Histamine & Antihistaminics.pptx

Dr. Vikram Sharma
SR
Pharmacology
Histaminics &
Antihistaminics

Autocoids
• Derived from Greek w:
- Aut- Self
- Ak s- Healing substance or remedy
• Diverse substances produced by a wide
variety of cells in the body having
intense biological activity
Unique attribute f aut c id:
• They act locally (e.g. within
inflammat ry pckets) at the site o
f
synthesis & release.

• They have also been called‘ as l cal
h rm nes'.
Differ from 'h rm nes' in 2 ways-
1. Hormones are produced by
specific cells
2. They are transp rted through
circulation to act on distant target
tissues.

The classical autac ids are- 5 types
A. Amine autac ids:
• Histamine, 5-Hydroxytryptamine
(Serotonin)
B. Lipid derived autac ids:
• Prostaglandins, Leukotrienes,
activating factor (PAF)
Platelet

C. Peptide autac ids:
• Plasma kinins (Bradykinin,
Angiotensin
Kallidin),
D. Cyt kines:
• interleukins, TNF-α etc.
E. Several peptides:
• Like gastrin, somatostatin,
intestinal peptide and many
vasoactive
thers

HISTAMINE
• Histamine- 'tissue amine’
L cati n:
1. Mast cell
• Mostly within storage Granules of
mast cells.
• Tissues rich in histamine are:
– skin
– gastric and intestinal mucosa
– lungs, liver and placenta.
Mast cell leukemia.jpg, Ayman
Qasrawi at English Wikipedia - Transferred
from en.wikipedia to Commons. Public Domain.
https://commons.wikimedia.org/wiki/File:Mast_c
ell_leukemia.jpg#/media/File:Mast_cell_leukemi
a.jpg Created: 17 November 2008.

2. Nn- mast cell histamine occurs in brain, epidermis, gastric
mucosa and growing regions.
• It is also present in blood, body secretions, venoms and
pathological fluids.

Difference between mast cell and nn mast cell histamine
• T urnver of mast cell histamine is sl w
• while that of non-mast cell histamine is fast

Q&A
1. Among local and systemic which one is
the action of autocoids?
2. Name autocoid which is called as
tissue amine.
3. Give example of lipid derived
autocoid.
1
1

Synthesis, st rage and destructi n
• Histamine is β-imidaz lylethylamine.
• Synthesized locally from - - - > amin
histidine
acid
• Degraded rapidly by - - - > oxidation &
methylation.

• In mast cells
histamine (positively charged)
within intracellular granules there is acidic protein & heparin
(negatively charged).

• Release f Histamine: Exocytosis
Sdium ions in e.c.f. exchange with histamine to release it free.
• Cntr l f histamine release: intracellular cAMP
inhibits histamine release.
• Histamine is inactive rally liver degrades all histamine

Histamine R:
Histaminergic R were classified by Asch and Schild (1966) into
– H1, H2 and H3
– H3 R
Serves primarily as an auto receptor
control histamine release from neurons in brain

PHARMACOLOGICAL ACTION OF HISTAMINE

Triple Acti n f histamine: Injected intradermally:
Elicits the triple response consisting of:
I. Red spt: due to intense capillary dilatation
II. Wheal: due to exudation of fluid from capillaries & venules.
I I I . Flare: i.e. redness in the surr undings area due to arteriole
dilatation mediated by axon reflex.

Q&A
Quiz-Attendance/Feedback:
https://forms.gle/MYnno5MoKVGC8VnW6
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8

REFERENCE
• K. D. Tripathi. Essentials of Medical Pharmacology, 6th
edition. Jaypee Publication Pg. No. 151- 161.

Prof. Shaikh Abusufiyan
Part-I I Aut c ids:
Histamine and anti-histaminics

At the end f this e- learning sessi n yu are able t …
Discuss pharmacological action of
histamine.
Explain its pathological role.
Classify anti-histaminic drugs.
2
1

PHARMACOLOGICAL ACTIONS
1. Bl d vessels
• Dilatation - - - - > smaller blood vessels
• Constriction - - - > larger arteries and veins

• On s.c. injectin-
- Flushing, increased HR & CO with little r n
fall in BP
• Rapid i.v. injectin - - - > causes fall in BP
– Increase - - - - > capillary permeability

2. Heart
• I s lated heart of guinea pig-
– rate as well as force of contraction
is increased.

3. Visceral sm th muscle:
Br nchi:
• Causes bronchoconstriction
patients
sensitive.
of asthma - - - - - > highly

4. Intestine:
• Large dses
contractions
- - - > increases intestinal
causes abdominal cramps and colic

5. Uterus:
• Guinea pig uterus is contracted while that
of rat is relaxed
• Human uterus - not much affected
Sm th muscle c ntracti n – H 1 response.
In few instances - - > H2 mediated relaxation is also seen

Q&A
1. What is effect of histamine on smaller blood
vessels?
2. Why asthmatic patients are more sensitive to
histamine?
3.Which histaminergic
muscle contraction?
receptors mediate smooth
2
8

4. Glands (GIT)
• H2-receptors mediate activati n
ATPase pump.
H-K.
Marked increase in gastric secretion (acid &
pepsin)

5. Sens ry nerve endings:
• Itching- injected i.v. or intracutaneously.
• Higher concentrations injected more deeply
cause pain.
reflect the capacity of histamine to stimulate
nerve endings.
Aut n mic ganglia and adrenal medulla
• Stimulation release of Adrenaline
secondary rise in BP.

d brain barrier - - > no central
6. CNS
• Des nt penetrate bl
effects (On IV)
• However, intracerebro-ventricular administration
produces:
- Rise in BP
- cardiac stimulation
- behavioral arousal
- hypothermia
- vomiting & ADH release
Mediated thr ugh b th H1 and H2 R.

PATHOPHYSIOLOGICAL ROLES
1.Gastric secreti n:
• Histamine has dominant physiological role in
secretion of HCL in the stomach.
H2 bl ckers suppresses acid secretion

2. Allergic phen men n:
• Mediate Immediate type
- Urticaria
- Angioedema
- Bronchoconstriction
- Anaphylactic shock
f hypersensitivity reactin-
H1 antag nists are effective

3. As transmitter
• Act as a afferent transmitter
Initiates the sensation of itch and pain at sensory nerve ending
4. Inflammatin
• Implicated as a mediator of vasodilatation & inflammation.

5. T issue gr wth and repair
• Play an essential role in the process of growth & repair.
6. Headache
• Implicated in certain vascular headaches
• n cnclusive evidence

H1- ANTAGONISTS
(Cnventinal anti-histaminics)

H1-ANTAGONISTS
I. Highly sedative:
• Diphenhydramine
• Promethazine
II. M derately sedative
- Pheniramine
- Cyproheptadine
- Cinnarizine
I I I . Mild sedative
• Chlorpheniramine
• Dexchlorpheniramine
• Dimethindene
IV. Sec nd generati n
anti-histaminics
• Fexofenadine
• Cetirizine

Q&A
https://forms.gle/Vt6Ank1vHvHsNEUR6
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8

Part-I I I Aut c ids:
Histamine and anti-histaminics

 Discuss pharmacological action of H1 anti-
histamine.
 Explain its side effects and symptoms of acute
overdose.
 Discuss indications for use of anti-histaminic
drugs.
4
1

1. Antag nism f histamine
• can effectively block Histamine induced
effect:
- Bronchoconstriction
- Cntracti n of intestinal & other smooth
muscle - - - > Larger blood vessel
- Triple resp nse - - - > wheal, flare and itch.
- Release f Adrenaline from adrenal
medulla

2. Anti-allergic acti n
• Many manifestations of immediate
hypersensitivity - - > are suppressed.
 Urticaria, itching and angio-edema - - - - - > are well
controlled.
 Anaphylactic fall in BP - - - - - - > partially
prevented.
 Asthma in man - - - - - > practically unaffected

3.CNS
• The older antihistamines - - - - > variable degree of CNS
depression.
Depend on the ability of drug to penetrate BBB & its
affinity f r the central H1 receptors.

3.CNS
• Individuals also experience stimulant effects - - - - - >
restlessness & insomnia.
• Excitement and convulsions - - - - > seen at toxic doses.
• The second generation anti-histaminics - - - - >
practically non sedating.

4. Antich linergic
• Many H1 bl ckers - - - - > antagonize muscarinic
actions of Ach.
- Eg. Promethazine
Diphenhydramine

5. Local anaesthetic
• Pheniramine: have strong while others have weak
membrane stabilizing property.
6. BP
• Most anti-histaminics cause a fall in BP on i.v.
injection (direct smooth muscle relaxation).
not evident on oral administration.

Q&A
1. Name allergic reactions controlled by H1-
antihistaminics?
2. Which factors determine degree of CNS depression
produced by older anti-histaminics?
3.Among older and second generation anti-histaminic
drugs which one are non sedative in nature?
4
8

PHARMACOKINETICS
• The classical H1 antihistaminics are well absorbed
from oral and parenteral routes
• Metab lized in the liver and excreted in urine.
• They are widely distributed in the body and enter
brain.
• The newer cmp unds penetrate brain poorly.
• Durati n f acti n of most agents is 4.4 hours, except
meclizine, I oratadine, cetirizine and fexofenadine
which act for 12-24 hrs or more.

S IDE EFFECT S AND T OXI CI T Y
 Sedation,
concentration
Diminished alertness and
 Motor incoordination
 Fatigue
 Tendency to fall a sleep.
• Cauti ned
– not to operate motor vehicles or machinery
• Alc h l synergizes

 Dryness of mouth
 Alteration of bowel movement
 Urinary hesitancy and blurring of vision
antich linergic pr perty

• L cal applicati n - - - > can cause contact
dermatitis.
• Acute
excitation
muscular
flushing,
verd se produces central
- - - > tremors,
incoordination,
hallucinations,
convulsions,
hypotension, fever and some
other features of bellad nna pis ning.
• Death is due to
cardiovascular failure.
- - - > respiratory and

SECOND GENERATION
ANTIHISTAMNICS

• The sec nd generati n anti-histaminics (SGAs) are defined as those H1-
receptor blockers
Marketed after 1980 & have ne r m re f the fll wing pr perties :
- Higher H1 selectivity - - - > no anti-cholinergic SE.
- Absence of - - - > CNS depressant property.
- Additi nal anti-allergic mechanisms:
- Action on leukotrienes
- or having antiplatelet activating effect.

Advantages:
• Not impairing psychomotor
performance - - - > (driving need not
be contraindicated)
• No sleepiness
• Do not p tentiate alcohol or
benzodiazepines.

f 2nd
• The principal indicati ns
generati n anti-histaminics:
(i) Allergicrhinitis, cnjunctivitis, hay
fever & pllin sis-
- Control sneezing, runny but nt
bl cked
eyes.
nse & red watering itchy

(ii) Urticaria, derm graphism, at pic eczema.
Dermatographism on forearm of a 19 year old college student taken at Cornell College. JAguayo18 - Own
work. CC BY-SA 4.0. File:Physical Urticaria Dermatographism.jpg. Created: 24 April 2016

(iii) Acute allergic reacti ns to drugs and foods.
They have p r anti-pruritic, antiemetic and Anti-tussive actions.

Q&A
https://forms.gle/4tGFhrfCcuQdBmjL7
5
9

Part-IV Aut c ids:
Anti-histaminics and 5 - HT

 Discuss pharmacological action of cetirizine.
 Give uses of anti-histaminics.
 Explain salient features of H2 & H3 anti-
histaminics.
 Discuss synthesis and destruction of 5-HT
 Explain different types of serotonin receptors.
6
2

Cetirizine
• It is a metab lite of hydroxyzine
with marked affinity f r peripheral
H1 R.
• Penetrates the brain poorly
• It is nt metab liz ed
Drug I nteracti n:
• P tentiate arrhythmias when given
along with erythromycin/ketoconazole.

• I t Inhibits release f
– Histamine
– Cytotoxic mediators
• I t attains high & longer lasting concentration in skin
May be resp nsible for superior efficacy in urticaria
/atopic dermatitis
Indicatins:
• It is indicated in upper respiratory allergies,
pollinosis, urticaria and atopic dermatitis
• Also used as adjuvant in seasonal asthma.

Uses f anti-histaminics
1. Allergic disorders
2. Antipruritic action
3. Common cold
4. Motion sickness
5. Vertigo
6. Pre-anaesthetic medicati n - Promethazine has been used for
its antich linergic and sedative pr perties.
7. Cugh: eg chlorpheniramine, diphenhydramine and promethazine

8. Parkinsonism:
Promethazine and some other - - - > provide mild
symptomatic relief in early cases of
parkinsonism.
9. As sedative, hypnotic, anxiolytic
antihistamines with CNS depressant action - - - >
especially in children.

H2-antihistaminics:
• Cimetidine was introduced in 1977
• Other widely used H2 antihistaminics:
– Ranitidine, famotidine, roxatidine
• They are primarily used in:
- peptic ulcer
- gastric hypersecretory state

H3 antag nist
• Selective H3 antagonist ex. thi peramide has been
produced
not found any clinical utility.

Q&A
1. Give example of drug which potentiate arrhythmia
when given along with cetrizine.
2. Enlist few indications for the use of cetirizine?
3.Enlist few uses anti-histaminic drugs?
4. Justify why cetrizine has superior efficacy in
urticaria /atopic dermatitis.
7
1

71
5 –HYDROXY TRYPTAMIN
(SEROTONIN) AND ITS
ANTAGONISTS

5-HYDROXYTRYPTAMINE
(5-HT, Serotonin)
• Ser tnin
Vas c nstrict r (Appeared when bl d cl tted).
• Enteramine
The sm th muscle cntracting substance present in
(enterochromaffin cells of gut mucosa).
72

L cati n:
• About 90% f b dy's cntent
intestines
• The rest is in platelets and brain
• It is also found in scorpion sting
73
- - - > localized in the
& plants (banana,
• Widely distributed in invertebrates
pear, pineapple, tomato, stinging nettle).

Q&A
https:/ / forms.gle/DJ C1c4Yg6Qf5GvsV6
7
5

Part-V Autocoids:
5 - Hydroxy Tryptamine

Discuss synthesis and degradation of 5-
HT
Explain different types of serotonin
receptors.
Discuss its Pharmacological action & role
in pathophysiology.
7
8

SYNTHESIS AND DEGRADATION
• 5-HT is β-aminoethyl-5-hydroxy indole.
Degradati n:
• Primarily by MAO (MAO-A)
• And to a small extent by a dehydrogenase.
78

SEROTONERGIC (5-HT) RECEPTORS AND THEIR MECHANISM
• Gaddum and Picarelli (1957) classified 5-HT R into musculotropic (D type) &
neurotropic (M type)
• Four families of 5 - HT R (5-HT1 to 5-HT4)
• 5 - HT R (except 5 - HT3) are G protein coupled receptors
• 5 - HT-3 - - - - > Ligand gated cation (Na, K-) channel
which on activation elicits fast depolarization
79

Pharmac l gical acti n:
CVS
• Arteries are
– cnstricted
– dilated (through release of EDRF)
• Releases Adr from adrenal medulla
Evokes CVS reflexes.
• Larger arteries and veins - - - > constricted.
• Is lated heart - - - > stimulation
CONSTRICTION / DILATATION OF ARTERIES
AND STIMULATION OF HEART
80

TRIPHESIC RESPONSE OF 5HT
• Seen on i.v. injection of 5 - HT in animals.
– Early sharp fall in BP
– Brief rise in BP
– Prolonged fall in BP
81

Sm th muscles
GIT:
• Several subtypes of 5-HT R are present
in the gut.
Increases peristalsis Diarrhea
82

Br nchi
• Bronchial - - - > cnstricti n
less potent than histamine.
83

Gland
• 5-HT inhibits gastric secretion
(both acid & pepsin)
• Increases mucus production
ulcer protective property.
84

Nerve endings and adrenal medulla:
• Afferent nerve endings are activated - - - > tingling, pricking
sensation & pain.
Respirati n:
• brief stimulation of respiration
hyperventilation
• Large d ses can cause transient apnea
85

Platelets
• Causes changes in shape of
platelets
• weak platelets aggregator.
86

 CNS
• Poorly crosses bl d-brain barrier.
Direct injecti n in the brain pr duces
• Sleepiness
• Changes in body temperature
• Hunger
• Variety of behavioral effects.
87

Q&A
1. What is the precursor of 5-HT.
2. Name 2 enzymes which metabolizes 5-HT.
3. Give pharmacological action of 5-HT on gastric
gland.
4. What is triphasic response of 5-HT?
8
9

PATHO PHYSIOLOGICAL ROLES
Neur transmitter:
• 5-HT is a neurotransmitter in the brain
in affective
Imbalance may result
disrders & schiz phrenia
89

Precurs r f melat nin:
• Act as precurs r of melatonin
Regulate
rhythm).
Act on pineal gland
bi l gical cl ck (circadian
Neur endcrine functin:
• Regulated by serotonergic mechanism.
90

Nausea and vomiting
• cytotoxic drugs or radiotherapy
Evoked nausea & vomiting by its action
on 5-HT3 R in the gut
91

Migraine
• Initiate
migraine
the vas c nstrict r phase of
Methylsergide (5-HT
effective prophylactic
antagonist) is an
& sumatriptan (5-HT1B/1D agonist) can
control an attack.
92

 Hem stasis
Platelets release 5-HT at the site of
injury to blood vessel.
Accelerates platelet aggregation &
clot formation.
93

Variant angina
• Thromboxane A2 + 5-HT released from
platelets
Causes c r nary spasm & variant angina.
94

Hypertensi n
• Increased responsiveness to 5-HT - - - > demonstrated in hypertensive
patients.
• Ketanserin (5HT R antag nist) - - - > antihypertensive property.
Intestinal m tility
• Regulate peristalsis and local reflexes in the gut.
Carcin id syndr me
• Bowel hypermotility and bronchoconstriction in carcinoid is due to 5-HT.
95

Q&A
https://forms.gle/UnqBhBKi78x5ivMx7
9
7

REFERENCE
• K. D. Tripathi. Essentials of Medical Pharmacology, 6th
edition. Jaypee Publication Pg. No. 151- 173.

Part-VI Aut c ids: 5 - HT
Antag nist

Classify 5-HT antagonists.
Explain pharmacology of cyproheptadine,
ketanserin & Ergotamine.
Discuss adverse effects and contraindications
of 5-HT receptor antagonist.
1
0
0

5 - HT ANTAGONISTS CLASSIFICATION
A. Erg t derivatives: (Ergotamine, LSD, 2-
bromo LSD, methylsergide)
B. Adrenergic α bl ckers: (phenobenzamine)
C. Antihistaminic: (cyproheptadine, cinnarizine)
D. Chl rpr mazine
E. Mrphine etc.
• These are nonselective
several other receptors.
and interact with
101

Cypr heptadine
• It bl cks - - - > 5-HT-R
• Additional Pharmacological action:
– H1 antihistaminic
– anticholinergic
– and sedative properties.
101

• Used in
– allergies
– And for antipruritic action
• Rec mmended in children - - - > to increase
appetite
• P r eaters to promote weight gain.
An acti n n growth
may be responsible.
hormone secretion
102

• Control intestinal manifestations of - - - >
carcin id and pst-gastrect my
Anti-5HT Acti n may be responsible
• SE:
- drowsiness
- dry mouth
- confusion
- ataxia
- weight gain.
103

Ketanserin
•It has selective 5 - HT2 R bl cking property
•antag nized 5 - HT induced
- platelet aggregation
- contraction of airway smooth muscle
• does not antagonize contraction of guinea
pig ileum or rat stomach
•Use: Effective antihypertensive
104

ERGOT ALKALOIDS
•Ergot is obtained from a fungus - - > Claviceps
purpurea
•Epidemics of erg t pis ning (erg tism):- - - >
due to consumption of contaminated grains
Dry gangrene
become black
f hands and feet - - - >
106
It
Drgnu23 at English Wikipedia - Drgnu23 - Taken in
my practice.CC BY-SA 3.0.
https://commons.wikimedia.org/wiki/File:Dry_gange
ne_4th_toe.jpg#/media/File:Dry_gangene_4th_toe.j
pg. Dry gangene 4th toe.jpg. Created: 27 December
2004

Pharmac l gical acti n:
• Miscarriages - - - > in women & cattle.
• A c nvulsi n - - - > in some patients.
• It c ntains a h st
substances:-
- alkaloids
- LSD
- histamine
- Ach
- tyramine
f pharmacologically active
- and other amines, sterols etc.
106

Natural erg t alkal ids:
•Tetracyclic indole containing compounds (derivatives of lysergic
acid).
Chemical structure of Lysergic acid. NadirSH - Own work.
https://commons.wikimedia.org/wiki/File:Lysergic_acid.svg
#/media/File:Lysergic_acid.svg .CC BY-SA 4.0. Lysergic
acid.svg. Created: 21 April 2020
107

 They are divided into:-
(a) Amine alkaloid: Ergometrine - - > oxytocic
(b) Amino acid alkaloids: I) Ergotamine,
II) Ergotoxine
(mixture of ergocristine + ergocornine + ergocryptine)
vasoconstrictor & α adrenergic blocker.
108

Q&A
1. Give example of adrenergic blocking drug with 5-HT
receptor antagonistic activity.
2. Enlist few clinical uses of Cyproheptadine.
3.Which 5-HT antagonist drug can
Miscarriages.
4. What is chemical composition of ergotoxine?
induce
1
1
0

Pharmacl gical Acti ns:
Erg tamine:
• Partial ag nist & antag nist - - - > α adrenergic & all subtypes of 5-HT1 &
5-HT2 R
•It pr duces
– Sustained vasoconstriction
– Visceral smooth muscle - - - > contraction
– Vasomotor centre - - - > dépression
– Antagonizes the action of - - - > NA and 5-HT on smooth muscles.
110

• Potent - - > emetic (thr ugh CTZ)
• Moderately potent - - > oxytocic.
• At high d ses - - - > CNS stimulation
• On chronic exposure - - - > ergot poisoning
vasoconstriction accompanied by damage to capillary endothelium - - - >
- thrombosis
- vascular stasis and gangrene
111

Dihydr erg tamine (DHE):
• Hydr genati n of ergotamine
reduces 5HT and α-adrenergic agonistic actions
but enhances α– R blocking property.
• I t is a less potent vasoconstrictor
• I t is a weaker emetic & oxytocic
• but has some antidopaminergic action.
112

Dihydr-oergotoxine (Mixture)
• a more potent α blocker.
• In the brain it having:
• A variety of partial agonistic/
antagonistic actions on 5 - HT R
• Causes enhancement of - - - > Ach release
in cerebral cortex
treatment of dementia
113

Pharmac kinetics
• Oral bioavailability of amino acid erg t alkal ids and their hydr genatec
derivatives is p r (< 7%) due to slow and incomplete absorption as well as high
first pass-metabolism.
• Bi availability is better after sublingual and rectal administration
• Ergotamine is sequestrated in tissues - produces longer lasting actions compared
to its plasma half life of 2 hours.
• Ergot alkaloid-effectively cross blood-brain barrier.
114

Adverse effects
• Nausea, vomiting
• abdominal pain,
• weakness
• paresthesia
muscle cramps
• coronary and other vascular spasm
• chest pain
115

These drugs are c ntraindicated in presence f
• ischemic heart disease
• peripheral vascular disease
• hypertension
• pregnancy
• liver and kidney diseases
116

Q&A
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1
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Histamine & Antihistaminics.pptx

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