Postoperative hepatic dysfunction is usually associated with factors such as blood transfusions,
hypovolemic shock, and other surgical stresses rather than anesthetic toxicity.

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The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in
animals have implicated the formation of reactive metabolites that either cause direct
hepatocellular damage (e.g, free radical intermediates) or initiate immune-mediated responses.
2) NEPHROTOXICITY:
Metabolism of enflurane and sevoflurane leads to the formation of fluoride ions which causes the
Nephrotoxicity.
3) MALIGNANT HYPERTHERMIA:
Malignant hyperthermia is an autosomal dominant genetic disorder of skeletal muscle that
occurs in susceptible individuals undergoing general anesthesia with inhaled agents and muscle
relaxants characterized by,
o Rapid onset of tachycardia and hypertension,
o Severe muscle rigidity,
o Hyperthermia,
o Hyperkalemia,
o And acid-base imbalance with acidosis, following exposure to a triggering agent.
Malignant hyperthermia is a rare but important cause of anesthetic morbidity and mortality.
The specific biochemical abnormality is an increase in free calcium concentration in skeletal
muscle cells.
Treatment includes administration of dantrolene (which prevents calcium release from the
sarcoplasmic reticulum) and appropriate measures to reduce body temperature and restore
electrolyte and acid-base balance.
4) HEMATOTOXICITY:
Prolonged exposure to nitrous oxide decreases methionine synthase activity and causes
megaloblastic anemia.
Under normal conditions, most modern and many older inhaled anesthetics are neither mutagens
nor carcinogens.
MAC-Measurement Of Anesthetic Potency
(Min Alveolar Conc.)
For inhalational anesthetics, anesthetic potency is measured in MAC units, with 1 MAC defined as
the minimum alveolar concentration that prevents movement in response to surgical stimulation
in 50% of subjects.
The potency of intravenous agents is defined as the free plasma concentration (at equilibrium)
that produces loss of response to surgical incision (or other end points) in 50% of subjects
1) INTRODUCTION:
HALOTHANE

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• This agent is the prototype
• Halothane (FLUOTHANE) is a volatile liquid at room temperature.
• Because halothane is light-sensitive and subject to spontaneous breakdown, it is marketed in
amber bottles with thymol added as a preservative.
When halothane was introduced, its ability to induce the anesthetic state rapidly and to allow
quick recovery and the fact that it was nonexplosive made it an anesthetic of choice.
2) P.K:
• Halothane has a relatively high blood:gas partition coefficient and high fat:blood partition
coefficient. Induction with halothane therefore is relatively slow.
• Because halothane is soluble in fat and other body tissues, it will accumulate during prolonged
administration. Therefore, the speed of recovery from halothane is lengthened as a function of
duration of administration.
• Trifluoroacetic acid, bromine, and chlorine all can be detected in the urine.
Trifluoroacetylchloride, an intermediate in oxidative metabolism of halothane, can
trifluoroacetylate several proteins in the liver. An immune reaction to these altered proteins
may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis
• Approximately 60% to 80% of halothane taken up by the body is eliminated unchanged via the
lungs in the first 24 hours after its administration → approximately 1% of halothane
metabolized.
3) CLINICAL USE:
Halothane, introduced in 1956, was the first of the modern, halogenated inhalational
anesthetics used in clinical practice
• used for maintenance of anesthesia.
• It is not pungent and is therefore well tolerated for inhalation induction of anesthesia.
• This is most commonly done in children, in whom preoperative placement of an intravenous
catheter can be difficult.
• Replaced by newer agents → newer inhalational agents with better pharmacokinetic and side-
effect profiles.
4) SIDE EFFEDTS:
Cardiovascular System.
Respiratory System.
Malignant hyperthermia:
Hepatotoxicity.
• Low volatility
• Can’t be used for induction.
• This halogenated anesthetic is widely used.
Isoflurane

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• It is a very stable molecule that undergoes little metabolism; as a result, little fluoride is produced.
• Isoflurane is not tissue toxic.
• Unlike the other halogenated anesthetic gases, isoflurane does not induce cardiac arrhythmias and
does not sensitize the heart to the action of catecholamines.
• However, it produces concentration-dependent hypotension due to peripheral vasodilation.
• It also dilates the coronary vasculature, increasing coronary blood flow and oxygen consumption by
the myocardium. This property may make it beneficial in patients with ischemic heart disease.
• Sevoflurane has low pungency, allowing rapid uptake without irritating the airway during induction,
thus making it suitable for induction in children. It has replaced halothane for this purpose.
• Smooth induction.
• The drug has low solubility in blood and is rapidly taken up and excreted.
• Recovery is faster than with other anesthetics.
• It is metabolized by the liver, releasing fluoride ions; thus, like enflurane, it may prove to be
nephrotoxic.
LOCAL ANESTHETICS
DEFINITION:
“Local anesthetic blocks reversibly the conduction of sodium along the nerve axons or other
excitable membrane, utilizing the sodium channel as a primary mean of potential generation
(impulse generation).”
Local anesthetics bind reversibly to a specific receptor site within the pore of the Na+
channels in nerves
and block ion movement through this pore.
HISTORY:
Cocaine, the first such agent, was isolated by Niemann in 1860.
It was introduced into clinical use by Koller in 1884 as an ophthalmic anesthetic. Cocaine was soon
found to be strongly addicting but was widely used, for 30 years, since it was the only local anesthetic
drug available.
In an attempt to improve the properties of cocaine, Einhorn in 1905 synthesized procaine, which became
the dominant local anesthetic for the next 50 years.
Since 1905, many local anesthetic agents have been synthesized. The goals of these efforts were
Reduction of local irritation and tissue damage,
Minimization of systemic toxicity,
Faster onset of action,
And longer duration of action.
Lidocaine, still a popular agent, was synthesized in 1943 by Löfgren and may be considered the
prototype local anesthetic agent.
PROPERTIES OF A GOOD L.ANESTHETIC:
None of the currently available local anesthetics are ideal, and development of newer agents is still
continued.
Sevoflurane

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However, while it is relatively easy to synthesize a chemical with local anesthetic effects, it is very
difficult to reduce the toxicity significantly below that of the current agents. The major reason for this
difficulty is the fact that the much of the serious toxicity of local anesthetics represents extensions of the
therapeutic effect on the brain and the circulatory system.
Less/ No irritation.
Long duration of action.
Rapid onset of action.
Should have no systemic toxicity.
CHEMICAL STRUCTURE:
Most local anesthetic agents consist of a,
Aromatic ring → lipophilic
Ester or amide linkage (connects lipophilic & hydrophilic parts)
An ionizable group( usually tertiary amine) → hydrophilic
Ester/amide
In addition to the general physical properties of the molecules, specific stereochemical configurations
are associated with differences in the potency of stereoisomers for a few compounds, e.g, bupivacaine,
ropivacaine. Since ester links (as in procaine) are more prone to hydrolysis than amide links, esters
usually have a shorter duration of action.
CLASSIFICATION:
A) BASED ON CHEMISTRY:
I. Ester derivatives:
• Cocaine
• Procaine
• Tetracaine
• Benzocaine
II. Amide derivatives:
• Lidocaine
• Prilocaine
• Bupivacaine
• Mepivacaine
• Etidocaine
B) BASED ON DURATION/ONSET OF ACTION:
I. Short acting:
• Procaine → 60-90mins (duration) → slow (onset)
• Chlorprocaine → 30-60 mins → rapid
II. Intermediate acting:
• Mepivacaine → 120-240mins → fast
• Prilocaine → 120-240mins → fast
• Lidocaine → 90-200mins → fast
Lipophilic group Hydrophilic group

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III. Long acting:
• Tetracaine → 180-600mins → slow
• Bupivacaine → 180-600mins → intermediate
• Etidocaine → 180-600mins → fast
The onset of local anesthesia can be accelerated by the use of solutions saturated with carbon
dioxide ("carbonated"). The high tissue level of CO2 results in intracellular acidosis (CO2 crosses
membranes readily), which in turn results in intracellular accumulation of the cationic form of the
local anesthetic.
The anesthetic effect of the agents with short and intermediate durations of action can be prolonged
by increasing the dose or by adding a vasoconstrictor agent (eg, epinephrine or phenylephrine).
MECHANISM:
All local anesthetics are membrane stabilizer; they reversibly decrease the depolarization and
repolarization of excitable membranes.
Block the initiation & propagation of action potential by preventing the voltage dependent increase
in Na+
conductance.
Local anesthetic activity is also highly effected by pH, b/c of basic nature & non-ionize form (local
anesthetic high pH ie basic pH) → ↑ lipid soluble → cross axonal membrane → block the sodium
channel by combining to the inner side of membrane.
Local anesthetics may also block nicotinic channels in the spinal cord.
Acidosis such as caused by inflammation partly reduces action of local anesthetic. This is because
most anesthetics are ionized & therefore unable to cross the membrane to reach to its site of
action.
FACTORS EFFECTING LOCAL ANESTHETICS:
Hydrophobicity increases both the potency and the duration of action of the local anesthetics
because association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites
of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes.
Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more
hydrophobic drugs.
Molecular size influences the rate of dissociation of local anesthetics from their receptor sites.
Smaller drug molecules can escape from the receptor site more rapidly. This characteristic is
important in rapidly firing cells, in which local anesthetics bind during action potentials and
dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during
action potentials causes the frequency- and voltage-dependence of their action.
ADVERSE EFFECTS:
1. CNS:
Following absorption, local anesthetics may cause,
CNS) stimulation → due to suppression of inhibitory neurons,
Is followed by depression; death usually is caused by respiratory failure. Airway control and
ventilatory support are essential features of treatment in the late stage of intoxication.
Producing restlessness and tremor → that may progress to clonic convulsions.
In general ↑ potent the anesthetic → ↑ convulsions may be produced.

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Drowsiness is the most frequent complaint that results from the CNS actions of local anesthetics,
Lidocaine may produce dysphoria or euphoria and muscle twitching.
Both Lidocaine + procaine → loss of consciousness that is preceded only by symptoms of
sedation.
Cocaine has a particularly prominent effect on mood and behavior.
Benzodiazepines or rapidly acting barbiturates administered intravenously are the drugs of
choice for both the prevention and arrest of convulsions.
Alterations of CNS activity are thus predictable from the local anesthetic agent in question and the
blood concentration achieved
2. CVS:
Myocardial depression → Due to Na+
channel blockade → ↓ intracellular Ca+
level → ↓
myocardial muscles activity.
Arteriolar dilation →
o Direct vasodilator action on B.vessels.
o ↓ Sympathetic system activity → vasodilation.
Leading to severe ↓ in BP which is sudden & life threatening.
Local anesthetics decrease electrical excitability, conduction rate, and force of contraction.
Untoward cardiovascular effects usually are seen only after high systemic concentrations are
attained and effects on the CNS are produced.
Lower doses of some local anesthetics will cause cardiovascular collapse and death, probably
due to either an action on the pacemaker or the sudden onset of ventricular fibrillation.
Ventricular tachycardia and fibrillation are relatively uncommon.
3. NEUROTOXICITY:
When applied at excessively high concentrations, all local anesthetics can be toxic to nerve
tissue.
Chlorprocaine and Lidocaine appear to be more neurotoxic than other local anesthetics when
used for spinal anesthesia, producing so-called transient radicular irritation. It has been
suggested that this toxicity results from pooling of high concentrations of the local anesthetic in
the cauda equina.
Although the mechanism of this neurotoxic action has not been established, both interference with
axonal transport and disruption of calcium homeostasis have been shown to occur and could be
responsible. Spinal neurotoxicity does not result from excessive sodium channel blockade.
4. HEMATOLOGIC EFFECTS:
The administration of large doses (> 10 mg/kg) of Prilocaine during regional anesthesia may lead
to,
Accumulation of the metabolite o-toluidine, an oxidizing agent capable of converting hemoglobin
to methemoglobin → methemoglobinemia.
The treatment of methemoglobinemia involves the intravenous administration of reducing agents
(eg, methylene blue or ascorbic acid), which rapidly convert methemoglobin to hemoglobin.
5. HYPERSENSITIVITY:
Rare individuals are hypersensitive to local anesthetics,
Displaying allergic dermatitis or
A typical asthmatic attack.
It is important to distinguish allergic reactions from toxic side effects and from effects of
coadministered vasoconstrictors.

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Hypersensitivity seems to occur more frequently with local anesthetics of the ester type and
frequently extends to chemically related compounds.
Local anesthetic preparations containing a vasoconstrictor also may elicit allergic responses
due to the sulfite added as an antioxidant.
Sedative & Hypnotics
(Anxiolytic & Hypnotic)
Introduction:
• A sedative drug decreases activity, moderates excitement, and calms the recipient. An effective
sedative (anxiolytic) agent should reduce anxiety and exert a calming effect
• A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state
of sleep. Hypnotic effects involve more pronounced depression of the central nervous system than
sedation, and this can be achieved with many drugs in this class simply by increasing the dose.
Anxiety:
Anxiety is a physiological & psychological state characterized by somatic, emotional, cognitive &
behavioral commutative functions.
Symptoms:
Anxiety can create,
Worry
Fear
Dread (Extreme fear)
Uneasiness
Clinical conditions:
Clinical condition related to anxiety include,
Phobic anxiety &
Panic anxiety.
Phobic anxiety → Triggered by social interactions e.g. by looking to something like spider,
cockroach, looking in open space, travelling in train etc.
While in panic disorder attacks of over-welling fear occur in association with somatic symptoms
such as sweating, tachycardia, fear, tremors, etc → all these b/c of hormonal release.
Sedation refers to decreased responsiveness to any level of stimulation; is associated with some
decrease in motor activity and ideation.

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Graded dose-dependent depression of central nervous system function is a characteristic of most
sedative-hypnotics.
Dose-response curves for two hypothetical sedative-hypnotics.
The linear slope for drug A is typical of many of the older sedative-hypnotics, including the
barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis
may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress
respiratory and vasomotor centers in the medulla, leading to coma and death.
Deviations from a linear dose-response relationship, as shown for drug B, require proportionately
greater dosage increments to achieve central nervous system depression more profound than
hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have
a similar mechanism of action.
Sedative-hypnotic drugs depress the CNS in a dose-dependent fashion,
Producing calming or drowsiness (sedation) → sleep (pharmacological hypnosis) → unconsciousness
→ coma → surgical anesthesia →and fatal depression of respiration and cardiovascular regulation
Hypnotic drug → at ↓ doses → produce sedation.
Sedative Drug → at ↑ doses → produce hypnosis.
There is no sharp difference b/w sedatives & hypnotics.
→ Sedative produce calmness in anxious & restless person along with sleep (no normal sleep) with no
effect on the normal person.
→ Hypnotics can easily produce sleep which resembling the normal sleep.
Classification:
I. Barbiturates:
Further divided on duration basis
A) Long acting:
Barbitone

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Phenobarbitone
D-O-A → ↑ than 6 hours
B) Medium acting:
Amilobarbitone
Butobarbitone
Cyclobarbitone
Secobarbitone
Pentobarbitone
D-O-A → ↑ than 3 & ↓ than 6 hours
C) Short acting:
Quinolbarbitone
Aprobarbitone
D-O-A → ↓ than 3 hours
D) Ultra-short acting:
Thiopental
Methohexital
Thiomylol
D-O-A → 20-30 minutes
Used as anesthetics (for induction)
II. Benzodiazepines:
A) Ultra short acting:
Triazolam → as hypnotic
Midazolam → as pre-anesthetic
D-O-A → less than 6 hours
B) Short acting:
Lorazepam (Ativan®)
Oxazepam
Temazepam
Lometazepam
Bromazepam → commonly used
D-O-A → 12-18hours
C) Medium acting:
Alprazolam
Nitrazepam
D-O-A → 24 hours
Manly used as anxiolytic and hypnotic
D) Long acting:
Diazepam
Chlordiazepoxide → used in alcohol withdrawal also
Flurazepam
Clonazepam → antidepressant & Anticonvulsant (no active metabolite)
D-O-A → 24-48 hours

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III. 5-HT31A receptor agonist:
Buspirone
Anxiolytic & Non-sedative
IV. Β-Blockers:
Propranolol
V. Miscellaneous:
Antihistaminic drug → Diphenhydramine
Meprobamate
Paraldehyde
Chloral hydrate
Barbiturates
Introduction:
These are Barbituric acid derivatives.
Today, they have been largely replaced by the benzodiazepines → primarily because barbiturates
induce tolerance physical dependence, and are associated with very severe withdrawal symptoms,
foremost is their ability to cause coma in toxic doses.
Certain barbiturates, such as the very short-acting thiopental, are still used to induce anesthesia.
History:
In 1903 Barbitone introduced into the market & were used for sleep → sleeping pill.
1912 → phenobarbitone-Na for sleep inducing & Epilepsy.
Now upto 2500 different derivatives are developed.
Chemistry:
Barbituric acid is 2, 4, 6-trioxohexahydropyrimidine. This compound lacks central depressant
activity, but the presence of alkyl or aryl groups at position 5 confers sedative-hypnotic and
sometimes other activities.
P-K:
• Barbiturates are well absorbed from the GIT.
• They are widely distributed in the body.
• The rate of entry into CNS is dependent on lipid solubility.
o Highly-lipid soluble thiopentone
o Less lipid-soluble ones pentobarbitone
Hypnotic Antianxiety Anticonvulsant
Diazepam
Flurazepam
Nitrazepam
Alprazolam
Temazepam
Triazolam
Diazepam
Chlordiazepoxide
Oxazepam
Lorazepam
Alprazolam
Diazepam
Lorazepam
Clonazepam

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o Very less lipid soluble Phenobarbitone
• Plasma protein binding varies with the compound, e.g. thiopentone 75%, phenobarbitone 20%.
• Barbiturates cross placenta and are secreted in milk can produce effects on the foetus and
suckling infant.
• significantly excreted unchanged in urine.
Sites & Mechanism Of Action:
Barbiturates act throughout the CNS & has got no selectivity like BDZ. That’s why it develops
anesthetic effects & coma.
Non-anesthetic doses preferentially suppress polysynaptic responses. Facilitation is diminished, and
inhibition usually is enhanced.
Sites:
Presynaptic → Higher centers of brain
Postsynaptic → in spinal cord
The sedative-hypnotic action of the barbiturates is due to their interaction with GABAA receptors,
which enhances GABAergic transmission. The binding site is distinct from that of the
benzodiazepines. Barbiturates potentiate GABA action on chloride entry into the neuron by
prolonging the duration of the chloride channel openings.
In addition, barbiturates can block excitatory glutamate receptors.
Depress voltage gated Ca++ Thas why also used in epilepsy.
Anesthetic concentrations of pentobarbital also block high-frequency sodium channels.
voltage-dependent K+ conductances are reduced
All of these molecular actions lead to decreased neuronal activity.
Barbiturates also enhance the binding of GABA to GABAA receptors in a chloride-dependent
Barbiturates potentiate GABA-induced chloride currents by prolonging periods during which
bursts of channel opening occur rather than by increasing the frequency of these bursts, as
benzodiazepines do
Only α and β(not Gamma) sub-units are required for barbiturate action
Barbiturate-induced increases in chloride conductance are not affected by the deletion of the
tyrosine and threonine residues in the subunit that govern the sensitivity of GABAA receptors to
activation by agonists
Barbiturates BDZ (Benzodiazepines)
• ↑ duration of Cl- ion channel opening
• Generalized effect
• Exert also non-synaptic membrane effect
• ↑ pronounce central effect
• GABA-mimetic action
• ↑ frequency of channel opening
• Selective effect
• On synaptic membranes having BDZ
receptors
• Central effects are ↓ than Barbiturates.
• Having specific BDZ receptors.

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A model of the GABAA receptor-chloride ion. GABA appears to interact with or subunits triggering chloride
channel opening with resultant membrane hyperpolarization.
Pharmalogical Effects:
o CNS effects
o Peripheral nervous system
o Other Peripheral effects
A) CNS Effects:
The barbiturates can produce all degrees of depression of the CNS, ranging from mild sedation to
general anesthesia.
The anti-anxiety properties of the barbiturates are inferior to those exerted by the benzodiazepines.
Except for the anticonvulsant activities of Phenobarbital and its congeners, the barbiturates possess
a low degree of selectivity and therapeutic index. Thus, it is not possible to achieve a desired effect
without evidence of general depression of the CNS.
Pain perception and reaction are relatively unimpaired until the moment of unconsciousness, and in
small doses, the barbiturates increase the reaction to painful stimuli. Hence they cannot be relied on
to produce sedation or sleep in the presence of even moderate pain.
Barbiturates produce dose-dependent effects:
sedation → sleep → anesthesia → coma.
• Effects on Stages of Sleep
Hypnotic doses of barbiturates increase the total sleep time and alter the stages of sleep in a dose-
dependent manner.
Like the benzodiazepines, these drugs decrease sleep latency, the number of awakenings, and the
durations of REM and slow-wave sleep.
During repetitive nightly administration, some tolerance to the effects on sleep occurs within a few
days, and the effect on total sleep time may be reduced by as much as 50% after 2 weeks of use.

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Stages of sleep.
Stage-0 (awake)
From lying down to falling asleep and occasional nocturnal awakenings; constitutes 1-2% of sleep
time. Eye movement are irregular or slowly rolling
Stage 1 (dozing)
Eye movements are reduced but there may be less rolling.
Neck muscles relax. Occupies 3-6% of sleep time.
Stage 2 (unequivocal sleep)
little eye movement, subject arousable. This comprises 40-50% of sleep time.
Stage 3 (deep sleep transition)
Eye movements are few; subjects are not arousable; comprises 5-8% of sleep time.
Stage 4(cerebral sleep)
Eyes are practically fixed; Subjects are difficult to arouse. Night terror may occur at this time. It
comprises 10-20% of sleep time.
During stage 2, 3 and 4 heart rate, BP and respiration are steady, and muscles are relaxed. Stages 3
and 4 together called Slow Wave Sleep (SWS).
Two major phases:
• REM sleep (Rapid eye movement sleep).
• NREM sleep (Non Rapid Eye Movement sleep).
REM(Paradoxical sleep) occur in cycles at an interval of 80-90 minutes. The REM sleep cause 20-25%
of the total sleep.
In this Phase the HR is ↑, irregular breathing, ↑ secretions, muscle tone is ↑, neurotransmitter
secretion is also ↑.
NREM 75-80% of the total sleep. The greater proportion and time has got by this phase.
In case of barbiturates REM and stage 3, 4 sleep are decreased; REM-NREM sleep cycle is disrupted.
B) Peripheral nervous system:
• Barbiturates selectively depress transmission in autonomic ganglia and reduce nicotinic excitation
by choline esters. This effect may account for the fall in blood pressure produced by intravenous
oxybarbiturates and by severe barbiturate intoxication.
• At skeletal neuromuscular junctions, the blocking effects of both tubocurarine and decamethonium
are enhanced during barbiturate anesthesia. These actions probably result from the capacity of
barbiturates at hypnotic or anesthetic concentrations to inhibit the passage of current through
nicotinic cholinergic receptors.
C) Other Peripheral effects:
CVS
• Hypnotic doses of barbiturates produce a slight decrease in BP and heart rate: magnitude of change
not differing from that during normal sleep.
• Toxic doses produce marked fall in BP due to ganglionic blockade, vasomotor centre depression and
direct decrease in cardiac contractility.
• Reflex tachycardia can occur, though pressor reflexes are depressed.

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• However, the dose producing cardiac arrest is about 3 times larger than that causing respiratory
failure.
Respiratory
• Barbiturates depress both the respiratory drive and the mechanisms responsible for the rhythmic
character of respiration. The neurogenic drive is diminished by hypnotic doses but usually no more so
than during natural sleep.
• The barbiturates only slightly depress protective reflexes until the degree of intoxication is sufficient
to produce severe respiratory depression.
• Coughing, sneezing, hiccoughing, and laryngospasm may occur when barbiturates are employed as
intravenous anesthetic agents. Indeed, laryngospasm is one of the chief complications of barbiturate
anesthesia.
GIT
• The oxybarbiturates tend to decrease the tone of the gastrointestinal musculature and the amplitude
of rhythmic contractions → constipation.
• The locus of action is partly peripheral and partly central, depending on the dose.
Liver
The best known effects of barbiturates on the liver are those on the microsomal drug-metabolizing
system. Acutely, the barbiturates combine with several CYPs and inhibit the biotransformation of a
number of other drugs and endogenous substrates, such as steroids, other substrates may
reciprocally inhibit barbiturate biotransformations.
Kidney
Barbiturates tend to reduce urine flow by decreasing BP and increasing ADH release. Oliguria
attends barbiturate intoxication.
Therapeutic uses
Anesthesia:
Selection of a barbiturate is strongly influenced by the desired duration of action. The
ultrashortacting barbiturates, such as thiopental, are used intravenously to induce anesthesia.
Anticonvulsant:
Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, and
eclampsia. Phenobarbital has been regarded as the drug of choice for treatment of young children
with recurrent febrile seizures. However, phenobarbital can depress cognitive performance in
children, and the drug should be used cautiously. Phenobarbital has specific anticonvulsant activity
that is distinguished from the nonspecific CNS depression.
Anxiety:
Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia.
When used as hypnotics, they suppress REM sleep more than other stages. However, most have been
replaced by the benzodiazepines.
Side effects:
CNS:
Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness.
The CNS depressant effects of barbiturates synergize with those of ethanol.
Drug hangover:

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Hypnotic doses of barbiturates produce a feeling of tiredness
well after the patient wakes. This drug hangover may lead to
impaired ability to function normally for many hours after
waking. Occasionally, nausea and dizziness occur.
Liver:
As noted previously, barbiturates induce the P450 system and,
therefore, may decrease the duration of action of drugs that
are metabolized by these hepatic enzymes. Barbiturates
increase porphyrin synthesis, and are contraindicated in
patients with acute intermittent porphyria.
Physical dependence:
Abrupt withdrawal from barbiturates may cause tremors,
anxiety, weakness, restlessness,
nausea and vomiting, seizures, delirium, and cardiac arrest.
Withdrawal is much more severe than that associated with
opiates and can result in death.
Poisoning:
Barbiturate poisoning has been a leading cause of death resulting
from drug overdoses for many decades.
Severe depression of respiration is coupled with central
cardiovascular depression, and results in a shock-like condition
with shallow, infrequent breathing.
• Treatment includes artificial respiration and purging the
stomach of its contents if the drug has been recently taken. No
specific barbiturate antagonist is available.
Hemodialysis may be necessary If large quantities have been
taken. Alkalinization of the urine often aids in the elimination
of Phenobarbital .
Benzodiazepines
Introduction:
• Benzodiazepines are the most widely used anxiolytic drugs.
• They have largely replaced barbiturates and Meprobamate in the treatment of anxiety, because
the benzodiazepines are safer and more effective.
• high therapeutic index.
• Causes less distortion of sleep
• Hypnotic doses do not affect respiration or cardiovascular functions
History:

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• In the middle of the nineteenth century, bromide was the first agent to be introduced specifically
as a sedative-hypnotic.
• Barbital in 1903 and phenobarbital in 1912.
• The barbiturates were so dominant that less than a dozen other sedative-hypnotics were
marketed successfully before 1960.
• Chlordiazepoxide and diazepam were introduced round 1960 as antianxiety drugs.
Chemistry:
• The term benzodiazepine refers to the portion of the structure composed of
o A benzene ring
o Fused to a seven-membered diazepine ring
o And a 5-aryl substituent
P-K:
Absorption
• The benzodiazepines are lipophilic, and they are rapidly and completely absorbed
• after oral administration and distribute throughout the body.
• Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by
acid hydrolysis in the stomach.
Distribution:
• Distribute throughout the body
• The half-lives of the benzodiazepines are very important clinically (discussed in classification.
• All the benzodiazepines cross the placental barrier and may depress the CNS of the newborn if
given before birth. Nursing infants may also become exposed to the drugs in breast milk.
Metabolism:
• Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic
microsomal system to compounds that are also active.
• For these benzodiazepines, the apparent half-life of the drug represents the combined actions of
the parent drug and its metabolites.
Excretion:
• Benzodiazepines are excreted in the urine as glucuronides or oxidized metabolites.
Site & Mechanism Of Action:
Benzodiazepines act preferentially on midbrain ascending reticular formation (which maintains
wakefulness) and on limbic system (thought and mental functions). Muscle relaxation is produced by
a primary medullary site of action and ataxia is due to action on cerebellum. BZDs act by enhancing
presynaptic/postsynaptic inhibition through a specific BZD receptor.
A major isoform of the GABAA receptor that is found in many regions of the brain consists of two αααα1111
and two ββββ2222 subunits and one γγγγ2222 subunit.
In this isoform, the binding sites for GABA are located between adjacent a1 and b2 subunits, and the
binding pocket for benzodiazepines (the BZ site of the GABAA receptor) is between an αααα1111 and the
γγγγ2222 subunit.

Tahir Muhammad
53
Benzodiazepines are believed to bind at the interface between αααα and γγγγ subunits, and both subunits
determine the pharmacology of the benzodiazepine binding site.
Benzodiazepines increase the frequency of channel openings produced by GABA. The influx of chloride
ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing
threshold and, thus, inhibits the formation of action potentials.
Pharmalogical Effects:
Central Nervous System
The benzodiazepines do not produce the same degrees of neuronal depression as do barbiturates and
volatile anesthetics.
As the dose of a benzodiazepine is increased, sedation progresses to hypnosis and then to stupor.
Sedation
Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with
concomitant reduction of anxiety at relatively low doses.
In most cases, however, the anxiolytic actions of sedative-hypnotics are accompanied by some
depressant effects on psychomotor and cognitive functions.
Hypnosis
By definition, all of the sedative-hypnotics induce sleep if high enough doses are given.. The general
effects of benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as follows:
the latency of sleep onset is decreased (time to fall asleep);
the duration of stage 2 NREM sleep is increased;
the duration of stage 4 NREM slow-wave sleep is decreased.
the duration of REM sleep is decreased; and
Anesthesia
High doses of certain sedative-hypnotics depress the central nervous system to the point known as
stage III of general anesthesia However, the suitability of a particular agent as an adjunct in

Tahir Muhammad
54
anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and
duration of effect.
Anticonvulsant effects
Many sedative-hypnotics are capable of inhibiting the development and spread of epileptiform
electrical activity in the central nervous system.
Some selectivity exists in that some members of the group can exert anticonvulsant effects without
marked central nervous system depression (although psychomotor function may be impaired).
Several benzodiazepines including clonazepam, Nitrazepam, lorazepam, and diazepam are
sufficiently selective to be clinically useful in the management of seizures .
Muscle relaxation
Some sedative-hypnotics, particularly members of the carbamate (eg, Meprobamate) and
benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial
transmission and at high doses may also depress transmission at the skeletal neuromuscular
junction.
Effects on respiration:
Therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with
pulmonary disease. Effects on respiration are dose-related, and depression of the medullary
respiratory center is the usual cause of death due to overdose of sedative-hypnotics.
Effects on Cardiovascular :
At doses up to those causing hypnosis, no significant effects on the cardiovascular system are
observed in healthy patients.
However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular
function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a
result of actions on the medullary vasomotor centers.
At toxic doses, myocardial contractility and vascular tone may both be depressed by central and
peripheral effects, leading to circulatory collapse.
Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given
intravenously.
Gastrointestinal Tract
Benzodiazepines are thought to improve a variety of "anxiety related" gastrointestinal disorders.
There is a paucity of evidence for direct actions. Benzodiazepines partially protect against stress
ulcers in rats, and diazepam markedly decreases nocturnal gastric secretion in human beings. Other
agents are considerably more effective in acid-peptic disorders
Uses:
Anxiety disorders:
Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder,
generalized anxiety disorder, social anxiety disorder, performance anxiety, posttraumatic stress
disorder, obsessive-compulsive disorder, and the extreme anxiety sometimes encountered with
specific phobias, such as fear of flying. The benzodiazepines are also useful in treating the anxiety
that accompanies some forms of depression and schizophrenia.
Muscular disorders:

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