Autacoids.pptx

Cells communicate using?
Chemical signals. That are usually proteins or other molecules.
Chemical signals are released in the extra-cellular spaces by sending cells
Cell Signaling
Signaling molecule is called?
Ligand
Ligand binds to what?
Its Receptor

When a ligandbinds to its receptor the receptor pass on a chain of chemical messengers in the
cell.
It leads to changes in the cell
Gene expression.
Or any other activity like cell division.
Cell Signaling
Thus, the INTERCELLULAR (between-cells) signal is convertedinto INTRACELLULAR (within-
cell) signals.

Cell Signaling
Forms of Signaling
Not all sending and receiving cells are net-doorneighbors.
Therefore, cell signaling is classified on the basis of distance that the signals travel to reachthe
target.
1. Paracrine signaling
2. Synaptic signaling
3. Autocrine signaling
4. Endocrine signaling
5. Signaling through cell to cell contact

Cell Signaling
1. Paracrine
Signaling
In this type of signaling cells communicate over relatively short distance.
Cells locally coordinate activities with their neighbors.

Cell Signaling
2. Synaptic Signaling
Signal transmission fromaxon of one neuron to the dendrites
of other neuron at the synapse is calledsynaptic signaling.
When impulse reaches synapse it triggers the release of
NEUROTRANSMITTERSthat binds to the receptors of receiving
neurons.
The neurotransmitters that are release at the synapse are quickly
degraded or takin back up by the sending cell in order to prepare
For the next signal.

Cell Signaling
3. Autocrine
Signaling
In this type cell signals its self.
Cells release a ligand that binds to receptor on its own surface.
It is important duringdevelopment, helping cells take on and reinforce their correct identities.
This type of signalingalso takes place during cancer.
Figure: Difference
between Paracrine
and Autocrine
signaling.

Cell Signaling
4. Endocrine
Signaling
When cells need to transmit signals over long distance they useendocrine signaling.
In this type circulatory systemis used as a distribution network for the message to send.
What is the example?
Hormones (growth hormone release by pituitary gland and promote
growth in bones and cartilage)

Cells bind to one anotherwiththe help of surface receptors and transmit the signals.
This type of signalingis important in immune system, where immune
cells use cell-surface markers to recognize “self” cells
(bodies own cells) and cells infectedby pathogens.
Cell Signaling
5. Signaling through Cell-Cell
contact
Figure: Cell-Cell
contact signaling
Figure: NK immune cell recognizes a healthy cell of the
body to a “self” marker on the cell’s surface.
Naturel killer
(NK) cell
Healthy cell

Name derivedfromthe words, “AUTOS” means “self” and “ÄKOS” means healingsubstance.
Produced by a wide variety of cells in the body, having intense activity, and act locally at the site
of synthesis and release.
They are alsocalled“local hormones”.
Question: They are different fromhormones in what way?
Autacoids

Autacoids
Classification of
Autacoids
They are classified into four major classes:
1. Amine Autacoids
• Histamine
• Serotonin
2. Lipid-derivedAutacoids
• Prostaglandins
• Leukotrienes
• Platelet-activating factor
3. Peptide Autacoids
• Plasma Kinins (Bradykinin, Kallidin)
• Angiotensin
4. Other Autacoids
• Gastric Autacoids (Gastrin)
• Cytokines
• Somatostatin
• Vasoactive Intestinal Peptides
• Endothelins
• ets

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Histamine
• Histamine meaning “Tissue Amine”, (Histos- tissue).
• It is abundantly present in animal Tissues and also in plants like “stingingnettle”.
•Histamine mostly is present in mast cells bound to acidic protein and heparin
(negativelycharged) because histamine possesses positive charge.
• Tissues rich in histamine are: skin, gastric and intestinal mucosa, lungs, liver and
placenta.
• Non-mast cells histamine is present in: CNS (neurotransmitter), epidermis,
gastric mucosa and growing regions.
• Turnover of non-mast cells histamine is fast than the mast cells histamine.

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Histamine
Histamine
Lipid mediators:
Leukotrienes
and Prostaglandins
Cytokines
IL-4,
IL-13
TNF-α
Mast-cell
activation
• increase vascular permeability
• smooth muscle contraction
• promotes Th2 differentiation
• promotes IgE production
• promotes tissue inflammation
• increase vascular permeability
• cause smooth muscle contraction
• stimulates mucus secretion
• Chemoattractants for T cells,
eosinophils, mast cells & basophils

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Histamine Synthesis & Metabolism
• Histamine is formed by theDecarboxylationof the amino acid(AA)
histidine by the enzymeL-Histidinedecarboxylase.
• There are two pathways of its metabolism
1. Methylation:
Histamine is convertedintoN-Methyl histamine by N-
methyltransferase and further intoN-MethylImidazole Acetic
Acidby monoamine oxidase-B.
2. Oxidative deamination:
Histamineis convertedinto Imidazoleacetic Acidby Di-amine
oxidase andfurther intoImidazole Acetic AcidRiboside by
Phosphoribosyl Transferase.
• Non-mastcell sites of histamine production contribute significantly to
the daily excretionof histamine metabolitesin the urine.

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Histamine Storage
1. Histamine foundin individual organs and tissues is synthesized
locally and stored.
2. Mastcells (withintissues) and basophils (withinblood)
synthesize histamine andstore it in secretory granules.
3. It is also foundin non-mastcells, including the hypothalamus
regionof the brainwhere it functions as a neurotransmitter.
4. In secretory granules the pHis of 5.5, positively charged
histamine is foundin complexwithnegatively chargedacidic
groups on other granular constituents, primarily proteases and
heparinor chondroitinsulphate proteoglycans.
*Basophils: Are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating
white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as
well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce
compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, heparin that prevents blood
clotting.

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Histamine Storage
1. Non-mastcell sites of histamine formation include the epidermis, enterochromaffin-like cells of
gastricmucosa*, neurons in the CNS andcells in regenerating or rapidly growing tissues.
*Enterochromaffin-like cells of gastric mucosa: Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric mucosa that control acid
secretion by releasing histamine as a paracrine stimulant.

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Release of Histamine fromStorage sites
1. Histamine is releasedfromthe mast cells by exocytotic or non-exocytotic
mechanisms.
• Exocytotic includes the release of histamine fromhistaminic
granules/vesicles out of the cells.
• Non-exocytotic includes the release of histamine by mastcell lysis,
modificationof mastcell membranes, and physical displacement of
histamine e.g., Mechanical injury.
• Non-exocytotic pathway is followedwhenantigen directly interacts
withthe mast cells or basophils.
• In the exocytoticpathway the stimuli include components of
complement systemC3a and C5a, which interacts withspecific
surface receptors andthe combinationof antigenwith IgE
antibodies.
Mast cell
Nucleus
Granules
Histamine
Receptor site
IgE
sensitized
Mast cell
IgE sensitized
mast cell with
allergen bound
IgE
Degranulation. Release of histamine.
Antihistamines
Pharmacological effects
Allergen

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• In commonwithmany secretory processes, histamine release is
initiatedby a rise in cytosolic Ca+2.
Mast cell
Nucleus
Granules
Histamine
Receptor site
IgE
sensitized
Mast cell
IgE sensitized
mast cell with
allergen bound
IgE
Degranulation. Release of histamine.
Antihistamines
Pharmacological effects
Allergen
2. Modulationof Histamine release
• Certainendogenous and exogenous compounds modulate the
antigen-mediatedrelease of histamine fromsensitizedtissues.
• Histamine inhibits its ownrelease in skinmastcells and blood
basophils by binding to H2 histamine receptors, which whenactivated,
inhibit degranulation.
• This feedback inhibition does not appear to occur in lung mast cells.
• Various basic drugs, such as morphine and tubocurarine, release
histamine.
• Agents that increase cAMP formation(e.g. β-adrenoceptor agonists)
inhibit histamine secretion.
• Muscarinic and α-adrenergicagonists enhance mastcell

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 Histamine release by Drugs, Peptides, Venoms and other agents:
• Mechanical injury and many compoundsstimulate the release of histamine frommast cells.
• Responses most likely occur following intravenous injections of several substances.
• Tubocurarine, succinylcholine, morphine, some antibiotics, radiocontrast media (iodine contrast media for the
circulatory system, angiography; Bariumfor the digestive system), andcertaincarbohydrate plasma expanders
(dextrose, hydroxyethyl starch) also may elicit the response.
• Basicpolypeptides oftenare effective histamine releasers, and over a limitedrange, their potency generally
increases withthe number of basic groups. For example, bradykininis a poor histamine releaser, whereas
kallidin (Lys-bradykinin) and substance P, withmore positively chargedamino acids (lysine, arginine,
histideine), are more active.
• Some Venoms, such as that of the wasp, containpotent histamine-releasing peptides.

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Succinylcholine MOA
Tubocurarine MOA

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Histamine Receptors
H1 H2 H3
a H4
G protein Coupling
(Second Messenger)
Gq/11
( Ca+2, NO, and
cGMP)
GS
( cAMP)
Gi/o
( cAMP, MAP
Kinase)
Gi/o
( cAMP)
Distribution
Smooth muscles,
endothelial cells, CNS
Gastric parietal cells,
Cardiac muscles,
mast cells, CNS
CNS: Pre- and Post-
Synaptic.
Cells of
hematopoietic origin
Representative
Agonist
Chlorpheniramine Ranitidine Tiprolisant JNJ7777120

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 Activationof H1 receptors on vascular
endotheliumstimulates eNOS to
produce NO, which diffuses to nearby
smooth muscle cells to increase cyclic
GMP andcause relaxation. Stimulation
of H1 receptors on smooth muscle
mobilize Ca2+ and cause contraction.
 Activationof H2 receptors on the same
smooth muscle cell will link via Gs to
enhancedcyclicAMP accumulation,
activationof PKA, and thento
relaxation.

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Histamine Receptors

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 Physiological and Pharmacological effects of Histamine
1. H1 and H2 receptors:
• H1 and H2 receptors are distributedwidely in the periphery andin the CNS and their activationby
histamine can exert local or widespreadeffects
• Histamine causes itching and stimulatessecretionfromnasal mucosa.
• It contracts many smooth muscles, such as those of the bronchi and gut, but markedly relaxes others,
including those in small bloodvessels.
• Is a potent stimulus of gastric acid secretion.
• Less-prominenteffects include the formationof edemaand stimulationof sensory nerve endings.
• Bronchoconstrictionand contractionof the gut are mediatedby H1 receptors.
• In the CNS, H1 activationinhibits appetite and increases wakefulness.
• Gastricsecretion results fromthe activationof H2 receptors.
• Vascular dilation, are mediatedby bothH1 and H2 receptor stimulation.

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1. H3 and H4 receptors:
• The H3 receptors are expressedmainly in the CNS, especially in the basal ganglia, hippocampus, and cortex.
• PresynapticH3 receptors functionas autoreceptors on histaminergic neurons, inhibiting histamine release
and modulating the release of other neurotransmitters.
• H3 receptors are also foundpostsynaptically, especially in the basal ganglia, but their function is still being
unraveled.
• H3 agonists promote sleep, and H3 antagonists promote wakefulness.
• The H4 receptors primarily are foundin eosinophils, dendritic cells, mast cells, monocytes, basophils, and T
cells but have also been detectedin the GI tract, dermal fibroblasts, CNS, andprimary sensory afferent
neurons.
• Activationof H4 receptors has been associatedwithinductionof cellular shape change, chemotaxis, secretion
of cytokines, and upregulationof adhesionmolecules, suggesting that H4 antagonists may be useful
inhibitors of allergicand inflammatory responses

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1. Cardiovascular System(CVS):
• Histamine dilates resistance vessels, increase capillary permeability and lower systemic bloodpressure.
• Vasodilationis due to H1 or H2 receptors. H1 receptors have a higher affinity for histamine and cause Ca2+-
dependentactivationof eNOS in endothelial cells; NO diffuses to vascular smooth muscle, increasing cyclic
GMP andcausing rapidand short-livedvasodilation. By contrast, activation of H2 receptors on vascular
smooth muscle stimulates the cyclicAMP–PKApathway, causing dilationthat develops more slowly and is
more sustained.
• Histamine’seffect on small vessels resultsin efflux of plasma proteinand fluidintothe extracellular spaces
and an increase in lymph flow, causing edema(H1 receptors).
• On heart, It increases the force of contractionof both atrial andventricular muscle by promoting the influx
of Ca2+ thus increases heart rate.
• It reduces bloodpressure.
• Histamine directly contracts or, more rarely, relaxes various extravascular smooth muscles.

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1. Cardiovascular System(CVS):
• Histamine stimulates various nerve endings, causing sensory effects. In the epidermis, it causes itch; in the
dermis, it evokes pain, sometimes accompaniedby itching.
• Histamine givenin large doses or releasedduring systemic anaphylaxis causes a profoundand progressive
fall in bloodpressure. Also, due to Dilationof small bloodvessels plasma escapes fromcirculation.
• Decrease bloodvolume, reduce venous return, andgreatly lower cardiac output.
• Histamine is the toxinin foodpoisoning fromspoiledscombroidfish such as tuna. Symptoms include severe
nausea, vomiting, headache, flushing, and sweating.
• Histamine toxicity also canfollowred wine consumptionin persons with a diminishedability to degrade
histamine. The symptoms of histamine poisoning can be suppressedby H1 antagonists.

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2. Extra Vascular smooth muscles:
• Histamine directly contracts or, more rarely, relaxes various extravascular smooth muscles.
• Contractionis due to activationof H1 receptors on smooth muscle to increase intracellular Ca2+, and
relaxationis mainly due to activationof H2 receptors.
• Although the spasmogenicinfluence of H1 receptors is dominantin humanbronchial muscle, H2 receptors
withdilator functionalso are present.
• Patientswithbronchial asthma and certainother pulmonary diseases are much more sensitive to the
bronchoconstrictor effects of histamine.
• Pregnant womensuffering anaphylactic reactions may abort as a result of histamine-induced uterine
contractions.

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3. Bronchiolar smooth muscles:
• Histamine causes bronchoconstriction mediatedby H1 receptors. Bronchoconstrictionto histamine can be
blockedby autonomic-blocking drugs such as ganglion-blocking agents (Hexamethoniumand nicotine) as
well as by H1-receptor antagonists.
• Curiously, a fewspecies (eg, rabbit) respondto histamine with bronchodilation, reflecting the dominance of
the H2 receptor in their airways.
• Histamine causes contractionof intestinal smooth muscles. This action of histamine is mediatedby H1
receptors

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4. Peripheral nerve endings:
• Histamine stimulates various nerve endings, causing sensory effects.
• In the epidermis, it causes itch; in the dermis, it evokes pain, sometimes accompaniedby itching.
• Stimulantactions on nerve endings contribute to the “flare” component of the triple response andto indirect
effects of histamine on the bronchi and other organs.
 Triple response:
• If histamine is injectedintradermally, it elicits a characteristic phenomenonknownas the triple response.
This consists of the following:
• A localized“reddening” aroundthe injectionsite, appearing withina few seconds, and maximal at about 1
min.
• A “flare” or red flush extending about 1 cm beyondthe original red spot and developing more slowly.
• A “wheal” or swelling that is discernible in 1–2 minat the injectionsite.

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 Triple response:
• The initial redspot (a few millimeters) results fromthe direct vasodilating effect of histamine (H1
receptor–mediated NOproduction).
• The flare is due to histamine-inducedstimulationof axon reflexes that cause vasodilation, and
• the wheal reflects histamine’scapacity to increase capillary permeability (edemaformation)

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5. Secretory tissues:
• Histamine has long been recognized as a powerful stimulant of gastric acidsecretionand, to a lesser extent,
of gastric pepsinand intrinsic factor production. The effect is causedby activationof H2 receptors on gastric
parietal cells and is associatedwithincreasedadenylyl cyclase activity, cAMP concentration, andintracellular
Ca2+ concentration.
• Histamine also stimulates secretionin the small and large intestine. In contrast, H3-selective histamine
agonists inhibit acidsecretionstimulatedby foodor pentagastrinin several species.
• Histamine has much smaller effects on the activity of other glandular tissue at ordinary concentrations.
Very high concentrations cancause catecholamine release fromthe adrenal medulla.

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6. Histamine Shock:
• Histamine givenin large doses or releasedduring systemic anaphylaxis causes a profoundand progressive
fall in bloodpressure.
• As the small bloodvessels dilate, they traplarge amounts of blood, their permeability increases, and plasma
escapes fromthe circulation.
• These effects, resembling surgical or traumatic shock, diminish effective bloodvolume, reduce venous return,
and greatly lower cardiac output.

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7. Histamine toxicity:
• Adverse effects of histamine release, like those following administrationof histamine, are dose related.
Flushing, hypotension, tachycardia, headache, urticaria, bronchoconstriction, and gastrointestinal upset are
noted.
• These effects are also observedafter the ingestion of spoiledfish (scombroidfish poisoning), and histamine
producedby bacterial actionin the flesh of improperly stored fish is the major causative agent.

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 Histamine receptor antagonists
1. FirstGenerationAntihistamines:
• DoxepinHCl.
• Carbinoxamine Maleate.
• Clemastine fumarate.
• Diphenhydramine HCl.
• Dimenhydrinate.
• Chlorpheniramine maleate.
• Brompheniramine maleate.
• Hydroxyzine HCl.
• Hydroxyzine pamoate.
• Cyclizine HCl.
• Meclizine HCl.
• Promethazine HCl.
• Cyproheptadine HCl.

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2. SecondGenerationAntihistamines:
• Olopatadine HCl.
• Acrivastine.
• Cetrizine HCl.
• Levocetrizine HCl.
• Alcaftadine.
• Bepotastine besilate.
• Desloratadine.
• Fexofenadine HCl.
• Ketotifenfumarate.
• Loratadine.
• Azelastine HCl.
• Emedastine.
• Epinastine.
• Ebastine.

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1. Effects of antihistamines on physiological system:
• Smooth Muscles:
 Inhibitvasodilator effect on vascular smooth muscles.
 Inhibitcontractionof respiratory smooth muscles.
 Also inhibits venous constriction.
 Strongly block the increasedcapillary permeability and formationof edemaand wheal causedby
histamine.
 H1 antagonists suppress the action of histamine on nerve endings, including the flare component of
the triple response and the itching causedby intradermal injection.
 H1 antagonists do not suppress gastricsecretion. However, the antimuscarinic properties of many H1
antagonists may contribute to lessened secretion.
 They possess anticholinergiceffects.

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 Histamine receptor antagonist:
Anticholinergic effects of 1st generationantihistamines

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• MastCell–Stabilizing and Anti-inflammatory Properties:
 Act as mast cells stabilizers tooduring allergic response(Many secondgeneral H1 blockers: citrizine,
fexofenedine etc).
 These agents also have anti-inflammatory properties, which can include reducedcytokine secretion,
decreasedadhesionmolecule expression, and inhibitionof eosinophil infiltration.
 These effects can be both H1 receptor dependent and independent, but precise mechanisms are still
unclear, and it is unknownwhat role they play at normal therapeutic doses of these drugs.

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• CNS:
 H1 antagonists can bothstimulate and depress the CNS.
 Stimulationoccasionally is encounteredin patients given conventional doses; the patients become
restless, nervous, and unable to sleep.
 Central excitationalso is a striking feature of overdose, which commonly results in convulsions,
particularly in infants.
 Central depressionincludes, Diminishedalertness, slowedreactiontimes, and somnolence are
commonmanifestations. Patients vary in their susceptibility and responses to individual drugs.
 Firstgenerationcause sedation, therefore these drugs cannot be toleratedor usedsafely by many
patients except at bedtimes.
 Patientsmay experience an antihistamine “hangover” in the morning, resulting in sedationwithor
withoutpsychomotor impairment.

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• CNS:
 Second-generationH1 antagonists are termed nonsedating because they do not cross the blood-
brainbarrier appreciably. This is due to their decreasedlipophilicity and because they are substrates
of P-glycoprotein*, which pumps themout of the blood-brainbarrier capillary endothelial cells and
back intothe capillary lumen.
*P-glycoprotein 1 (permeability glycoprotein,) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-
family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps
many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists
in animals, fungi, and bacteria, and it likely evolved as a defense mechanism against harmful substances.

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• Local anestheticeffects:
 Some H1 antagonists have local anestheticactivity. However, the concentrations requiredfor this
effectare much higher than those that antagonize histamine’s interactions with its receptors.

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2. Pharmacokinetics (ADME) of antihistamines:
 Well absorbedfromGI tract after oral administration.
 Peak plasmaconcentrationis achievedin 1 to 3 hours.
 Firstgenerationantihistamines’ effects last for 4 to 6 hours.
 Secondgenerationantihistamineshave much longer effects.
 These agents are distributedwidely throughout the body, including the CNS for the first-generation
agents.
 Peak concentrations of these drugs in the skinmay persist long after plasmalevels have declined.
Thus, inhibitionof “wheal-and-flare” responses to the intradermal injectionof histamine or allergen
can persistfor 36 h or more after initial treatment and up to 7 days after discontinuationof
treatmentin patients who regularly use an H1 antagonist for 1 week or more.
 All first-generationand mostsecond-generation H1 antagonists are metabolizedby CYPs and little
is excretedunchangedin the urine.

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 Exceptions are: Citrizine and Acrivastin, <40%metabolized.
• Fexofenadine, levocetirizine, andepinastine, <10%metabolized.
 Cetirizine, levocetirizine, and acrivastine are excretedprimarily intothe urine.
 fexofenadine is mainly excretedin the feces
 Epinastine is excretedboth in urine and feaces.
 The H 1 antagonists that are metabolized are eliminatedmore rapidly by children thanby adults
and more slowly in those withsevere liver disease.
 These antagonists also have higher potential for drug interactions. For example, plasma levels of H1
antagonists may be reducedwhencoadministered with drugs that induce CYP synthesis (e.g.,
benzodiazepines) or elevatedwhen takenwithdrugs that compete withor inhibit the same CYP
isoform(e.g., erythromycin, ketoconazole, antidepressants).

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 Clinically relevantinteractions are more likely with first-generationthansecond-generationdrugs.
 However, two second-generationH1 antagonists marketedpreviously, terfenadine and astemizole,
were foundin rare cases to prolong the QTc interval and induce a potentially fatal
 arrhythmia, due to their capacity to inhibit a cardiac K+ channel whentheir metabolismwas
impairedand their plasmaconcentrations rose toohigh, due, for instance, to liver disease or to
drugs that inhibitedthe CYP3A family.
 This led to the withdrawal of terfenadine and astemizole fromthe market.
 Astemizole and an active hydroxylatedmetabolite naturally have very long half-lives.
 Terfenadine is a prodrug, metabolizedby hepatic CYP3A4 to fexofenadine, which is its replacement
and lacks noticeable cardiotoxicity.

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3. Therapeuticuses of antihistamines:
 H1 antagonists for acute allergic reactions that present with symptoms of rhinitis, urticaria, and
conjustivitis.
 In bronchial asthmabut not usedas a sole therapy.
 In the treatment of systemicanaphylaxis where autocoids other thanhistamine are important, the
mainstay of therapy is epinephrine; histamine antagonists have only a subordinate and adjuvant
role.
 The same is true for severe angioedema, in which laryngeal swelling constitutes a threat to life.
 Urticaria(a raised, itchy rash that appears on the skin).
 Contact dermatitis (an itchy rash causedby direct contact witha substance or an allergic reaction to
it.) although topical corticosteroids are more effective.
 H1 antagonists can be usedin combating the commoncold. The weakanticholinergic effects of the
older agents may tendto lessenrhinorrhea, but this drying effect may do more harm thangood.

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Adverse Effects of antihistamines:
 The mostfrequentside effectof first-generationH1 antagonists is sedation.
 Concurrent ingestionof alcohol or other CNS depressants produces an additive effect that impairs
motor skills.
 Other untowardcentral actions include dizziness, tinnitus, lassitude (state of physical or mental
weakness or lethargy), incoordination, fatigue, blurredvision, diplopia(double visionor seeing
double), euphoria, nervousness, insomnia, and tremors.
 Other potential side effects, including loss of appetite, nausea, vomiting, epigastric distress, and
constipationor diarrhea, may be reducedby taking the drugs with meal.
 H1 antagonists such as cyproheptadine may increase appetite and cause weight gain.
 Other side effects, owing to the antimuscarinic actions of some first-generationH1 antagonists,
include dryness of the mouth and respiratory passages (sometimes inducing cough), urinary
retentionor frequency, and dysuria.

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 Hypersensitivity reactions include drug fever and photosensitization.
 Hematological complications, such as leukopenia (low white bloodcell count ), agranulocytosis
(Agranulocytosis is a life-threatening blooddisorder. It happens whenthe body doesn'tmake
enough of a type of white bloodcells calledneutrophils), and hemolytic anemia(Hemolytic anemia is
a disorder in which red bloodcells are destroyedfaster than they can be made.), are very rare.
 H1 antihistamines cross the placenta, caution is advisedfor womenwho are or may become
pregnant.
 Antihistamines can be excretedin small amounts in breast milk, and first-generation
antihistamines takenby lactating mothers may cause symptoms such as irritability, drowsiness, or
respiratory depressionin the nursing infant.

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 In acute poisoning with first-generationH1 antagonists, their central excitatory effects constitute the
greatest danger. The syndrome includes hallucinations, excitement, ataxia, incoordination,
athetosis, andconvulsions, fixed, dilatedpupils with a flushed face, together withsinus tachycardia,
urinary retention, dry mouth, andfever.
 The syndrome exhibits a remarkable similarity to that of atropine poisoning.
 Terminally, there is deepening coma with cardiorespiratory collapse and death usually within2–18
h.
 First-generationantihistamines are not recommendedfor use in childrenbecause their sedative
effects canimpair learning and school performance

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 Histamine and anti-histamines
 Biosynthesis and Distribution of Histamine.
 Histamine is produced by decarboxylation of the amino acid histidine.
 (1) It la synlhe1ized in the mast cells and basophils of the immune system, in
the enterochramaffin-like cells (ECL) of the gastric mucosa, and in different
neurons of the central nervous system (CNS).
(a) Mast cells and basophils store histamine in secretory granules. Its
release is induced by immunoglobulin B (lgB) fixation to mast cells
(sensitization) and subsequent exposure to a specific antigen.
i. Allergic processes or anaphylaxis can trigger degranulation.
(b) ECL cells and histaminergic CNS neurons continuously release
histamine as required for gastric acid secretion and
neurotransmission, respectively.

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 Physiological effects of Histamine.
 All four receptor subtypes H1, H2, H3 and H4 are GPCRs.
1. Histamine (H1) Receptors
 Located in smooth muscles, vascular endothelium and brain.
 They are Gq coupled and activate the second messenger inositol triphosphate (IP3)
and diacylglycerol (DAG).
 H1 receptors commonly mediate inflammatory and allergic reactions. Activation
in the:
(a) Lungs can lead to bronchoconstriction and asthma-like symptoms.
(b) Vascular smooth muscle may cause vasodilation, leading to erythema
(redness of the skin caused by injury or another inflammation-causing condition).
(c) Vascular endothelium can lead to edema.
(d) Peripheral nerves can lead to itchiness and pain.

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 Physiological effects of Histamine.
(1) These receptors are commonly found in parietal cells and cardiac muscles.
(2) They are Gs coupled and lead to the activation of adanylyl cyclase and
increased cyclic AMP (cAMP) production.
(3) Activation of H2-receptors:
(a) Increases gastric acid production, potentially leading to increased risk of
peptic ulcer disease or heartburn.
(b) May also cause minor increases in heart rate.
3. H3 and H4 receptors are located in the brain, hematopoietic cells, and thymus.
(1) There is no approved drugs that act through these receptor.

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 Anti histamine classification
First Generation Antihistamines:
• Doxepin HCl.
• Carbinoxamine Maleate.
• Clemastine fumarate.
• Diphenhydramine HCl.
• Dimenhydrinate.
• Chlorpheniramine maleate.
• Brompheniramine maleate.
• Hydroxyzine HCl.
• Hydroxyzine pamoate.
• Cyclizine HCl.
• Meclizine HCl.
• Promethazine HCl.
• Cyproheptadine HCl.

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 Anti histamine classification
Second Generation Antihistamines:
• Olopatadine HCl.
• Acrivastine.
• Cetrizine HCl.
• Levocetrizine HCl.
• Alcaftadine.
• Bepotastine besilate.
• Desloratadine.
• Fexofenadine HCl.
• Ketotifen fumarate.
• Loratadine.
• Azelastine HCl.
• Emedastine.
• Epinastine.
• Ebastine.

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 Histamine (H1) receptor antagonist.
a) Mechanism of action. These drugs are competitive inhibitors at the H1-receptor.
 They relax histamine-induced contraction of bronchial smooth muscle and
have some use in allergic bronchospasm.
 They block the vasodilator action of histamine and inhibit histamine-
induced increases in capillary permeability.
 They do not affect the release of histamine from secretory granules and
are more effective when given prior to histamine release.

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a) First-generation agents
 Diphenhydramine HCl, Dimenhydrinate, Chlorpheniramine maleate, Cyclizine
HCl, Meclizine HCl, Promethazine HCl
 As a class, these agents are lipid soluble, readily cross the blood-brain
barrier, and have significant CNS actions, mediated in large part by their
anticholinergic activity.
1) Their structures are similar to antimuscarinic agents.
 Indications:
a.These agents are commonly used for management of alIergic symptoms,
insomnia, motion sickness, and nausea and vomiting.

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 Adverse effects:
a. Include sedation (synergistic with alcohol and other depressants), dizziness,
and loss of appetite.
b. They also produce anticholinergic effects (dry mouth, blurred vision, and
urine retention).
b) Second-generation agents
 Cetrizine HCl, Levocetrizine HCl, Fexofenadine HCl, Loratadine, desloratadine,
Ebastine
 These agents are lipophobic and were developed to avoid the sedation and
anticholinergic activity of the first-generation drugs.
 Indications:
a.These agents are preferred over first-generation agents for the treatment of
allergic rhinitis, as they have similar efficacy and less CNS effects.

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 Adverse effects:
a. Significantly reduced with second-generation agents.
a) Mechanism of action. These agents are competitive antagonists at the H2
receptor in the gastric parietal cell; they inhibit gastric acid secretion.
b) Specific agents:
Cimetidine, Ranitidine, famotidine, and nizatidine.
c) Indications:
They are used in the treatment of heartburn and acid-induced indigestion.
They promote the healing of gastric and duodenal ulcers and are used in the
management of gastroesophageal reflux disease (GERD).

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d) Adverse Effects:
H2 antagonists are very safe drugs, and adverse effects are rare. Cimetidine is
an androgen-receptor antagonist and may cause gynecomastia (increase in the
amount of breast gland tissue in boys or men, caused by an imbalance of the
hormones estrogen and testosterone.) and Impotence
e) Drug interactions:
Cimetidine is also a potent cytochrome P-450 (CYP450) inhibitor and has the
potential for many drug interactions.

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 Mast cells stabilizers.
a) Mechanism of action. Mast cell stabilizers inhibit the release of histamine and
other autocoids from mast cells..
b) Specific agents:
Cromolyn and nedocromil.
c) Indications:
a. Cromolyn is available in several dosage forms:
1) Oral solution for systemic mastocytosis (a rare condition caused by an
excess number of mast cells gathering in the body's tissues).
2) Oral inhalation (nebulization) for asthma and prevention of
bronchospasm
3) Nasal spray for allergic rhinitis
4) Ophthalmic solution for conjunctivitis and keratitis.

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c) Indications:
Nedocromil is available as an ophthalmic solution for allergic conjunctivitis.
d) Adverse effects
Include headache, dry mouth, and dry eyes.

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 Serotonin agonist and Antagonist
 Serotonin (5-hydraxytryptllmine, 5-HT)
1. Biosynthesis and Distribution:
a) Serotonin is synthesized from the amino acid tryptophan by
hydroxylation and decarboxylation, in a two-step pathway.
b) Most serotonin is synthesized in the ECL cel1s of the gastrointestinal
(GI) tract. It is also found in platelets and neurons of the CNS and
enteric nervous system.
1. In the CNS, cells in the raphe nuclei of the brainstem predominantly
synthesize serotonin.
c) Serotonin is also a precursor of melatonin.

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 Physiological actions of serotonin:
a) There are multiple 5-IIT-receptor subtypes that mediate a wide variety of
physiological effects.
b) 5-HT1-receptors are Gi, coupled and Inhibit adenylyl cyclase and
decrease cAMP.
(1) These receptors are located in the brain and smooth muscle
tissues.
c) 5-HT2 receptors are Gq coupled and increase Phospholipase C
activity.
(1) These receptors are located in the CNS and mediate
hallucinogenic effects.
(2) Stimulation can also cause contraction of vascular and intestinal

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 Physiological actions of serotonin:
smooth muscle, increase microcirculation and vascular permeability,
and lead to platelet aggregation.
d) 5-HT3 receptors are ligand gated sodium and potassium ion channels.
(1) Stimulation in the area postrema causes nausea and vomiting.
(2) Stimulation on peripheral sensory neurons causes pain.
e) 5-HT4-receptors are Gs coupled and stimulate adenylyl cyclase and
increase cAMP.
(1) In the GI tract, they mediate an increase in secretion and
peristalsis.

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 Serotonin Agonists:
1) Buspirone
(a) Mechanism of Action: Buspirone is a 5-HT1A selective partial
agonist It also possess weak dopamine receptor antagonism.
(b) Indication: It is used for the management of generalized anxiety
disorder.
(1) It may take 2 weeks for the beneficial effects to appear.
(2) It does not affect GABA receptors; therefore, it is not addictive
and causes less sedation than other anxiety medications like
benzodiazepines.
(C) Adverse effects: dizziness, drowsiness, and nasuea.

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2) Triptans
(a) Specific Agents include: Sumatriptan, rizatriptan, eletriptan,
zolmitriptan, almotriptan, frovatriptan, and naratriptan.
(1) All are available as oral agents. Some are also available as nasal
sprays and subcutaneous injection.
(b) Mechanism of Action: Triptans are 5HT1B/1D-receptor agonists.
They cause vasoconstriction and reduce inflammation in intracranial
blood vessels and sensory nerves of the trigeminal system.
(C) Indications: They are commonly used for the treatment of acute
migraines and cluster headaches. About 50%-80% of patients report
relief from pain within 2 hours.

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(D) Adverse effects: May include dizziness, drowsiness, flushing, and
chest pain.
(1) They can cause coronary vasospasm and are contraindicated in
patients with coronary artery diseases (CAD) or angina.

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 Serotonin Antagonists:
(a) Mechanism of Action: They block serotonin receptors centrally in
the chemoreceptor trigger zone and peripherally on vagal nerve
terminals.
(b) Specific agents: Ondansetron, granisetron, dolasetron, and
palonosetron.
(c) Indication: They are used for the prevention of nausea and
vomiting due to chemotherapy and radiation therapy. They are also
used to prevent postoperative nausea and vomiting.
(d) Adverse effects: Include headache and constipation. They also have
the potential to cause QTs prolongation and arrhythmias.

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 Serotonin Antagonists:
 Alosetron is a 5-HT3 antagonist approved for diarrhoea-predominant
irritable bowel syndrome in women. It may cause serious GI side
effects, including ischemic colitis and severe constipation.

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 It includes
 Prostaglandins
 Leukotrienes
 Platelet-activating factor (non-eicosanoids)

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 Eicosanoids are a large group of autocoids with potent effects on many tissues in the
body.
 Eicosanoids are biologically active lipid derivatives of unsaturated fatty acids
containing 20 carbons.
 Eicosanoids are locally acting bioactive hormones that act near the point of hormone
synthesis and included in the class of paracrine hormones.
 Eicosanoids are derived from arachidonic acid and related polyunsaturated fatty acids
(PUFAs) such as eicosapentaenoic acid (EPA).
 The eicosanoids include the prostaglandins, thromboxanes, leukotrienes,
hydroperoxyeicosatetraenoic acids (HPETEs), and hydroxyeicosatetraenoic acids
(HETEs).
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 Synthesis of eicosanoids
 Primary precursor and synthesis
(a) The primary precursor of the prostaglandins and other related
eicosanoids is the Arachidonic acid, containing 20 carbons.
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(b) Arachidonic acid is primarily the constituent of cell membrane
phospholipids, mainly found in phosphatidylinositol and in other
complex forms of lipid.
(c) The release of free arachidonic acid, associated with phospholipids, is
performed mainly by the activity of an enzyme called phospholipase
A2 and other acyl hydrolases also play some role.
(d) The release of free arachidonic acid is under controlled of hormones
and other stimuli.
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1. Eicosanoids are synthesized by two pathways: Cyclooxygenase and
Lipoxygenase.
a. Cyclooxygenase (COX) pathway (there are two forms of COX)
 The COX-1 enzyme is located in the kidney, GI tract, and
platelets, as well as many other locations.
(1) It is expressed at fairly constant level and provides
protective action on gastric mucosa, the endothelium,
and in the kidney.
 The COX-2 enzyme is found in great abundance in connective
tissues, in the kidney, and in the endothelium. It is highly
inducible by numerous factors associated with inflammation.
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 The cox pathway produces thromboxane (TXA2),
prostaglandin E(PGE), prostaglandin F(PGF), prostaglandin D
(PGD), and prostacyclin (PGI2).
b. Lipoxygenase (LOX) pathway
 5-LOX association with 5-LOX-activating protein (FLAP)
produces 5-HPETEs, which are subsequently converted to 5-
HETBs and then to leukotrienes.
2. Eicosanoids are synthesized through out the body (often tissue specific)
and have various physiological effects.
 PGI2 is synthesized in endothelial and vascular smooth muscle
cells.
 Thromboxane synthesis occurs primarily in platelets.
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 Thromboxane synthesis occurs primarily in platelets.
 HPETEs, HETEs, and the leukotrienes are synthesized
predominantly in mast cells, white blood cells, airway
epithelium, and platelets.
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Table: Location and
physiological actions of
Eicosanoids.

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 Indications of eicosanoids
1. Cervical Ripening: Dinoprostone (PGE2), naturally occurring
prostaglandin, reduces the collagen network within the cervix.
It softens the cervix and relaxes the smooth muscles, allowing
dilation and passage of the fetus through the birth canal.
2. Termination of pregnancy: Carboprost tromethamine
(PGF2α) and dinoprostone stimulate uterine
contractions similar to natural labor contractions.
Currently, these prostaglandins are
combined with mifepristone, an
antiprogesterone, which blocks the effects
Of progesterone to cause contraction-
inducing activity in the myometrium.
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3. Maintenance of ductus arteriosus*: Alprostadil (PGE1) will maintain
patency of the ductus arteriosus, which may be desirable before surgery.
4. Nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers:
Misoprostol (PGE1 analog) replaces the protective prostaglandins
(gastromucosal defense mechanisms) consumed with prostaglandin-inhibiting
therapies, such as NSAIDs.
5. Erectile dysfunction: Alprostadil (PGE1) can be injected directly into the
corpus cavernosum or administered as a transurethral suppository to cause
vasodilation and enhance tumescence.
It relaxes trabecular smooth muscle, which allows blood flow to the
lacunar spaces of the penis.
6. Glaucoma: Latanoprost (PGF2α analog) reduces intraocular pressure by
increasing the outflow of aqueous humor.
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*Ductus arteriosus: Before a baby is born, the fetus's blood does not
need to go to the lungs to get oxygenated. The ductus arteriosus is a
hole that allows the blood to skip the circulation to the lungs.
However, when the baby is born, the blood must receive oxygen in the
lungs and this hole is supposed to close. If the ductus arteriosus is still
open (or patent) the blood may skip this necessary step of circulation.
The open hole is called the patent ductus arteriosus.

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7. Pulmonary hypertension: PGI2 analogs (epoprostenol, treprostinil, and
iloprost) are strong vasodilators of pulmonary and systemic vascular beds.
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 Adverse effects of eicosanoids
Adverse effects of eicosanoids include
1. Local pain
2. Irritation
3. Bronchospasm
4. GI disturbances, Including nausea Vomiting, cramping, and
diarrhoea.
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 Inhibitors and Antagonists
1. NSAIDs are used to suppress the symptoms of inflammation and relieve pain
(analgesic action) and fever (antipyretic action).
2. Anti-inflammatory effect
a) PGE2 and PGl2 are primarily involved with inflammation. They promote
blood flow in the inflamed region, enhance edema formation, and enhance
leukocyte infiltration.
b) The anti-inflammatory effect of NSAIDs is due to the inhibition of COX-
1 and COX-2. COX-2 plays an important role in the inflammatory
process, although the effect of its inhibition on Inflammation is not fully
understood.
(1) Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation
of a specific serine residue. This distinguishes it from other
NSAIDs, which reversibly inhibit COX-1 and COX-2.
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(2) COX-2 selective agents inhibit COX-2 more than COX-1. They
inhibit COX-2-mediated prostacyclin synthesis in the vascular
endothelium.
a) Rationale for development: Inhibition of COX-2 would
reduce the inflammatory response and pain but not inhibit the
cytoprotective action of prostaglandins in the stomach.
Unfortunately, this caused an increased risk for serious
cardiovascular thrombotic events.
(3) NSAIDs have no effect on lipoxygenase and therefore do not
inhibit the production of leukotrienes
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3. Analgesic effect (decrease pain): PGE2 and PGl2 are the most important
prostaglandins involved in pain. They are hyperalgesic in the periphery and
centrally. Inhibition of their synthesis is a primary mechanism of NSAID-
mediated analgesia.
4. Antipyretic effect: The antipyretic effect of NSAIDs is believed to be related
to inhibition of production of prostaglandins induced by interleukin-1 (IL-1)
and interleukin-6 (lL-6) in the hypothalamus and the resetting of the
thermoregulatory system, leading to vasodilatation and increased heat loss.
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 Indications
1. NSAIDs are first-line drugs used to arrest inflammation and the accompanying
pain of rheumatic and nonrheumatic diseases.
a. They are used in rheumatoid arthritis, juvenile arthritis, osteo arthritis,
psoriatic arthritis, ankylosing spondylitis, reactive arthritis (Reiter
syndrome), dysmenorrhea, bursitis, and tendonitis.
1. NSAIDs suppress the signs of underlying inflammatory
response but may not reverse or resolve the inflammatory
process.
b. Treatment of chronic inflammation requires higher doses than those
used for analgesia and antipyresis; consequently, the incidence of
adverse drug effects is increased.
c. In some cases, anti-inflammatory effects may develop only after several
weeks of treatment.
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 Rheumatoid arthritis: Rheumatoid arthritis, or RA, is an autoimmune and
inflammatory disease, which means that your immune system attacks healthy cells
in your body by mistake, causing inflammation (painful swelling) in the affected
parts of the body. RA mainly attacks the joints, usually many joints at once.
 Juvenile arthritis: The most common type of childhood arthritis is juvenile
idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis. Childhood
arthritis can cause permanent physical damage to joints. This damage can make it
hard for the child to do everyday things like walking or dressing and can result in
disability.
 Osteo arthritis: Osteoarthritis (OA) is the most common form of arthritis. Some
people call it degenerative joint disease or “wear and tear” arthritis. It occurs most
frequently in the hands, hips, and knees. With OA, the cartilage within a joint
begins to break down and the underlying bone begins to change.
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 Psoriatic arthritis: Psoriatic arthritis is a type of arthritis linked with psoriasis, a
chronic skin and nail disease. Psoriasis causes red, scaly rashes and thick, pitted
fingernails. Psoriatic arthritis is similar to rheumatoid arthritis (RA) in symptoms
and joint swelling (inflammation). But it tends to affect fewer joints than RA.
 Ankylosing spondylitis: Ankylosing spondylitis is a type of arthritis that causes
inflammation in the joints and ligaments of the spine. Normally, the joints and
ligaments in the spine help us move and bend. If you have ankylosing spondylitis,
over time, the inflammation in the joints and tissues of the spine can cause
stiffness.
 Reactive arthritis (Reiter syndrome): Reactive arthritis is joint pain and
swelling triggered by an infection in another part of the body — most often the
intestines, genitals or urinary tract. This condition usually targets the knees, ankles
and feet. Inflammation also can affect the eyes, skin and the tube that carries urine
out of the body (urethra).
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 Dysmenorrhea: Menstrual cramps (dysmenorrhea) are throbbing or cramping
pains in the lower abdomen. Many women have menstrual cramps just before and
during their menstrual periods. For some women, the discomfort is merely
annoying.
 Bursitis: A painful condition that affects the small, fluid-filled sacs — called
bursae (bur-SEE) — that cushion the bones, tendons and muscles near your joints.
Bursitis occurs when bursae become inflamed. The most common locations for
bursitis are in the shoulder, elbow and hip.
 Tendinitis: Tendinitis is inflammation or irritation of a tendon — the thick fibrous
cords that attach muscle to bone. The condition causes pain and tenderness just
outside a joint. While tendinitis can occur in any of your tendons, it's most
common around your shoulders, elbows, wrists, knees and heels.
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 Indications
2. NSAIDs are used to alleviate mild to moderate pain.
a. They are more effective for pain associated with integumental structures
(pain of muscular and vascular origin, arthritis, and bursitis) than with
pain associated with the viscera.
b. They are less effective than opioids.
3. NSAIDs are used to reduce elevate body temperature. They have little effect on
normal body temperature.
4. Aspirin reduces the formation of thrombi.
a. At low doses, aspirin is more selective for COX-1.
b. It has significantly greater antithrombotic activity than other NSAIDs and is
useful in preventing or reducing the risk of myocardial infarction in patients
with a history of myocardial infarction, angina, cardiac surgery, and cerebral
or peripheral vascular disease.
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 Indications
c. It is also used prophylactically to reduce recurrent transient ischemia,
unstable angina, and the incidence of thrombosis after coronary artery by
pass grafts.
5. Salicylic acid is used topically to treat plantar warts, fungal infections, and
corns.
a. It causes destruction of keratinocytes and dermal epithelia by the free acid.
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 Adverse Effects
1. Gastrointestinal events
GI problems are the most common adverse effects. These may include
nausea, vomiting, diarrhea, constipation, dyspepsia, epigastric pain,
bleeding, and ulceration of stomach, duodenum, and small intestine.
Elderly patients and patients with a history of GI bleeding or peptic ulcer
disease are at greatest risk.
These effects are most likely due to a decrease in the production and
cytoprotective activity of prostaglandins, as well as a direct chemical
effect on gastric cells.
Substitution of enteric-coated or timed-release preparations, or the use of
nonacetylated salicylates, may decrease gastric irritation.
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 Adverse Effects
2. Hypersensitivity (intolerance) (also known as aspirin or NSAID-
exacerbated respiratory disease)
Hypersensitivity is relatively uncommon, but can result in rash,
bronchospasm, rhinitis, edema, or an anaphylactic reaction with shock,
which may be life-threatening. The incidence is highest in patients with
asthma and nasal polyps.
Cross-hypersensitivity may exist between aspirin and other NSAIDs.
It is thought that inhibiting the COX pathway diverts arachidonic acid
metabolites to the lipoxygenase pathway, leading to increased synthesis
of cysteinyl leukotrienes (proinflammatory mediators that have an
important role in the pathophysiology of asthma).
Leukotriene-modifying agents, such as a leukotriene-receptor antagonist
(montelukast or zafirlukast), can help prevent exacerbations.
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 Adverse Effects
3. Reye syndrome
Reye syndrome is an illness characterized by vomiting, hepatic
disturbances, and encephalopathy.
It occurs when aspirin or other salicylates are used to control fever during
viral infections (influenza and chickenpox) in children and adolescents.
Acetaminophen is recommended as a substitute for children with fever of
unknown etiology.
4. Renal impairment
NSAIDs may reduce renal blood flow and compromise existing renal
function.
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 Adverse Effects
5. Cardiovascular events
Although aspirin has cardioprotective effects, other NSAIDs can cause an
increased risk of serious cardiovascular thrombotic events, such as
myocardial infarction or stroke.
Compared to other nonselective NSAIDs, COX-2 selective inhibitors
have an increased incidence of heart attack and stroke.
One potential reason for the increased risk of serious (and potentially
fatal) adverse cardiovascular thrombotic events: inhibition of COX-2-
mediated production of the vasodilator, PGl21 by endothelial cells, while
not affecting the prothrombotic actions of COX-I in platelets, increases
the chance of blood clots.
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 Adverse Effects
5. Cardiovascular events
Prolonged bleeding time Platelet adhesion and aggregation may be
decreased. Patients on anticoagulant therapy or with coagulation disorders
must be monitored closely.
Aspirin irreversibly inhibits platelet COX-1 and COX-2 and, therefore,
irreversibly inhibits TXA2 production, suppressing platelet adhesion and
aggregation.
Sulfonamide allergy COX-2 selective inhibitors contain the sulfonamide
structure; therefore, caution must be used in those with a sulfa allergy.
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 Drug Interactions
1. Anticoagulants and antiplatelet agents
The antiplatelet properties of salicylates and NSAIDs in combination
with other anticoagulant or antiplatelet agents may increase the risk of
bleeding.
2. Sulfonylureas (glyburide or Glibenclamide, glimepiride, glipizide)
The hypoglycemic action of sulfonylureas may be enhanced when given
with aspirin and certain NSAIDs due to displacement from their binding
sites on serum albumin.
3. Methotrexate
a. NSAIDs or salicylates should not be given in combination with
methotrexate due to the risk of methotrexate toxicity, which may include
hematologic toxicity (neutropenia, thrombocytopenia), naphrotoxicity, and
hepatotoxicity.
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 Drug Interactions
 There are several potential mechanisms for this interaction, including
decreased renal excretion of methotrexate.
4. Alcohol
Patients should be advised that regularly consuming alcohol when taking
NSAIDs or salicylates could increase the bleeding risk.
5. Aspirin interaction with NSAIDs
Some nonselective NSAIDs may exhibit greater affinity than aspirin for
the active site on the COX enzyme, limiting aspirin's irreversible inhibition
of COX.
COX-2 selective NSAIDs have less risk for this potential interaction.
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 NSAIDs classification:
Propionic acid derivative&
a)Ibuprofen, naproxen, fenoprofen, and ketoprofen
Acetic acid derivatives
a)Indomethacin, sulindac, ketorolac, and diclofenac
b)Diclofenac is a potent anti-inflammatory agent
c)Ketorolac is a potent analgesic and is used for the management of
moderately severe acute pain that requires analgesia at the opioid level.
Due to the potential for severe adverse effects, it is only indicated for
short-term use (use should not exceed 5 days).
Oxicam derivatives
a)Piroxicam
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Fenamate derivatives
a)Mefenamate and meclofenamate
Ketones
a)Nabumetone
COX-2 selective agents
a)Celecoxib
2. Lipid derived
Autacoids

Autacoids
2. Lipid derived
Autacoids

Autacoids
 Other anti-inflammatory drugs:
Other anti-Infammatory drugs are used in the more advanced stages of
some rheumatoid diseases.
1. Gold sodium Thiomalate and auranofin
a. These are gold compounds that may retard the destruction of
bone and joints by an unknown mechanism.
b. These agents can produce serious GI disturbances, dermatitis,
and mucous membrane lesions.
c. Less common effects may include hematologic disorders such
as aplastic anemia and proteinuria, with occasional nephrotic
syndrome.
2. Lipid derived
Autacoids

Physiological Regulation of
Arterial Blood Pressure
Maaz Bin NASIM, PhD.
Assistant Professor

Objectives
By the end of this session, the student should be able to:
a) Outline the different mechanisms involved in regulation of
ABP.
b) Discuss the role of reflexes especially baroreceptor reflex in
regulation of ABP.
c) Discuss the role of renin-angiotensin system in regulation of
ABP.
d) Discuss the role of renal-body fluid in long-term regulation of
ABP.

Mechanisms Involved for Regulation of Arterial
Blood Pressure

Changes in mean arterial
pressure after rapid
hemorrhage
A-return of MAP to normal
by compensatory
mechanism
B-failure of compensatory
mechanism leading to
hypovolemic shock and
death

Mechanisms Involved for Regulation of Arterial
Blood Pressure
Rapidly acting mechanism for regulation of blood pressure
Mostly the nervous control mechanism
• Baro receptor feed back mechanism
• Central nervous system ischemic mechanism
• Chemoreceptor mechanism
Intermediate acting mechanism for control of blood pressure
• Renin angiotensin vasoconstrictor mechanism
• Stress relaxation of vasculature
• Fluid shift across the capillary for adjustment of blood
volume
Long term mechanism for control of blood pressure
• Renal blood volume pressure control mechanism

Sympathetic
nervous
control of
circulation

The baroreceptor
system for controlling
arterial pressure

Role of the Nervous System in Rapid
Control of Arterial Pressure
Nervous control of arterial pressure is by far the most rapid of all our
mechanisms for pressure control.
When there is drop in arterial blood pressure there are three
major changes that occur simultaneously, each of which helps
to increase arterial pressure. They are as follows
1. Most arterioles of the systemic circulation are constricted.
2. The veins especially (but the other large vessels of the
circulation as well) are strongly constricted. This displaces
blood out of the large peripheral blood vessels toward the
heart, thus increasing the volume of blood in the heart
chambers.
3. Finally, the heart itself is directly stimulated by the
autonomic nervous system, further enhancing cardiac
pumping.

Reflex Mechanisms for Maintaining Normal Arterial
Pressure

Reflex Mechanisms for Maintaining Normal Arterial
Pressure
Baroreceptor reflex
•It is the baroreceptor arterial pressure control system and it is
the best known nervous mechanism for control of arterial
pressure.
•Basically, this reflex is initiated by stretch receptors, called
either baroreceptors or pressoreceptors, located at specific
points in the walls of several large systemic arteries.
•Baroreceptors are spray-type nerve endings that lie in the walls
of the arteries; they are stimulated when stretched. They are
extremely abundant in (1) the wall of each internal carotid artery
slightly above the carotid bifurcation, an area known as the
carotid sinus, and (2) the wall of the aortic arch, the aortic sinus.

•The baroreceptors respond much more to a rapidly changing
pressure than to a stationary pressure.
•Carotid sinus <Hering’s nerve<Glossopharyngeal nerve<NTS in
the medulla; Aortic sinus < vagus nerve< NTS in medulla
•Excitation of the baroreceptors by high pressure in the arteries
reflexly causes the arterial pressure to decrease because of both
a decrease in peripheral resistance and a decrease in cardiac
output. Conversely, low pressure has opposite effects, reflexly
causing the pressure to rise back toward normal.
•Function of the Baroreceptors -During Changes in Body Posture
•Because the baroreceptor system opposes either increases or
decreases in arterial pressure, it is called a pressure buffer
system and the nerves from the baroreceptors are called buffer
nerves.
•The long-term regulation of mean arterial pressure by the
baroreceptors requires interaction with additional systems,
principally the renal-body fluid-pressure control system (along with
its associated nervous and hormonal mechanisms).

Changes in mean aortic pressure in response to 8% blood
loss in three groups of individual (2)

Control of Arterial Pressure by the Carotid and Aortic
Chemoreceptors-chemoreceptor reflex
•Whenever the arterial pressure falls below a critical level, the
chemoreceptors become stimulated because diminished blood
flow causes decreased oxygen, as well as excess buildup of
carbon dioxide and hydrogen ions that are not removed by the
slowly flowing blood. The signals transmitted from the
chemoreceptors excite the vasomotor center, and this elevates
the arterial pressure back toward normal.
•However, this chemoreceptor reflex is not a powerful arterial
pressure controller until the arterial pressure falls below 80 mm
Hg. Therefore, it is at the lower pressures that this reflex
becomes important to help prevent further decreases in arterial
pressure

Atrial and Pulmonary Artery Reflexes Regulate Arterial Pressure
Both the atria and the pulmonary arteries have in their walls
stretch receptors called low-pressure receptors
These low-pressure receptors play an important role, especially
in minimizing arterial pressure changes in response to changes
in blood volume
They do detect simultaneous increases in pressure in the low-
pressure areas of the circulation caused by increase in volume,
and they elicit reflexes parallel to the baroreceptor reflexes to
make the total reflex system more potent for control of arterial
pressure

Atrial Reflexes That Activate the Kidneys-The "Volume
Reflex."
•Stretch of the atria also causes significant reflex dilation of
the afferent arterioles in the kidneys. Signals are also
transmitted simultaneously from the atria to the hypothalamus
to decrease secretion of antidiuretic hormone (ADH).
Combination of these two effects-increase in glomerular
filtration and decrease in reabsorption of the fluid-increases
fluid loss by the kidneys and reduces an increased blood
volume back toward normal
•Atrial stretch caused by increased blood volume also elicits a
hormonal effect on the kidneys-release of atrial natriuretic
peptide-that adds still further to the excretion of fluid in the
urine and return of blood volume toward normal

Atrial Reflex Control of Heart Rate (the Bainbridge Reflex)
•An increase in atrial pressure also causes an increase in heart
rate, sometimes increasing the heart rate as much as 75
percent
•The stretch receptors of the atria that elicit the Bainbridge
reflex transmit their afferent signals through the vagus nerves to
the medulla of the brain. Then efferent signals are transmitted
back through vagal and sympathetic nerves to increase heart
rate and strength of heart contraction. Thus, this reflex helps
prevent damming of blood in the veins, atria, and pulmonary
circulation
Central Nervous System Ischemic
Response
This arterial pressure elevation in response to cerebral
ischemia is known as the central nervous system (CNS)
ischemic response. It is one of the most powerful of all the
activators of the sympathetic vasoconstrictor system

The Renin-Angiotensin System: Its Role in Arterial
Pressure Control

Components of the Renin-Angiotensin System
Renin is synthesized and stored in an inactive form called
prorenin in the juxtaglomerular cells (JG cells) of the
kidneys.
The JG cells are modified smooth muscle cells located in the
walls of the afferent arterioles immediately proximal to the
glomeruli.
When the arterial pressure falls, intrinsic reactions in the
kidneys themselves cause many of the prorenin molecules
in the JG cells to split and release renin.
Most of the renin enters the renal blood and then passes out
of the kidneys to circulate throughout the entire body

Renin-angiotensin
vasoconstrictor
mechanism for
arterial pressure
control

Angiotensin II is an extremely powerful vasoconstrictor, and it
also affects circulatory function in other ways as well.
During its persistence in the blood, angiotensin II has two
principal effects that can elevate arterial pressure.
i. The first of these, vasoconstriction in many areas of the
body, occurs rapidly. Vasoconstriction occurs intensely in
the arterioles and much less so in the veins. Constriction of
the arterioles increases the total peripheral resistance,
thereby raising the arterial pressure.
ii. The second principal means by which angiotensin II
increases the arterial pressure is to decrease excretion of
both salt and water by the kidneys. This long-term effect,
acting through the extracellular fluid volume mechanism, is
even more powerful than the acute vasoconstrictor
mechanism in eventually raising the arterial pressure.

Angiotensin II causes the kidneys to retain both salt and water
in two major ways:
1. Angiotensin II acts directly on the kidneys to cause salt and
water retention.
2. Angiotensin II causes the adrenal glands to secrete
aldosterone, and the aldosterone in turn increases salt and
water reabsorption by the kidney tubules.
Thus both the direct effect of angiotensin on the kidney and
its effect acting through aldosterone are important in long-
term arterial pressure control. However, research has
suggested that the direct effect of angiotensin on the
kidneys is perhaps three or more times as potent as the
indirect effect acting through aldosterone-even though the
indirect effect is the one most widely known.

Stress Relaxation ofVasculature

Delayed Compliance in a Venous Segment

Delayed compliance (Stress relaxation) of vessels
The principle of delayed compliance is the mechanism by
which a blood vessels attempts to return back to its original
pressure when it is loaded with blood or blood is withdrawn
from it , this is a property of smooth muscles and is exhibited
by blood vessels as well as hollow viscera like urinary
bladder
When a segment of a vein is exposed to increased volume ,
then immediately its pressure increases but after some time
the pressure returns back to normal due to stretching of the
vessel wall, similarly after drop in original volume due to any
fluid loss the blood pressure decreases for some time and
then it returns back to normal due to changes in the
arrangement of smooth muscle. Similar phenomenon can be
seen in urinary bladder.

Fluid shift across the capillary for adjustment of
blood volume

•The arterial hypotension, arteriolar constriction, and reduced
venous pressure during hemorrhagic hypotension lower
hydrostatic pressure in the capillaries. The balance of these
forces promotes the net reabsorption of interstitial fluid into the
vascular compartment
•Considerable quantities of fluid may thus be drawn into the
circulation during hemorrhage. About 0.25 mL of fluid per
minute per kilogram of body weight may be reabsorbed by the
capillaries. Thus, approximately 1 L of fluid per hour might be
autoinfused from the interstitial spaces into the circulatory
system of an average individual after acute blood loss
•Substantial quantities of fluid may shift slowly from the
intracellular to the extracellular space. This fluid exchange is
probably mediated by secretion of cortisol from the adrenal
cortex in response to hemorrhage. Cortisol appears to be
essential for the full restoration of plasma volume after

Role of renal-body fluid control mechanism in
long-term regulation of ABP

An increase in arterial pressure in the human of only a few mm
Hg can double renal output of water, which is called pressure
diuresis, as well as double the output of salt, which is called
pressure natriuresis.

Control of renal NaCl and water excretion
Renal Sympathetic Nerves (↑ Activity: ↓ NaCl Excretion)
↓GFR
↑ Renin secretion
↑ Na+ reabsorption along the nephron
Renin-Angiotensin-Aldosterone (↑ Secretion: ↓ NaCl Excretion)
↑ Angiotensin II stimulates reabsorption of Na+ along the nephron
↑ Aldosterone stimulates Na+ reabsorption in the thick ascending limb of
Henle's loop, distal tubule, and collecting duct
↑ Angiotensin II stimulates secretion of ADH
Natriuretic Peptides: ANP, BNP, and Urodilatin (↑ Secretion: ↑ NaCl
Excretion)
↑ GFR
↓ Renin secretion
↓ Aldosterone secretion (indirect via ↓ in angiotensin II and direct on the adrenal
gland)
↓ NaCl and water reabsorption by the collecting duct
↓ ADH secretion and inhibition of ADH action on the distal tubule and collecting
duct
ADH (↑ Secretion: ↓ H O Excretion)

Renal Urinary Output Curve
The approximate average effect
of different arterial pressure
levels on urinary volume output
by an isolated kidney,
demonstrating markedly
increased urine volume output
as the pressure rises. This
increased urinary output is the
phenomenon of pressure
diuresis.
Not only does increasing the
arterial pressure increase urine
volume output, but it causes
approximately equal increase in
sodium output, which is the

Increases in cardiac
output, urinary output,
and arterial pressure
caused by increased
blood volume in dogs
whose nervous pressure
control mechanisms had
been blocked. This figure
shows return of arterial
pressure to normal after
about an hour of fluid
loss into the urine

Near infinite feedback gain
This return of the arterial
pressure always back to the
equilibrium point is the near
infinite feedback gain principle
for control of arterial pressure
by the renal-body fluid
mechanism.

Two ways in which the
arterial pressure can be
increased:
A, by shifting the renal
output curve in the right-
hand direction toward a
higher pressure level or
B, by increasing the
intake level of salt and
water

Summary
a) Outline the different mechanisms involved in regulation
of ABP.
b) Discuss the role of reflexes especially baroreceptor
reflex in regulation of ABP.
c) Discuss the role of renin-angiotensin system in
regulation of ABP.
d) Discuss the role of renal-body fluid in long-term
regulation of ABP.

Cardiovascular Pharmacology
Receptor Distribution

Classification of Drugs Used in management of CVS
pathologies
1. Angiotensin converting enzyme inhibitors
Captopril
Enalapril
Lisinopril
Ramipril
Mechanism of Action:
 ACE (angiotensin converting enzyme) cleaves inactive
angiotensin I to active angiotensin II which is a potent
vasoconstrictor.
 It is also involved in breakdown of bradykinin, a peptide
that increases production of nitric oxide and prostacyclin,
both of which are potent vasodilators.
 ACE inhibitors competitively inhibit ACE and
inhibit conversion of angiotensin I to angiotensin II.

 It results in prevention of:
• Pressor effect of angiotensin II.
• Stimulation of aldosterone synthesis and release
resulting in decreased sodium and water retention.
• Metabolism of bradykinin by ACE.
 Thus, vasodilation of both arterioles and veins occur as
a result of decreased vasoconstriction (due to
decreased angiotensin II) and enhanced vasodilation
(due to increased bradykinin).

pathologies
1. Angiotensin converting enzyme inhibitors
Captopril
Enalapril
Lisinopril
Ramipril

pathologies
Angiotensin converting enzyme inhibitors Adverse effects
These agents have the potential to
cause a dry, nonproductive cough,
which resolves when therapy is
discontinued (mostlikely due to
increased bradykinin levels).
Angioedema (life-threatening airway
swelling and obstruction) is rare but
can occur at any time, especially
after the first dose (most likely due
to increased bradykinin levels).
Hyperkalemia is also a common
adverse effect due to reduced
aldosterone levels.

pathologies
Angiotensin converting enzyme inhibitors Adverse effects
Modest reductions in glomerular
filtration rate (GFR) and small
increases in serum creatinine) may
Occur with ACE inhibitors.
Hypotension and dizziness are also
potential adverse effects.
Contraindications:
Drugs that act on the
renin-angiotensin system are
teratogenic and should be
discontinued in pregnancy.

pathologies
2. Angiotensin receptor blockers
Losartan
Candesartan
Valsartan
Telmisartan
 These agents bind to the AT1
angiotensin II receptor and prevent
angiotensin II from binding; this blocks
the effects of angiotensin II, including
aldosterone release and
vasoconstriction.

pathologies
2. Angiotensin receptor blockers
Losartan
Candesartan
Valsartan
Telmisartan
 AT1 receptors are coupled to the Gq
protein and IP3 signal transduction
pathway.
 ARBs have similar effects to ACE
inhibitors, including reduced preload
and afterload and decreased cardiac
remodelling.
 Bradykinin levels are not increased
since ARBs do not inhibit ACE.

pathologies

3.Diuretics
Carbonic anhydrase Inhibitors
Acetazolamide, Dorzolamide,
Brinzolamide
Loop diuretics
Furosemide, bumetanide,
Torsemide, Ethacrynic acid
Thiazide diuretics
Hydrochlorothiazide,
Chlorothiazide, chlorthalidone
(thiazide-like)
K+ sparing diuretics
Spironolactone, eplerenone,
Amiloride, triamterene

3.Diuretics
SGLT2 Inhibitors
Canagliflozin, dapagliflozin,
Empagliflozin.
Osmotic diuretics
Mannitol
ADH antagonists
Conivaptan, Tolvaptan,
Demeclocycline

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