BP 503 T

Pharmacology II
UNIT I
Unit I: Pharmacology of drugs acting on cardio

vascular system
 Description about the
hemodynamic &
electrophysiology of heart.
 Hemodynamic of heart

 Hemodynamics refers to the study of movement of blood through

circulatory system.
 Major function of cardiovascular system is to pump the blood and to
circulate it through different parts of the body.
 It is essential for the maintenance of pressure and other physical
factors within the blood vessels, so that the volume of blood
supplied to different parts of the body is adequate.
 Blood supply of heart: Heart muscle is supplied by two
coronary arteries, namely right and left coronary arteries.
 Coronary arteries are the first branches of aorta.
 Arteries encircle the heart in the manner of a crown, hence the
name coronary arteries.
 Right coronary artery supplies blood to the right atrium,
ventricle, SA (sinoatrial) and AV (atrioventricular) nodes.
 Left coronary artery supplies blood to the left atrium and
ventricle.
 Heart rate: Number of beats per minutes (72 beats/min.)

 Tachycardia: Tachycardia is the increase in heart rate above 100/minute.

 Bradycardia: Bradycardia is the decrease in heart rate below 60/minute.

 Heart rate is maintained within normal range constantly

 Heart rate is regulated by the nervous mechanism, which consists of three

components:
 Vasomotor center
 Motor (efferent) nerve fibers to the heart
 Sensory (afferent) nerve fibers from the heart
 Cardiac output: is the amount of blood pumped from each ventricle.
Usually, it refers to left ventricular output through aorta.
 Cardiac output is the most important factor in cardiovascular system,
because rate of blood flow through different parts of the body depends
upon cardiac output.
 Cardiac output is maintained (determined) by four factors:
 Venous return
 Force of contraction
 Heart rate
 Peripheral resistance
 Minute volume (Cardiac output): Minute volume is the amount of
blood pumped out by each ventricle in one minute. It is the product of
stroke volume and heart rate:
 Minute volume = Stroke volume × Heart rate

 Stroke volume: is the amount of blood pumped out by each ventricle

during each beat.
 Normal value: 70 mL (60 to 80 mL) when the heart rate is
normal (72/minute).

 Minute volume = Stroke volume × Heart rate

= 70 x 72
= 5L/ventricle/minute
 Blood pressure: Generally, the term ‘blood pressure’ refers to arterial
blood pressure.
 Arterial blood pressure is defined as the lateral pressure exerted by the
column of blood on wall of arteries / The pressure is exerted when
blood flows through the arteries..
 Arterial blood pressure is expressed in four different terms:
 Systolic blood pressure
 Diastolic blood pressure
 Pulse pressure
 Mean arterial blood pressure
 „Systolic blood pressure: Systolic blood pressure (systolic pressure) is
defined as the maximum pressure exerted in the arteries during systole of
heart.
 Normal systolic pressure: 120 mm Hg (110 mm Hg to 140 mm
Hg).
 Diastolic blood pressure: Diastolic blood pressure (diastolic pressure) is
defined as the minimum pressure exerted in the arteries during diastole of
heart.
 Normal diastolic pressure: 80 mm Hg (60 mm Hg to 80 mm Hg).
 „Pulse pressure: Pulse pressure is the difference between the systolic
pressure and diastolic pressure.
 Normal pulse pressure: 40 mm Hg (120 – 80 = 40).
 „Mean arterial blood pressure: Mean arterial blood pressure is the
average pressure existing in the arteries.
 It is not the arithmetic mean of systolic and diastolic pressures. It is the
diastolic pressure plus one third of pulse pressure.
 To determine the mean pressure, diastolic pressure is considered than the
systolic pressure. It is because, the diastolic period of cardiac cycle is
longer (0.53 second) than the systolic period (0.27 second).
Normal mean arterial pressure: 93 mm Hg (80 + 13= 93).
Formula to calculate mean arterial blood pressure:
Mean arterial blood pressure
= Diastolic pressure + 1/3 of pulse pressure
= 80 + 40/3= 93.3 mm Hg
  Cardiac Cycle
 Cardiac cycle is defined as the succession of (sequence of)
coordinated events taking place in the heart during each beat.
 Each heartbeat consists of two major periods called systole and
diastole. During systole, heart contracts and pumps the blood through
arteries. During diastole, heart relaxes and blood is filled in the heart.
 All these changes are repeated during every heartbeat, in a cyclic
manner.
 Events of cardiac cycle are classified into two:
1. Atrial events
2. Ventricular events.
 When the heart beats at a normal rate of 72/minute, duration of
each cardiac cycle is about 0.8 second.

 „Atrial events
Atrial events are divided into two divisions:
1. Atrial systole = 0.11 (0.1) sec
2. Atrial diastole = 0.69 (0.7) sec.
 „Ventricular events
Ventricular events are divided into two divisions:
1. Ventricular systole = 0.27 (0.3) sec
2. Ventricular diastole = 0.53 (0.5) sec.
 Ventricular Systole (0.27 sec)
Time duration in sec.
 Isometric contraction = 0.05
 Ejection period = 0.22
 Ventricular Diastole (0.53 sec)
 Protodiastole = 0.04
 Isometric relaxation = 0.08
 Rapid filling = 0.11
 Slow filling = 0.19
 Last rapid filling = 0.11
Video link 1:
https://www.youtube.com/watch?v=IS9TD9fHFv0&ab_channel=AlilaMedic
alMedia
Video link 2:
https://www.youtube.com/watch?v=RYZ4daFwMa8&ab_channel=AlilaMedi
calMedia
 Description about the
hemodynamic &
electrophysiology of heart.
 Electrophysiology of heart

 Electrophysiology of heart includes: impulse generation, conduction,

excitbility and refractory period or excitability, rhythmicity,
conductivity and contactility.
 On the basis of electrophysiology cardiac muscle fibers are
categorized into two types:
 Nonautomatic fibers: These are the ordinary working
myocardial fibers; cannot generate an impulse of their own.
 Automatic fibers (muscle fibers of SA and AV nodes):
specialized to generate an impulse by their own.
 Resting Membrane Potential
Resting membrane potential in:
• Single cardiac muscle fiber : – 85 to – 95 mV
• Sinoatrial (SA) node : – 55 to – 60 mV
• Purkinje fibers : – 90 to – 100 mV
 Action Potential
Action potential in cardiac muscle is different from that of other
tissues such as skeletal muscle, smooth muscle and nervous tissue.
Duration of the action potential in cardiac muscle is 250 to 350 msec
(0.25 to 0.35 sec).
Phases of action potential: Action potential in a single cardiac muscle
fiber occurs in four phases:
• Initial depolarization
• Initial repolarization
• A plateau or final depolarization
• Final repolarization
1. Initial depolarization
Initial depolarization is very rapid and it lasts for about 2 msec (0.002
sec). Amplitude of depolarization is about + 20 mV
2. Initial Repolarization: Immediately after depolarization, there is an initial
rapid repolarization for a short period of about 2 msec. The end of rapid
repolarization is represented by a notch.

3. Plateau or Final Depolarization: Afterwards, the muscle fiber remains in

depolarized state for sometime before further repolarization. It forms the plateau
(stable period) in action potential curve. The plateau lasts for about 200 msec in
atrial muscle fibers and for about 300 msec in ventricular muscle fibers. Due to
long plateau in action potential, the contraction time is also longer in cardiac
muscle by 5 to 15 times than in skeletal muscle.

4. Final Repolarization: Final repolarization occurs after the plateau. It is a

slow process and it lasts for about 50 to 80 msec before the re-establishment of
resting membrane potential.
 „IONIC BASIS OF ACTION POTENTIAL

1. Initial depolarization: Initial depolarization (first phase) is because of rapid

opening of fast sodium channels and the rapid influx of sodium ions, as in the case
of skeletal muscle fiber.

2. Initial repolarization: Initial repolarization is due to the transient (short duration)

opening of potassium channels and efflux of a small quantity of potassium ions
from the muscle fiber. Simultaneously, the fast sodium channels close suddenly and
slow sodium channels open, resulting in slow influx of low quantity of sodium ions.
3. Plateau or Final Depolarization:
 Plateau is due to the slow opening of calcium channels. These channels are
kept open for a longer period and cause influx of large number of calcium
ions.
 Already the slow sodium channels are opened, through which slow influx of
sodium ions continues.
 Because of the entry of calcium and sodium ions into the muscle fiber,
positivity is maintained inside the muscle fiber, producing prolonged
depolarization, i.e. plateau.
 Calcium ions entering the muscle fiber play an important role in the
contractile process.
4. Final Repolarization:
 Final repolarization is due to efflux of potassium ions.
 Number of potassium ions moving out of the muscle fiber exceeds the number
of calcium ions moving in.
 It makes negativity inside, resulting in final repolarization.
 Potassium efflux continues until the end of repolarization.
 Restoration of Resting Membrane Potential:
 At the end of final repolarization, all sodium ions, which had entered
the cell throughout the process of action potential move out of the
cell and potassium ions move into the cell, by activation of sodium-
potassium pump.
 Simultaneously, excess of calcium ions, which had entered the
muscle fiber also move out through sodium calcium pump. Thus,
the resting membrane potential is restored.
 Automatic fibers

Pacemaker is the structure of heart from which the impulses for heartbeat
are produced. It is formed by the pacemaker cells called P cells. In
mammalian heart, the pacemaker is sinoatrial node (SA node). It was Lewis
Sir Thomas, who named SA node as pacemaker of heart, in 1918.
 ELECTRICAL POTENTIAL IN SA NODE
 Resting Membrane Potential: Resting membrane potential in
Pacemaker (SA node) potential is the unstable.
 It is also called prepotential. Electrical potential in SA node is different
from that of other cardiac muscle fibers.
 In SA node, each impulse triggers the next impulse.
 It is mainly due to the unstable resting membrane potential.
 Resting membrane potential in SA node has a negativity of –55 to –60
mV.
 It is different from the negativity of –85 to –95 mV in other cardiac
muscle fibers.
 Action Potential
 Depolarization starts very slowly and the threshold level of –40 mV is
reached very slowly.
 After the threshold level, rapid depolarization occurs up to +5 mV. It is
followed by rapid repolarization.
 Once again, the resting membrane potential becomes unstable and
reaches the threshold level slowly
 Ionic Basis of Electrical Activity in Pacemaker
 Pacemaker potential or resting membrane potential
 Resting membrane potential is not stable in the SA node.
 To start with, the sodium ions leak into the pacemaker fibers
and cause slow depolarization.
 This slow depolarization forms the initial part of pacemaker
potential.
 Then, the calcium channels start opening. At the
beginning, there is a slow influx of calcium ions causing
further depolarization in the same slower rate. It forms the
later part of the pacemaker potential.
 Thus, the initial part of pacemaker potential is due to slow
influx of sodium ions and the later part is due to the slow
influx of calcium ions.
 Depolarization
When the negativity is decreased to –40 mV, which is the threshold
level, the action potential starts with rapid depolarization. The
depolarization occurs because of influx of more calcium ions. Unlike
in other tissues, the depolarization in SA node is mainly due to the
influx of calcium ions, rather than sodium ions.
 Repolarization
After rapid depolarization, repolarization starts.
It is due to the efflux of potassium ions from pacemaker
fibers.
Potassium channels remain open for a longer time, causing
efflux of more potassium ions.
It leads to the development of more negativity, beyond the
level of resting membrane potential.
It exists only for a short period.
Then, the slow depolarization starts once again, leading to
the development of pacemaker potential,which triggers the
next action potential.
 „Conductivity
Human heart has a specialized conductive system, through which impulses
from SA node are transmitted to all other parts of the heart
Components of Conductive System in Human Heart
 AV node
 Bundle of His
 Right and left bundle branches
 Purkinje fibers.

 Contractility
Heart muscles works on ALL or NONE phenomenon, According to all-or-none
law, when a stimulus is applied, whatever may be the strength, the whole
cardiac muscle gives maximum response or it does not give any response at all.
Below the threshold level, i.e. if the strength of stimulus is not adequate, the
muscle does not give response
 Refractory period
Pharmacologically, the effective refractory period (ERP) which is the
minimum interval between two propagating APs, is the most important. It is
closely related to the AP duration (APD).

 Velocity of impulses at different parts of conductive system

 Atrial muscle fibers : 0.3 meter/second
 Internodal fibers : 1.0 meter/second
 AV node : 0.05 meter/second
 Bundle of His : 0.12 meter/second
 Purkinje fibers : 4.0 meter/second
 Ventricular muscle fibers : 0.5 meter/second
Video link:

https://www.youtube.com/watch?v=v7Q9BrNfIpQ&ab_channel=Alila
MedicalMedia
 Antihypertensive drugs
RENIN-ANGIOTENSIN SYSTEM
 Adrenergic receptor in CVS

 Alpha (α1 and 2) receptor: Vasoconstriction

 Beta (β1) receptor: cardiac stimulation, increase
force of contraction, increase heart rate
 Normal Blood pressure: 120/80 mm of Hg
 Hypertension is defined conventionally as a sustained
increase in blood pressure ≥140/90 mm Hg
 History

 Before 1950 hardly any effective and tolerated antihypertensive was

available. Veratrum and Sod. thiocyanate could lower BP, but were toxic

and difficult to use.

 The ganglion blockers developed in the 1950s were effective, but

inconvenient.

 Reserpine was a breakthrough, but produced mental depression.

 The therapeutic potential of hydralazine could not be tapped fully because

of marked side effects when it was used alone.

 Guanethidine introduced in 1961 was an improvement on ganglion

blockers.
 The antihypertensives of the 1960–70s were methyldopa, β blockers,

thiazide and high ceiling diuretics and clonidine.

 The status of β blockers and diuretics was consolidated in the 1970s and

selective α1 blocker prazosin broke new grounds.

 The antihypertensives of the 1980–90s are angiotensin II converting

enzyme (ACE) inhibitors and calcium channel blockers.

 Angiotensin receptor blockers (losartan, etc.) were added soon after,

and the direct renin inhibitor aliskiren is the latest drug.

 CLASSIFICATION
1. Diuretics:
 Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide
 High ceiling: Furosemide, etc.
 K+ Sparing: Spironolactone, Amiloride
2. ACE inhibitors:
 Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc.
3. Angiotensin (AT1 receptor) blockers:
 Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan
4. Direct renin inhibitor:
 Aliskiren
5. Calcium channel blockers:
 Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine,
Nitrendipine, Lacidipine, etc.
6. β Adrenergic blockers:
 Propranolol, Metoprolol, Atenolol, etc.
7. β + α Adrenergic blockers:
 Labetalol, Carvedilol
8. α Adrenergic blockers:
 Prazosin, Terazosin, Doxazosin, Phentolamine,
Phenoxybenzamine
9. Central sympatholytics:
 Clonidine, Methyldopa
10. Vasodilators:
 Arteriolar: Hydralazine, Minoxidil, Diazoxide
 Arteriolar + venous: Sodium nitroprusside
  Diuretics
 Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide
 High ceiling: Furosemide, etc.
 K+ Sparing: Spironolactone, Amiloride
Site I: Proximal
tubule

Site II:
Ascending limb
of loop of Henle

Site III: Cortical

diluting segment
of loop of Henle

Site IV: Distal

tubule (DT) and
collecting duct
(CD)
  Thiazides

MOA: inhibit Na+–Cl¯ symport at the luminal membrane

 These drugs gain access to their site of action via organic acid
secretory pathway in PT and then along the tubular fluid to the early
DT, where they bind to specific receptors located on the luminal
membrane.
 Na+-Cl¯ symporter is also a glycoprotein with 12 membrane spanning
domains that binds thiazides but not furosemide or any other class of
diuretics

 Some of the thiazides and related drugs have additional CAse inhibitory
action in PT; intensity of this action differs among different compounds
 Under thiazide action, increased amount of Na+ is presented to the
distal nephron, more of it exchanges with K+, urinary K+ excretion is
increased in parallel to the natriuretic response

 The extrarenal actions of thiazides consist of a slowly developing fall

in BP in hypertensives and elevation of blood sugar in some patients
due to decreased insulin release which probably is a consequence of
hypokalaemia.
 Pharmacokinetics
 All thiazides and related drugs are well absorbed orally.
 There are no injectable preparations of these drugs.
 Their action starts within 1 hour, but the duration varies from 6–48 hours.
 The more lipid-soluble agents and agents have high protein binding have larger
volumes of distribution, lower rates of renal clearance and are longer acting.
 Most of the agents undergo little hepatic metabolism and are excreted as such.
 They are filtered at the glomerulus as well as secreted in the PT by organic anion
transport.
 Tubular reabsorption depends on lipid solubility: the more lipid soluble ones are
highly reabsorbed—prolonging duration of action.
 USES
 Edema
 Hypertension
 Diaetes isipidus
 Hypercalciuria
 Adverse effect
 Hypokalemia
 Acute saline depletion
  High ceiling

 MAO: The major site of action is the thick AscLH (therefore also
known as loop diuretics) where furosemide inhibits Na+- K+-2Cl¯
cotransport
  Potassium sparing

 MAO: They antagonize the action of aldosterone / they are aldosterone

antagonist (working of Na+ K+ ATPase pump get disturbed or blocked)
  Calcium channel blockers
 Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine,
Nitrendipine, Lacidipine, etc.

 Classes of calcium channel blockers are:

 Verapamil—a phenyl alkylamine, hydrophilic papaverine congener.
 Nifedipine—a dihydropyridine (lipophilic).
 Diltiazem—a hydrophilic benzothiazepine
  Calcium channels
Three types of Ca2+ channels have been described in smooth muscles
(other excitable cells as well):
 Voltage sensitive channel Activated when membrane potential drops to
around –40 mV or lower.
 Receptor operated channel Activated by Adr and other agonists—
independent of membrane depolarization (NA contracts even
depolarized aortic smooth muscle by promoting influx of Ca2+ through
this channel and releasing Ca2+ from sarcoplasmic reticulum).
 Leak channel Small amounts of Ca2+ leak into the resting cell and are
pumped out by Ca2+ATPase. Mechanical stretch promotes inward
movement of Ca2+, through the leak channel or through separate stretch
sensitive channel
 The voltage sensitive Ca2+ channels are heterogeneous: three
major types have been identified

L-type
(Long
lasting
current)

Types of Voltage
sensitive calcium
channels

T-type N-type
(transient (neuronal
current) type)
 All voltage sensitive Ca2+ channels are membrane spanning funnel shaped
glycoproteins that function as ion selective valves. They are composed of a
major α1 subunit which encloses the ion channel and other modulatory
subunits like α2,β, γ and δ. In L-type Ca2+ channels each subunit exists in
multiple isoforms which may be site specific, e.g.
 Skeletal muscle L-channels are: α1s . α2/δa . β1 . γ
 Cardiac muscle L-channels are: α1ca . α2/δc . β2
 Smooth muscle L-channels are: α1cb . α2/δ . β3
 Only the voltage sensitive L-type channels are blocked by the CCBs.
 The 3 groups of CCBs viz. phenylalkylamines (verapamil),
benzothiazepine (diltiazem) and dihydropyridines (nifedipine) bind to their
own specific binding sites on the α1 subunit; all restricting Ca2+ entry.
 Further, different drugs may have differing affinities for various site
specific isoforms of the L-channels
 Pharmacokinetics

 Adverse effects: Frequent side effects are palpitation, flushing, ankle

edema, hypotension, headache, drowsiness and nausea. These are related
to peaks of drug level in blood: can be minimized by low starting dose or
fractionation of dose or use of retard formulation

 Nitrendipine: A DHP with oral bioavailability of 10–30% and

elimination t½ of 4–12 hours. It has been shown to release NO from the
endothelium and inhibit cAMP phosphodiesterase. These may be the
additional mechanisms of vasodilator action.
  Vasodilators
 Arteriolar: Hydralazine, Minoxidil, Diazoxide
 Arteriolar + venous: Sodium nitroprusside

 Hydralazine/Dihydralazine Introduced in the 1950s, it is a directly

acting arteriolar vasodilator with little action on venous capacitance
vessels.
 Reduces t.p.r. and causes greater decrease in diastolic than in
systolic BP.

 The mechanism of vascular smooth muscle relaxant action of

hydralazine is not clearly known. Interference with Ca2+ release,
opening of certain K+ channels and/or NO generation may be
involved.
 Minoxidil: It is a powerful vasodilator, the pattern of action resembling
hydralazine, i.e. direct relaxation of arteriolar smooth muscle
 Minoxidil is a prodrug—converted to an active metabolite (by sulfate
conjugation) which is an opener of ATP operated K+ channels; acts by
hyperpolarizing smooth muscle
 Antianginal drugs
 ANGINA PECTORIS

 Angina pectoris:
 Is a pain syndrome
 Occurs due to induction of an adverse oxygen
supply/demand situation in a portion of the myocardium.
 Type Angina pectoris

 Classical angina
 Attacks are predictably provoked (stable angina) by exercise, emotion,
eating.
 subside when the increased energy demand is withdrawn.
 Pathological reason is arterioslerotic plaque, decreases the blood flow
 Classical angina
 Attacks occur at rest or during sleep and are unpredictable
 recurrent localized coronary vasospasm
 Unstable angina
 due to rupture of an atheromatous plaque attracting platelet deposition
and progressive occlusion of the coronary artery
 CLASSIFICATION
1. Nitrates
 Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)
 Long acting: Isosorbide dinitrate (short acting by sublingual route),
Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate
2. β Blockers
 Propranolol, Metoprolol, Atenolol and others.
3. Calcium channel blockers
 Phenyl alkylamine: Verapamil
 Benzothiazepine: Diltiazem
 Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine,
Nimodipine, Lacidipine, Lercanidipine, Benidipine
4. Potassium channel opener
 Nicorandil
5. Others: Dipyridamole, Trimetazidine, Ranolazine, Ivabradine, Oxyphedrine
  Clinical classification

 Used to abort or terminate attack GTN, Isosorbide dinitrate (sublingually).

 Used for chronic prophylaxis All other drugs
 Nitrates
 Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)
 Long acting: Isosorbide dinitrate (short acting by sublingual route),
Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol
tetranitrate
 All organic nitrates share the same action; differ only in time course. The
only major action is direct nonspecific smooth muscle relaxation

Preload reduction: The most prominent action is exerted on vascular smooth

muscle. Nitrates dilate veins more than arteries → peripheral pooling of blood
→ decreased venous return, i.e. preload on heart is reduced → end diastolic size
and pressure are reduced → decreased cardiac work

Afterload reduction: Nitrates also produce some arteriolar dilatation →

slightly decrease total peripheral resistance (t.p.r.) or afterload on heart; BP falls
somewhat; systolic more than diastolic. This action contributes to the reduction
in cardiac work.
  M.O.A of Nitrates

 Organic nitrates are rapidly denitrated enzymatically in the smooth muscle

cell to release the reactive free radical nitric oxide (NO)
 The released NO, activates cytosolic guanylyl cyclase
 Activated guanylyl cyclase converts the GTP into cGMP
 Increased cGMP causes dephosphorylation of myosin light chain kinase
(MLCK) through a cGMP dependent protein kinase
 Reduced availability of phosphorylated (active) MLCK interferes with
activation of myosin → it fails to interact with actin to cause contraction.
Consequently relaxation occurs. Raised intracellular cGMP may also
reduce Ca2+ entry—contributing to relaxation.
 M.O.A of Nitrates
  Pharmacokinetics
 Organic nitrates are lipid soluble: well absorbed from buccal mucosa,
intestines and skin.
 Ingested orally, all except isosorbide mononitrate undergo extensive and
variable first pass metabolism in liver.
 They are rapidly denitrated by a glutathione reductase and a
mitochondrial aldehyde dehydrogenase.
 The partly denitrated metabolites are less active, but have longer t½.
 Though nitrates have been traditionally classified into short-acting and
long-acting.
 It is the rate of absorption from the site of administration and the rate of
metabolism that govern the duration of action of a particular nitrate. For
example, GTN and isosorbide dinitrate are both short-acting from
sublingual but longer-acting from oral route.
 Adverse effects
 These are mostly due to vasodilatation.
1. Fullness in head, throbbing headache; some degree of tolerance
develops on continued use.
2. Flushing, weakness, sweating, palpitation, dizziness and fainting; these
are mitigated by lying down. Erect posture and alcohol accentuate these
symptoms.
3. Methemoglobinemia: is not significant with clinically used doses.
However, in severe anaemia, this can further reduce O2 carrying capacity
of blood.
4. Rashes are rare, though relatively more common with pentaerythritol
tetranitrate.
 Potassium channel opener

 Opens the ATP sensitive K+ Channel

 hyperpolarizing vascular smooth muscle
 Like nitrates it also acts as a NO donor—relaxes blood vessels by
increasing cGMP.
 Nicorandil is well absorbed orally, nearly completely metabolized in liver
and is excreted in urine
 Side effects of nicorandil are flushing, palpitation, weakness, headache,
dizziness, nausea
 Large painful aphthous ulcers in the mouth, which heal on stopping
nicorandil have been reported.
 Antiarrhythmic drugs
 Electrocardiography

 Electrocardiography is the technique by which electrical activities of the

heart are studied.
 The spread of excitation through myocardium produces local electrical
potential. This low-intensity current flows through the body.
 This current can be picked up from surface of the body by using suitable
electrodes and recorded in the form of electrocardiogram.
 This technique was discovered by Dutch physiologist, Einthoven Willem,
who is considered the father of electrocardiogram (ECG).
 Electrocardiograph

 Electrocardiograph is the instrument (machine) by which electrical

activities of the heart are recorded.
 Electrocardiogram

 Electrocardiogram is the record or graphical registration/represention

of electrical activities of the heart, which occur prior to the onset of
mechanical activities.
 It is the summed electrical activity of all cardiac muscle fibers
recorded from surface of the body.
Normal ECG
  Arrhythmia

 Arrhythmia refers to irregular heartbeat or disturbance in the rhythm of

heart.
 In arrhythmia, heartbeat may be fast or slow or there may be an extra
beat or a missed beat.
 It occurs in physiological and pathological conditions.

 Abnormal automaticity or impaired conduction or both underlie cardiac

arrhythmias.
  Classification of Arrhythmia

 In arrhythmia, SA node may or may not be the pacemaker.

 If SA node is not the pacemaker, any other part of the heart such as atrial
muscle, AV node and ventricular muscle becomes the pacemaker.
 Arrhythmia is classified into two types:
 Normotopic arrhythmia
 Ectopic arrhythmia
 Normotopic arrhythmia is the irregular heartbeat, in which SA node is
the pacemaker.
 Normotopic arrhythmia is of three types:
 Sinus arrhythmia
 Sinus tachycardia
 Sinus bradycardia
 Sinus arrhythmia is a normal rhythmical increase and decrease in heart
rate, in relation to respiration. It is also called respiratory sinus
arrhythmia (RSA).
Normal sinus rhythm means the normal heartbeat with SA node as
the pacemaker. Normal heart rate is 72 per minute. However, under
physiological conditions, in a normal healthy person, heart rate varies
according to the phases of respiratory cycle. Heart rate increases during
inspiration and decreases during expiration.
 Sinus tachycardia is the increase in discharge of impulses from SA
node, resulting in increase in heart rate. Discharge of impulses from SA
node is very rapid and the heart rate increases up to 100/minute and
sometimes up to 150/minute.
 ECG is normal in sinus tachycardia, except for short R-
Rintervals because of increased heart rate

 Sinus bradycardia is the reduction in discharge of impulses from SA

node resulting in decrease in heart rate. Heart rate is less than
60/minute.
• ECG shows prolonged waves and prolonged R-R interval
  Ectopic arrhythmia

 Ectopic arrhythmia is the abnormal heartbeat, in which one of the

structures of heart other than SA node becomes the pacemaker.
 Impulses produced by these structures are called ectopic foci.

 Subtypes of Ectopic Arrhythmia

Ectopic arrhythmia is further divided into two subtypes:
1. Homotopic arrhythmia, in which the impulses for heartbeat arise
from any part of conductive system
2. Heterotopic arrhythmia, in which the impulses arise from the
musculature of heart other than conductive system.
 Extrasystoles (ES): are premature ectopic beats
due to abnormal automaticity or after
depolarization arising from an ectopic focus in the
atrium (AES).

 Paroxysmal supraventricular tachycardia

(PSVT): is sudden onset episodes of atrial
tachycardia (rate 150–200/min) mostly due to
circus movement type of reentry occurring within
or around the A-V node or using an accessory
pathway between atria and ventricle (Wolff-
Parkinson-White syndrome or WPW).
 Atrial flutter (AFI): Atria beat at a rate of 200-
350/min. This is mostly due to a stable re-entrant
circuit in the right atrium, but some cases may be
due to rapid discharge of an atrial focus.

 Atrial fibrillation (AF): Atrial fibres are activated

asynchronously at a rate of 350–550/min (due to
electrophysiological inhomogeneity of atrial
fibres), associated with grossly irregular and often
fast (100–160/min) ventricular response. Atria
remain dilated and quiver like a bag of worms.
 Ventricular tachycardia (VT): is a run of 4 or
more consecutive ventricular extrasystoles. It may
be a sustained or nonsustained arrhythmia, and is
due either to discharges from an ectopic focus,
after-depolarizations or single site (monomorphic)
or multiple site (polymorphic) reentry circuits.

 Ventricular fibrillation (VF): is grossly irregular,

rapid and fractionated activation of ventricles
resulting in incoordinated contraction of its fibres
with loss of pumping function. It is fatal unless
reverted within 2–5 min; is the most common cause
of sudden cardiac death.
 Atrio-ventricular (A-V) block: is due to
depression of impulse conduction through the
A-V node and bundle of His, mostly due to
vagal influence or ischaemia.
 Congestive Heart Failure
  Congestive Heart Failure

 Heart failure or cardiac failure is the condition in which the

heart looses the ability to pump sufficient amount of blood to all
parts of the body. Heart failure may involve left ventricle or right
ventricle or both. It may be acute or chronic.
 Congestive heart failure is a general term used to describe the
heart failure resulting in accumulation of fluid in lungs and
other tissues.
 When heart is not able to pump blood through aorta, the blood
remains in heart. It results in dilatation of the chambers and
accumulation of blood in veins (vascular congestion).
 Fluid retention and pulmonary edema also occur in this
condition
  TREATMENT OF CHF

There are two distinct goals of drug therapy inCHF:

 Relief of congestive/low output symptoms and restoration of cardiac
performance. This can be achieved by:
 Inotropic drugs: Digoxin, dobutamine/dopamine, amrinone/milrinone
 Diuretics: Furosemide, thiazides
 RAS inhibitors: ACE inhibitors/ARBs
 Vasodilators: hydralazine, nitrate,nitroprusside
 β blocker—Metoprolol, bisoprolol,carvedilol, Nebivolol
 Arrest/reversal of disease progression and prolongation of survival, possible
with:
 ACE inhibitors/ ARBs, β blockers
 Aldosterone antagonist—Spironolactone, eplerenone
  Types of drugs effects on heart

Classified into four types:

1. Chronotropic action: heart rate
2. Inotropic action: force of contraction
3. Dromotropic action: conduction of impulse
4. Bathmotropic action: excitability of cardiac muscle
  CARDIAC GLYCOSIDES

 These are glycosidic drugs having cardiac inotropic property.

 They increase myocardial contractility and output in a hypodynamic
heart without a proportionate increase in O2 consumption.
 Thus, efficiency of failing heart is increased. In contrast, ‘cardiac
stimulants’ (Adr, theophylline) increase O2 consumption rather
disproportionately and tend to decrease myocardial efficiency.
 Cardiac glycosides are found in several plants and in toad skin
(Bufotoxin). Digitalis lanata is the source of Digoxin, the only
glycoside that is currently in use. Others like Digitoxin (from
Digitalis purpurea) and Ouabain (from Strophanthus gratus), etc.
are no longer clinically used or marketed.

 The cardiac glycosides consist of an aglycone (genin) to which

are attached one or more sugar (glucose or digitoxose) moieties
 Mechanism of actions:

Increases the force of contraction, Decreases heart rate

 Antihyperlipidaemic drugs
  Lipoprotein

 Lipids are carried in plasma in lipoproteins after getting associated

with several apoproteins; plasma lipid concentrations are dependent on
the concentration of lipoproteins.
 The core of lipoprotein globules consists of triglycerides (TGs) or
cholesteryl esters (CHEs) while the outer polar layer has
phospholipids, free cholesterol (CH) and apoproteins.
 The lipoproteins have been divided into 6 classes on the basis of
their particle size and density.
 Dietary lipids are absorbed in the intestine with the help of bile acids.
Chylomicrons (Chy) are formed and passed into lacteals—reach blood
stream via thoracic duct.
 During their passage through capillaries, the endothelium bound
lipoprotein lipase hydrolyses the TGs into fatty acids which pass into
muscle cells to be utilized as energy source and in fat cells to be
reconverted into TGs and stored.
 The remaining part—chylomicron remnant (Chy. rem.) containing mainly
CHE and little TG is engulfed by liver cells, which have receptors for the
surface apoproteins of Chy. rem., and digested.
 Free CH that is liberated is either stored in liver cells after reesterification
or incorporated into a different lipoprotein and released in blood or
excreted in bile as CH/bile acids.
 Liver secretes very low density lipoproteins (VLDL) containing mainly TG
and some CHE into blood.
 VLDL is acted upon by endothelial lipoprotein lipase in the same way as on
Chy and the fatty acids pass into adipose tissue and muscle; the remnant
called intermediate density lipoprotein (IDL) now contains more CHE than
TG.
 About half of the IDL is taken back by the liver cells by attachment to
another receptor (LDL receptor), while the rest loses the remaining TGs
gradually and becomes low density lipoprotein (LDL) containing only CHE.
 The LDL circulates in plasma for a long time; its uptake into liver and other
tissues is dependent on the need for CH.
 The rate of LDL uptake is regulated by the rate of LDL receptor synthesis in
a particular tissue.
 The excess lipoproteins in plasma are phagocytosed by
macrophages for disposal.
 When too much of lipoproteins have to be degraded in this manner,
CH is deposited in atheromas (in arterial walls) and xanthomas (in
skin and tendons).
 Raised levels of VLDL, IDL and LDL (rarely Chy and Chy. rem.
also) are atherogenic, while HDL may be protective, because HDL
facilitates removal of CH from tissues.
 Biosynthesis of cholesterol
  CLASSIFICATION

1. HMG-CoA reductase inhibitors (Statins):

 Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin,
Pitavastatin
2. Bile acid sequestrants (Resins):
 Cholestyramine, Colestipol
3. Lipoprotein lipase activators (PPARα activators, Fibrates):
 Clofibrate, Gemfibrozil, Bezafibrate, Fenofibrate.
4. Lipolysis and triglyceride synthesis inhibitor:
 Nicotinic acid.
5. Sterol absorption inhibitor:
 Ezetimibe.
 BP 503 T
Pharmacology II
UNIT - II
 Diuretics
  Diuretics

 Diuretics increase the rate of urine flow and sodium excretion and

are used to adjust the volume and/or composition of body fluids in a

variety of clinical situations, including hypertension, heart failure,

renal failure, nephrotic syndrome, and cirrhosis.

 CLASSIFICATION
1. High efficacy diuretics (Inhibitors of Na+- K+-2Cl¯ cotransport)
 Sulphamoyl derivatives Furosemide, Bumetanide, Torasemide
2. Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport)
 Benzothiadiazines (thiazides): Hydrochlorothiazide, Benzthiazide,
Hydroflumethiazide, Bendroflumethiazide
 Thiazide like (related heterocyclics): Chlorthalidone, Metolazone,
Xipamide, Indapamide, Clopamide
3. Weak or adjunctive diuretics
 Carbonic anhydrase inhibitors: Acetazolamide
 Potassium sparing diuretic:
 Aldosterone antagonist: Spironolactone, Eplerenone
 Inhibitors of renal epithelial Na+ channel: Triamterene,
Amiloride.
 Osmotic diuretics: Mannitol, Isosorbide, Glycerol
 High efficacy diuretics (Inhibitors of Na+- K+-2Cl¯ cotransport)
 Na+-K+-2Cl¯ cotransporter is a glycoprotein having 12 membrane
spanning domains.
 Furosemide is rapidly absorbed orally but bioavailability is about 60%.
 Lipid-solubility is low, and it is highly bound to plasma proteins.
 It is partly conjugated with glucuronic acid and mainly excreted
unchanged by glomerular filtration as well as tubular secretion.
 Some excretion in bile and directly in intestine also occurs.
 Plasma t½ averages 1–2 hour but is prolonged in patients with
pulmonary edema, renal and hepatic insufficiency.
 Bumetanide It is similar to furosemide in all respects, but is 40 times
more potent. It induces very rapid diuresis and is highly effective in
pulmonary edema.
 Bumetanide is more lipid-soluble; oral bioavailability is 80–100%. It is
preferred for oral use in severe CHF
 Torasemide (Torsemide) Another high ceiling diuretic with properties
similar to furosemide, but 3 times more potent.
 Oral absorption is more rapid and more complete.
 The elimination t½ (3.5 hours) and duration of action (4–8 hours) are
longer.
 Torasemide has been used in edema and in hypertension.

 Used in the management of:

 Edema
 Acute pulmonary edema
 Cerebral edema
 Hypertension
 Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport)
 Like the Na+-K+-2Cl¯ cotransporter, the Na+-Cl¯ symporter is also a
glycoprotein with 12 membrane spanning domains that binds thiazides but
not furosemide or any other class of diuretics.they
 These drugs gain access to their site of action via organic acid secretory
pathway in PT and then along the tubular fluid to the early DT, where they
bind to specific receptors located on the luminal membrane (inhibit Na+ -
Cl¯ symport at the luminal membrane)
 Some of the thiazides and related drugs have additional CAse inhibitory
action in PT; intensity of this action differs among different compounds
 All thiazides and related drugs are well absorbed orally. There are no
injectable preparations of these drugs. Their action starts within 1 hour,
but the duration varies from 6–48 hours.
 Most of the agents undergo little hepatic metabolism and are excreted as
such.
 They are filtered at the glomerulus as well as secreted in the PT by organic
anion transport.
 Tubular reabsorption depends on lipid solubility: the more lipid soluble
ones are highly reabsorbed—prolonging duration of action.
 Complications/Adverse effects of high ceiling and thiazide type diuretic
therapy

 Hypokalaemia
 Acute saline depletion
 Dilutional hyponatraemia
 GIT and CNS disturbances
 Hearing loss
 Allergic manifestations
 Hyperuricaemia
 Hyperglycaemia and hyperlipidemia
 Magnesium depletion
  CARBONIC ANHYDRASE INHIBITORS

 Carbonic anhydrase (CAse) is an enzyme which catalyses the reversible

reaction H2O + CO2….H2CO3.
 Carbonic acid spontaneously ionizes H2CO3….H+ + HCO3 ¯.
 Carbonic anhydrase thus functions in CO2 and HCO3 ¯ transport and in H+
ion secretion.
 The enzyme is present in renal tubular cell (especially PT) gastric mucosa,
exocrine pancreas, ciliary body of eye, brain and RBC.
 In these tissues a gross excess of CAse is present, more than 99% inhibition is
 required to produce effects.
 Acetazolamide

 It is a sulfonamide derivative which noncompetitively but reversibly

inhibits CAse (type II).
 In PT cells resulting in slowing of hydration of CO2- decreased
availability of H+ to exchange with luminal Na+ through the Na+-H+
antiporter.
 Inhibition of brush border CAse (type IV) retards dehydration of H2CO3
in the tubular fluid so that less CO2 diffuses back into the cells.
 The net effect is inhibition of HCO3¯ (and accompanying Na+)
reabsorption in PT.
 However, the resulting alkaline diuresis is only mild.
 The extrarenal actions of acetazolamide are:

 Lowering of intraocular tension due to decreased formation of aqueous

humour (aqueous is rich in HCO3¯).
 Decreased gastric HCl and pancreatic NaHCO3 secretion: This action
requires very high doses—not significant at clinically used doses.
 Raised level of CO2 in brain and lowering of pH, sedation and
elevation of seizure threshold.
 Alteration of CO2 transport in lungs and tissues. These actions are
masked by compensatory mechanisms.

 Acetazolamide is well absorbed orally and excreted unchanged in

urine. Action of a single dose lasts 8–12 hours.
 Adverse effects are frequent.
 Acidosis, hypokalaemia, drowsiness, paresthesias, fatigue, abdominal
discomfort.
 Hypersensitivity reactions—fever, rashes.
 Bone marrow depression is rare but serious.
 It is contraindicated in liver disease: may precipitate hepatic coma by
interfering with urinary elimination of NH3 (due to alkaline urine).
 Acidosis is more likely to occur in patients of COPD.
  POTASSIUM SPARING DIURETICS

 Aldosterone antagonists and renal epithelial Na+ channel inhibitors

indirectly conserve K+ while inducing mild natriuresis, and are called
‘potassium sparing diuretics’.
 Spironolactone
 It is a steroid, chemically related to the mineralocorticoid aldosterone.
Aldosterone penetrates the late DT and CD cells and acts by
combining with an intracellular mineralocorticoid receptor (MR)
induces the formation of ‘aldosterone-induced proteins’ (AIPs).
 The AIPs promote Na+ reabsorption by a number of mechanisms and
K+ secretion.
 Spironolactone acts from the interstitial side of the tubular cell,
combines with MR and inhibits the formation of AIPs in a competitive
manner.
 It has no effect on Na+ and K+ transport in the absence of aldosterone,
while under normal circumstances, it increases Na+ and decreases K+
excretion.
 The oral bioavailability of spironolactone from microfine powder tablet
is 75%.
 It is highly bound to plasma proteins and completely metabolized in
liver; converted to active metabolites, the most important of which is
Canrenone that is responsible for 1/2–2/3 of its action in vivo.
 The t½ of spironolactone is 1–2 hours, while that canrenone is ~18
hours. Some enterohepatic circulation occurs.
  OSMOTIC DIURETICS
Mannitol is a nonelectrolyte of low molecular weight (182) that is
pharmacologically inert - can be given in large quantities sufficient to raise
osmolarity of plasma and tubular fluid. It is minimally metabolized in the
body; freely filtered at the glomerulus and undergoes limited reabsorption:
therefore excellently suited to be used as osmotic diuretic. Mannitol
appears to limit tubular water and electrolyte reabsorption in a
variety of ways:
1. Retains water isoosmotically in PT—dilutes luminal fluid which
opposes NaCl reabsorption.
2. Inhibits transport processes in the thick AscLH by an unknown
mechanism.
3. Expands extracellular fluid volume.
 Mannitol is contraindicated in acute tubular necrosis, anuria, pulmonary
edema; acute left ventricular failure, CHF, cerebral haemorrhage.
https://www.youtube.com/watch?v=9_h0ZXx1lFw&ab_channel=A
lilaMedicalMedia
 Anti-diuretics
  Antidiuretics

 Antidiuretics (more precisely ‘anti-aquaretics’, because they inhibit

water excretion without affecting salt excretion) are drugs that

reduce urine volume, particularly in diabetes insipidus (DI) which

is their primary indication. Drugs are:

 1. Antidiuretic hormone (ADH, Vasopressin), Desmopressin,

Lypressin, Terlipressin

 2. Thiazide diuretics, Amiloride.

 3. Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine.

 Diabetes Insipidus (DI)

 Diabetes insipidus is a rare disorder that occurs when a person's

kidneys pass an abnormally large volume of urine that is insipid—
dilute and odorless.

https://www.niddk.nih.gov/health-information/kidney-disease/diabetes-insipidus
  Antidiuretic hormone/Vasopressin/AVP(argenine vasopressin)

1. It is a nonapeptide secreted by posterior pituitary (neurohypophysis) along

with oxytocin.
2. It is synthesized in the hypothalamic (supraoptic and paraventricular) nerve
cell bodies as a large precursor peptide along with its binding protein
‘neurophysin’.
3. Osmoreceptors present in hypothalamus and volume receptors present in left
atrium, ventricles and pulmonary veins primarily regulate the rate of ADH
release governed by body hydration.
4. Osmoreceptors are also present in the hepatic portal system which sense
ingested salt and release ADH even before plasma osmolarity is increased
by the ingested salt.
5. Impulses from baroreceptors and higher centres also impinge on the nuclei
synthesizing ADH and affect its release.
6. The two main physiological stimuli for ADH release are rise in plasma
osmolarity and contraction of e.c.f. volume.
  ADH (Vasopressin) receptors

 These are G protein coupled cell membrane receptors; two subtypes V1

and V2 have been identified, cloned and structurally characterized. V1
Receptors All vasopressin receptors except those on renal CD cells,
AscLH cells and vascular endothelium are of the V1 type.
 These are further divided into V1a and V1b subtypes. V1a receptors are
present on vascular smooth muscle (including that of vasa recta in renal
medulla), uterine and other visceral smooth muscles, interstitial cells in
renal medulla, cortical CD cells, adipose tissue, brain, platelets, liver, etc.
The V1b receptors are localized to the anterior pituitary, certain areas in
brain and in pancreas.
 V2 Receptors These are located primarily on the collecting duct (CD)
principal cells in the kidney—regulate their water permeability through
cAMP production.
 Some V2 receptors are also present on AscLH cells which activate
Na+K+2Cl¯ cotransporter. Vasodilatory V2 receptors arepresent on
endothelium of blood vessels.
 The V2 receptors are more sensitive (respond at lower concentrations) to
AVP than are V1 receptors.
 Actions
 Kidney AVP acts on the collecting duct (CD) principal cells to
increase their water permeability— water from the duct lumen
diffuses to the interstitium.
 In man, maximal osmolarity of urine that can be attained is 4 times
higher than plasma.
 When AVP is absent, CD cells remain impermeable to water → dilute
urine is passed as such.
 Graded effect occurs at lower concentrations of AVP: urine volume
closely balances fluid intake.
  Mechanism of Action
The V2 subtype of ADH receptors are present on the basolateral membrane of
principal cells in CDs.

1. Activation of these receptors (GPCR) increases cAMP formation

intracellularly (by activating adenylyl cyclase)

2. Activation of cAMP dependent protein kinase A

3. Phosphorylation of relevant proteins which promote exocytosis of

‘aquaporin-2’ water channel containing vesicles (WCVs) through the
apical membrane

4. More aqueous channels get inserted into the apical membrane.

5. The rate of endocytosis and degradation of WCVs is concurrently reduced.

The water permeability of CD cells is increased in proportion to the
population of aquaporin-2 channels in the apical membrane at any given
time.
 Continued V2 receptor stimulation (during chronic water deprivation) in
addition upregulates aquaporin-2 synthesis through cAMP response element
of the gene encoding aquaporin-2
 To achieve maximum concentration of urine, activation of V2 receptors
increases urea permeability of terminal part of CDs
 Recently, V2 receptor mediated actions of AVP on AscLH have also been
demonstrated which further reinforce medullary hypertonicity by
translocating to luminal membrane and activating the Na+K+2Cl¯
cotransporter in the short-term and increasing its synthesis in the long-term.
 The V1 receptors also participate in the renal response to AVP.
 Activation of V1 receptors constricts vasa recta to diminish blood flow to inner
medulla which reduces washing off effect and helps in maintaining high
osmolarity in this region, thus, it contributes to antidiuresis.
 On the other hand, activation of medullary interstitial cell V1 receptors enhance
PG synthesis which attenuate cAMP generation in CD cells and oppose V2
mediated antidiuresis.
 V1 receptors are also present on CD cells. Their stimulation activates PKc which
directly diminishes responsiveness of CD cells to V2 receptors and restrains V2
mediated water permeability.
 The logic of this apparent paradox may lie in the fact that these V1 actions are
produced at much higher concentrations of AVP, so that physiologically they may
serve to restrict V2 effects only when blood levels of AVP are very high.
 All V2 receptor (V2R) mediated actions are exerted through the adenylyl cyclase (AC)-
cyclic AMP (cAMP) pathway, while the V1a receptor (V1aR) mediated action is exerted
via the phospholipase C—IP3: DAG pathway.
 Rapid actions
1. Translocation of water channel containing vesicles (WCVs) and exocytotic insertion of
aquaporin 2 water channels into the apical membrane of principal cells of collecting ducts;
the primary action responsible for antidiuresis.
2. Inhibition of endocytotic removal of aquaporin 2 channels from the apical membrane.
3. Activation of vasopressin regulated urea transporter (VRUT) at apical membrane of
collecting ducts in the inner medulla.
4. Translocation of Na+K+2Cl¯ cotransporter to the luminal membrane of cells in thick
ascending limb of loop of Henle (AscLH).
5. Activation of Na+K+2Cl¯ cotransporter in AscLH cells.
6. V1a receptor (V1aR) mediated vasoconstriction of vasa recta
 Long-term actions
7. Gene mediated increased expression of aquaporin 2 channels in collecting duct cells.
8. Gene mediated increased expression of Na+K+2Cl¯ cotransporter in AscLH cells.
 AVP is inactive orally because it is destroyed by trypsin.
 It can be administered by any parenteral route or by intranasal application.
 The peptide chain of AVP is rapidly cleaved enzymatically in many organs,
especially in liver and kidney; plasma t½ is short ~25 min.
 However, the action of aqueous vasopressin lasts 3–4 hours.
 VASOPRESSIN ANALOGUES

 Lypressin: It is 8-lysine vasopressin, less potent than AVP, it acts on bothV1

and V2 receptors and has longer duration of action (4–6 hours). It is being
used in place of AVP—mostly for V1 receptor mediated actions.

 Terlipressin: This synthetic prodrug of vasopressin is specifically used for

bleeding esophageal varices; may produce less severe adverse effects than
lypressin.
 Desmopressin: This synthetic peptide is a selective V2 agonist; 12 times more
potent antidiuretic than AVP, but has negligible vasoconstrictor activity.
 It is also longer acting because enzymatic degradation is slow; t½ 1–2 hours;
duration of action 8–12 hours.
 Desmopressin is the preparation of choice for all V2 receptor related
indications.
 The intranasal route is preferred, though bioavailability is only 10–20%.
 An oral formulation has been recently marketed with a bioavailability of 1–2%;
oral dose is 10–15 times higher than intranasal dose, but systemic effects are
produced and nasal side effects are avoided.
  Uses
 Diabeted insipidus
 Bedwetting in children and nocturia in adults
 Haemophilia
 Renal concentration test
 Bleeding esophageal varices: Vasopressin/ terlipressin often stop bleeding
by constricting mesenteric blood vessels and reducing blood flow through the
liver to the varices, allowing clot formation. Terlipressin stops bleeding in
~80% and has been shown to improve survival. It has replaced AVP because
of fewer adverse effects and greater convenience in use.
 Adverse effects Because of V2 selectivity, desmopressin produces
fewer adverse effects than vasopressin, lypressin or terlipressin.
However, transient headache and flushing are frequent. Nasal irritation,
congestion, rhinitis, ulceration and epistaxis can occur on local
application. Systemic side effects are: belching, nausea, abdominal
cramps, pallor, urge to defecate, backache in females (due to uterine
contraction). Fluid retention and hyponatraemia may develop.
AVP can cause bradycardia, increase cardiac afterload and precipitate
angina by constricting coronary vessels. It is contraindicated in
patients with ischaemic heart disease, hypertension, chronic nephritis
and psychogenic polydipsia. Urticaria and other allergies are possible
with any preparation.
  THIAZIDES

Diuretic thiazides paradoxically exert an antidiuretic effect in DI. High

ceiling diuretics are also effective but are less desirable because of their short
and brisk action. Thiazides reduce urine volume in both pituitary origin as
well as renal DI. They are especially valuable for the latter in which AVP is
ineffective. However, their efficacy is low; urine can never become
hypertonic as can occur with AVP in neurogenic DI.

The mechanism of action is not well understood, possible

explanation is:Thiazides induce a state of sustained electrolyte depletion so
that glomerular filtrate is more completely reabsorbed iso-osmotically in PT.
Further, because of reduced salt reabsorption in the cortical diluting segment,
a smaller volume of less dilute urine is presented to the CDs and the same is
passed out.
 Amiloride is the drug of choice for lithium induced nephrogenic DI

 Indomethacin has also been found to reduce polyuria in renal DI to some extent
by reducing renal PG synthesis. It can be combined with a thiazide ± amiloride
in nephrogenic DI.

 Chlorpropamide: It is a long-acting sulfonylurea oral hypoglycaemic, found to

reduce urine volume in DI of pituitary origin but not in renal DI. It sensitizes the
kidney to ADH action; thus its efficacy depends on small amounts of the
circulating hormone; it is not active when ADH is totally absent.

 Carbamazepine It is an antiepileptic which reduces urine volume in DI of

pituitary origin, but mechanism of action is not clear. Higher doses are needed;
adverse effects are marked; it is of little value in treatment of DI.
  VASOPRESSIN ANTAGONISTS

 Tolvaptan, Mozavaptan (V2 selective antagonist)

 Conivaptan (V1a+V2 antagonist)

 Haematinics
  Haematinics

These are substances required in the formation of blood, and are used for
treatment of anaemias.
Anaemia occurs when the balance between production and destruction of
RBCs is disturbed by:
 Blood loss (acute or chronic)
 Impaired red cell formation due to:
 Deficiency of essential factors, i.e. iron, vitamin B12, folic acid.
 Bone marrow depression (hypoplastic anaemia), erythropoietin
deficiency.
 Increased destruction of RBCs (haemolytic anaemia)
  Required components

 Iron

 Maturation factors: Vit. B12, Folic acid

 Erythropoietin
  IRON

 Iron has for long been considered important for the body. Lauha bhasma
(calcined iron) has been used in ancient Indian medicine.
 According to Greek thought Mars is the God of strength, and iron is
dedicated to Mars: as such, iron was used to treat weakness, which is
common in anaemia.
 In 1713 iron was shown to be present in blood.
 In the early 19th century Blaud developed his famous ‘Blaud’s pill’
consisting of ferrous sulfate and potassium carbonate for anaemia.
  Distribution of iron in body

Iron is an essential body constituent. Total body iron in an adult is 2.5–5 g

(average 3.5 g). It is more in men (50 mg/kg) than in women (38 mg/kg).
It is distributed into:
 Haemoglobin (Hb) : 66%
 Iron stores as ferritin and haemosiderin : 25%
 Myoglobin (in muscles) : 3%
 Parenchymal iron (in enzymes, etc.) : 6%
 Haemoglobin is a protoporphyrin; each molecule having 4 iron
containing haeme residues
 Iron is stored only in ferric form, in combination with a large protein
apoferritin.

 Ferritin can get saturated to different extents; at full saturation it can

hold 30% iron by weight.
 The most important storage sites are reticuloendothelial (RE) cells..
 Parenchymal iron occurs as prosthetic group in many cellular
enzymes—cytochromes, peroxidases, catalases, xanthine oxidase and
some mitochondrial enzymes.
 The primary reflection of iron deficiency occurs in blood, severe
deficiency affects practically every cell.
 Daily requirement To make good average daily loss, iron requirements are:
 Adult male : 0.5–1 mg (13 μg/kg)
 Adult female (menstruating) : 1–2 mg (21 μg/kg)
 Infants : 60 μg/kg
 Children : 25 μg/kg
 Pregnancy (last 2 trimesters) : 3–5 mg (80 μg/kg)

 Dietary sources of iron

 Rich : Liver, egg yolk, oyster, dry beans, dry fruits, wheat germ, yeast.
 Medium : Meat, chicken, fish, spinach, banana, apple.
 Poor : Milk and its products, root vegetables.
 Iron absorption
 Factors facilitating iron absorption
 Acid: by favouring dissolution and reduction of ferric iron.
 Reducing substances: ascorbic acid, amino acids containing SH radical.
These agents reduce ferric iron and form absorbable complexes.
 Meat: by increasing HCl secretion and providing haeme iron.

 Factors impeding iron absorption

 Alkalies (antacids) render iron insoluble, oppose its reduction.
 Phosphates (rich in egg yolk)
 Phytates (in maize, wheat)
 Tetracyclines
 Presence of other foods in the stomach.
 Iron formulation:
 Oral formulations:
 Some simple oral preparations are:
 Ferrous sulfate: (hydrated salt 20% iron, dried salt 32% iron) is the cheapest;
may be preferred on this account. It often leaves a metallic taste in mouth;
FERSOLATE 200 mg tab.
 Ferrous gluconate (12% iron): FERRONICUM 300 mg tab, 400 mg/15 ml
elixer.
 Ferrous fumarate (33% iron): is less water soluble than ferrous sulfate and
tasteless; NORI-A 200 mg tab.
 Colloidal ferric hydroxide (50% iron): FERRI DROPS 50 mg/ml drops.
 Carbonyl iron: It is highly purify metallic iron in very fine powder form
(particle size < 5 μM), prepared by decomposition of iron pentacarbonyl, a
highly toxic compound. It is claimed to be absorbed from intestines over a long
time, and gastric tolerance may be better. However, bioavailability is about
3/4th that of ferrous sulfate.
 Other forms of iron present in oral formulations are:
 Ferrous succinate (35% iron)
 Iron choline citrate
 Iron calcium complex (5% iron)
 Ferric ammonium citrate (20% iron)
 Ferrous aminoate (10% iron)
 Ferric glycerophosphate
 Ferric hydroxy polymaltose
  Adverse effects of oral iron

 These are common at therapeutic doses and are related to elemental iron
content. Individuals differ in susceptibility.
 Side effects are: Epigastric pain, heartburn, nausea, vomiting, bloating,
staining of teeth, metallic taste, colic, etc.
 Tolerance to oral iron can be improved by initiating therapy at low dose
and gradually escalating to the optimum dose.
 Constipation is more common (believed to be due to astringent action of
iron) than diarrhoea (thought to reflect irritant action).
 However, these may be caused by alteration of intestinal flora as well.
  Parenteral iron

 Iron therapy by injection is indicated only when:

 Oral iron is not tolerated: bowel upset is too much.
 Failure to absorb oral iron: malabsorption; inflammatory bowel disease.
Chronic inflammation (rheumatoid arthritis) decreases iron absorption, as well
as the rate at which iron can be utilized.
 Non-compliance to oral iron.
 In presence of severe deficiency with chronic bleeding.
 Along with erythropoietin: oral ion may not be absorbed at sufficient rate to
meet the demands of induced rapid erythropoiesis.
  ACUTE IRON POISONING

 It occurs mostly in infants and children: 10–20 iron tablets or equivalent of

the liquid preparation (> 60 mg/kg iron) may cause serious toxicity in them.
 It is very rare in adults.
 Manifestations are vomiting, abdominal pain, haematemesis, diarrhoea,
lethargy, cyanosis, dehydration, acidosis, convulsions; finally shock,
cardiovascular collapse and death.
 In few cases death occurs early (within 6 hours), but is typically delayed to
12– 36 hours, with apparent improvement in the intervening period.
 The pathological lesion is haemorrhage and inflammation in the gut, hepatic
necrosis and brain damage.
 Treatment It should be prompt.
 To prevent further absorption of iron from gut
(a) Induce vomiting or perform gastric lavage with sodium bicarbonate
solution—to render iron insoluble.
(b) Give egg yolk and milk orally: to complex iron. Activated charcoal
does not adsorb iron.
 To bind and remove iron already absorbed

 Desferrioxamine is the drug of choice.

 It should be injected i.m. (preferably) 0.5–1 g (50 mg/kg) repeated
4–12 hourly as required, or i.v. (if shock is present) 10–15
mg/kg/hour; max 75 mg/kg in a day till serum iron falls below 300
μg/dl.
 Early therapy with desferrioxamine has drastically reduced mortality
of iron poisoning.
 Alternatively DTPA or calcium edetate may be used if
desferrioxamine is not available.
 BAL (Dimercaprol) is contraindicated because its iron chelate is also
toxic.
 Supportive measures:
 Fluid and electrolyte balance should be maintained and acidosis
corrected by appropriate i.v. infusion.
 Respiration and BP may need support.
 Diazepam i.v. should be cautiously used to control convulsions,
if they occur.
  MATURATION FACTORS

 Deficiency of vit B12 and folic acid, which are B group vitamins,
results in megaloblastic anaemia characterized by the presence of
large red cell precursors in bone marrow and their large and short
lived progeny in peripheral blood.
 Vit B12 and folic acid are therefore called maturation factors.
 Apart from haemopoietic, other rapidly proliferating tissues also
suffer.
  VITAMIN-B12

 Cyanocobalamin and hydroxocobalamin are complex cobalt containing

compounds present in the diet and referred to as vit B12.
 Vit B12 occurs as water soluble, thermostable red crystals. It is synthesized in
nature only by microorganisms; plants and animals acquire it from them.

 Dietary sources
 Liver, kidney, sea fish, egg yolk, meat, cheese are the main vit B12
containing constituents of diet.
 The only vegetable source is legumes (pulses) which get it from
microorganisms harboured in their root nodules.
 Vit B12 is synthesized by the colonic microflora, but this is not available for
absorption in man.
 The commercial source is Streptomyces griseus; as a byproduct of
streptomycin industry.
  Daily requirement 1–3 μg, pregnancy and lactation 3–5 μg.

 Metabolic functions
 Vit B12 is intricately linked with folate metabolism in many
ways; megaloblastic anaemia occurring due to deficiency of
either is indistinguishable.
 In addition, vit B12 has some independent metabolic functions as
well. The active coenzyme forms of B12 generated in the body
are deoxyadenosyl-cobalamin (DAB12) and methyl-cobalamin
(methyl B12).
 Vit B12 is essential for the conversion of homocysteine to methionine.
Methionine is needed as a methyl group donor in many metabolic reactions
and for protein synthesis. This reaction is also critical in making
tetrahydrofolic acid (THFA) available for reutilization. In B12 deficiency
THFA gets trapped in the methyl form and a number of one carbon transfer
reactions suffer
 Purine and pyrimidine synthesis is affected primarily due to defective ‘one
carbon’ transfer because of ‘folate trap’. The most important of these is
inavailability of thymidylate for DNA production.

 Conversion of malonic acid into succinic acid is an important step in

propionic acid metabolism. It links the carbohydrate and lipid metabolisms.
This reaction does not require folate and has been considered to be
responsible for demyelination seen in B12 deficiency, but not in pure folate
deficiency. That myelin is lipoidal, supports this contention.
 Help in the conversion of methionine in to S-adenosyl methionine, may be
more important in the neurological damage of B12 deficiency, because it is
needed in the synthesis of phospholipids and myelin.

 Vit B12 is essential for cell growth and multiplication.

  Utilization of vit B12

 Vit B12 is present in food as protein conjugates and is released by cooking or by

proteolysis in stomach facilitated by gastric acid.
 Intrinsic factor (a glycoprotein, MW60,000) secreted by stomach forms a
complex
 with B12—attaches to specific receptors present on intestinal mucosal cells and
is absorbed by active carrier mediated transport.
 This mechanism is essential for absorption of vit B12 ingested in physiological
amounts.
 However, when gross excess is taken, a small fraction is absorbed without the
help of intrinsic factor.
 Vit B12 is transported in blood in combination with a specific β globulin
transcobalamin II (TCII).
 Congenital absence of TCII or presence of abnormal protein (TCI or TCIII,
in liver and bone marrow disease) may interfere with delivery of vit B12 to
tissues.
 Vit B12 is especially taken up by liver cells and stored: about 2/3 to 4/5 of
body’s content (2–8 mg) is present in liver.
 Vit B12 is not degraded in the body.
 It is excreted mainly in bile (3–7 μg/day); but 0.5–1 μg of this is
reabsorbed—considerable enterohepatic circulation occurs.
 Thus, in the absence of intrinsic factor or when there is malabsorption, B12
deficiency develops much more rapidly than when it is due to nutritional
 deficiency.
 It takes 3–5 years of total absence of B12 in diet to deplete normal body
stores.
 Vit B12 is directly and completely absorbed after i.m. or deep s.c. injection.
Normally, only traces of B12 are excreted in urine, but when
pharmacological doses (> 100 μg) are given orally or parenterally—a large
part is excreted in urine, because the plasma protein binding sites get
saturated and free vit B12 is filtered at the glomerulus.
 Hydroxocobalamin is more protein bound and better retained than
cyanocobalamin.
  Deficiency

Vit B12 deficiency occurs due to:

 Addisonian pernicious anaemia: is an autoimmune disorder which results in
destruction of gastric parietal cells → absence of intrinsic factor in gastric
juice (along with achlorhydria) → inability to absorb vit B12.It is rare in
India.
 Other causes of gastric mucosal damage, e.g. chronic gastritis, gastric
carcinoma, gastrectomy, etc.
 Malabsorption (damaged intestinal mucosa), bowel resection, inflammatory
bowel disease.
 Consumption of vit B12 by abnormal flora in intestine (blind loop
syndrome) or fish tape worm.
 Nutritional deficiency: is a less common cause; may occur in strict
vegetarians.
 Increased demand: pregnancy, infancy.
 Manifestations of deficiency are:

 Megaloblastic anaemia (generally the first manifestation), neutrophils with

hypersegmented nuclei, giant platelets.
 Glossitis, g.i. disturbances: damage to epithelial structures.
 Neurological: subacute combined degeneration of spinal cord; peripheral
neuritis—diminished vibration and position sense, paresthesias, depressed
stretch reflexes; mental changes—poor memory, mood changes,
hallucinations, etc. are late effects.
 Uses
1. Treatment of vit B12 deficiency: vit B12 is used
2. Prophylaxis
3. Mega doses of vit B12 have been used in neuropathies, psychiatric disorders,
cutaneous sarcoid and as a general tonic to allay fatigue, improve growth—
value is questionable.
4. Tobacco amblyopia: hydroxocobalamin is of some benefit—it probably traps
cyanide derivedfrom tobacco to form cyanocobalamin.

 Adverse effects
Even large doses of vit B12 are quite safe. Allergic reactions have occurred on
injection, probably due to contaminants. Anaphylactoid reactions (probably to
sulfite contained in the formulation) have occurred on i.v. injection: this route
should never be employed.
  FOLIC ACID

 It occurs as yellow crystals which are insoluble in water, but its sodium salt
is freely water soluble.
 Chemically it is Pteroyl glutamic acid (PGA) consisting of pteridine +
paraaminobenzoic acid (PABA) + glutamic acid.

 Wills (1932–37) had found that liver extract contained a factor, other than
vit B12, which could cure megaloblastic anaemia. Mitchell in 1941 isolated
an antianaemia principle from spinach and called it ‘folic acid’ (from leaf).
Later the Will’s factor was shown to be identical to folic acid.
 Dietary sources
 Liver, green leafy vegetables (spinach), egg, meat, milk. It is synthesized
by gut flora, but this is largely unavailable for absorption.

 Daily requirement
 For an adult is < 0.1 mg but dietary allowance of 0.2 mg/day is
recommended. During pregnancy, lactation or any condition of high
metabolic activity, 0.8 mg/day is considered appropriate.
  Utilization
 Folic acid is present in food as polyglutamates; the additional glutamate residues are
split off primarily in the upper intestine before being absorbed.
 Reduction to DHFA and methylation also occurs at this site.
 It is transported in blood mostly as methyl-THFA which is partly bound to plasma
proteins.
 Small, physiological amounts of folate are absorbed by specific carrier mediated
active transport in the intestinal mucosa.
 Large pharmacological doses may gain entry by passive diffusion, but only a fraction
is absorbed.
 Folic acid is rapidly extracted by tissues and stored in cells as polyglutamates.
 Liver takes up a large part and secretes methyl-THFA in bile which is mostly
reabsorbed from intestine: enterohepatic circulation occurs.
 Alcohol interferes with release of methyl-THFA from hepatocytes.
 The total body store of folates is 5–10 mg.
 Normally, only traces are excreted, but when pharmacological doses are given, 50–
90% of the absorbed dose may be excreted in urine.
  Metabolic functions
 Folic acid is inactive as such and is reduced to the coenzyme form in two
steps: FA → DHFA → THFA by folate reductase (FRase) and dihydrofolate
reductase (DHFRase).
 THFA mediates a number of one carbon transfer reactions by carrying a
methyl group
 Conversion of homocysteine to methionine
 Generation of thymidylate, an essential constituent of DNA
 Conversion of serine to glycine
 Purine synthesis: de novo building of purine ring requires formyl-
THFA and methenyl-THFA (generated from methylene-THFA) to
introduce carbon atoms at position 2 and 8
 Histidine metabolism
  Deficiency Folate deficiency occurs due to

 Inadequate dietary intake

 Malabsorption: especially involving upper intestine— coeliac disease,
tropical sprue, regional ileitis, etc. Deficiency develops more rapidly as
both dietary and biliary folate is not absorbed.
 Biliary fistula; bile containing folate for recirculation is drained.
 Chronic alcoholism: intake of folate is generally poor. Moreover, its
release from liver cells and recirculation are interfered.
 Increased demand: pregnancy, lactation, rapid growth periods, haemolytic
anaemia and other diseases with high cell turnover rates.
 Drug induced: prolonged therapy with anticonvulsants (phenytoin,
phenobarbitone, primidone) and oral contraceptives—interfere with
absorption and storage of folate.
  Manifestations of deficiency are
 Megaloblastic anaemia,
 Epithelial damage: glossitis, enteritis, diarrhoea, steatorrhoea.
 Neural tube defects, including spina bifida in the offspring, due to
maternal folate deficiency.
 General debility, weight loss, sterility. However, neurological symptoms
do not appear in pure folate deficiency.
  ERYTHROPOIETIN
Erythropoietin (EPO) is a sialoglycoprotein hormone (MW 34000) produced by
peritubular cells of the kidney that is essential for normal erythropoiesis. Anaemia
and hypoxia are sensed by kidney cells and induce rapid secretion of EPO → acts
on erythroid marrow and:
 Stimulates proliferation of colony forming cells of the erythroid series.
 Induces haemoglobin formation and erythroblast maturation.
 Releases reticulocytes in the circulation. EPO binds to specific receptors on
the surface of its target cells.
The EPO receptor is a JAK-STAT-binding receptor that alters phosphorylation of
intracellular proteins and activates transcription factors to regulate gene
expression. It induces erythropoiesis in a dose dependent manner, but has no effect
on RBC lifespan.

 The recombinant human erythropoietin (Epoetin α, β) is administered by i.v. or

s.c. injection and has a plasma t½ of 6–10 hr, but action lasts several days.
  Use
The primary indication for epoetin is anaemia of chronic renal failure which is
due to low levels of EPO. Only smptomatic patients with Hb ≤ 8 g/dl should be
considered for EPO therapy.
Most patients have low iron stores; require concurrent parenteral/oral iron
therapy for an optimum response. Other uses are:
 Anaemia in AIDS patients treated with zidovudine.
 Cancer chemotherapy induced anaemia.
 Preoperative increased blood production for autologous transfusion during
surgery.
  Adverse effects
 Epoetin is nonimmunogenic.
 Adverse effects are related to sudden increase in haematocrit, blood
viscosity and peripheral vascular resistance (due to correction of
anaemia).
 These are—increased clot formation in the A-V shunts (most patients are
on dialysis), hypertensive episodes, serious thromboembolic events,
occasionally seizures.
 Flu like symptoms lasting 2–4 hr occur in some patients.
 Plasma volume expanders
  PLASMA EXPANDERS

 These are high molecular weight substances which exert colloidal osmotic
(oncotic) pressure, and when infused i.v. retain fluid in the vascular
compartment.
 They are used to correct hypovolemia due to loss of plasma/blood.
 Human plasma or reconstituted human albumin would seem to be the best.
However, the former carries risk of transmitting serum hepatitis, AIDS, etc.,
and the latter is expensive.
 Therefore, synthetic colloids are more often used.
 Substances employed are:

 Human Albumin

 Dextran

 Polygeline

 Hetastarch
  Human albumin
 It is obtained from pooled human plasma; 100 ml of 20% human albumin solution
is the osmotic equivalent of about 400 ml of fresh frozen plasma or 800 ml of
whole blood.
 It can be used without regard to patient’s blood group and does not interfere with
coagulation.
 Unlike whole blood or plasma, it is free of risk of transmitting serum hepatitis
because the preparation is heat treated. There is also no risk of sensitization with
repeated infusions.
 The 20% solution draws and holds additional fluid from tissues: crystalloid
solutions must be infused concurrently for optimum benefit.
 Apart from burns, hypovolemia, shock, etc., it has been used in acute
hypoproteinaemia, acute liver failure and dialysis.
 Dilution of blood using albumin and crystalloid solutions can be used before
cardiopulmonary bypass. Febrile reaction to human albumin occurs occasionally.
 It is expensive.
Human albumin 20%: ALBUDAC, ALBUPAN 50,
100 ml inj., ALBUMED 5%, 20% infusion (100 ml)
  Dextran

 It is a polysaccharide obtained from sugar beat, and is available in two forms.

 Dextran-70 (MW 70,000): DEXTRAN-70, LOMODEX-70; 6% solution in
dextrose or saline, 540 ml vac.
 Dextran-40 (MW 40,000; low MW dextran): LOMODEX 10% solution in
dextrose or saline, 540 ml vac.
 The more commonly used preparation is dextran-70.
 It expands plasma volume for nearly 24 hours, and is slowly excreted by
glomerular filtration as well as oxidized in the body over weeks.
 Some amount is deposited in RE cells.
 Dextran has nearly all the properties of an ideal plasma expander except:
 It may interfere with blood grouping and cross-matching.
 Though the dextran used clinically is not antigenic, its structure is similar to
other antigenic polysaccharides.
 Some polysaccharide reacting antibodies, if present, may cross react with
dextran and trigger anaphylactic reaction.
 Urticaria, itching, bronchospasm, fall in BP occur occasionally; anaphylactic
shock is rare.
 It can interfere with coagulation and platelet function, and thus prolong bleeding
time; should not be used in hypofibrinogenaemia, thrombocytopenia or in
presence of bleeding.
 Dextran-40, acts more rapidly than dextran-70.
 It reduces blood viscosity and prevents RBC sludging that occurs in shock by
coating them and maintaining their electronegative charge.
 Microcirculation may improve.
 However, it is rapidly filtered at the glomerulus: expands plasma volume for a
shorter period, and may get highly concentrated in the tubule if oliguria
develops—tubular obstruction may occur.
 The total dose should not exceed 20 ml/kg in 24 hr.
 Dextrans can be stored for 10 years and are cheap.
 They are the most commonly used plasma expanders.
  Polygeline (Degraded gelatin polymer)

 It is a polypeptide with average MW 30,000 which exerts oncotic pressure

similar to albumin and is not antigenic; hypersensitivity reactions are rare, but
should be watched for.
 It does not interfere with grouping and cross-matching of blood and remains
stable for three years.
 It is not metabolized in the body; excreted slowly by the kidney.
 Expansion of plasma volume lasts for 12 hours. It is more expensive than
dextran.
 It can also be used for priming of heart-lung and dialysis machines.
 Hypersensitivity reactions like flushing, rigor, urticaria, wheezing and
hypotension can occur. HAEMACCEL,SERACCEL 500 ml vac. (as 3.5%
solution in balanced electrolyte medium).
  Hetastarch

 It is a complex mixture of ethoxylated amylopectin of various molecular sizes;

average MW 4.5 lac.
 The colloidal properties of 6% hetastarch approximate those of human albumin.
 Plasma volume expands slightly in excess of the volume infused.
 Haemodynamic status is improved for 24 hour or more.
 Hetastarch is incompatible with many drugs; no injectable drug should be added to
the infusion. Blood grouping and cross matching may be vitiated.
 Smaller molecules (MW < 50,000) are excreted rapidly by kidney; 40% of
infused dose appears in urine in 24 hr.
 Larger molecules are slowly broken down to smaller ones and eliminated
with a t½ of 17 days. Adverse effects are vomiting, mild fever, itching, chills,
flu like symptoms, swelling of salivary glands.
 Urticaria, periorbital edema and bronchospasm are the anaphylactoid
reactions.
 It has also been used to improve harvesting of granulocytes because it
accelerates erythrocyte sedimentation. EXPAN 6% inj (100, 500 ml vac)
  Use of plasma expanders

 These colloidal solutions are used primarily as substitutes for plasma in

conditions where plasma has been lost or has moved to extravascular
compartment, e.g. in burns (acute phase only), hypovolemic and endotoxin
shock, severe trauma and extensive tissue damage.
 They can also be used as a temporary measure in cases of whole blood loss till
the same can be arranged, but they do not have O2 carrying capacity.
 Apart from albumin, other plasma expanders should not be used for
maintenance of plasma volume in conditions like burns, where proteins
leakout with fluids for several days.

 Contraindications to plasma expanders are: severe anaemia, cardiac

failure, pulmonary edema, liver disease, renal insufficiency.
 Coagulants
  COAGULANTS

 These are substances which promote coagulation, and are indicated

in haemorrhagic states.

 Fresh whole blood or plasma provide all the factors needed for

coagulation and are the best therapy for deficiency of any clotting

factor; also they act immediately.

 Other drugs used to restore haemostasis are:
1. Vitamin K
 K1 (from plants, fat-soluble): Phytonadione (Phylloquinone)
 K3 (synthetic)
 Fat-soluble : Menadione, Acetomenaphthone
 Water-soluble : Menadione sod. Bisulfite : Menadione sod.
diphosphate
2. Miscellaneous
 Fibrinogen (human)
 Antihaemophilic factor
 Desmopressin
 Adrenochrome monosemicarbazone
 Rutin, Ethamsylate
 Dam (1929) produced bleeding disorder in chicken by feeding deficient
diet.
 This was later found to be due to decreased concentration of
prothrombin in blood and that it could be cured by a fat soluble fraction
of hog liver.
 This factor was called Koagulations vitamin (vit K) and soon its
structure was worked out.
 A similar vitamin was isolated in 1939 from alfalfa grass and labelled vit
K1, while that from sardine (sea fish) meal was labelled K2.
 Synthetic compounds have been produced and labelled K3.
 Chemistry: Vit K has a basic naphthoquinone structure, with or without a
side chain (R) at position 3. The side chain in K1 is phytyl, in K2 prenyl,
while in K3 there is no side chain.

 Dietary sources: green leafy vegetables, such as cabbage, spinach; and liver,
cheese, etc.
 Daily requirement: It is uncertain, because a variable amount of
menaquinone (vit K2) produced by colonic bacteria becomes available. Even
3–10 μg/day external source may be sufficient. However, the total requirement
of an adult has been estimated to be 50–100 μg/day.
  Action
 Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation
proteins: prothrombin, factors VII, IX and X.
 The vit K dependent change (γ carboxylation of glutamate residues of these
zymogen proteins) confers on them the capacity to bind Ca2+ and to get bound
to phospholipid, surfaces properties essential for participation in the
coagulation cascade
  Utilization

 Fat-soluble forms of vit K are absorbed from the intestine via lymph and
require bile salts for absorption, while water-soluble forms are absorbed
directly into portal blood.
 An active transport process in the jejunum has been demonstrated for K1, while
K2 and K3 are absorbed by simple diffusion.
 Vit K is only temporarily concentrated in liver, but there are no significant
stores in the body.
 It is metabolized in liver by side chain cleavage and glucuronide conjugation;
metabolites are excreted in bile and urine.
  Deficiency

 Deficiency of vit K occurs due to liver disease, obstructive jaundice,

malabsorption, long-term antimicrobial therapy which alters intestinal
flora. However, deficient diet is rarely responsible.
 The most important manifestation is bleeding tendency due to lowering of
the levels of prothrombin and other clotting factors in blood.
 Haematuria is usually first to occur; other common sites of bleeding are
g.i.t., nose and under the skin ecchymoses.
  Use

 The only use of vit K is in prophylaxis and treatment of bleeding due

to deficiency of clotting factors in the following situations:
 Dietary deficiency
 Prolonged antimicrobial therapy
 Obstructive jaundice or malabsorption syndromes
 Liver disease (cirrhosis, viral hepatitis): associated bleeding responds
poorly to vit K. Because of hepatocellular damage, synthesis of
clotting factors is inadequate despite the presence of vit K. However,
vit K may be of some use if its absorption had been affected due to
lack of bile salts.
 Overdose of anticoagulants
 Prolonged high dose salicylate therapy causes hypoprothrombinemia;
vit K should be given prophylactically.
  Overdose of oral anticoagulants

 This is the most important indication of vit K. Phytonadione (K1) is the

preparation of choice, because it acts most rapidly; dose depends on the
severity of hypoprothrombinaemia and bleeding.
 Unnecessary high dose is to be avoided because it will render the patient
unresponsive to oral anticoagulants for several days.
 Severe: 10 mg i.m. followed by 5 mg 4 hourly; bleeding generally stops in
6–12 hours, but normal levels of coagulation factors are restored only after
24 hr. This dose of vit K will block anticoagulant action for 7–10 days.
 Moderate: 10 mg i.m. followed by 5 mg once or twice according to
response.
 Mild: Just omit a few doses of the anticoagulant
  Newborns

 All newborns have low levels of prothrombin and other clotting factors.
Further decrease occurs in the next few days.
 The cause is both lower capacity to synthesize clotting factors as well as
deficiency of vit K. The defect is exaggerated in the premature infant.
 Vit K 1 mg i.m. soon after birth has been recommended routinely. Some
prefer administering 5–10 mg i.m. to the mother 4–12 hours before delivery.
 Haemorrhagic disease of the newborn can be effectively prevented/treated
by such medication. Menadione (K3) should not be used for this purpose.
  Adverse effects

 Phytonadione injected i.m. or given orally hardly produces any adverse

effect; allergic reactions are rare. Severe anaphylactoid reactions can occur on
i.v. injection of emulsified formulation; this route should not be used.
 Menadione and its water-soluble derivatives can cause haemolysis in a dose-
dependent manner. Patients with G-6-PD deficiency and neonates are
especially susceptible. In the newborn menadione or its salts can precipitate
kernicterus:
 by inducing haemolysis and increasing bilirubin load.
 by competitively inhibiting glucuronidation of bilirubin. Glucuronide
conjugation is, as such, inadequate in neonates.
Because of poor efficacy and higher toxicity, there is little justification to use
menadione and its water soluble salts for any indication.
 Fibrinogen: The fibrinogen fraction of human plasma is employed to control
bleeding in haemophilia, antihaemophilic globulin (AHG) deficiency and acute
afibrinogenemic states; 0.5 g is infused i.v. FIBRINAL 0.5 g/bottle for i.v.
infusion.

 Antihaemophilic factor: It is concentrated human AHG prepared from pooled

human plasma. It is indicated (along with human fibrinogen) in haemophilia and
AHG deficiency. It is highly effective in controlling bleeding episodes, but action
is short-lasting (1 to 2 days). Dose: 5–10 U/kg by i.v. infusion, repeated 6–12
hourly. FIBRINAL-H, ANTIHAEMOPHILIC FACTOR: 150 U or 200 U +
fibrinogen 0.5 g/bottle for i.v. infusion.
 Desmopressin: It releases factor VIII and von Willebrand’s factor from vascular
endothelium and checks bleeding in haemophilia and von Willebrand’s disease.
MINIRIN 100 μg/ml nasal spray (10 μg per actuation); 100 μg/ml intranasal
solution in 2.5 ml bottle with applicator; 0.1 mg tablets; 4 μg/ml inj.

 Adrenochrome monosemicarbazone: It is believed to reduce capillary fragility,

control oozing from raw surfaces and prevent microvessel bleeding, e.g. epistaxis,
haematuria, secondary haemorrhage from wounds, etc. Its efficacy is uncertain.
Dose: 1–5 mg oral, i.m. STYPTOCHROME 3 mg/2 ml inj., STYPTOCID: 2 mg/ 2
ml inj.

 Rutin: It is a plant glycoside claimed to reduce capillary bleeding. It has been

used in a dose of 60 mg oral BD–TDS along with vit C which is believed to
facilitate its action. Its efficacy is uncertain. In CADISPER-C 60 mg tab.
 Ethamsylate: It reduces capillary bleeding when platelets are adequate;
probably exerts antihyaluronidase action or corrects abnormalities of platelet
adhesion, but does not stabilize fibrin (not an antifibrinolytic).
Ethamsylate has been used in the prevention and treatment of
capillary bleeding in menorrhagia, after abortion, PPH, epistaxis, malena,
hematuria and after tooth extraction, but efficacy is unsubstantiated. Side effects
are nausea, rash, headache, and fall in BP (only after i.v. injection).
Dose: 250–500 mg TDS oral/i.v.; ETHAMSYL, DICYNENE,
HEMSYL, K. STAT 250, 500 mg tabs; 250 mg/2 ml inj.
 Coagulation of blood occurs through a series of reactions due to the
activation of a group of substances. Substances necessary for clotting are
called clotting
 factors.

 Thirteen clotting factors are identified:

• Factor I: Fibrinogen
• Factor II: Prothrombin
• Factor III: Thromboplastin (Tissue factor)
• Factor IV: Calcium
• Factor V: Labile factor (Proaccelerin or accelerator globulin)
• Factor VI: Presence has not been proved
• Factor VII: Stable factor
• Factor VIII: Antihemophilic factor (Antihemophilic globulin)
• Factor IX: Christmas factor
• Factor X: Stuart-Prower factor
• Factor XI: Plasma thromboplastin antecedent
• Factor XII: Hageman factor (Contact factor)
• Factor XIII: Fibrin-stabilizing factor (Fibrinase).
  ANTICOAGULANTS

These are drugs used to reduce the coagulability of blood.

 Used in vivo
 Parenteral anticoagulants
 Indirect thrombin inhibitors: Heparin, Low molecular weight
heparins, Fondaparinux, Danaparoid
 Direct thrombin inhibitors: Lepirudin, Bivalirudin, Argatroban
 Oral anticoagulants
 Coumarin derivatives: Bishydroxycoumarin (dicumarol), Warfarin
sod, Acenocoumarol (Nicoumalone), Ethylbiscoumacetate
 Indandione derivative: Phenindione.
 Direct factor Xa inhibitors: Rivaroxaban
 Oral direct thrombin inhibitor: Dabigatran etexilate
 Used in vitro
 Heparin: 150 U to prevent clotting of 100 ml blood.
 Calcium complexing agents: Sodium citrate: 1.65 g for 350
ml of blood; used to keep blood in the fluid state for
transfusion;
  HEPARIN
 In 1916, McLean, a medical students discovered that liver contains a
powerful anticoagulant.
 Howell and Holt (1918) named it ‘heparin’ because it was obtained
from liver.
 However, it could be used clinically only in 1937 when sufficient
degree of purification was achieved.
 Chemistry and occurrence Heparin is a non-uniform mixture of straight
chain mucopolysaccharides with MW 10,000 to 20,000. It contains polymers
of two sulfated disaccharide units:
 D-glucosamine-L-iduronic acid
 D-glucosamine-L-glucuronic
 Heparin carries strong electronegative charges and is the strongest organic
acid present in the body.
 It occurs in mast cells as a much bigger molecule (MW ~75,000) loosely
bound to the granular protein.
 Thus, heparin is present in all tissues containing mast cells; richest sources are
lung, liver and intestinal mucosa.
 Commercially it is produced from ox lung and pig intestinal mucosa.
  ACTIONS
1. Anticoagulant
 Heparin is a powerful and instantaneously acting anticoagulant, effective
both in vivo and in vitro.
 It acts indirectly by activating plasma antithrombin III (AT III, a serine
proteinase inhibitor).
 The heparin-AT III complex then binds to clotting factors of the intrinsic
and common pathways (Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates
them but not factor VIIa operative in the extrinsic pathway.
 At low concentrations of heparin, factor Xa mediated conversion of
prothrombin to thrombin is selectively affected.
 The anticoagulant action is exerted mainly by inhibition of factor Xa as well
as thrombin (IIa) mediated conversion of fibrinogen to fibrin.
  Low concentrations of heparin prolong aPTTwithout significantly
prolonging PT. High concentrations prolong both.
 Thus, low concentrations interfere selectively with the intrinsic
pathway, affecting amplification and continuation of clotting, while
high concentrations affect the common pathway as well.
2. Antiplatelets
 Heparin in higher doses inhibits platelet aggregation and prolongs
bleeding time.
3. Lipaemia clearing
 Injection of heparin clears turbid post-prandial lipaemic plasma by
releasing a lipoprotein lipase from the vessel wall and tissues, which
hydrolyses triglycerides of chylomicra and very low density
lipoproteins to free fatty acids
  PHARMACOKINETICS
 Heparin is a large, highly ionized molecule; therefore not absorbed orally.
 Injected i.v. it acts instantaneously, but after s.c. injection anticoagulant
effect develops after ~60 min.
 Bioavailability of s.c. heparin is inconsistent.
 Heparin does not cross blood-brain barrier or placenta (it is the
anticoagulant of choice during pregnancy).
 It is metabolized in liver by heparinase and fragments are excreted in
urine.
 Heparin released from mast cells is degraded by tissue macrophages—it
is not a physiologically circulating anticoagulant.
 After i.v. injection of doses < 100 U/kg, the t½ averages 1 hr.
Beyond this, dose-dependent inactivation is seen and t½ is
prolonged to 1–4 hrs. The t½ is longer in cirrhotics and kidney
failure patients, and shorter in patients with pulmonary embolism.
 Heparin should not be mixed with penicillin, tetracyclines,
hydrocortisone or NA in the same syringe or infusion bottle.
 Heparinized blood is not suitable for blood counts (alters the shape of
RBCs and WBCs), fragility testing and complement fixation tests.
  Dosage
 Heparin is conventionally given i.v. in a bolus dose of 5,000–10,000 U
(children 50–100 U/kg), followed by continuous infusion of 750–1000 U/hr.
Intermittent i.v. bolus doses of UFH are no longer recommended.
 The rate of infusion is controlled by aPTT measurement which is kept at 50–80
sec. or 1.5–2.5 times the patient’s pretreatment value.
 If this test is not available, whole blood clotting time should be measured and
kept at ~2 times the normal value.
 Deep s.c. injection of 10,000–20,000 U every 8–12 hrs can be given if i.v.
infusion is not possible.
 Needle used should be fine and trauma should be minimum to avoid
haematoma formation. Haematomas are more common with i.m. injection - this
route should not be used.
  Low dose (s.c.) regimen
 5000 U is injected s.c. every 8–12 hours, started before surgery and
continued for 7–10 days or till the patient starts moving about.
 This regimen has been found to prevent postoperative deep vein thrombosis
without increasing surgical bleeding.
 It also does not prolong aPTT or clotting time.
 However, it should not be used in case of neurosurgery or when spinal
anaesthesia is to be given.
 The patients should not be receiving aspirin or oral anticoagulants.
 It is ineffective in high-risk situations, e.g. hip joint or pelvic surgery.
  Adverse effects
 Bleeding due to overdose is the most serious complication of heparin therapy.
Haematuria is generally the first sign. With proper monitoring, serious
bleeding occurs only in 1–3% patients.
 Thrombocytopenia is another common problem. Generally it is mild and
transient; occurs due to aggregation of platelets. Occasionally serious
thromboembolic events result. In some patients antibodies are formed to the
heparin-platelet complex and marked depletion of platelets occurs—heparin
should be discontinued in such cases. Even low molecular weight (LMW)
heparins are not safe in such patients.
 Transient and reversible alopecia is infrequent.
 Serum transaminase levels may rise.
 Osteoporosis may develop on long-term use of relatively high doses.
 Hypersensitivity reactions are rare; manifestations are urticaria, rigor, fever
and anaphylaxis. Patients with allergic diathesis are more liable.
  Contraindications

 Bleeding disorders, history of heparin induced thrombocytopenia.

 Severe hypertension (risk of cerebral haemorrhage), threatened abortion,
piles, g.i. ulcers (risk of aggravated bleeding).
 Subacute bacterial endocarditis, large malignancies, tuberculosis.
 Ocular and neurosurgery, lumbar puncture.
 Chronic alcoholics, cirrhosis, renal failure.
 Aspirin and other antiplatelet drugs should be used very cautiously during
heparin therapy
  Low molecular weight (LMW) heparins
 Heparin has been fractionated into LMW forms (MW 3000–7000) by
different techniques.
 LMW heparins have a different anticoagulant profile; i.e. selectively inhibit
factor Xa with little effect on IIa.
 They act only by inducing conformational change in AT III and not by
providing a scaffolding for interaction of AT III with thrombin.
 As a result, LMW heparins have smaller effect on aPTT and whole blood
clotting time than unfractionated heparin (UFH) relative to antifactor Xa
activity.
 Also, they have lesser antiplatelet action—less interference with
haemostasis.
 Better subcutaneous bioavailability (70–90%) compared to UFH (20–30%)
  Fondaparinux
The pentasaccharide with specific sequence that binds to AT III with high affinity
to selectively inactivate factor Xa without binding thrombin (factor IIa), has been
recently produced synthetically and given the name fondaparinux.
It is being increasingly used and has been marketed in India as well.
The bioavailability of fondaparinux injected s.c. is 100% and it is longer acting
(t½ 17 hours).
Metabolism is minimal, and it is largely excreted unchanged by the kidney.
As such, it is not to be used in renal failure patients. Fondaparinux is less likely to
cause thrombocytopenia compared to even LMW heparins.
Risk of osteoporosis after prolonged use is also minimal.
Fondaparinux does not require laboratory monitoring of aPTT, and is a longer
acting alternative to LMW heparins with the above advantages.
 Danaparoid is a preparation containing mainly heparan sulfate
which is a heparin-like substance found in many tissues, having less
potent anticoagulant action than heparin. Danaparoid is obtained
from pig gut mucosa, and is used in cases with heparin induced
thrombocytopenia.
  DIRECT THROMBIN INHIBITORS

 Lepirudin: This recombinant preparation of hirudin (a polypeptide

anticoagulant secreted by salivary glands of leech) binds firmly to the catalytic
as well as the substrate recognition sites of thrombin and inhibits it directly.
Injected i.v., it is indicated only in patients who are at risk of heparin induced
thrombocytopenia. On repeated/prolonged administration, antibodies against the
lepirudin-thrombin complex may develop resulting in prolonged anticoagulant
effect and possibility of anaphylaxis. Its action cannot be reversed by protamine
or any other antidote.

 Bivalirudin: It is a smaller peptide prepared synthetically which has actions and

uses similar to lepirudin. However, its action is slowly reversible due to
cleavage of its peptide bonds by thrombin itself.
 Argatroban: This is a synthetic nonpeptide compound which binds
reversibly to the catalytic site of thrombin, but not to the substrate recognition
site. As such, it produces a rapid and short-lasting antithrombin action.
Administered by i.v. infusion, it can be used in place of lepirudin for short-
term indications in patients with heparin induced thrombocytopenia
  HEPARIN ANTAGONIST

 Protamine sulfate: It is a strongly basic, low molecular weight protein

obtained from the sperm of certain fish. Given i.v. it neutralises heparin
weight for weight, i.e. 1 mg is needed for every 100 U of heparin.
In the absence of heparin, protamine itself acts as a weak
anticoagulant by interacting with platelets and fibrinogen. Being basic in nature
it can release histamine in the body. Hypersensitivity reactions have occurred.
Rapid i.v. injection causes flushing and breathing difficulty.
 ORAL ANTICOAGULANTS

 A haemorrhagic disease was described in cattle in 1924 which was due to

feeding them on spoiled sweet clover hay.
 The disorder was found to be due to prothrombin deficiency and the toxic
principle was identified as bishydroxycoumarin in 1939. It was cured by
feeding alfalfa grass.
 First clinical use of bishydroxycoumarin was made in 1941 and many
congeners were added later.
 Warfarin was initially used as rat poison; demonstration of its safety led to
clinical trial; it is now a commonly employed oral anticoagulant.
  Warfarin

 Warfarin and its congeners act as anticoagulants only in vivo, not in vitro.
 This is so because they act indirectly by interfering with the synthesis of vit K
dependent clotting factors in liver.
 They apparently behave as competitive antagonists of vit K and lower the plasma
levels of functional clotting factors in a dose-dependent manner.
 They inhibit the enzyme vit K epoxide reductase (VKOR) and interfere with
regeneration of the active hydroquinone form of vit K which acts as a cofactor for
the enzyme γ-glutamyl carboxylase that carries out the final step of γ
carboxylating glutamate residues of prothrombin and factors VII, IX and X.
 This carboxylation is essential for the ability of the clotting factors to bind Ca2+
and to get bound to phospholipid surfaces, necessary for the coagulation sequence
to proceed.
 The synthesis of clotting factors diminishes within 2–4 hours of warfarin
administration, anticoagulant effect develops gradually over the next 1–3 days as
the levels of the clotting factors already present in plasma decline progressively.
 Therapeutic effect occurs when synthesis of clotting factors is reduced by 40–
50%.
 Racemic Warfarin sod. It is the most popular oral anticoagulant. The
commercial preparation of warfarin is a mixture of R (dextrorotatory) and S
(levorotatory) enantiomers. The S form is more potent and is metabolized
relatively faster by ring oxidation carried out by CYP2C9, while R form is
less potent and degraded by side chain reduction carried out by CYP1A and
CYP3A4. and undergo some enterohepatic circulation; finally excreted in
urine.
 Warfarin is rapidly and completely absorbed from intestines and is 99%
plasma protein bound. It crosses placenta and is secreted in milk;
however, quantity of active form is generally insufficient to affect the
suckling infant.
 Bishydroxycoumarin (Dicumarol) It is slowly and unpredictably absorbed
orally. Its metabolism is dose dependent—t½ is prolonged at higher doses.
Has poor g.i. tolerance; not preferred now. DICOUMAROL 50 mg tab.
 Acenocoumarol (Nicoumalone) The t½ of acenocoumarol as such is 8 hours,
but an active metabolite is produced so that overall t½ is about 24 hours.
Acts more rapidly. ACITROM, 1, 2, 4 mg tabs.
 Ethyl biscoumacetate It has a rapid and brief action; occasionally used to
initiate therapy, but difficult to maintain.
 Phenindione Apart from risk of bleeding, it produces more serious organ
toxicity; should not be used.
  Adverse effects

 Bleeding as a result of extension of the desired pharmacological

action is the most important problem causing ecchymosis, epistaxis,
hematuria, bleeding in the g.i.t.
 Intracranial or other internal haemorrhages may even be fatal.
 Bleeding is more likely if therapy is not properly monitored.
  Factors enhancing effect of oral anticoagulants

 Debility, malnutrition, malabsorption and prolonged antibiotic

therapy: the supply of vit K to liver is reduced in these
conditions.
 Liver disease, chronic alcoholism: synthesis of clotting
factors may be deficient.
 Hyperthyroidism: the clotting factors are degraded faster.
 Newborns: have low levels of vit K and clotting factors.
  Factors decreasing effect of oral anticoagulants

 Pregnancy: plasma level of clotting factors is higher.

 Nephrotic syndrome: drug bound to plasma protein is lost in urine.
 Genetic warfarin resistance: the affinity of warfarin (as well as of
vit K epoxide) to bind to the reductase (VKOR) enzyme, which
generates the active vit K hydroquinone, is low. Dose of oral
anticoagulant is 4–5 times higher
  Contraindications

 Oral anticoagulants should not be used during pregnancy.

 Warfarin given in early pregnancy increases birth defects, especially
skeletal abnormalities. It can produce foetal warfarin syndrome-
hypoplasia of nose, eye socket, hand bones, and growth retardation.
 Given later in pregnancy, it can cause CNS defects, foetal
haemorrhage, foetal death and accentuates neonatal
hypoprothrombinemia.
  Drug interactions

A large number of drugs interact with oral anticoagulants at

pharmacokinetic or pharmacodynamic level, and either enhance or
decrease their effect. These interactions are clinically important and
may involve more than one mechanism
  Interactions which Enhanced anticoagulant action

 Broad-spectrum antibiotics: inhibit gut flora and reduce vit K production.

 Newer cephalosporins (ceftriaxone, cefoperazone) cause
hypoprothrombinaemia by the same mechanism as warfarin —additive action.
 Aspirin: inhibits platelet aggregation and causes g.i. bleeding—this may be
hazardous in anticoagulated patients. High doses of salicylates have synergistic
hypoprothrombinemic action and also displace warfarin from protein binding
site.
 Long acting sulfonamides, indomethacin, phenytoin and probenecid: displace
warfarin from plasma protein binding.
 Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol,
amiodarone and metronidazole: inhibit warfarin metabolism.
 Tolbutamide and phenytoin: inhibit warfarin metabolism and vice versa.
 Liquid paraffin (habitual use): reduces vit K absorption.
  Interactions which Reduce anticoagulant action

 Barbiturates (but not benzodiazepines), carbamazepine, rifampin and

griseofulvin induce the metabolism of oral anticoagulants. The dose of
anticoagulant determined during therapy with these drugs would be
higher: if the same is continued after withdrawing the inducer—
marked hypoprothrombinemia can occur—fatal bleeding is on record.
 Oral contraceptives: increase blood levels of clotting factors.
  DIRECT FACTOR Xa INHIBITORS

 Rivaroxaban: It is an orally active direct inhibitor of activated factor Xa which

has become available for prophylaxis and treatment of DVT.
 Its anticoagulant action develops rapidly within 3–4 hours of ingestion and lasts
for ~24 hours.
 It is largely metabolized, but also excreted unchanged in urine; plasma t½ is 7–
11 hours.
 Another advantage is that it requires no laboratory monitoring of PT or aPTT,
and is recommended in a fixed dose of 10 mg once daily starting 6–10 hours
after surgery for prophylaxis of venous thromboembolism following total
knee/hip replacement.
 Rivaroxaban has also been found equally effective as warfarin for preventing
stroke in patients with atrial fibrillation.
 Side effects reported are bleeding, nausea, hypotension, tachycardia and edema.
  ORAL DIRECT THROMBIN INHIBITOR

 Dabigatran etexilate It is a prodrug which after oral administration is rapidly

hydrolysed to dabigatran, a direct thrombin inhibitor which reversibly blocks the
catalytic site of thrombin and produces a rapid (within 2 hours) anticoagulant action.
 Though oral bioavailability is low, the anticoagulant effect is consistent, and no
laboratory monitoring is required.
 The plasma t½ is 12–14 hours and duration of action 24 hours.
 Administered in a dose of 110 mg (75 mg for elderly > 75 years) once daily.
 Adverse effects are bleeding and less commonly hepatobiliary disorders.
  USES OF ANTICOAGULANTS
The aim of using anticoagulants is to prevent thrombus extension and embolic
complications by reducing the rate of fibrin formation. They do not dissolve
already formed clot, but prevent recurrences. Heparin is utilized for rapid and
short lived action, while oral anticoagulants are suitable for maintenance
therapy. Generally, the two are started together; heparin is discontinued after 4–
7 days when warfarin has taken effect.
 Deep vein thrombosis
 Myocardial infarction
 Rheumatic heart disease; Atrial fibrillation (AF)
 Unstable angina
 Cerebrovascular disease
 Defibrination syndrome
 Vascular surgery, prosthetic heart valves, retinal vessel thrombosis,
extracorporeal circulation, haemodialysis
 FIBRINOLYTICS (Thrombolytics)

 These are drugs used to lyse thrombi/clot to recanalize occluded blood

vessels (mainly coronary artery). They are therapeutic rather than
prophylactic and work by activating the natural fibrinolytic system.
 Haemostatic plug of platelets formed at the site of injury to blood vessels is
reinforced by fibrin deposition to form a thrombus.
 Once repair is over, the fibrinolytic system is activated to remove the fibrin.
 The enzyme responsible for digesting fibrin is a serine protease Plasmin
generated from plasminogen by tissue plasminogen activator (t-PA), which
is produced primarily by vascular endothelium.
 Plasminogen circulates in plasma as well as remains bound to fibrin.
 The t-PA selectively activates fibrin-bound plasminogen within the thrombus,
and any plasmin that leaks is inactivated by circulating antiplasmins.
 Fibrin bound plasmin is not inactivated by antiplasmins because of common
binding site for both fibrin and antiplasmin.
 The t-PA itself is inactivated by plasminogen activator inhibitor-1 and -2 (PAI-
1, PAI-2).
 When excessive amounts of plasminogen are activated (by administered
fibrinolytics), the α2 antiplasmin is exhausted and active plasmin persists in
plasma.
 Plasmin is a rather nonspecific protease: degrades coagulation factors (including
fibrinogen) and some other plasma proteins as well.
 Thus, activation of circulating plasminogen induces a lytic state whose major
complication is haemorrhage.
  Streptokinase
 Streptokinase (Stk) Obtained from β haemolytic Streptococci group C, it is the
first fibrinolytic drug to be used clinically.
 Streptokinase is inactive as such; combines with circulating plasminogen
molecules to form an activator complex which then causes limited proteolysis
of other plasminogen molecules to generate the active enzyme plasmin.
 Stk. is non-fibrin specific, i.e. activates both circulating as well as fibrin bound
plasminogen.
 Therefore, it depletes circulating fibrinogen and predisposes to bleeding.
 Plasma t½ is estimated to be 30–80 min.
 Stk is antigenic-can cause hypersensitivity reactions; anaphylaxis occurs in 1-
2% patients.
 It cannot be used second time due to neutralization by antibodies generated in
response to the earlier dose. Fever, hypotension and arrhythmias are reported.
  Urokinase
 It is an enzyme isolated from human urine; but commercially prepared from
cultured human kidney cells.
 It activates plasminogen directly and has a plasma t½ of 10–15 min.
 It is non-antigenic.
 Fever occurs during treatment, but hypotension and allergic phenomena are
rare.
 Urokinase is Indicated in patients in whom streptokinase has been given for
an earlier episode.
  Alteplase (recombinant tissue plasminogen activator (rt-PA)

 Produced by recombinant DNA technology from human tissue culture, it is

moderately specific for fibrin-bound plasminogen, so that circulating
fibrinogen is lowered only by ~ 50%.
 It is rapidly cleared by liver and inactivated by plasminogen activator
inhibitor-1 (PAI-1).
 The plasma t½ is 4–8 min.
 Because of the short t½, it needs to be given by slow i.v. infusion and often
requires heparin co-administration.
 It is non-antigenic, but nausea, mild hypotension and fever may occur.
 It is expensive.
 Reteplase

 It is a modified form of rt-PA that is longer acting, but

somewhat less specific for fibrin-bound plasminogen.
  Tenecteplase

 This genetically engineered substitution mutant of native t-PA has higher fibrin
selectivity, slower plasma clearance (longer duration of action) and resistance to
inhibition by PAI-1.
 It is the only fibrinolytic agent that can be injected i.v. as a single bolus dose over
10 sec, while alteplase requires 90 min infusion.
 Risk of non-cerebral bleeding may be lower with tenecteplase, but cranial
bleeding incidence is similar.
 Uses of fibrinolytics

 Acute myocardial infarction

 Deep vein thrombosis
 Pulmonary embolism
 Peripheral arterial occlusion
 Stroke
 Antifibrinolytic drugs

 These are drugs which inhibit plasminogen activation and dissolution of clot,
and are used to check fibrinolysis associated bleeding.
  Epsilon amino-caproic acid (EACA)
 It is a lysine analogue which combines with the lysine binding sites of
plasminogen and plasmin so that the latter is not able to bind to fibrin and lyse it.
 It is a specific antidote for fibrinolytic agents and has been used in many
hyperplasminaemic states associated with excessive intravascular fibrinolysis
resulting in bleeding.
 The primary indication is to counteract the effect of fibrinolytic drugs and
bleeding due to their use.
 In haemophiliacs, it has adjunctive value for controlling bleeding due to tooth
extraction, prostatectomy, trauma, etc.
 It can cause intravascular thrombosis.
 Rapid i.v. injection results in hypotension, bradycardia and may be arrhythmias.
 It should be used cautiously when renal function is impaired. Myopathy occurs
rarely.
  Tranexamic acid
 Like EACA, it binds to the lysine binding site on plasminogen and prevents
its combination with fibrin leading to fibrinolysis. It is 7 times more potent
than EACA and is preferred for prevention/control of excessive bleeding
due to:
 Fibrinolytic drugs
 Cardio-pulmonary bypass surgery
 Tonsillectomy, prostatic surgery, tooth extraction in haemophiliacs
 Menorrhagia, especially due to IUCD
 Recurrent epistaxis, hyphema due to ocular trauma, peptic ulcer
 Main side effects are nausea and diarrhoea. Thromboembolic events,
disturbed colour vision and allergic reactions are infrequent.
Thrombophlebitis of injected vein can occur.
 ANTIPLATELET DRUGS
(Antithrombotic drugs)

 These are drugs which interfere with platelet function and are useful
in the prophylaxis of thromboembolic disorders.
 Platelets express several glycoprotein (GP) integrin receptors on their surface.
 Reactive proteins like collagen are exposed when there is damage to vascular
endothelium, and they react respectively with platelet GPIa and GPIb receptors.
 This results in platelet activation and release of proaggregatory and
vasoconstrictor mediators like TXA2, ADP and 5-HT.
 The platelet GPIIb/IIIa receptor undergoes a conformational change favouring
binding of fibrinogen and vonWillebrand factor (vWF) that crosslink platelets
inducing aggregation and anchorage to vessel wall/other surfaces.
 Thus, a ‘platelet plug’ is formed.
 In veins, due to sluggish blood flow, a fibrinous tail is formed which traps RBCs
‘the red tail’.
  Aspirin
 It acetylates and inhibits the enzyme COX1 and TX-synthase—inactivating
them irreversibly.
 Because TXA2 is the major arachidonic acid product generated by platelets,
and that platelets are exposed to aspirin in the portal circulation before it is
deacetylated during first pass in the liver, and because platelets cannot
synthesize fresh enzyme, TXA2 formation is suppressed at very low doses and
till fresh platelets are formed.
 Thus, aspirin induced prolongation of bleeding time lasts for 5–7 days.
 Effect of daily doses cumulates and it has now been shown that doses as low
as 40 mg/day have an effect on platelet aggregation. Maximal inhibition of
platelet function occurs at 75–150 mg aspirin per day.
 Aspirin inhibits the release of ADP from platelets and their sticking to each
other, but has no effect on platelet survival time and their adhesion to damaged
vessel wall.
  Dipyridamole

 It is a vasodilator that was introduced for angina pectoris.

 It inhibits phosphodiesterase as well as blocks uptake of adenosine to increase
platelet cAMP which in turn potentiates PGI2 and interferes with aggregation.
 Levels of TXA2 or PGI2, are not altered, but platelet survival time reduced by
disease is normalized.
 Dipyridamole has also been used to enhance the antiplatelet action of aspirin.
 This combination may additionally lower the risk of stroke in patients with
transient ischaemic attacks (TIAs), but trials have failed to demonstrate
additional benefit in prophylaxis of MI.
  Ticlopidine

 It is the first thienopyridine which alters surface receptors on platelets and inhibits
ADP as well as fibrinogen-induced platelet aggregation.
 The Gi coupled P2Y12 (also labelled P2YAC) type of purinergic receptors which
mediate adenylyl cyclase inhibition due to ADP are blocked irreversibly by the
active metabolite of ticlopidine.
 As a result, activation of platelets is interfered.
 Fibrinogen binding to platelets is prevented without modification of GPIIb/IIIa
receptor. There is no effect on platelet TXA2, but bleeding time is prolonged and
platelet survival in extra-corporeal circulation is increased.
 Because of different mechanism of action, it has synergistic effect on platelets with
aspirin. Their combination is a potent platelet inhibitor.
  Clopidogrel
 This newer and more potent congener of ticlopidine has similar
mechanism of action.
 Like ticlopidine, clopidogrel is also a prodrug, About 50% of the ingested
dose is absorbed, and only a fraction of this is slowly activated in liver by
CYP2C19, while the rest is inactivated by other enzymes.
 It is a slow acting drug; antiplatelet action takes about 4 hours to start and
develops over days.
 Since CYP2C19, exhibits genetic polymorphism, the activation of
clopidogrel and consequently its antiplatelet action shows high
interindividual variability. Some patients are nonresponsive.
 Omeprazole, an inhibitor of CYP2C19, reduces metabolic activation of
clopidogrel and its antiplatelet action.
 However, like ticlopidine, the action of clopidogrel lasts 5–7 days due to
irreversible blockade of platelet P2Y12 receptors.
  Abciximab
 It is the Fab fragment of a chimeric monoclonal antibody against GP IIb/IIIa,
protein, but is relatively nonspecific and binds to some other surface proteins
as well.
 After a bolus dose, platelet aggregation remains inhibited for 12–24 hr, while
the remaining antibody is cleared from blood with a t½ of 10–30 min.

 Eptifibatide
 It is a synthetic cyclic peptide that selectively binds to platelet surface
GPIIb/IIIa receptor and inhibits platelet aggregation.
 Its plasma t½ (2.5 hours) is longer than that of abciximab, platelet inhibition
reverses in a shorter time (within 6–10 hours) because it quickly dissociates
from the receptor.
 Uses of antiplatelet drugs

 Coronary artery disease

 Acute coronary syndromes
 Cerebrovascular disease
 Venous thromboembolism
 Peripheral vascular disease
  Shock

 Shock is a critical condition brought on by the sudden drop in

blood flow through the body

 When you don’t have enough blood circulating through your

system to keep organs and tissues functioning properly.
 The main symptom of shock is low blood pressure.
 Other symptoms include rapid, shallow breathing, cold
and clammy skin, rapid, weak pulse, dizziness, fainting
and weakness.
  Types of Shock

 Cardiogenic
 Hypovolumic
 Septic
 Anaphylectic
  Cardiogenic shock

 Cardiogenic shock is a life-threatening condition where your

heart suddenly stops pumping enough oxygen-rich blood to
your body.
 This condition is an emergency situation that is usually brought
on by a heart attack.
 It is discovered as it happens and requires immediate treatment
in the hospital.
  Causes
 A severe heart attack can damage the heart’s main pumping chamber (left
ventricle). When this happens, the body can’t get enough oxygen-rich blood.
 In rare cases of cardiogenic shock, the bottom right chamber of the heart (right
ventricle) is damaged. The right ventricle pumps blood to the lungs, where it gets
oxygen and then goes to the rest of the body.
 Other conditions that make the heart weak and can lead to cardiogenic shock
include:
 Myocarditis: Inflammation of the heart muscle
 Endocarditis: An infection of the heart’s inner lining and valves
 Arrhythmias: An abnormal heart rhythm
 Pericardial tamponade: Too much fluid or blood around the heart
 Pulmonary embolism: An artery in the lung is suddenly blocked, usually by a
blood clot
  Hypovolemic shock

 Hypovolemic shock is an emergency condition in which severe blood or

other fluid loss makes the heart unable to pump enough blood to the
body. This type of shock can cause many organs to stop working.
  Causes
 Losing about one fifth or more of the normal amount of blood in your body
causes hypovolemic shock.
 Blood loss can be due to:
 Bleeding from cuts
 Bleeding from other injuries
 Internal bleeding, such as in the gastrointestinal tract
 The amount of circulating blood in your body also may drop when you lose
too much body fluid from other causes. This can be due to:
 Burns
 Diarrhea
 Excessive perspiration
 Vomiting
 Septic shock

 Sepsis is the result of an infection, and causes drastic changes in

the body. It can be very dangerous and potentially life-threatening.

 It occurs when chemicals that fight infection by triggering

inflammatory reactions are released into the bloodstream.
 Doctors have identified three stages of sepsis:
 Sepsis is when the infection reaches the bloodstream and causes
inflammation in the body.
 Severe sepsis is when the infection is severe enough to affect the
function of your organs, such as the heart, brain, and kidneys.
 Septic shock is when you experience a significant drop in blood
pressure that can lead to respiratory or heart failure, stroke, failure
of other organs, and death.
 It is thought that the inflammation resulting from sepsis causes tiny
blood clots to form. This can block oxygen and nutrients from reaching
vital organs.

 The inflammation occurs most often in older adults or those with a

weakened immune system. But both sepsis and septic shock can happen
to anyone.
 Early symptoms of sepsis should not be ignored. These include:
 fever usually higher than 101˚F (38˚C)
 low body temperature (hypothermia)
 fast heart rate
 rapid breathing, or more than 20 breaths per minute
 Severe sepsis is defined as sepsis with evidence of organ damage that usually
affects the kidneys, heart, lungs, or brain.
 Symptoms of severe sepsis include:
 noticeably lower amounts of urine
 acute confusion
 dizziness
 severe problems breathing
 bluish discoloration of the lips (cyanosis)
 A bacterial, fungal, or viral infection can cause sepsis. Any of the infections
may begin at home or while you are in the hospital for treatment of another
condition.
 Sepsis commonly originates from:
 abdominal or digestive system infections
 lung infections like pneumonia
 urinary tract infection
 reproductive system infection
  Anaphylactic shock
 Anaphylactic shock is a rare but severe allergic reaction that can be
deadly if you don't treat it right away.
 It's most often caused by an allergy to food, insect bites, or certain
medications.
 The terms "anaphylaxis" and "anaphylactic shock" are often used to mean
the same thing. They both refer to a severe allergic reaction.
 Shock is when your blood pressure drops so low that your cells (and
organs) don't get enough oxygen.
 Symptoms of anaphylaxis include:
 skin reactions such as hives, flushed skin, or paleness
 suddenly feeling too warm
 feeling like you have a lump in your throat or difficulty swallowing
 nausea, vomiting, or diarrhea
 abdominal pain
 a weak and rapid pulse
 runny nose and sneezing
 swollen tongue or lips
 wheezing or difficulty breathing
 a sense that something is wrong with your body
  Treatment

 Cardiogenic shock treatment focuses on reducing the damage from lack of oxygen to your
heart muscle and other organs.

 Life support to restore blood flow to major organs

 intravenous antibiotics to fight infection in case of septic shock
 Fluid (saline) transfusion, blood transfusion and plasma expanders in case of hypovolemic
shock
 A shot of epinephrine in your thigh is needed right away, in case of anaphylactic shock
 Vasopressors: These medications are used to treat low blood pressure. They include
dopamine, epinephrine (Adrenaline, Auvi-Q), norepinephrine (Levophed) and others.
 Inotropic agents: These medications, which help improve the pumping function of the
heart, may be given until other treatments start to work. They include dobutamine,
dopamine and milrinone.
 Aspirin: Aspirin is usually given immediately to reduce blood clotting and
keep blood moving through a narrowed artery. Take an aspirin yourself while
waiting for help to arrive only if your doctor has previously told you to do so
for symptoms of a heart attack.
 Antiplatelet medication: Emergency room doctors might give you drugs
similar to aspirin to help prevent new clots from forming. These medications
include clopidogrel (Plavix), tirofiban (Aggrastat) and eptifibatide
(Integrilin).
 Other blood-thinning medications: You'll likely be given other
medications, such as heparin, to make your blood less likely to form clots.
IV or injectable heparin usually is given during the first few days after a
heart attack.
 https://www.mayoclinic.org/diseases-conditions/cardiogenic-shock/diagnosis-
treatment/drc-20366764
 https://www.healthline.com/health/anaphylactic-shock
 https://medlineplus.gov/ency/article/000167.htm
 https://www.healthline.com/health/septic-shock#outlook
 https://my.clevelandclinic.org/health/diseases/17837-cardiogenic-shock
THANK YOU
 B.PHARM 5TH SEMESTER

PHARMACOLOGY-II BP503T UNIT-III

AUTACOID

The word autacoid comes from the Greek: ¨autos (self) & ¨akos (medicinal agent, or remedy)

INTRODUCTION:

 Histamine, serotonin, prostaglandins, & some vasoactive peptides belong to a group of compounds called
autacoids .
 They all have the common feature of being formed by the tissues on which they act so they function as local
hormones
 The autacoids also differ from circulating hormones in that they are produced by many tissues rather than in
specific endocrine glands.

TYPES: The important autacoids include:

• Histamine,
• Hydroxytryptamine (5-HT, serotonin),
• Prostaglandins,
• Leukotrienes, and
• Kinins.

HISTAMINE

Histamine (Beta-aminoethyl-imidazole) is formed from decarboxylation of Imidazole ring containing amino

acid histidine. Histamine is a basic amine, stored in mast cell and basophil granules, and secreted when C3a and
C5a interact with specific membrane receptors or when antigen interacts with cell-fixed immunoglobulin E.
Histamine plays a central role in immediate hypersensitivity (Type 1) and allergic responses.

The actions of histamine on bronchial smooth muscle and blood vessels account for many of the symptoms of the
allergic response. In addition, certain clinically useful drugs can act directly on mast cells to release histamine,
thereby explaining some of their untoward effects.

Histamine has a major role in the regulation of gastric acid secretion and also modulates neurotransmitter release.
Stimulation of IgE receptors also activates phospholipase A2 (PLA2), leading to the production of a host of
mediators, including platelet-activating factor (PAF) and metabolites of arachidonic acid. Leukotriene D4, which
1
is generated in this way, is a potent contractor of the smooth muscle of the bronchial tree.

Kinins also are generated during some allergic responses. Thus the mast cell secretes a variety of inflammatory
mediators in addition to histamine, each contributing to the major symptoms of the allergic response.
Epinephrine and related drugs that act through b2 adrenergic receptors increase cellular cyclic AMP and
thereby inhibit the secretory activities of mast cells. So are given in anaphylactic shock treatment.
However, the beneficial effects of b adrenergic agonists in allergic states such as asthma are due mainly to their
relaxant effect on bronchial smooth muscle.

Cromolyn or Cromoglicate sodium is used clinically because it inhibits the release of mediators from mast
and other cells in the lung.

Drug which release histamine: Tubocurarine, succinylcholine, morphine, Polymyxin B, bacitracin,

Vancomycin-induced "red-man syndrome" involving upper body and facial flushing and hypotension may be
mediated through histamine release. Bradykinin is a poor histamine releaser, whereas kallidin (Lys-bradykinin)
and substance P, with more positively charged amino acids, are more active.

 Histamine produces effects by acting on H1, H2 or H3 (and possibly H4) receptors on target cells.
 The main actions in humans are:
o Stimulation of gastric secretion (H2)
o Contraction of most smooth muscle, except blood vessels (H1)
o Cardiac stimulation (H2)
o Vasodilatation (H1)
o Increased vascular permeability (H1).
 Injected intradermally, histamine causes the 'triple response': reddening (local
vasodilatation), weal (direct action on blood vessels) and flare (from an 'axon'
reflex in sensory nerves releasing a peptide mediator).
 The main pathophysiological roles of histamine are:
o as a stimulant of gastric acid secretion (treated with H2-receptor antagonists)
o as a mediator of type I hypersensitivity reactions such as urticaria and hay fever
(treated with H1- receptor antagonists).
 H3 receptors occur at presynaptic sites and inhibit the release of a variety of neurotransmitters.

2
H1 antagonists

A. Sedating H1 antagonists (1st generation antihistaminics)

1. Chlorpheniramine , Clemastine
2. Diphenhydramine- Mainly used as a mild hypnotic, also show significant antimuscarinic effects
3. Cyproheptadine - Used also for migraine due to additional 5-hydroxytryptamine antagonist activity
4. Promethazine- Also used for motion sickness, Used for anaesthetic premedication
to prevent post- operative vomiting, , weak blockade at α1 adrenoceptors
5. Hydroxyzine – used also to treat anxiety
6. Alimemazine- Used for premedication
7. Doxylamine, Triprolidine - Mainly used as an ingredient of proprietary decongestant and other
medicines

B. Non-sedating H1 antagonists (2nd generation antihistaminics, Do not penetrate the

blood-brain barrier)
1. Desloratidine: Metabolite of loratidine
2. Fexofenadine: Metabolite of Terfenadine
3. Levocetrizine: Isomer of cetrizine
4. Terfenadine: Grapefruit juice inhibits metabolism; rare fatal
arrhythmias or QT interval prolongation as it blocks the K+
conduction in heart leading to ventricular tachycardia. The arrhythmiac

3
 potential increases when given with erythromycin, ketoconazole etc.
5. Mizolastine: May cause QT interval prolongation
6. Azelastine: in addition to inhibit histamine release, it also inhibits
inflammation triggered by leukotrienes and given as nasal spray for
rhinitis.
7. Acrivastine
8. Loratidine

Some important drugs:

I. Antihistaminic which increases the appetite and weight gain: Buclizine

II. (used for underweight children), Cyproheptadine, Astimazol
III. Appetite suppressant
While the adnergic drugs called anorectics like Fenfluramine and Desfluramine is appetite
suppressant.

IV. local anaesthetic property :

Mepyramine also have local anaesthetic property also or membrane stabilizing activity
(antiarrythimic)
V. Cinnarizine: is drug choice for vertigo, it is antihistaminic, anticholinergic, anti-5-

HT and vasodilator

It inhibits vestibular sensory nuclei, post-rotatary labyrinthine refluxes by reducing the

calcium influx from endolympth into vestibular sensory cells.

VI. Diphenhydramine is generally combined with Thecolic acid to reduce the sedative effect of
diphenhydramine.

H2 blockers: are used to treat ulcers and includes the drug like cimetidine, ranitidine etc.

4
 EICOSANOIDS

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release
lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids
are synthesized.
The cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a
variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation.
The discovery of cyclooxygenase isoforms (COX-1 and COX-2) led to the concepts that the constitutive
COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and
tends to facilitate the inflammatory response.
On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption
that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of
efficacy.
The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful
chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction
and alterations in vascular permeability.

Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are
complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the
neutrophil membranes produces oxygen-derived free radicals.

Superoxide anion is formed by the reduction of molecular oxygen, which may stimulate the production of
other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these
substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the
inflammatory process.

In mammals, the main eicosanoid precursor is arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid), a
20-carbon unsaturated fatty acid containing four double bonds (hence eicosa, referring to the 20 carbon
atoms, and tetraenoic, referring to the four double bonds).
In most cell types, arachidonic acid is esterified in the phospholipid pool, and the concentration of the
free acid is low. The principal eicosanoids are the prostaglandins, the thromboxanes and the
leukotrienes, although other derivatives of arachidonate, for example the lipoxins, are also produced.

5
In most instances, the initial and rate-limiting step in eicosanoid synthesis is the liberation of arachidonate,
either in a one-step process or a two-step process, from phospholipids by the enzyme phospholipase A2
(PLA2).
Several species exist, but the most important is probably the highly regulated cytosolic PLA2. This
enzyme generates not only arachidonic acid (and thus eicosanoids) but also lysoglyceryl-
phosphorylcholine (lyso-PAF), the precursor of platelet activating factor, another inflammatory
mediator.

The free arachidonic acid is metabolised by several pathways, including the following.
 Fatty acid cyclo-oxygenase (COX). Two main isoform forms, COX-1 and COX-2,
transform arachidonic acid to prostaglandins and thromboxanes.
 Lipoxygenases. Several subtypes synthesize leukotrienes, lipoxins or other compounds

6
7
The term prostanoids encompasses the prostaglandins and the thromboxanes.

 PGI2 (prostacyclin), predominantly from vascular endothelium, acts on IP receptors,

producing vasodilatation and inhibition of platelet aggregation.
 Thromboxane (TX) A2, predominantly from platelets, acts on TP receptors, causing
platelet aggregation and vasoconstriction.
 PGE2 is prominent in inflammatory responses and is a mediator of fever. Main effects are:
o EP1 receptors: contraction of bronchial and gastrointestinal tract (GIT) smooth muscle
o EP2 receptors: relaxation of bronchial, vascular and GIT smooth muscle
o EP3 receptors: inhibition of gastric acid secretion, increased gastric mucus
secretion, contraction of pregnant uterus and of GIT smooth muscle, inhibition of
lipolysis and of autonomic neurotransmitter release.
 PGF2α acts on FP receptors, found in uterine (and other) smooth muscle, and corpus luteum,

8
producing contraction of the uterus and luteolysis (in some species).

9
  PGD2 is derived particularly from mast cells and acts on DP receptors, causing
vasodilatation and inhibition of platelet aggregation.

Prostaglandins of the E series are also pyrogenic (i.e. they induce fever). High concentrations are found
in cerebrospinal fluid during infection, and there is evidence that the increase in temperature (attributed to
cytokines) is actually finally mediated by the release of PGE2. NSAIDs exert antipyretic actions by
inhibiting PGE2 synthesis in the hypothalamus.

Clinical uses of prostanoids

 Gynecological and obstetric
o termination of pregnancy: Gemeprost or misoprostol (a metabolically stable prostaglandin
(PG)
(PG E analogue)
o induction of labour: Dinoprostone (PGE2 analogue) or misoprostol
o Postpartum haemorrhage: Carboprost ( 15-α methyl PGF2α analogue)
 Gastrointestinal
o to prevent ulcers associated with non-steroidal anti-inflammatory drug use: misoprostol
 Cardiovascular
o to maintain the patency of the ductus arteriosus until surgical correction of the
defect in babies with certain congenital heart malformations: Alprostadil (PGE1)
o to inhibit platelet aggregation (e.g. during haemodialysis): Epoprostenol or
Cicaprost (PGI2 analogue ), especially if heparin is contraindicated
o Primary pulmonary hypertension: Epoprostenol.
 Ophthalmic
o Open-angle glaucoma: latanoprost (PGF2α analogue) eye drops.

Dinoprostone (PGE2 analogue)

Carboprost(15-αmethylPGF2α

latanoprost (PGF2α analogue)

Misoprostol (PGE1 analogue)

10
Misoprostol is approved for use in the prevention of NSAID-induced gastric ulcers. It acts upon gastric
parietal cells, inhibiting the secretion of gastric acid via G-protein coupled receptor-mediated inhibition of
adenylate cyclase, which leads to decreased intracellular cyclic AMP levels and decreased proton pump
activity at the apical surface of the parietal cell.

Because other classes of drugs, especially H2-receptor antagonists and proton pump inhibitors, are more effective for
the treatment of acute peptic ulcers, Misoprostol is only indicated for use by people who are both taking NSAIDs and
are at high risk for NSAID-induced ulcers, including the elderly and people with ulcer complications.
Misoprostol is sometimes co-prescribed with NSAIDs to prevent their common adverse effect of gastric ulceration (e.g.
with Diclofenac in Arthrotec). Misoprostol may stimulate increased secretion of the protective mucus that lines the
gastrointestinal tract and increase mucosal blood flow, thereby increasing mucosal integrity—however, these effects are
not pronounced enough to warrant prescription of misoprostol at doses lower than those needed to achieve gastric acid
suppression

11
12
 BRADYKININ

BK is a nonapeptide 'clipped' from a plasma α-globulin, kininogen, by kallikrein.

 It is converted by kininase I to an octapeptide, BK1-8 (des-Arg9-BK), and inactivated by kininase II

(angiotensin-converting enzyme) in the lung.
 Pharmacological actions:
o vasodilatation (largely dependent on endothelial cell nitric oxide and prostaglandin I2)
o increased vascular permeability
o stimulation of pain nerve endings
o stimulation of epithelial ion transport and fluid secretion in airways and gastrointestinal tract
o Contraction of intestinal and uterine smooth muscle.
 There are two main subtypes of BK receptors: B2, which is constitutively present, and B1,
which is induced in inflammation.

Leukotrienes

 5-Lipoxygenase oxidises arachidonate to give 5-hydroperoxyeicosatetraenoic acid (5-

HPETE), which is converted to leukotriene (LT) A4. This, in turn, can be converted to either
LTB4 or to a series of glutathione adducts, the cysteinyl-leukotrienes LTC4, LTD4 and LTE4.
 LTB4 mainly involves in inflammatory cells, acting on specific receptors, causes adherence,
chemotaxis and activation of polymorphs and monocytes, and stimulates proliferation and
cytokine production from macrophages and lymphocytes.
 The cysteinyl-leukotrienes cause:
o Contraction of bronchial muscle mainly LTC4, LTD4

13
o Vasodilatation in most vessels, but coronary vasoconstriction.
o LTB4 is an important mediator in all types of inflammation; the cysteinyl-leukotrienes
are of particular importance in asthma.

o The CysLT-receptor or leukotriene antagonist zafirlukast and montelukast are

now in use in the treatment of asthma. Cysteinyl-leukotrienes may mediate the
cardiovascular changes of acute anaphylaxis.

14
15
 ASTHMA

Asthma is defined as recurrent reversible airway obstruction, with attacks of wheeze, shortness of breath
and often nocturnal cough. Severe attacks cause hypoxaemia and are life-threatening. Essential features
include: airways inflammation, which causes bronchial hyper-responsiveness, which in turn results in
recurrent reversible airway obstruction. Pathogenesis involves exposure of genetically disposed individuals
to allergens; activation of Th2 lymphocytes and cytokine generation promote:

o Differentiation and activation of eosinophils

o IgE production and release
o Expression of IgE receptors on mast cells and eosinophils.
o Important mediators include leukotriene B4 and cysteinyl leukotrienes (C4 and D4);
interleukins IL- 4, IL-5, IL-13; and tissue-damaging eosinophil proteins.

DRUGS USED TO TREAT ASTHMA

There are two categories of antiasthma drugs: bronchodilators and anti-inflammatory agents.
Bronchodilators reverse the bronchospasm of the immediate phase; anti-inflammatory agents inhibit or
prevent the inflammatory components of both phases.
Theophylline and leukotriene antagonists, such as montelukast, also exert a corticosteroid-sparing effect
Cromoglicate (see below) has only a weak effect and is now seldom used.

BRONCHODILATORS
The main drugs used as bronchodilators are β2-adrenoceptor agonists; others include xanthines, cysteinyl
leukotriene receptor antagonists and muscarinic receptor antagonists.
β-Adrenoceptor agonists

Two categories of β2-adrenoceptor agonists are used in asthma.

 Short-acting agents: Salbutamol and Terbutaline, duration of action is 3-5 hours.

 Longer-acting agents: e.g. Salmeterol and Formoterol, the duration of action is 8-12 hours.
 Others are Adrenaline, Ephedrine, Isoprenaline

16
Xanthine drugs

There are three pharmacologically active, naturally occurring methylxanthines: theophylline , theobromine
and caffeine . Theophylline (1,3-dimethylxanthine), which is also used as theophylline ethylenediamine
(known as aminophylline ), is the main therapeutic drug of this class.

17
Actions

Antiasthmatic. Methylxanthines have long been used as bronchodilators.

Central nervous system. Methylxanthines stimulate the CNS, increasing alertness. They can cause tremor
and nervousness, and can interfere with sleep and have a stimulant action on respiration. This may be
useful in patients with COPD and reduced respiration evidenced by a tendency to retain CO2 (see below).

Cardiovascular. Methylxanthines stimulate the heart having positive chronotropic and inotropic
actions, while relaxing vascular smooth muscle. They cause generalised vasodilatation but constrict
cerebral blood vessels.

Kidney. Methylxanthines are weak diuretics, although this effect is not therapeutically useful.

Mechanisms of action

The relaxant effect on smooth muscle has been attributed to inhibition of the phosphodiesterase (PDE)
isoenzymes, with resultant increase in cAMP and/or cGMP . However, the concentrations necessary to
inhibit the isolated enzymes exceed the therapeutic range of plasma concentrations.

Competitive antagonism of adenosine at adenosine A1 and A2 receptors may contribute, but the PDE inhibitor
enprofylline, which is a potent bronchodilator, is not an adenosine antagonist.

Type IV PDE is implicated in inflammatory cells and non-specific methylxanthines may have some anti-
inflammatory effect. (Roflumilast, a type IV PDE inhibitor.

Clinical use of theophylline

 As a second-line drug, in addition to steroids, in patients whose asthma

does not respond adequately to β2-adrenoceptor agonists.
 Intravenously (as aminophylline ,
a combination of theophylline
with ethylenediamine to increase its solubility in water) in acute
severe asthma.

Muscarinic receptor antagonists

The main compound used as a bronchodilator is ipratropium, is a quaternary derivative of N-isopropylatropine.

18
Cysteinyl leukotriene receptor antagonists

All the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) act on the same high-affinity cysteinyl leukotriene
receptor termed CysLT1. Two receptors have been cloned, CysLT1 and CysLT2, and both are expressed in
respiratory mucosa and infiltrating inflammatory cells, but the functional significance of each is unclear.
The 'lukast' drugs (montelukast and zafirlukast ) antagonise only CysLT1.

19
Used for some patients with chronic obstructive pulmonary disease, especially long-acting drugs (e.g.

tiotropium). ANTI-INFLAMMATORY AGENTS

The main drugs used for their anti-inflammatory action in asthma are the

glucocorticoids. Glucocorticoids

Systemic : Prednisolone, Hydrocortisone

Inhalational: Triamcinolone, Beclomethasone

They are not bronchodilators but prevent the progression of chronic asthma and are effective in acute severe asthma.

Actions and mechanism

The basis of the anti-inflammatory action of glucocorticoids . An important action, of relevance for asthma,
is that they decrease formation of cytokines), in particular the Th2 cytokines that recruit and activate
eosinophils and are responsible for promoting the production of IgE and the expression of IgE receptors .
Glucocorticoids also inhibit the generation of the vasodilators PGE2 and PGI2, by inhibiting
phospholipase A2. By inducing annexin 1, they could inhibit production of leukotrienes and platelet-
activating factor, although there is currently no direct evidence that the release of this protein is involved
in the antiasthma effects of glucocorticoids. The main compounds used are beclometasone, budesonide ,
fluticasone, mometasone and ciclesonide.

Cromoglicate and nedocromil ('mast cell stabiliser')

These drugs are now hardly used for the treatment of asthma. Cromoglicate is a 'mast cell stabiliser',
20
preventing hista release from mast cells.

Anti-IgE treatment
Omalizumab is a humanised monoclonal anti-IgE antibody. It is effective in patients with allergic as allergic rhinitis.

21
COUGH

Cough is a protective reflex that removes foreign material and secretions from the bronchi and
bronchioles. It is a very common adverse effect of angiotensin-converting enzyme inhibitors.
Drugs for cough

Codeine (methylmorphine) is a weak opioid. Dextromethorphan and pholcodine are believed to

have fewer adverse effects.

22
 NSAIDS

They provide symptomatic relief from pain and swelling in chronic joint disease such as occurs in osteo-
and rheumatoid arthritis, and in more acute inflammatory conditions such as sports injuries, fractures,
sprains and other soft tissue injuries. They also provide relief from postoperative, dental and menstrual
pain, and from the pain of headaches and migraine.

COX-1 is a constitutive enzyme expressed in most tissues, including blood platelets. It has a
'housekeeping' role in the body, being involved in tissue homeostasis, and is responsible for the
production of prostaglandins involved in, for example, gastric cytoprotection platelet aggregation renal
blood flow auto regulation and the initiation of parturition.
In contrast, COX-2 is induced in inflammatory cells when they are activated, and the primary
inflammatory cytokines-interleukin (IL)-1 and tumour necrosis factor (TNF)-α are important in this
regard. Thus the COX-2 isoform is responsible for the production of the prostanoid mediators of
inflammation although there are some significant exceptions. For example, there is a considerable pool of
'constitutive' COX-2 present in the central nervous system (CNS) and some other tissues, although its
function is not yet completely clear.

Most 'traditional' NSAIDs are inhibitors of both isoenzymes of COX by inhibiting dioxygenation step.
although they vary in the degree to which they inhibit each isoform. It is believed that the anti-
inflammatory action (and probably most analgesic actions) of the NSAIDs is related to their inhibition of
COX-2, while their unwanted effects-particularly those affecting the gastrointestinal tract-are
largely a result of their inhibition of COX-1. Compounds with a selective inhibitory action on COX-2
are now in clinical use, but expectations that these inhibitors would transform the treatment of
inflammatory conditions have received a setback because of an increase in cardiovascular risk
(Rolecoxib)

Normal body temperature is regulated by a centre in the hypothalamus that controls the balance between
heat loss and heat production. Fever occurs when there is a disturbance of this hypothalamic 'thermostat',
which leads to the set point of body temperature being raised. NSAIDs 'reset' this thermostat. The
NSAIDs exert their antipyretic action largely through inhibition of prostaglandin production in the
hypothalamus. During an inflammatory reaction, bacterial endotoxins cause the release from
macrophages of a pyrogen-IL-1 which stimulates the generation, in the hypothalamus, of E-type

23
prostaglandins that elevate the temperature set point. COX-2 may have a role here, because it is
induced by IL-1 in vascular endothelium in the hypothalamus.

So NASIDS have following actions:

 Anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin

reduces vasodilatation and, indirectly, oedema. Accumulation of inflammatory cells is
not reduced.

24
  An analgesic effect: decreased prostaglandin generation means less sensitisation of
nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-
hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-
mediated vasodilatation.
 An antipyretic effect: interleukin-1 releases prostaglandins in the central nervous
system, where they elevate the hypothalamic set point for temperature control, thus
causing fever. NSAIDs prevent this.

Classification

A. Nonselective COX inhibitors

1. Salicylates: Aspirin, Diflunisal
2. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone
3. Anthranilic acid derivatives: Mephenamic acid
4. Aryl acetic acid derivatives: Diclofenac
5. Indole derivatives: Indomethacin, Sulindac
6. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flubiprofen
7. Oxicam derivatives: Piroxicam, Tenoxicam
8. Pyrrolo-pyrrole derivatives: Ketorolac
B. Preferential COX-2 inhibitors: Nimesulide, Meloxicam, Nabumetone
C. Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib, Parecoxib (Prodrug of valdecoxib)
D. Analgesic-antipyretic with poor anti-inflammatory: Paracetamol
1. Pyrozolone derivatives: Metamizole (Dipyrone), Propiphenazone
2. Benzoxazocine derivatives: Nefopam

25
Some important points:

1. NSAIDS which are prodrugs: Sulindac, Fenoprofen, Nabumetone

2. NSAIDS which reduce chemotaxis of leukocytes and useful in acute gout:
Indomethacin, Naproxen, Piroxicam
3. Drugs for post-operative pain: Ketorolac, Nefopam, Etodolac
4. Gastric intolerance to conventional NASIDS uses Rofecoxib or selective COX-2 inhibitors.
5. Patients with history of asthma or anaphylaxis:

Nimesulide Some adverse effects of NASIDS:

 Aspirin cause local damage to the gastric mucosa directly or some gastric bleeding.
Oral administration of prostaglandin analogues such as misoprostol (PGE1 analogue) can
diminish the gastric damage produced by these agents.
 Severe rashes or idiosyncratic reaction are common with Mefenamic acid and Sulindac.
 Analgesic nephropathy characterised by chronic nephritis and renal papillary necrosis
is caused by chronic NSAID consumption i.e. Phenacetin (Prodrug of Paracetamol)
one of its metabolite but paracetamol is safe.
 Paracetamol over dose can cause liver toxicity. This occurs when the liver enzymes
catalysing the normal conjugation reactions are saturated, causing the drug to be
metabolised instead by mixed function oxidases. The resulting toxic metabolite, N-
acetyl-p-benzoquinone imine, is inactivated by conjugation with glutathione, but when
glutathione is depleted the toxic intermediate accumulates and reacts with nucleophilic
constituents in the cell. This causes necrosis in the liver and also in the kidney tubules.
The liver damage can be prevented by giving agents that increase glutathione
formation in the liver (N-acetylcysteine intravenously, or methionine orally).
 Rolecoxib severe cardiovascular toxicity and hence banned.
 Phenylbutazone severe agranulocytosis and fluid retention.

Aspirin

Aspirin is rapidly hydrolysed by esterases in the plasma and the tissues-particularly the liver-yielding
salicylate. Salicylate is oxidized, some is conjugated to give the glucuronide or sulfate before excretion.
Aspirin cause Salicylism and Reye's syndrome (a rare disorder of children that is characterised by
hepatic encephalopathy following an acute viral illness).
26
Salicylate poisoning is a result of disturbances of the acid-base and the electrolyte balance that may be
seen in patients treated with high doses of salicylate-containing drugs and in attempted suicides. These
drugs can uncouple oxidative phosphorylation (mainly in skeletal muscle), leading to increased oxygen
consumption and thus increased production of carbon dioxide. This stimulates respiration, which is also
stimulated by a direct action of the

27
drugs on the respiratory centre. The resulting hyperventilation causes a respiratory alkalosis that is
normally compensated by renal mechanisms involving increased bicarbonate excretion. Larger doses can
cause a depression of the respiratory centre, which leads eventually to retention of carbon dioxide and
thus an increase in plasma carbon dioxide. Because this is superimposed on a reduction in plasma
bicarbonate, an uncompensated respiratory acidosis will occur. This may be complicated by a metabolic
acidosis, which results from the accumulation of metabolites of pyruvic, lactic and acetoacetic acids (an
indirect consequence of interference with carbohydrate metabolism)

 Aspirin causes a potentially hazardous increase in the effect of warfarin, partly by

displacing it from plasma proteins so increase the risk of bleeding.
 Aspirin being a weak acid also interferes with the effect of uricosuric agents such as
probenecid and sulfinpyrazone , and because low doses of aspirin may, on their own,
reduce urate excretion, so aspirin
should not be used in gout.
 Aspirin potentiates the hypoglycemic effect of oral hypoglycemic drugs like Tolbutamide,
Glibenclamide

28
29
Meloxicam: The drug is popular in Europe and many other countries for most rheumatic diseases and has
recently been approved for treatment of osteoarthritis in the USA. Meloxicam is known to inhibit
synthesis of thromboxane A2; it appears that even at supratherapeutic doses its blockade of thromboxane
A2 does not reach levels that result in decreased in vivo platelet function.

Valdecoxib has no effect on platelet aggregation or bleeding time. Valdecoxib was withdrawn from the
market in the USA in early 2005 in response to FDA concerns about cardiovascular risks and Stevens-
Johnson syndrome, but the drug is still available in other countries.

Diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes
an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the
glucuronide to again release the active moiety.

Etodolac provides good postoperative pain relief after coronary artery bypass operations, although
transient impairment of renal function has been reported.

Ketorolac drug is an effective analgesic and has been used successfully to replace morphine in some
situations involving mild to moderate postsurgical pain. It is most often given intramuscularly or
intravenously.

Nefopam is a nonopioid analgesic which does not inhibit PG synthesis. It also has anticholinergic activity. It
provides good postoperative pain relief

Indomethacin is an indole derivative. It is a potent nonselective COX inhibitor and may also inhibit
phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation.
Indomethacin is more effective in relieving inflammation than is aspirin or any of the other
NSAIDs. Indomethacin is indicated for use in rheumatic conditions and is particularly popular for gout
and ankylosing spondylitis. In addition, it has been used to treat patent ductus arteriosus. Indomethacin
can cause CNS effects are dizziness, vertigo, light-headedness, and mental confusion and hence avoided
during the driving of vehicles.

Piroxicam an oxicam is a nonselective COX inhibitor that at high concentrations also inhibits
polymorphonuclear leukocyte migration or chemotaxis of leukocytes, decreases oxygen radical

19
production, and inhibits lymphocyte function. Its long half-life permits once-daily dosing.

Naproxen is potent particularly inhibiting leukocyte migration and hence suitable for acute

gout. Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and

lipoxygenase.

19
Nabumetone is prodrug and the only nonacid NSAID in current use; it is converted to the active acetic
acid derivative in the body. It is given as a ketone prodrug that resembles naproxen in structure.

Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite, which is
excreted in bile and then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of
action. In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis; it
may inhibit the development of colon, breast, and prostate cancer in humans.

Phenylbutazone has powerful anti-inflammatory effects but weak analgesic and antipyretic activities.
Phenylbutazone is prescribed chiefly in short term therapy of acute gout and in acute rheumatoid arthritis
when other NSAID agents have failed. Phenylbutazone is extensively bound to plasma proteins. This
property causes displacement of warfarin, oral hypoglycemics and sulfonamides from binding sites on
plasma proteins, causing transient elevations in the free fraction of these drugs. The most serious adverse
effects are agranulocytosis and aplastic anemia. Other side effects include fluid and electrolyte (sodium
and chloride) retention, with resulting edema and decreased urine volume. Phenylbutazone reduces the
uptake of iodine by the thyroid gland, sometimes resulting in goiter and myxedema.

Diclofenac is approved for long-term use in the treatment of rheumatoid arthritis, osteoarthritis and
ankylosing spondylitis. It is more potent than indomethacin or naproxen. Diclofenac accumulates in
synovial fluid.

Acetaminophen or Paracetamol and Phenacetin act by inhibiting prostaglandin synthesis in the

CNS. This explains their antipyretic and analgesic properties. They have less effect on cyclooxygenase in
peripheral tissues, which accounts for their weak anti-inflammatory activity. Acetaminophen and
phenacetin do not affect platelet function or increase blood clotting time, and they lack many of the side-
effects of aspirin. Phenacetin can no longer be prescribed in the United States because of its
potential for renal toxicity. Acetaminophen is the analgesic-antipyretic of choice for children with viral
infections or chicken pox (aspirin increases the risk of Reye's syndrome). Acetaminophen does not
antagonize the uricosuric agent probenecid and therefore may be used in patients with gout taking that
drug. Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of aspirin in those
patients with gastric complaints and in those for whom prolongation of bleeding time would be a
disadvantage or who do not require the anti- inflammatory action of aspirin.

20
Under normal circumstances, acetaminophen is conjugated in the liver to form inactive glucuronidated or
sulfated metabolites. A portion of acetaminophen is hydroxylated to form N-acetyl-benzoquinoneimine--
a highly reactive and potentially dangerous metabolite that reacts with sulfhydryl groups. At normal doses
of acetaminophen, the N- acetyl-benzoquinoneimine reacts with the sulfhydryl group of glutathione,
forming a nontoxic substance. Acetaminophen and its metabolites are excreted in the urine. With large
doses of acetaminophen, the available glutathione in the liver becomes depleted and N-acetyl-
benzoquinoneimine reacts with the sulfhydryl groups of hepatic proteins, forming covalent bonds.
Hepatic necrosis, a very serious and potentially life-threatening

20
condition, can result. Administration of N-acetylcysteine, which contains sulfhydryl groups to which the toxic
metabolite can bind, can be life-saving if administered within 10 hours of the overdose.

Ibuprofen is safest NASIDS among the conventional NASIDS. Flurbiprofen is mostly used as ocular
anti- inflammatory.

20
 ANTI-GOUT DRUGS

Gout is a metabolic disease in which plasma uriate concentration is raised because of overproduction
(sometimes linked to indulgence in alcoholic beverages, especially beer, or purine-rich foods such as
offal, or increased cell turnover as in haematological malignancies, particularly when treated with
cytotoxic drugs) or impaired excretion of uric acid. It is characterised by very painful intermittent attacks
of acute arthritis produced by the deposition of crystals of sodium urate (a product of purine
metabolism) in the synovial tissue of joints and elsewhere.
When an inflammatory response is evoked, involving activation of the kinin, complement and plasmin
systems, generation of lipoxygenase products such as leukotriene B4 and local accumulation of
neutrophil granulocytes. These engulf the crystals by phagocytosis, releasing tissue-damaging toxic
oxygen metabolites and subsequently causing lysis of the cells with release of proteolytic enzymes.
Urate crystals also induce the production of IL-1 and possibly other cytokines too.

Drugs used to treat gout may act in the following ways:

 By inhibiting uric acid synthesis: Allopurinol (Main prophylactic drug)
 By increasing uric acid excretion (uricosuric agents: Probenecid , Sulfinpyrazone both are also used
as prophylactic drug)
 By inhibiting leucocyte migration into the joint (Colchicine for acute attack)
 By a general anti-inflammatory and analgesic effect (NSAIDs).

Allopurinol is an analogue of hypoxanthine and reduces the synthesis of uric acid by competitive
inhibition of xanthine oxidase. Some inhibition of de novo purine synthesis also occurs.
Allopurinol is converted
to alloxanthine by xanthine oxidase, and this metabolite, which remains in the tissue for a considerable
time, is an effective non-competitive inhibitor of the enzyme. The pharmacological action of allopurinol
is largely due to alloxanthine. Allopurinol reduces the concentration of the relatively insoluble urates
and uric acid in tissues, plasma and urine, while increasing the concentration of their more soluble
precursors, the xanthines and hypoxanthines. The deposition of urate crystals in tissues (tophi) is reversed,
and the formation of renal stones is inhibited. Allopurinol is the drug of choice in the long-term
treatment of gout, but it is ineffective in the treatment of an acute attack and may even exacerbate the
inflammation.

20
Allopurinol can cause potentially fatal skin diseases (Stevens-Johnson
syndrome and toxic epidermal necrolysis-a horrible disorder where skin peels
away in sheets as if scalded) are rare but devastating.

 Allopurinol increases the effect of mercaptopurine , an

antimetabolite used in cancer chemotherapy and also that of
azathioprine (an immunosuppressant used to prevent transplant
rejection which is metabolised to mercaptopurine) . Allopurinol
also enhances the effect of another anticancer drug,
cyclophosphamide
.

Colchicine:

Colchicine is drug choice for acute attack. Colchicine an alkaloid extracted from
the autumn crocus. It has a specific effect in gouty arthritis and can be used both to
prevent and to relieve acute attacks.
It prevents migration of neutrophils into the joint, apparently by binding to
tubulin, resulting in the depolymerisation of the microtubules and reduced cell
motility.
Colchicine-treated neutrophils develop a 'drunken walk'. Colchicine may also
prevent the production of a putative inflammatory glycoprotein by
neutrophils that have phagocytosed urate crystals, and other mechanisms may also
be important in bringing about its effects.
References:

1. Conceptual Review of Pharmacology for NBE, Ranjan Kumar Patel, Fourth Edition,CBS

Publication

2. KD Tripathi,Essentials of Medical pharmacology,8th Edition.

3. Lippincott Illustrated Reviews Pharmacology, Karen Whalen,6th Edition.

4.Pharmacology for Medical graduates,Tara V Shanbhag,3rd Edition.

5.Medical Pharmacology,Padmaja Udayakumar,5th Edition.

Prepared by

Mr. Prasanta Kumar Biswal

Associate Professor

Dadhichi College Of Pharmacy

Vidya-Vihar, Sundargram, Cuttack

 BP 503 T
Pharmacology II
UNIT - III
  Autacoid
 This term is derived from Greek: autos—self, akos—healing substance
or remedy.
 These are diverse substances produced by a wide variety of cells in the
body, having intense biological activity, but generally act locally (e.g.
within inflammatory pockets) at the site of synthesis and release.
 They have also been called ‘local hormones’.
 However, they differ from ‘hormones’ in two important ways—
hormones are produced by specific cells, and are transported through
circulation to act on distant target tissues.
 Autacoids are involved in a number of physiological and
pathological processes (especially reaction to injury and
immunological insult).
 Some autacoids, in addition, serve as transmitters or modulators in
the nervous system, but their role at many sites is not precisely
known.
 A number of useful drugs act by modifying their action or
metabolism.
 Amine autacoids: Histamine, 5-Hydroxytryptamine

(Serotonin)

 Lipid derived autacoids: Prostaglandins, Leukotrienes,

Platelet activating factor

 Peptide autacoids: Plasma kinins (Bradykinin, Kallidin),

Angiotensin
 In addition, cytokines (interleukins, TNFα, GM-CSF, etc.) and

several peptides like gastrin, somatostatin, vasoactive intestinal

peptide and many others may be considered as autacoids.

GM-CSF: Granulocyte-macrophage colony-stimulating factor

HISTAMINE
  HISTAMINE

 Histamine, meaning ‘tissue amine’ (histos—tissue) is almost ubiquitously

present in animal tissues and in certain plants, e.g. stinging nettle.
 Its pharmacology was studied in detail by Dale in the beginning of the
20th century. It was implicated as a mediator of hypersensitivity
phenomena and tissue injury reactions.
 It is now known to play important physiological roles.
 Histamine is present mostly within storage granules of mast cells.
 Tissues rich in histamine are skin, gastric and intestinal mucosa,
lungs, liver and placenta.
 Nonmast cell histamine occurs in brain, epidermis, gastric mucosa
and growing regions.
 Turnover of mast cell histamine is slow, while that of nonmast cell
histamine is fast.
 Histamine is also present in blood, most body secretions, venoms and
pathological fluids.
  Synthesis, storage and destruction

 Histamine is β imidazolylethylamine.
 It is synthesized locally from the amino acid histidine and degraded rapidly
by oxidation and methylation.
 In mast cells, histamine (positively charged) is held by an acidic protein and
heparin (negatively charged) within intracellular granules.
 When the granules are extruded by exocytosis, Na+ ions in e.c.f. exchange
with histamine to release it free.
 Increase in intracellular cAMP (caused by β adrenergic agonists and
methylxanthines) inhibits histamine release.
 Histamine is inactive orally because liver degrades all histamine that is
absorbed from the intestines.
  Histamine receptors

 Four types of histaminergic receptors have now been clearly delineated and
cloned. Analogous to adrenergic α and β receptors, histaminergic receptors
were classified by Asch and Schild (1966) into H1 and H2 : those blocked by
then available antihistamines were labelled H1.
 Sir James Black (1972) developed the first H2 blocker burimamide and
confirmed this classification.
 A third H3 receptor, which serves primarily as an autoreceptor controlling
histamine release from neurones in brain was identified in 1983.
 Though some selective H3 agonists and antagonists have been produced,
none has found any clinical application.
 Molecular cloning has revealed yet another (H4) receptor in 2001.
 It has considerable homology with H3 receptor and binds many H3
ligands.
 4-Methyl histamine, earlier considered to be a specific H2 agonist, has
shown greater affinity and selectivity for the H4 receptor, and is now
labelled a H4 agonist.
 However, the H4 receptor is pharmacologically less distinct.
 Eosinophils, mast cells and basophils are the primary cells expressing H4
receptors.
 Activation of H4 receptors enhances chemotaxis of these cells.
 The H4 receptor may be playing a role in allergic inflammation.
 H4 antagonists are being explored as potential drugs for allergic
inflammatory conditions like rhinitis and asthma.
 Intestines and brain are the other sites where H4 receptors have been
located.
  PHARMACOLOGICAL ACTIONS

 Blood vessels
 Histamine causes marked dilatation of smaller blood vessels, including
arterioles, capillaries and venules.
 On s.c. injection flushing, especially in the blush area, heat, increased heart
rate and cardiac output, with little or no fall in BP are produced.
 Heart
 Direct effects of histamine on in situ heart are not prominent, but the isolated
heart, especially of guinea pig, is stimulated—rate as well as force of
contraction is increased.
 These are primarily H2 responses but a H1 mediated negative dromotropic
(slowing of A-V conduction) effect has also been demonstrated.
 Visceral smooth muscle
 Histamine causes bronchoconstriction; guinea pigs and patients of asthma
are highly sensitive.
 Large doses cause abdominal cramps and colic by increasing intestinal
contractions.
 Guineapig uterus is contracted while that or rat is relaxed; human uterus is
not much affected as are most other visceral smooth muscles.
 Smooth muscle contraction is a H1 response.
 Glands
 Histamine causes marked increase in gastric secretion—primarily of acid but
also of pepsin. This is a direct action exerted on parietal cells through H2
receptors and is mediated by increased cAMP generation, which in turn
activates the membrane proton pump (H+ K+ ATPase).

 Sensory nerve endings

 Itching occurs when histamine is injected i.v. or intracutaneously.
 Higher concentrations injected more deeply cause pain.
 These are reflections of the capacity of histamine to stimulate nerve endings.
 Autonomic ganglia and adrenal medulla
 These are stimulated and release of Adr occurs, which can cause a
secondary rise in BP.

 CNS
 Histamine does not penetrate bloodbrain barrier—no central
effects are seen on i.v. injection.
 However, intracerebroventricular administration produces rise in
BP, cardiac stimulation, behavioural arousal, hypothermia,
vomiting and ADH release.
 These effects are mediated through both H1 and H2 receptors.
 USES
Histamine has no therapeutic use. In the past it has been used to test acid
secreting capacity of stomach, bronchial hyperreactivity in asthmatics, and
for diagnosis of pheochromocytoma, but these pharmacological tests are
risky and obsolete now.

 BETAHISTINE
It is an orally active, somewhat H1 selective histamine analogue, which is
used to control vertigo in patients of Meniéré’s disease: possibly acts by
causing vasodilatation in the internal ear. It is contraindicated in asthmatics
and ulcer patients.
  HISTAMINE RELEASERS

A variety of mechanical, chemical and immunological stimuli are capable of releasing

histamine from mast cells.
 Tissue damage: trauma, stings and venoms, proteolytic enzymes, phospholipase A.
 Antigen: antibody reaction involving IgE antibodies.
 Polymers like dextran, polyvinyl pyrrolidone (PVP).
 Some basic drugs—tubocurarine, morphine, atropine, pentamidine, polymyxin B,
vancomycin and even some antihistaminics directly release histamine without an
immunological reaction.
 Surface acting agents like Tween 80, compound 48/80 etc. The primary
action of these substances is release of histamine from mast cells,
therefore they are called ‘histamine liberators’. They produce an
‘anaphylactoid’ reaction—itching and burning sensation, flushing,
urticaria, fall in BP, tachycardia, headache, colic and asthma. Most of
these symptoms are controlled by a H1 antihistaminic, better still if H2
blocker is given together.
 Mechanism of action of Histamine:

 The H1 histamine receptors couple to Gq/11 and activate the PLC–IP3–Ca2+

pathway and its many possible sequelae, including activation of protein kinase C
(PKC), Ca2+–calmodulin–dependent enzymes (eNOS and various protein
kinases), and PLA2.
 H2 receptors link to Gs to activate the adenylyl cyclase–cyclic AMP–protein
kinase A (PKA) pathway.
 H3 and H4 inactivate the adenylyl cyclase, decreased level of cAMP
  H1 ANTAGONISTS

 These drugs competitively antagonize actions of histamine at the H1 receptors.

 The first compounds of this type were introduced in the late 1930s.
 They are frequently used for a variety of purposes. More commonly employed now are
the less sedating/nonsedating second generation H1 antihistamines added after 1980.
 H1 antihistaminics have diverse chemical structures, but majority have a substituted
ethylamine side chain
  PHARMACOLOGICAL ACTIONS
Qualitatively all H1 antihistaminics have similar actions, but there are quantitative
differences, especially in the sedative property.
 Antagonism of histamine
 They effectively block histamine induced bronchoconstriction, contraction of
intestinal and other smooth muscle and triple response—especially wheal, flare and
itch.
 Fall in BP produced by low doses of histamine is blocked, but additional H2
antagonists are required for complete blockade of that caused by higher doses.
 Pretreatment with these drugs protects animals from death due to i.v. injection of
large doses of histamine.
 Release of Adr from adrenal medulla in response to histamine is abolished.
 Constriction of larger blood vessel by histamine is also antagonized.
 Antiallergic action
 Many manifestations of immediate hypersensitivity (type I reactions) are
suppressed. Urticaria, itching and angioedema are well controlled.
 Anaphylactic fall in BP is only partially prevented.
 Asthma in man is practically unaffected.

 Blood pressure
 Most antihistaminics cause a fall in BP on i.v. injection, However, this is not
evident on oral administration

 Local anaesthetic
 Some drugs like pheniramine, promethazine, diphenhydramine have strong
while others have weak membrane stabilizing property.
 However, they are not used clinically as local anaesthetic because they cause
irritation when injected s.c.
 Anticholinergic action
Many H1 blockers in addition antagonize muscarinic actions of ACh.
The anticholinergic action can be graded as:
 CNS
 The older antihistamines produce variable degree of CNS depression. This appears
to depend on the compound’s ability to penetrate the blood-brain barrier and its
affinity for the central (compared to peripheral) H1 receptors.
 Individual susceptibility to different agents varies considerably. The same drug and
dose may incapacitate some subjects, while others may remain alert.
 Some individuals also experience stimulant effects like restlessness and insomnia.
 Excitement and convulsions are frequently seen at toxic doses.
 Certain H1 antihistamines are effective in preventing motion sickness. It is
not clear whether this is due to antagonism of histamine in the brain or
reflects antimuscarinic property of these drugs.
 Promethazine also controls vomiting of pregnancy and other causes.
 Promethazine and few other antihistaminics reduce tremor, rigidity and
sialorrhoea of parkinsonism.
 Some older antihistamines, especially cyproheptadine, have appetite
stimulating effect. Some H1 antihistamines are also effective antitussives
 Pharmacokinetics
 The conventional H1 antihistaminics are well absorbed from oral and
parenteral routes, metabolized in the liver and excreted in urine.
 They are widely distributed in the body and enter brain.
 The newer compounds penetrate brain poorly accounting for their
low/absent sedating action.
 Duration of action of most agents is 4–6 hours, except meclozine,
chlorpheniramine, mesolastine, loratadine, cetirizine and fexofenadine
which act for 12–24 hours or more.
 Side effects and toxicity
 Side effects of first generation H1 antihistaminics are frequent, but generally
mild.
 Individuals show marked differences in susceptibility to side effects with
different drugs.
 Some tolerance to side effects develops on repeated use. Sedation, diminished
alertness and concentration, light headedness, motor incoordination, fatigue and
tendency to fall asleep are the most common.
 Objective testing shows impairment of psychomotor performance.
 Patients should be cautioned not to operate motor vehicles or machinery
requiring constant attention.
 Alcohol synergises in producing these effects as do other CNS depressants.
 Few individuals become restless, nervous and are unable to sleep.
 Second generation compounds are largely free of CNS effects.
 Regular use of conventional antihistamines is not advisable in children,
because the CNS depressant property may interfere with learning and
academic tasks.
 Dryness of mouth, alteration of bowel movement, urinary hesitancy and
blurring of vision can be ascribed to anticholinergic property.
 Epigastric distress and headache may be felt.
 Local application can cause contact dermatitis.
 Acute overdose produces central excitation, tremors, hallucinations, muscular
incordination, convulsions, flushing, hypotension, fever and some other
features of belladonna poisoning.
 Second generation antihistaminics

The second generation antihistaminics (SGAs) may be defined as those H1 receptor

blockers marketed after 1980 which have one or more of the following properties:

 Absence of CNS depressant property.

 Higher H1 selectivitiy: no anticholinergic side effects.

 Additional antiallergic mechanisms apart from histamine blockade: some also

inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet

activating factor effect.

 These newer drugs have the advantage of not impairing psychomotor performance

(driving etc. need not be contraindicated), produce no subjective effects, no

sleepiness, do not potentiate alcohol or benzodiazepines.

 Their principal indications are:

 Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing,

runny but not blocked nose, and red, watering, itchy eyes.

 Urticaria, dermographism, atopic eczema.

 Acute allergic reactions to drugs and foods. They have poor antipruritic,

antiemetic and antitussive actions.

 Fexofenadine: It is the active metabolite of terfenadine, the first nonsedating
SGA that was withdrawn because of several deaths due to polymorphic
ventricular tachycarida (Torsades de pointes) occurring with its higher doses or
when it was coadministered with CYP3A4 inhibitors (erythromycin,
clarithromycin, ketoconazole, itraconazole, etc.). This toxicity is based on
blockade of delayed rectifier K+ channels in the heart at higher concentrations.
Astemizole is another SGA banned for the same reason.

 Loratadine: Another long-acting selective peripheral H1 antagonist which lacks

CNS depressant effects and is fast acting. It is partly metabolized by CYP3A4 to
an active metabolite with a longer t½ of 17 hr, but has not produced cardiac
arrhythmia in overdose, though seizures are reported. No interaction with
macrolides or antifungals has been noted. Good efficacy has been reported in
urticaria and atopic dermatitis.
 Desloratadine: It is the major active metabolite of loratadine effective at half the
dose. Non-interference with psychomotor performance and cardiac safety are
documented.
 Cetirizine: It is a metabolite of hydroxyzine with marked affinity for peripheral H1
receptors; penetrates brain poorly, but mild sedation and subjective somnolence is
experienced by many recipients.
• It is not metabolized; does not prolong cardiac action potential or produce
arrhythmias when given with erythromycin/ketoconazole.
• Cetirizine in addition inhibits release of histamine and of cytotoxic mediators
from platelets as well as eosinophil chemotaxis during the secondary phase of the
allergic response.
• It attains high and longer lasting concentration in skin, which may be responsible
for superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing
despite elimination t½ of 7–10 hr.
• It is indicated in upper respiratory allergies, pollinosis, urticaria and atopic
dermatitis; also used as adjuvant in seasonal asthma.
 Levocetirizine: is the active R(–) enantiomer of cetirizine. It is effective at half

the dose and appears to produce less sedation and other side effects.

 Mizolastine This nonsedating antihistaminic is effective in allergic rhinitis and

urticaria by single daily dosing despite a t½ of 8–10 hr and no active metabolite.

 Ebastine: Another newer SGA that rapidly gets converted to the active

metabolite carbastine having a t½ of 10–16 hr. It is nonsedating and active in

nasal and skin allergies. Animal studies have found it to prolong Q-Tc interval

which makes it liable to arrhythmogenic potential and CYP3A4 interaction, but

actual reports are still few.

USES
The uses of H1 antihistaminics are based on their ability to block certain effects
of histamine released endogeneously, as well as on sedative and anticholinergic
properties.
 Allergic disorders
 Pruritides
 Common cold
 Motion sickness
 Vertigo
 Cough
 Acute muscle dystonia
 H2 antagonist

 The first H2 blocker Burimamide was developed by Black in 1972.

 Metiamide was the next, but both were not found suitable for clinical use.

 Cimetidine was introduced in 1977 and gained wide usage.

 Ranitidine, famotidine, roxatidine, and many others have been added

subsequently.

 They are primarily used in peptic ulcer, gastroesophageal reflux and other

gastric hypersecretory states.

5-HYDROXYTRYPTAMINE
  5-HYDROXYTRYPTAMINE
 (5-HT, Serotonin)

 Serotonin was the name given to the vasoconstrictor substance which appeared in
the serum when blood clotted and Enteramine to the smooth muscle contracting
substance present in enterochromaffin cells of gut mucosa.
 In the early 1950s both were shown to be 5-hydroxytryptamine (5-HT). About
90% of body’s content of 5-HT is localized in the intestines; most of the rest is in
platelets and brain.
 It is also found in wasp and scorpion sting, and is widely distributed in
invertebrates and plants (banana, pear, pineapple, tomato, stinging nettle, cow
hage).
  SYNTHESIS, STORAGE AND DESTRUCTION

 5-HT is β-aminoethyl-5-hydroxyindole.
 It is synthesized from the amino acid tryptophan and degraded primarily by
MAO and to a small extent by a dehydrogenase
 There is close parallelism between CAs and 5-HT.
 The decarboxylase is non-specific, acts on DOPA as well as 5-
hydroxytryptophan (5-HTP) to produce DA and 5-HT respectively.
 Like NA, 5-HT is actively taken up by an amine pump serotonin transporter
(SERT), a Na+ dependent carrier, which operates at the membrane of
platelets (therefore, 5-HT does not circulate in free form in plasma) and
serotonergic nerve endings.
 This pump is inhibited by selective serotonin reuptake inhibitors (SSRIs) and
tricyclic antidepressants (TCAs).
 Platelets do not synthesize 5-HT but acquire it by uptake during passage
through intestinal blood vessels.
 Again like CAs, 5-HT is stored within storage vesicles, and its uptake at the
vesicular membrane by vesicular monoamine transporter (VMAT-2) is
inhibited by reserpine, which causes depletion of CAs as well as 5-HT.
 The degrading enzyme MAO is also common for both. The isoenzyme
MAO-A preferentially metabolizes 5-HT.
  SEROTONERGIC (5-HT) RECEPTORS
 Four families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4-7) comprising of 14

receptor subtypes have so far been recognized.

 However, only some of these have been functionally correlated.

 Selective agonists/antagonists have been defined only for these subtypes.

 Knowledge of subtypes of 5-HT receptors has assumed importance because some newly

developed therapeutically useful drugs can only be described in terms of 5-HT receptor

subtype selective agonists or antagonists.

 All 5-HT receptors (except 5-HT3) are G protein coupled receptors which function through

decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-HT7) cAMP production or by

generating IP3/DAG (5-HT2) as second messengers. The 5-HT3 is a ligand gated cation

(Na+,K+) channel which on activation elicits fast depolarization.

  5-HT1 Receptors
 Five subtypes (5-HT1A, B, D, E, F) have been identified. The 5-HT1C receptor
is now designated 5HT2c.
 All subtypes of 5-HT1 receptor couple with Gi/Go protein and inhibit adenylyl
cyclase; 5-HT1A in addition activates K+ channels (resulting in
hyperpolarization) and inhibits Ca2+ channels.
 These receptors function primarily as autoreceptors in brain—inhibit firing of 5-
HT neurones or release of 5-HT from nerve endings.
 The most important location of 5-HT1A receptor is somatodendritic synapses in
raphe nuclei of brain stem; their activation serves to reduce firing of raphe
neurones.
 Hippocampus is another important site. The antianxiety drug buspirone acts
as a partial agonist of 5-HT1A receptor.
 The 5-HT1D receptor has been shown to regulate dopaminergic tone in
substantia nigra–basal ganglia, and 5-HT1D/1B (the same receptor is 5-
HT1D in humans and 5-HT1B in rat) to cause constriction of cranial blood
vessels.
 The antimigraine drug sumatriptan is a selective 5-HT1D/1B agonist.
 Other functions subserved by 5-HT1D receptors are inhibition of 5-HT
release from forebrain serotonergic neurones, NA release from sympathetic
nerve endings and that of inflammatory neuropeptides from nerve endings in
cranial blood vessels.
  5-HT2 Receptors

 There are 3 subtypes of 5-HT2 receptor; all are coupled to Gq protein→activate

phospholipase C and function through generation of IP3/DAG.

 5-HT2A receptor also inhibits K+ channels resulting is slow depolarization of

neurones.

 α-methyl 5-HT is a selective agonist for all 3 subtypes.

 5-HT2A is the most widely expressed postjunctional 5-HT receptor (designated

earlier as D type) located on vascular and visceral smooth muscle, platelets and

cerebral neurones especially prefrontal cortex.

 It mediates most of the direct actions of 5-HT like vasoconstriction,

intestinal, uterine and bronchial contraction, platelet aggregation and

activation of cerebral neurones.

 Ketanserin is a 5-HT2 antagonist more selective for 5-HT2A.

Contraction of rat gastric fundus is mediated by 5-HT2B receptor.

 5-HT2C receptor is located on vascular endothelium— elicits

vasodilatation through EDRF release. Choroid plexus expresses large

number of 5-HT2C receptors which may regulate CSF formation.

  5-HT3 Receptor
This is the neuronal 5-HT receptor which rapidly depolarizes nerve endings by
opening the cation channel located within it and corresponds to the original M type
receptor. It mediates the indirect and reflex effects of 5-HT at:
 Somatic and autonomic nerve endings → pain, itch, coronary chemoreflex
(bradycardia, fall in BP due to withdrawal of sympathetic tone, respiratory
stimulation or apnoea elicited by stimulation of receptors in the coronary bed),
other visceral reflexes.
 Nerve endings in myenteric plexus → augmentation of peristalsis, emetic reflex.
 Area postrema and nucleus tractus solitarious in brainstem → nausea, vomiting.
• Ondansetron is a selective 5-HT3 antagonist which inhibits vomiting by blocking
these receptors in the brainstem as well as in gut wall.
• 2-Methyl 5-HT is a selective 5-HT3 agonist.
  5-HT4–7 Receptors
 The 5-HT4 receptor couples to Gs protein, activates adenylyl cyclase and has been
demonstrated in the mucosa, plexuses and smooth muscle of the gut → probably
involved in augmenting intestinal secretion and peristalsis.
 It is also located in brain, especially hippocampus and the colliculi where it causes
slow depolarization by decreasing K+ conductance.
 Cisapride and renzapride are selective 5-HT4 agonists.
 The recently cloned 5-HT5, 5-HT6 and 5-HT7 receptors are closely related to the 5-
HT4 receptor. These are mainly located in specific brain areas, but their functional role
is not known.
 An interesting finding is that clozapine (atypical antipsychotic) has high affinity for 5-
HT6 and 5-HT7 receptors in addition to being a 5-HT2A/2C antagonist.
  ACTIONS
5-HT is a potent depolarizer of nerve endings. It thus exerts direct as well as reflex
and indirect effects. Tachyphylaxis is common with repeated doses of 5-HT.
 CVS
• Arteries are constricted (by direct action on vascular smooth muscle) as well as
dilated (through EDRF release) by 5-HT.
 Visceral smooth muscles
• 5-HT is a potent stimulator of g.i.t., both by direct action as well as through
enteric plexuses.
• Several subtypes of 5-HT recep-tors are present in the gut. Peristalsis is
increased and diarrhoea can occur.
• It constricts bronchi, but is less potent than histamine.
 Glands
• 5-HT inhibits gastric secretion (both acid and pepsin), but increases mucus
production. It thus has ulcer protective property. Effect on other glandular
secretions is not significant
 Nerve endings and adrenal medulla
Afferent nerve endings are activated causing tingling and pricking sensation, as
well as pain. Depolarization of visceral afferents elicits respiratory and
cardiovascular reflexes, nausea and vomiting. 5-HT is less potent than histamine in
releasing CAs from adrenal medulla.
 Respiration
A brief stimulation of respiration (mostly reflex from bronchial afferents) and
hyperventilation are the usual response, but large doses can cause transient apnoea
through coronary chemoreflex.
 Platelets
By acting on 5-HT2A receptors 5-HT causes changes in shape of platelets, but is a
weak aggregator. However, it does not induce the release reaction.
 CNS
Injected i.v., 5-HT does not produce central effects because of poor entry across
blood brain barrier. However, it serves as a transmitter, primarily inhibitory.
Direct injection in the brain produces sleepiness, changes in body temperature,
hunger and a variety of behavioural effects
 Pathophysiological roles

• Neurotransmitter
• Precursor of melatonin
• Neuroendocrine function
• Nausea and vomiting
• Migraine
• Haemostasis
• Raynaud’s phenomenon
• Variant angina
• Hypertension
• Intestinal motility
• Carcinoid syndrome
  DRUGS AFFECTING 5-HT SYSTEM

 5-HT precursor: Tryptophan increases brain 5-HT and produces behavioural

effects because tryptophan hydroxylase in brain is not saturated by the amount
of tryptophan available physiologically.
 Synthesis inhibitor: p-Chlorophenylalanine (PCPA) selectively inhibits
tryptophan hydroxylase (rate limiting step) and reduces 5-HT level in tissues.
It is not used clinically due to high toxicity.
 Uptake inhibitor: Tricyclic antidepressants inhibit 5-HT uptake along with
that of NA. The selective serotonin reuptake inhibitors (SSRI) like fluoxetine,
sertraline, etc. inhibit only 5-HT reuptake and have antidepressant, antianxiety
property.
 Storage inhibitor: Reserpine blocks 5-HT (as well as NA) uptake into storage
vesicles by inhibiting VMAT-2, and causes depletion of all monoamines.
Fenfluramine selectively releases 5-HT by promoting its reverse transport at
serotonergic nerve endings in the brain, followed by its prolonged depletion,
and has anorectic property.
 Degradation inhibitor: Nonselective MAO inhibitor (tranylcypromine) and
selective MAO-A inhibitor (chlorgyline) increase 5-HT content by preventing
its degradation.
 Neuronal degeneration: 5, 6 dihydroxytryptamine selectively destroys 5-HT
neurones.
 5-HT receptor agonists: A diverse range of compounds producing a variety of
actions have been found to activate one or more subtypes of 5-HT receptors. Notable
among these are:
 D-Lysergic acid diethyl amide (LSD)—Synthesized as an ergot derivative LSD was
found to be an extremely potent hallucinogen. It is a nonselective 5-HT agonist—
activates many subtypes of 5-HT receptors including 5-HT1A on raphe cell bodies,
5-HT2A/2C (probably responsible for the hallucinogenic effect) and 5-HT5-7 in
specific brain areas. However, it antagonizes 5-HT2A receptors in the ileum. A
number of other hallucinogens also interact with brain 5-HT receptors.
 Azapirones: like buspirone, gepirone and ipsapirone are a novel class of antianxiety
drugs which do not produce sedation. They act as partial agonists of 5-HT1A
receptors in the brain.
 Sumatriptan: and other triptans are selective 5-HT1D/1B agonists, constrict

cerebral blood vessels and have emerged as the most effective treatment of

acute migraine attacks.

 Cisapride: This prokinetic drug which increases gastrointestinal motility is a

selective 5-HT4 agonist. Renzapride is still more selective for 5-HT4 receptors.
  5-HT ANTAGONISTS

The ability to antagonize at least some actions of 5-HT is found in many

classes of drugs, e.g. ergot derivatives (ergotamine, LSD, 2-bromo LSD,
methysergide), adrenergic α blockers (phenoxybenzamine), antihistaminics
(cyproheptadine, cinnarizine), chlorpromazine, morphine, etc., but these are
nonselective and interact with several other receptors as well. Many are
partial agonists or antagonize certain actions of 5-HT but mimic others.
 The salient features of drugs which have been used clinically as 5-HT
antagonists and some newly developed selective antagonists are described
below:

 Cyproheptadine: It primarily blocks 5-HT2A receptors and has additional H1

antihistaminic, anticholinergic and sedative properties. Like other
antihistaminics, it has been used in allergies and is a good antipruritic, but the
anti 5-HT action has no role in these conditions. It increases appetite and has
been used in children and poor eaters to promote weight gain. The H1
antihistaminic action and an action on growth hormone secretion has been
suggested to account for this.
 The anti 5-HT activity of cyproheptadine has been utilized in controlling
intestinal manifestations of carcinoid and postgastrectomy dumping syndromes.
• Side effects drowsiness, dry mouth, confusion, ataxia, weight gain.
 Methysergide
 It is chemically related to ergot alkaloids; antagonizes action of 5-HT on smooth
muscles including that of blood vessels, without producing other ergot like effects:
does not interact with α adrenergic or dopamine receptors.
 Methysergide is a potent 5-HT2A/2C antagonist with some tissue specific agonistic
actions as well; but is nonselective— acts on 5-HT1 receptors also.
 It has been used for migraine prophylaxis, carcinoid and postgastrectomy dumping
syndrome.
 Prolonged use has caused abdominal, pulmonary and endocardial fibrosis, because of
which it has gone into disrepute.
 Ketanserin
 It has selective 5-HT2 receptor blocking property with negligible action on 5-
HT1, 5-HT3 and 5 HT4 receptors and no partial agonistic activity.
 Among 5-HT2 receptors, blockade of 5-HT2A is stronger than 5-HT2C
blockade.
 5-HT induced vasoconstriction, platelet aggregation and contraction of airway
smooth muscle are antagonized.
 It has additional weak α1, H1 and dopaminergic blocking activities.
 Ritanserin is a relatively more 5-HT2A selective congener of ketanserin.
 Clozapine
 In addition to being a dopaminergic antagonist, this atypical antipsychotic is a 5-
HT2A/2C blocker. Clozapine may also exert inverse agonist activity at cerebral 5-
HT2A/2C receptors which may account for its efficacy in resistant cases of
schizophrenia.
 Risperidone
 This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar
to clozapine.
 It especially ameliorates negative symptoms of schizophrenia, but produces
extrapyramidal side effects at only slightly higher doses.
 Other atypical antipsychotics like olanzapine and quetiapine are also combined 5-HT
and DA antagonists, but interact with other neurotransmitter receptors as well.
 Ondansetron
 It is the prototype of the new class of selective 5-HT3 antagonists that have
shown remarkable efficacy in controlling nausea and vomiting following
administration of highly emetic anticancer drugs and radiotherapy.
 It blocks the depolarizing action of 5-HT exerted through 5-HT3 receptors on
vagal afferents in the g.i.t. as well as in NTS and CTZ.
 Oral bioavailability of ondansetron is 60–70% due to first pass metabolism.
 It is hydroxylated by CYP1A2, 2D6 and 3A, followed by glucuronide and sulfate
conjugation.
 It is eliminated in urine and faeces, mostly as metabolites; t½ is 3–5 hrs, and
duration of action is 8–12 hrs
 Granisetron and Tropisetron are the other selective 5-HT3 antagonists.
 Prostaglandins,
Thromboxane and
Leukotrienes
 Prostaglandins (PGs) and Leukotrienes (LTs) are
biologically active derivatives of 20 carbon atom
polyunsaturated essential fatty acids that are released
from cell membrane phospholipids.
 They are the major lipid derived autacoids.
  CHEMISTRY, BIOSYNTHESIS AND
DEGRADATION

 Chemically, PGs may be considered to be derivatives of prostanoic

acid, though prostanoic acid does not naturally occur in the body.
 It has a five membered ring and two side chains projecting in
opposite directions at right angle to the plane of the ring (prostanoic
acid).
 There are many series of PGs and thromboxanes (TXs)
designated A, B, C....I, depending on the ring structure
and the substituents on it. Each series has members with
subscript 1, 2, 3 indicating the number of double bonds in
the side chains.
 Leukotrienes are so named because they were first
obtained from leukocytes (leuko)
 They have 3 conjugated double bonds (triene).
 They have also been similarly designated A, B, C.....F and
given subscripts 1, 2, 3, 4.
 In the body PGs, TXs and LTs are all derived from eicosa (referring to 20
C atoms) tri/tetra/penta enoic acids.
 Therefore, they can be collectively called eicosanoids.
 In human tissues, the fatty acid released from membrane lipids in largest
quantity is 5,8,11,14 eicosa tetraenoic acid (arachidonic acid).
 During PG, TX and prostacyclin synthesis, 2 of the 4 double bonds of
arachidonic acid get saturated in the process of cyclization, leaving 2
double bonds in the side chain.
 Thus, subscript 2 PGs are the most important in man, e.g. PGE2, PGF2α,
PGI2, TXA2.
 No cyclization or reduction of double bonds occurs during LT synthesis-
the LTs of biological importance are LTB4, LTC4, LTD4.
 Eicosanoids are the most universally distributed autacoids in the body.
 Practically every cell and tissue is capable of synthesizing one or more
types of PGs or LTs.
 There are no preformed stores of PGs and LTs.
 They are synthesized locally and the rate of synthesis is governed by the
rate of release of arachidonic acid from membrane lipids in response to
appropriate stimuli.
 These stimuli activate hydrolases, including phospholipase A, probably
through increased intracellular Ca2+.
 The cyclooxygenase (COX) pathway generates eicosanoids with a ring
structure (PGs, TXs, prostacyclin) while lipoxygenase (LOX) produces
open chain compounds (LTs).
 All tissues have COX—can form cyclic endoperoxides PGG2 and
PGH2 which are unstable compounds.
 Further course in a particular tissue depends on the type of isomerases
or other enzymes present in it.
 Lung and spleen can synthesize the whole range of COX products.
 Platelets primarily synthesize TXA2 which is—chemically unstable,
spontaneously changes to TXB2.
 Endothelium mainly generates prostacyclin (PGI2) which is also
chemically unstable and rapidly converts to 6-keto PGF1α.
 Lipoxygenase pathway appears to operate mainly in the lung, WBC and
platelets.
 Its most important products are the LTs, (generated by 5-LOX) particularly
LTB4 (potent chemotactic) and LTC4, LTD4 which together constitute the
‘slow reacting substance of anaphylaxis’ (SRS-A) described in 1938 to be
released during anaphylaxis.
 A membrane associated transfer protein called FLAP (five lipoxygenase
activating protein) carrys arachidonic acid to 5-LOX, and is essential for the
synthesis of LTs. Platelets have only 12-LOX.
  INHIBITION OF SYNTHESIS
 Synthesis of COX products can be inhibited by nonsteroidal
antiinflammatory drugs (NSAIDs).
 Aspirin acetylates COX at a serine residue and causes irreversible
inhibition while other NSAIDs are competitive and reversible inhibitors.
 Most NSAIDs are nonselective COX-1 and COX-2 inhibitors, but some
later ones like celecoxib, etoricoxib are selective for COX-2.
 The sensitivity of COX in different tissues to inhibition by these drugs
varies; selective inhibition of formation of certain products may be possible
at lower doses.
 NSAIDs do not inhibit the production of LTs: this may even be increased
since all the arachidonic acid becomes available to the LOX pathway.
 Zileuton inhibits LOX and decreases the production of LTs. It was
used briefly in asthma, but has been withdrawn.
 Other LOX inhibitors are: Masoprocol, Benoxaprofen, Licofelone
and velifapon.
 Glucocorticosteroids inhibit the release of arachidonic acid from
membrane lipids (by stimulating production of proteins called
annexins which inhibit phospholipase A2) indirectly reduce
production of all eicosanoids—PGs, TXs and LTs.
 Moreover, they inhibit the induction of COX-2 by cytokines at the
site of inflammation.
  Degradation
 Biotransformation of arachidonates occurs rapidly in most
tissues, but fastest in the lungs.
 Most PGs, TXA2 and prostacyclin have plasma t½ of a few
seconds to a few minutes.
 First a specific carrier mediated uptake into cells occurs, the side
chains are then oxidized and double bonds are reduced in a
stepwise manner to yield inactive metabolites.
 Metabolites are excreted in urine.
 PGI2 is catabolized mainly in the kidney.
  PROSTANOID RECEPTORS

 PGs, TX and prostacyclin act on their own specific receptors located

on cell membrane.
 Five families of prostanoid receptors have been designated (DP, EP,
FP, IP, TP ), each after the natural PG for which it has the greatest
affinity.
 All prostanoid receptors are G-protein coupled receptors which can be
functionally categorized into ‘excitatory’ or ‘contractile’ and
‘inhibitory’ or ‘relaxant’ groups.
 The contractile group (EP1, FP, TP) couple primarily with Gq protein
and activate PLCβ to generate IP3 and DAG.
 These second messengers release Ca2+ intracellularly resulting in
excitatory responses like smooth muscle contraction, platelet
aggregation, etc.
 The relaxant group (DP1, EP2, EP4 and IP) couple with Gs protein—
activate adenylyl cyclase to generate intracellular second messenger
cAMP. Smooth muscle relaxation, inhibition of platelet aggregation, etc.
are produced through cAMP dependent protein kinase (PKA).
 DP This receptor has strongest affinity for PGD2, but PGE2 can also
activate it.
 Two subtypes DP1 and DP2 have been identified, but both have
limited distribution in the body; DP1 is a relaxant receptor which
dilates certain blood vessels and inhibits platelet aggregation.
 The DP2 receptor couples with Gi protein and inhibits cAMP
generation.
 EP This receptor is characterized by highest affinity for PGE2; enprostil is a
selective agonist. Four subtypes have been recognized:
 EP1 is a contactile receptor—contracts visceral smooth muscle, but is less
abundant in the body.
 EP2 and EP4 are relaxant in nature, act by increasing cAMP in smooth
muscle, but the same second messenger enhances Cl¯ and water secretion by
the intestinal mucosa. While EP2 is present in few organs, EP4 has wide
distribution.
 EP3 is inhibitory, decreases cAMP generation by coupling with Gi protein.
The antilipolytic action of PGE2 is exerted by opposing cAMP generation in
adipose tissue. Distribution of PGE3 receptor in the body is wide.
 FP is contractile receptor is highly expressed in the female genital tract, and
is present in many other organs. It exhibits strong affinity for PGF2α;
fluprostenol is a selective agonist.
 IP is relaxant receptor is defined by highest affinity for PGI2, but PGE2 also
acts on it; cicaprost is a selective agonist. It is expressed in heart, lungs,
kidney, platelet (antiaggregatory), etc., but the highest density is in the
vasculature.
 TP Characterized by high affinity for TxA2, this contractile receptor is
abundant in platelets (aggregatory), cardiovascular system, immune cells and
many other organs. PGH2 can also activate TP. Apart from IP3/DAG—
Ca2+—PKc pathway, it utilizes other kinases as well to exert certain
biological effects.
  LEUKOTRIENE RECEPTORS

 Separate receptors for LTB4 (BLT1 and BLT2) and for the cysteinyl LTs
(LTC4, LTD4) have been defined.
 Two subtypes, cysLT1 and cysLT2 of the cysteinyl LT receptor have been
cloned.
 All LT receptors couple with Gq protein and function through the
IP3/DAG transducer mechanism.
 The BLT receptors are chemotactic and primarily expressed in leucocytes
and spleen.
 BLT1 receptor has high, while BLT2 receptor has lower affinity for
LTB4.
 The cysLT1 receptor is mainly expressed in bronchial and intestinal
muscle and has higher affinity for LTD4 than for LTC4.
 The primary location of cysLT2 receptor is leucocytes and spleen, and it
shows no preference for LTD4 over LTC4.
 The cysLT1 receptor antagonise, by Montelukast, Zafirlukast, etc. are
now valuable drugs for bronchial asthma
 ACTIONS AND PATHOPHYSIOLOGICAL ROLES
  Leukotrienes
 The straight chain lipoxygenase products of arachidonic acid are
produced by a more limited number of tissues (LTB4 mainly by
neutrophils; LTC4 and LTD4—the cysteinyl LTs—mainly by
macrophages), but probably they are pathophysiologically as important
as PGs.
 CVS and blood
 LTC4 and LTD4 injected i.v. evoke a brief rise in BP followed by a
more prolonged fall.
 These LTs markedly increase capillary permeability and are more
potent than histamine in causing local edema formation.
 Migration of neutrophils through capillaries and their clumping at sites
of inflammation in tissues is also promoted by LTB4.
 The cysteinyl LTs (C4, D4) are chemotactic for eosinophils.
 Smooth muscle
 LTC4 and D4 contract most smooth muscles.
 They are potent bronchoconstrictors and induce spastic contraction of
g.i.t. at low concentrations.
 They also increase mucus secretion in the airways.
 Afferent nerves
 Like PGE2 and I2, the LTB4 also sensitizes afferents carrying
pain impulses—contributes to pain and tenderness of
inflammation.
  USES
Clinical application of PGs and their analogues is rather restricted
because of limited availability, short lasting action, cost and frequent side
effects. However, their use in glaucoma and in obstetrics is now common
place.
 Medical termination of pregnancy (Abortion)
 Induction labour pain
 Postpartum haemorrhage
 Peptic ulcer
 Glaucoma
 To maintain patency of ductus arteriosus
 To avoid platelet damage