Skeletal muscle relaxants are used in various surgical procedures during anesthesia, because they decrease spasm and spasticity.

Classification:

Classified into three groups

1. Peripheral acting

2.   Centrally acting
3.   Locally / Directly acting

Peripherally and centrally acting drugs are also known as indirectly acting drugs.

Peripherally acting:

Non Depolarizing Neuromuscular Blockers:

(Act at NMJ/ Most commonly used/ Also called NM blocking agents/ antagonists)

1. Isoquinoline Derivatives:

d-Tubocurarine

Atracurium

Cisatracurium

Doxacurium

Mivacurium (shortest duration of action/slow onset/increase histamine release thus cause flushing, bronchospasm)

Metocurium

Miscellaneous:

Gallamine

2.  Steroid Derivatives

Panuronium (can cause moderate increase in heart rate and small increase in cardiac output but no effect on TPR, because:

1. Vagolytic action
2. Release of NE by nerve endings
3. Blockage of reuptake of NE)

Pipecuronium

Rapacuronium (short acting, now withdrawn)

Procuronium (fastest acting within 60-120 seconds, hence used for tracheal intubation)

Vecuronium

Procuronium and Vecuronium are intermediate acting. Panuronium and Pipecuronium are long acting.

Depolarizing Neuromuscular Blockers (agonists)

Suxamethonium

Suxethonium

Decamethonium

Centrally acting

(Act on CNS)

Benzodiazepines

Diazepam, clonazepam, Nitrazepam

GABA Analogues

Baclofen

Progabide

Propanediol Derivatives

Mephenesin
Meprobamate

Miscellaneous Compounds

Cyclobenzaprine

Methocarbamol

Orphenadrine

Tizanidine

Directly Acting:

(Act directly on muscles)

Dantrolene

Neuromuscular Junction

Motor end plate is a specialized area where there is junction of the nerve fiber with the muscle fiber. There is unusual distribution of ions in the muscle fiber:

There is more negative charge inside the membrane in the resting phase.

On arrival of the action potential, release of acetyl choline from nerve terminals occurs, which binds to post-synaptic nicotinic receptors. Stimulation of these receptors cause increased influx of Na+ ions, which leads to depolarization and contraction.

Fate of acetyl choline is that it is hydrolyzed by acetylcholine esterase.

Directly acting NM blocking agents do not interfere with the release of acetyl choline. They only interact with post-synaptic nicotinic receptors.

Botulinum Toxin A

Botulinum toxin A interferes with the release of acetyl choline. It is produced by anaerobic bacteria ‘Clostridium botulinum’. It occurs due to food poisoning and can lead to respiratory paralysis and even death of the patient. However, this is used therapeutically against bronchospasm in athletes, because of the repeated use of the limbs, there is damage to the wrist and knee joints and this toxin relaxes the muscles. It is given IM and effects start within a few days. They remain for a few months. Toxin can be repeated if required.

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Tubocurarine -Non Depolarizing Neuromuscular Blocker

Suxamethonium -Depolarizing Neuromuscular Blocker

Factors affecting actions of Neuromuscular blockers

Benzodiazepines as Centrally Acting Skeletal Muscle Relaxants

Baclofen and Progabide -GABA Analogues

Mephenesin and Meprobamate -Propandiol Derivatives

Cyclobenzaprine, Orphenadrine and Tizanidine

Tubocurarine -Non-depolarizing Neuromuscular Blocker

Tubocurarine is a non-depolarizing neuromuscular blocker. Non-depolarizing neuromuscular blockers interfere with the NM transmission. D-tubocurarine is a natural substance, obtained from curare, which was used in ancient times as an arrow head poison to kill animals. Source of curare is ‘Chondrodendron Tomentosum’ and Strychnas.

Chemistry:

It is a quaternary compound.

Mechanism of Action:

It competes with acetylcholine for post-synaptic nicotinic NM receptors and blocks them.

No flow of ions occurs, thus there is no contraction.

This blockage is competitive and reversible, the sequence of events for this blockage are:

1. Muscles capable of rapid movements like fingers, toes, eyes and jaw muscles are the first to go.

2. Muscles of neck, limbs and trunk are second to go.

3. Respiratory muscles, intercostal muscles and diaphragm at last. (Diaphragm paralyzes last and is the first to recover)

The recovery occurs in the opposite manner.

Pharmacological Actions:

1. Release of histamine (premedication with antihistaminics is useful, otherwise hypotension might occur)
2. Causes weak blockage of ganglion
3. Blocks adrenal medulla

Over dosage:

The effect of this drug can be antagonized by anticholine esterases e.g. neostigmine given in a dose of 1-2 mg I/V. Neostigmine is combined with atropine to block muscarinic effects.

Atropine has biphasic effect on heart, gives first bradycardia then tachycardia, so given shortly before neostigmine to prevent activation of cardiac muscarinic receptors.

Pharmacokinetics

Cannot of given orally is quaternary compound. If given orally, no absorption occurs. By I/V it is excreted as such in urine. Onset of action is 4-5 minutes. Duration of action is 30-60 minutes. Short duration is due to redistribution and not due to diminution. That is why it should not be given repeatedly; otherwise it will accumulate in fat tissue and cause toxicity.

Therapeutic Uses

1. Skeletal muscle relaxant for endotracheal intubation.
2. When this drug is used with general anesthetics, lesser dose of general anesthetics is required.
3. Used in chest crush injuries to relax chest muscle.
4. Given in convulsions
5. Is an antidote for strychnine poisoning

Adverse Effects

1. Hypotension (because of histamine release and ganglion blockage, vasodilatation)
2. Bronchospasm (histamine release)
3. Rash (histamine)
4. Vomiting (paralysis of sphincters and diplopia can be there due to paralysis of muscles)

Contraindications

1. Respiratory insufficiency –emphysema, bronchial asthma
2. Renal disease

Preparations

5-15 or 20 mg dose are available.

Dose should not exceed 400 mg.

Atracurium, Cisatracurium, Gallamine and Steroid Derivatives -Non Depolarizing Neuromuscular Blockers

Atracurium:

Actions are similar to those of d-tubocurarine. It is safer and more potent than d-tubocurarine because

1. It is eliminated through Hoffmann elimination
2. It is safer to be used in patients with renal and hepatic diseases
3. No histamine is released and no ganglion blockage and tachycardia is observed (can cause hypotension due to systemic histamine release)

Atracurium is broken down into ludanosine and quaternary acid.

Duration of action is 30-35 minutes.

Cisatracurium:

Cisatracurium is an analogue of atracurium (stereoisomer). It is more potent and safer than d-tubocurarine. Actions are similar to atracurium.

Gallamine:

Gallamine is a synthetic drug. It is less potent as compared to d-tubocurarine. It can cause ganglion blockage, histamine release and sometimes tachycardia.

Steroid derivatives:

Steroid derivative are synthetic drugs. They are 5 times more potent than d-tubocurarine.

No histamine is released, no ganglion blockage occurs. Tachycardia is sometimes present.

Suxamethonium -Depolarizing Neuromuscular Blocker:

Suxamethonium is the only drug used in the category of depolarizing neuromuscular blockers and is synthetic, consisting of 2 molecules of acetyl choline joined together.

Mechanism of Action

It binds to post-synaptic nicotinic receptors, activating them and opening ion channels, which causes depolarization and contraction.

Phase I Block

In contrast to acetyl choline, which is hydrolyzed in synaptic cleft, this suxamethonium is not rapidly metabolized. It remains attached to receptors for longer durations, leading to persistent depolarization of receptors. Muscle membrane becomes irresponsible to further stimulus and this is known as phase I block or depolarizing block. Small contractions of the muscle fibers and fasciculations are seen in this phase.

Phase II Block

After some time, the muscle membrane becomes desensitized to the effects of neurotransmitters, this is known as phase II block or the desensitizing block. In this phase, flaccid paralysis of the muscles is seen.

Over dosage

The effects of this drug cannot be antagonized by anti choline esterases.

Ventilatory support and supportive management is required as there is no antidote.

If injections are repeated within 5-10 minutes, severe bradycardia occurs, leading to cardiac arrest. Atropine is then given in a dose of 1.5 mg to prevent cardiac arrest. Reason of bradycardia is:

1. Direct myocardial effects
2. Increased muscarinic stimulation
3. Increased ganglionic stimulation

Stimulates Muscarinic & Nicotinic receptors:

This drug stimulates both nicotinic and muscarinic receptors;

1. In low doses, negative ionotropic and chronotropic effects
2. In high doses, positive ionotropic and chronotropic effects

Pharmacokinetics:

Given by I/V route.

Has rapid onset (in one minute)

Duration of action is 5-10 minutes (short) due to degradation by enzyme psudocholine esterase, metabolized into choline and succinic acid. (Succinyl choline broken into succinomonocholine, which gives choline and succinic acid)

Certain local anesthetics like procaine are also metabolized by pseudocholine esterase, which can potentiate the effects of succinyl choline (suxamethonium) when given together.

Therapeutic Uses:

1. For short surgical procedures (abdominal surgeries)
2. Bronchoscopy
3. Laryngeoscopy
4. Esophagoscopy
5. Can be used in electroconvulsive therapies to prevent convulsions and trauma e.g. status epilepticus
6. Also used in orthopedic manipulations

Adverse Effects

1. In patients with atypical pseudocholine esterases, suxamethonium is not metabolized, leading to prolonged respiratory paralysis and apnea. This may occur in liver disease or genetically atypical enzyme.
2. Can produce bradycardia if given for a prolonged period of time repeatedly.
3. Muscle pain may occur due to fasciculations (unsynchronized contractions of adjacent muscle fibers before paralysis)
4. Malignant hyperpyrexia, an idiosyncratic response. There is hyperthermia, hyertonia and hyperpyrexia along with hyperkalemia
5. Can lead to increased intragastric pressure (5-40 cm H2O) and can produce vomiting, aspiration pneumonia. Thus should be given on empty stomach. Following are more prone:
   a. Diabetics having delayed gastric emptying
   b. Trauma
   c. Obesity
   d. Esophageal dysfunction
6. Can increase intraocular pressure, due to contraction of intraocular muscles during phase I block or due to dilatation of intraocular choroidal blood vessels.
7. Hyperkalemia due to muscle damage, dangerous in patients predisposed to hyperkalemia like patients with wounds, trauma and peritoneal infections. It might lead to cardiac arrest.

Contraindications

1. Hyperkalemia
2. Atypical pseudocholine esterases
3. Liver diseases
4. Increased intraocular pressure as in glaucoma

Drug Interactions

Metabolized by pseudocholine esterase, all of drugs metabolized by same enzyme potentiate each other’s effects. Local anesthetics can potentiate the effects of suxamethonium e.g. Procaine or lidocaine can potentiate the effects.

Dose

Starting dose is 10 mg, which may be increased to 100 mg.

Factors affecting actions of Neuromuscular blockers:

Several factors influence the action of neuromuscular blockers, these include:

1. Blood flow to muscles

If blood flow is rapid, onset of action is rapid and duration of action is short.

2. Temperature

Hyperthermia potentiates the effects of non-depolarizing neuromuscular blockers, while hypothermia potentiates the effects of depolarizing neuromuscular blockers.

3. pH

Acidosis potentiates the effects of non-depolarizing neuromuscular blockers.

4. Potassium concentration

Hyperkalemia potentiates the effects of depolarizing neuromuscular blockers. Hypokalemia potentiates the effects of non-depolarizing neuromuscular blockers.

5. Antibiotics

Antibiotics like amino glycosides, streptomycin, decrease the release of acetylcholine at nerve terminals and thus potentiate the effects of non-depolarizing neuromuscular blockers.

6. Atypical Pseudo cholinesterase

Suxamethonium is metabolized by pseudo cholinesterase. If there is deficiency or presence of atypical pseudo cholinesterase, it might lead to respiratory paralysis or apnea.

7. Anti-arrhythmic drugs

Drugs like quinidine have curare like actions causing relaxation of muscles. They potentiate the effects of non-depolarizing neuromuscular blockers.

8. Myasthenia gravis

In myasthenia gravis, peripherally acting neuromuscular blockers are not administered.

9. Renal/ liver diseases

Care must be taken as Rapacuronium and Vecuronium are metabolized by the liver.

d-Tubocurarine and Metocurium are eliminated through the kidneys.

10. Calcium channel blockers

Calcium channel blockers potentiate the effects of depolarizing neuromuscular blockers and non-depolarizing neuromuscular blockers.

11. Diuretics

Thiazide diuretics produce hypokalemia, which potentiates the effects of non-depolarizing neuromuscular blockers.

Benzodiazepines as Centrally Acting Skeletal Muscle Relaxants:

Centrally acting muscle relaxants

Effects

They produce effects centrally in brain or spinal cord.

Decrease spasm

They are used to decrease the spasm and release spasticity as well as to reduce the pain.

Reasons for spasm

Spasm may be due to:

1. hyperactive stretch reflexes or

2.  increased activation of alpha motor neurons or

3. imbalance between excitatory and inhibitory neurotransmitters.

Conditions

1. Multiple sclerosis
2. Cerebral palsy
3. CVA

These drugs do not improve the power or functions of muscles; rather actually decrease the power of muscles.

Skeletal muscle relaxants

In patients of stroke, spasticity is important because it helps in walking, providing support. When skeletal muscle relaxants are given, they expose the weakness of limbs.

Mechanism of Action of centrally acting drugs

Decrease the hyperactivity of stretch reflex arc, as well as decrease the activation of alpha motor neurons.

This is achieved either by increasing the release of inhibitory neurotransmitters or decreasing the release of excitatory neurotransmitters. The pain encountered in these spasms is due to release of subs P, which is decreased by these drugs.

These drugs depress the pulse transmission in polysynaptic pathways.

Benzodiazepines:

Benzodiazepines are commonly used for relieving skeletal muscle spasms. They are safe as have fewer adverse effects.

Mechanism of Action

They produce their effects by GABAergic effect meaning that they potentiate the effects of GABA, without directly activating GABA receptors. They bind GABA A component of supramolecular complex.

Pharmacokinetics

They can be given orally or parentally. They can be given I/V for controlling the convulsions in status epilepticus, as well as in tetanus. They are metabolized by the liver.

Adverse effects

Mainly affect CNS, evident in the form of sedation, drowsiness, ataxia, impaired judgment. Only in increased doses can cause depression of CVS and respiratory system.

Dose

Given in a dose of 5 mg, which may be increased to 60 mg.

Clonazepam and Nitrazepam have similar actions to that of diazepam, but have shorter duration of action.

Baclofen and Progabide -GABA Analogues:

Baclofen

Baclofen acts as agonist at GABA receptors especially GABA B receptors. Ultimately there is hyper polarization due to:

1. Increased potassium conductance
2. Decreased release of excitatory neurotransmitters
3. Decreased release of subs P

Uses

1. Musculoskeletal disorders
2. Neuralgia
3. Muscle spasms

Adverse effects

1. Confusion
2. Sedation
3. Drowsiness
4. Weakness
5. Fatigue
6. Hypotonia

Contraindications

Psychiatric illness

Dose

Dose is 15 mg, which can be increased to 100 mg.

Progabide

Progabide is a less commonly used muscle relaxant acting at both GABA A and GABA B receptors. It produces muscle relaxant effects because of active metabolite.

Mephenesin and Meprobamate -Propandiol Derivatives

Mephenesin:

Mephenesin acts by decreasing the transmission in polysynaptic pathway. It produces muscle relaxant effects. It can be used in:

1. Strychnine over dosage

2. Convulsions

Adverse effects include sedation and drowsiness.

Dose is 1-3 grams daily in divided doses.

Meprobamate:

Meprobamate is less commonly used because of strong sedative effects which hinders normal activities of individual. It is an enzyme inducer and can interact with various drugs.

It is contraindicated in porphyria.

Cyclobenzaprine, Orphenadrine and Tizanidine

Cyclobenzaprine

It mainly acts at the level of brainstem. It has anticholinergic effect and is a good muscle relaxant. It is given orally and is metabolized by the liver.

It is usually given in combination with Methacarbamol (same group).

It is used in adjuvant therapy and in physiotherapy with other drugs.

Orphenadrine

Orphenadrine has anticholinergic activity. It has muscle relaxant effects and can be used in strychnine over dosage. However, it produces sedation, drowsiness and confusion.

Tizanidine

Tizanidine is a newer drug. It is a congener of Clonidine, which is antihypertensive drug. It acts as agonist at alpha 2 receptors and enhances pre and post synaptic inhibition.

It can be given orally but bioavailability is less because of extensive first pass metabolism. It is beneficial in patients on bed rest. Main adverse effects are similar to those of orphendadrine.

Dantrolene -Directly Acting Skeletal Muscle Relaxant:

Chemistry

Chemically dantrolene is hydantoin derivative.

Mechanism of Action

It decreases the release of calcium from sarcoplasmic reticulum by binding to special type of calcium receptors, known as Ryanidine receptors. Because of blockage, there is decrease in release of calcium and decrease in spasm.

It has no effects on smooth muscles and cardiac muscles.

Pharmacokinetics

It is given orally and has delayed onset of action. Half life is 8-15 hours. It is metabolized in the liver and is eliminated in bile and urine.

Therapeutic uses

Main use is in malignant hyperthermia, an idiosyncratic response seen with general anesthetics.

Besides dantrolene, bromocriptine may be given along with sponging for decreasing temperature.

Adverse effects

1. Hypotonia
2. Muscle weakness
3. Drowsiness
4. Sedation

Dose

Given carefully in renal/hepatic diseases. Starting dose is 25 mg, which may be increased to 100 mg.

Central sympathoplegics are also known as Alpha 2 Selective Adrenergic Agonists

These are NOT ANTAGONISTS, but are alpha 2 agonists. They still block the effects but are different from other blockers. These include:

1. Alpha methyldopa (Aldomet)
2.  Clonidine
3. Apraclonidine
4. Brimonidine (given topically in eye)
5. Guanfacine
6. Guanabenz

Their main site of action is CNS and are not peripherally acting.

Alpha Methyl Dopa

Alpha methyl dopa is a structural analog of levo dopa, but actions are totally different. It is a prodrug, and is centrally acting (although lipid insoluble) because of aromatic amino acids, so competes levo dopa, producing extra-pyramidal symptoms.

Mechanism of Action

Alpha Methyl Dopa is converted into alpha methyl dopamine in the presence of decarboxylase, which forms alpha methyl noradrenaline by virtue of beta hydroxylase.

Alpha methyl dopa is produced as a prodrug, and needs to be activated. It is actively transported to brain adrenergic neuron terminals, which use same enzymes as those of NE.

Alpha methyl dopa displaces noradrenaline and sits in its place. Guanethidine also does the same. Alpha methyl noradrenaline does not act as a false neurotransmitter. It shows response called pressor effect.

1. It is present in the storage vesicles. Auto receptors are present presynaptically, once stimulated (presynaptic alpha 2 receptors); further release of NE is inhibited by negative feedback, decreasing sympathetic outflow.
2. Alpha methyl dopa stimulates post synaptic alpha 2 receptors (brain stem, nucleus solitaries) to block sympathetic activity.

Tractus solitarius pathways stimulate sympathetic response. They act at alpha 2 receptors post synaptically. In appropriate neurons blocks sympathetic outflow.

Mechanism has been found indirectly. As:

1. Site of action is CNS
2. Are alpha 2 agonists
3. Need to be converted to active forms
4. Presynaptically block
5. Postsynaptically block sympathetic outflow in appropriate neurons

Evidence:

Evidence has been found in animal studies:

• Lower doses of alpha methyl dopa are required when used directly in the ventricles of brain, showing site of action is CNS
•  Alpha 2 selective blockers block anti hypertensive effect. Thus they are not antagonists.
•  DOPA decarboxylase inhibitors if given, anti hypertensive effect are blocked, pointing out that conversion of drug is required before it can act.

Pharmacological actions:

CVS:

1. Cause decrease in blood pressure and decrease in TPR.

2. Have minimum effects on the cardiac output, especially in young adults having normal muscular tone. In older people, cardiac output is reduced because of poor muscle tone.

3. After 12 weeks of therapy if left ventricular hypertrophy occurs (long standing hypertension), drugs relieve this ventricular hypertrophy. There is no valid reason. Evidence is based on studies.

4. No postural hypotension occurs because of only central action, baroreceptors are spared.

5. Actions are more pronounced in the regions where there is increased sympathetic activity.

Kidneys

The renal blood flow is maintained by alpha methyl dopa. Renin secretion is decreased but there is no relevance to hypertension.

When used for prolonged durations, long term pressure control by kidneys lead to salt and water retention, causing blunting of blood pressure. These drugs are usually combined with diuretics.

Pharmacokinetics

The bioavailability is 25% orally.

Onset of action is a little delayed. It takes 6-8 hours before effects become visible. Once the actions start, they persist for 12-24 hours after stoppage of drug intake.

The drug has to be actively transported to brain adrenergic neurons and has to replace noradrenaline.

Thus, it is not used in emergency conditions.

Adverse effects

CNS

1. Ascending reticular activating center sedation
2. dry mouth (central nuclei of medulla blocked)
3. extra pyramidal signs,
4. increased prolactin (dopamine blocks nigrostriatal pathways, producing Parkinsonism like picture; central hypothalamus action if blocked by alpha methyl dopa, increased production of prolactin takes place.

Rare

Positive Coomb’s test

This test is used to detect auto antibodies destroying RBCs producing immune mediated hemolytic anemias. Auto antibodies are also produced against the drug, which cross react with RBCs. This occurs in 10% of the patient.

Hepatotoxicity
Drug fever

These two effects disappear once the drug is withdrawn.

Endocrine

1. Due to decreased dopamine, increased prolactin

2. Gynaecomastia

3. Galactorrhea

Reproductive System

Decreased libido

Nose

Nasal stuffiness

Fever also occurs, disappearing when drug discontinued.

Therapeutic Uses

1. Alpha methyl dopa is still the favourite drug of gynecologists for pregnancy hypertension, because:

a. No teratogenicity is associated
b. No harmful effects in fetus are observed

For other types of hypertensions, it is only used as an add-on drug.

2. Pre-eclampsia or eclampsia

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Clonidine

Apraclonidine

Clonidine:

Clonidine is imadazoline derivative. It is centrally acting, and is not a prodrug. It is lipid soluble.

Mechanism of action

Mechanism of action of clonidine is different from that of alpha methyl dopa. It does not need to be converted to active metabolite and is active as such. It easily crosses the blood brain barrier and acts as agonist on alpha 2 receptors located in brainstem tractus solitaries.

1. It presynaptically inhibits noradrenaline release.
2. Postsynaptically, it decreases sympathetic conduction.
3. Imidazoline receptors are present in rostroventrolateral medulla which also act and have different action and increase the parasympathetic activity.

Pharmacological actions

CVS

Decreases blood pressure, total peripheral resistance and cardiac output. Because of interaction with receptors, apart from blocking sympathetic system, it also increases parasympathetic outflow (I receptors), leading to decreased heart rate, decreased force of contraction and decreased cardiac output.

Kidneys

Renal blood flow is maintained. Acting as alpha 2 agonist, renin might be decreased. There are chances of tolerance. Kidney functions are maintained.

Adverse effects

CNS

1. Sedation
2. Dryness of mouth
3. Sleep disturbances
4. Does not cause extra pyramidal signs
5. Does not cause increase in prolactin
6. Suicidal tendency

Nasal stuffiness

Contact dermatitis

Some patients are hypersensitive to skin patches of clonidine which are effective for 7 days. This might lead to contact dermatitis.

 Rebound hypertension

If Clonidine is withdrawn suddenly, hypertension crisis may occur, even with one to two missed doses. This is because alpha 2 receptors are down regulated due to agonist effect (block sympathetic outflow) while alpha 1 are not (circulating catecholamines produce increased response).

Clonidine has decreased usage now because of rebound hypertension.

Therapeutic uses of Clonidine:

1. Hypertension
2. Withdrawal from narcotics, alcohol and tobacco- to counter increased sympathetic activity during drug withdrawal, craving for drug is reduced by clonidine
3. Menopausal hot flushes –due to increased sympathetic activity
4. Diagnosis of pheochromocytoma

Patients have essential hypertension because of increased noradrenaline due to tumor of adrenal gland. Clonidine is given to control blood pressure, at the same time noradrenaline and adrenaline are decreased.

If patient has pheochromocytoma, blood pressure is controlled but there is persistence of levels of adrenaline and noradrenaline, which leads to diagnosis of pheochromocytoma.

5. To prevent diarrhea by diabetic neuropathy –clonidine producing alpha 2 effect, causes decreased salt and water release in lumen along with decreased cAMP, leading to decreased Cl- out flux and increased Na+ influx, This decreases water outflow, reducing diarrhea.

Alpha Methyl Dopa	Clonidine
Prodrug –conversion required	No conversion required
Decrease in sympathetic activity	Decreased sympathetic and increased parasympathetic outflow
Decrease TPR, no effect C.OC.O in elderly only	Decrease TPR and C.O
Slow onset	Rapid onset
Slow termination of effects	Rapid termination
Lipid insoluble, but crosses BBB	Lipid soluble
Reverses left ventricular hypertrophy	Cannot reverse
No rebound HTN	Rebound HTN

Apraclonidine:

It is topically used in the eye as eye drops, it does not cross blood brain barrier, and is given in low doses so there are less chances of hypertension.

It decreases intraocular pressure by:

1. Decreasing production of aqueous humor
2. Increasing outflow of aqueous humor

It is protective to neural tissue, thus possibly has some role in treatment of glaucoma.

Once impulse arrives, calcium moves in, resulting in excitation-secretion coupling. To save dopamine, it is taken up by storage vesicles because monoamine oxidase metabolizes any neurotransmitter present.

Drugs may:

1. Interfere with synthesis of noradrenaline (Methyrosine)
2. Interfere with storage of dopamine (Reserpine)
3. Interfere with release of noradrenaline (Guanethidine)

Drugs which prevent release of noradrenaline

• Guanethidine
• Guanadrel
• Bethanidine
• Debrisoquine
• Bretylium

Drugs that inhibit storage of noradrenaline

• Reserpine

Drugs that interfere with synthesis of noradrenaline:

Metyrosine

Guanethidine

Source and structure:

Synthetic drug, polar, thus it is difficult for it to cross the blood brain barrier. Has peripheral action, and not central. Half life is 5 days.

Mechanism of action

1. Reuptake 1 or uptake 1

This is necessary for the action to occur. After it is reuptaken, it blocks the release of noradrenaline.

2. Membrane stabilizing effect (MSA)

Guanethidine has local anaesthetic effect. It decreases the movement of ions across membrane, thus decreasing the action potential and NE release. It decreases the excitation-secretion coupling.

3. Displacement of noradrenaline

4. Substitute neurotransmitter

Once guanethidine displaces noradrenaline, it is located in the storage vesicles. Every time action potential arrives; guanethidine is released, which is devoid of activity on alpha and beta receptors. Thus acts as a false neurotransmitter.

5. Blocks sympathetic system

Pharmacokinetics

Very high volume of distribution, as drug is present within storage vesicles. Oral bioavailability is low i.e. 5-50%. Steady state concentration is achieved after 20 days. Any dose cannot be adjusted before this time. Sympathoplegia persists even after cessation of therapy for some time.

When taken orally, only fall in blood pressure occurs.

Half life is about 5 days.

Pharmacological effects

CVS

Causes decrease in blood pressure and decreased TPR as well as cardiac output. Sympathoplegia results in bradycardia, dilatation of capacitance venules occurs, thus pooling of blood takes place decreasing the venous return. This causes decreased cardiac output. TPR also decreases sympathoplegia.

Actions depend on the route of administration and how rapidly given:

1. If rapidly given I/V triphasic response of blood pressure is observed. Initial fall is followed by rise, which is followed by gradual fall:

Initial fall is due to the ability of drug to block noradrenaline. Once taken up, more drug reaches the cytoplasm and displaces noradrenaline. Overwhelming quantity of noradrenaline is displaced, some of which spills out of the nerve terminal and reaches the systemic circulation. This is responsible for the rise. After some time all neurotransmitter is displaced, and guanethidine behaves as a false neurotransmitter, then a decline is observed.

2. If given slowly I/V, only biphasic response is seen. There is no initial fall.

The drug is taken up by the storage vesicles, noradrenaline is released, thus rise is observed on slow I/V injection, once false neurotransmitter acts, fall is seen.

3. If drug is given orally, levels rise slowly, only monophasic response occurs.

Local anaesthetic activity occurs, and as substitute offsets the release of noradrenaline, MAO takes care of the noradrenaline released.

Increased sympathetic activity is associated with increased guanethidine activity.

Renal

Initially slightly decrease in blood flow occurs because of auto regulation. Later salt and water retention causes increase in plasma volume and increased blood pressure, thus pseudo tolerance is seen. Diuretics may be given as remedy.

GIT

Blocks sympathetic activity, increasing the parasympathetic activity, which leads to increased motility of gut. This might result in abdominal cramps, diarrhoea.

Eye

Dilator pupillae are blocked, parasympathetic sphincter has unopposed action causing miosis. Decrease in intraocular pressure is also observed.

CNS

Drug does not cross BBB, so has no effect.

Therapeutic uses

Hypertension

This was mainly used quite some time back, now its usage is obsolete. Better options are available having less toxicity. Also this drug blocks sympathetic system, thus super sensitivity occurs at catecholamine receptors.

Adverse effects

1. Postural Hypotension (under control baroreceptors, increased sympathetic discharge blocked so only acting peripherally)
2.  Weakness
3. Worsening of CCF (heart is not pumping enough, no Frank Starlings’ law and no increase in sympathetic activity.)
4. Fluid Retention(long term control HTN by kidneys. When blood pressure is decreased:

a. Redistribution of intra-renal blood flow occurs, independent of renin secretion, leading to salt and water retention.

b. Because of rennin secretion, stimulation of rennin-angiotensin-aldosterone axis occurs, leading to salt and water retention.

Antihypertensive effects are blunted by this fluid retention and tolerance develops. Thus these drugs work best when combined with diuretic.

5. Diarrhoea (over activity of parasympathetic system)
6. Delayed Ejaculation (retrograde ejaculation as sympathetic system is blocked)
7. Nasal Congestion (depending upon blood flow, increase in no. and decrease in size. Also increased blood flow because of sympathoplegia, there is increased size of turbinates in lateral wall leading to nasal congestion)

Drug Interactions:

If drug is not reuptaken, no effect is produced. TAD, cocaine and Phenylpropanolamine (nasal decongestant) completely block the actions. Thus they cannot be given together.

Guanethidine may cause super sensitivity of receptors, leading to up regulation of alpha 1 receptors causing intense vasoconstriction (HTN crisis).  

Guanethidine	Resperpine
Source-Synthetic	Natural
M.A.O- Reuptake 1	Blockage Mg++ ATP pump
Pharmacological Actions- tiphasic, biphasic, monophasic response	Gradual fall in blood pressure
Postural hypotension	No or mild postural hypotension
Therapeutic Uses
Non-antipsychotic	Anti-psychotic
No suicidal tendencies	Suicidal tendencies

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Reserpine

Bretylium

Reserpine:

Source and chemistry:

Natural alkaloid obtained from root of plant “rauwolfia serpentina” (snake root) which is abundant in the subcontinent (“chandan booti”)

Non polar, so can cross BBB rapidly. Central and peripheral action occurs (unlike guanethidine).

Mechanism of action:

1. Acting on Mg++- ATP pump, blocks it irreversibly (which is required for uptake of biogenic amines from cytoplasm into storage vesicles), thus depletion and decreased uptake of biogenic amines occurs in both central and peripheral neurons. As a result degradation of biogenic amines occurs.
2. Serotonin decreased
3. Conversion of dopamine into NE cannot take place, so synthesis of VMAT s required.

The drug crosses blood brain barrier.

Pharmacological actions:

CVS

Decreases blood pressure. The fall is gradual as the drug blocks storage pumps both centrally and peripherally acting drug. Surprisingly no or mild postural hypotension is seen. This is because centrally acting drugs do not produce postural hypotension. Baroreceptor sensitivity is increased even further (some spare baroreceptors).

CNS

Decrease in dopamine produces antipsychotic effects

Decrease in NE produces antihypertensive effects

Decrease in serotonin produces antiemetic effects.

Therapeutic uses

1. Hypertension (0.25 mg/day very low dose)
2. Antipsychotic

Two entities affect CNS, depression on one hand and psychosis on other. Depression is because of decrease in biogenic amines while psychosis is always due to increase in number of biogenic amines (amphetamines). All drugs or conditions decreasing the levels produce depression. Reserpine depletes the stores of these biogenic amines, and was used in older days as antipsychotic.

3. Anti emetic

Adverse effects:

CNS 

1. sedation
2. depression (producing suicidal tendencies, one reason why use discontinued)
3. extra pyramidal effects decreasing the levels of biogenic amines in nigrostriatal pathway (due to decrease in dopamine, parkinsonism like symptoms)
4.  nightmares

GIT

(block sympathetic system peripherally) 

1. Diarrhoea
2. Acidity (contraindicated in ulcers)

Nasal stuffiness

(due to increased blood flow)

Reproductive system

Decrease in libido

 Drug interactions

Interferes with action of drugs used in Parkinsonism like levo dopa.

Contraindications

Peptic ulcer

Depression

Guanethidine	Resperpine
Source-Synthetic	Natural
M.A.O- Reuptake 1	Blockage Mg++ ATP pump
Pharmacological Actions- tiphasic, biphasic, monophasic response	Gradual fall in blood pressure
Postural hypotension	No or mild postural hypotension
Therapeutic Uses
Non-antipsychotic	Anti-psychotic
No suicidal tendencies	Suicidal tendencies

Bretylium:

Bretylium is an adrenergic neuron blocker used as antiarrhythmic drug (class III). It prolongs the duration of ventricular action potential, thus used in treatment of ventricular fibrillation.

The effective refractory period of ischemic heart tissue is shortened which becomes more excitable, leading to rhythm disturbance. This drug is more effective in ischemic tissue as it prolongs the refractory period and is used in conditions where lignocaine and defibrillation have failed.

Mechanism of Action:

a. Has MSA (decreases release of NE)

b. Blocks K+ channels increasing duration of action potential and refractory period (blocks re-entry circuits)

Pharmacokinetics:

Given by oral route and having a half life of about 9 hours.

Uses:

1. Anti-arrhythmic
2. Antihypertensive

Adverse effects:

Postural hypotension

Bradycardia

Nausea/vomiting

Treatment of Ventricular Fibrillation:

1. Electrical defibrillation
2. Lignocaine
3. Bretylium
4. Amidorone

Also known as muscarinic receptor antagonists.

Muscarinic blockers block the muscarinic receptors. These include the naturally occurring alkaloids (Belladonna alkaloids), and have two prototype drugs:

1. Atropine from atropa belladonna
2. Hyoscine from hyoscyamus niger

Once the antagonist binds receptors, it prevents binding of agonist. This binding does not depend on the affinity of the receptor in muscarinic receptors, it depends on:

1. Parasympathetic tone and innervations and the functions regulated to parasympathetics.
2. Constitutively active receptors and their own intrinsic activity.

They prevent the binding of acetyl choline and shift equilibrium from active to inactive form. These are known as inverse agonists and include atropine, M1 selective drugs, Pirenzepine, methyl derivatives of Scopolamine (Hyosine) and trihexphenydle.

In smaller therapeutic doses, these drugs cause decreased salivary and bronchial secretions and decreased sweating. In larger doses, they cause dilated pupils, loss of accommodation and increased parasympathetic tone in young adults.

Classification:

Muscarinic Antagonists/Antimuscarinics

1.      Non-selective

a.      Natural

Atropine

Hyoscine (Scopolamine)

b.      Semi-synthetic/Synthetic

Tertiary amines

Quaternary amines

2. Selective

a. M1 antagonists

Pirenzepine

Telenzepine

Dicyclomine (irritable bowel syndrome)

b. M2 antagonists

AF-DX 116

Methoctramine

Gallamine

Tripitramine

Himbacine

c. M3 antagonists (urinary incontinence)

Darifenacin

Oxybutanin

Solefencicin

Tolterodine

Quaternary amines:

Trospium, Ipratropium, Propanetheline, Methanetheline, Glycopyrrolate, Anisotropine, Isopropamide

Tertiary amines:

Homatropine, Eucatropine, Tropicamide, Cyclopentolate, Oxybutynin, Dicylcomine

Chemistry
Tertiary amine alkaloids esters of tropic acid

Organic acid  + Base  =   esterification

Tropic acid + tropine    =    Atropine

Tropic acid + scopine    =   Scopolamine (Hyoscine)

Mandelic acid + Tropine  =  Homatropine (non-selective, longer duration, semi-synthetic)

Mechanism of action

• Antimuscarinic drugs block  the muscarinic receptors, which can be reversed by increasing the concentration of muscarinic  agonist.
• Antimuscarinic drugs prevents:
  a. the release of inositol triphosphate (IP3)

b. the inhibition of adenylcyclase (caused by muscarinic agonist)

Pharmacokinetics

• Tertiary amines are well absorbed from GIT
• Quaternary amines 10-30% absorbed from GIT
• Tertiary amines are widely distributed in the body
• Quaternary amines limited in their distribution
• Atropine is excreted largely as unchanged drug in urine
• Only about  1% of the oral dose of scopolamine is excreted in urine as unchanged
• Atropine effects in body remain only for a few hours but in the eye its effects persist for about 72 hours

Normally it is applied topically, as eye drops and ointments can get absorbed and through nasolacrimal gland, causing toxicity.

Pharmacological Properties Of Anticholinergics

Atropine is a competitive antagonist of acetyl choline and other muscarinic agonists on muscarinic receptors, it selectively reduce s or abolishes the muscarinic effects of acetyl choline. Actions are more marked in organs with high parasympathetic innervation.

Atropine and Hyosine are natural alkaloids which differ quantitatively, main differences being in the action on CNS.

• Atropine has stimulant effect initially in therapeutic doses
• Hyosine is CNS depressant
• In higher doses, both drugs have stimulant effect.

Effects on CNS

Scopolamine causes drowsiness, amnesia, fatigue and dreamless sleep.  It is effective in motion sickness. It has good absorption from skin, thus skin packs may be applied behind the ear.

Both may be used to treat extra pyramidal side effects of antipsychotic drugs (used in Parkinsonism, depression).

Toxic doses of both alkaloids produce CNS excitation- restlessness, irritability, disorientation, hallucination or delirium.  Stimulation is followed by depression, coma, medullary paralysis and death.

Effects on Eye

M1 receptors are present in the eye. Mydriasis produced due to blockade of the cholinergic stimulation of sphincter, this will allow adrenergic action on the radial muscles to dominate, resulting in unopposed dilator activity and weakness of contraction of ciliary muscles. Loss of ability to accommodate occurs.

Photophobia is due to mydriasis. Light reflex is lost.

Cycloplegia is the paralysis of ciliary muscles.

Reduction of lacrimal secretion occurs. The patient complains of dry and sandy eye when receiving large doses of anticholinergic drugs.

Intraocular pressure is increased in patients having narrow angle glaucoma.

Atropine has limited role therapeutically.

Effects on GIT

Therapeutic dose of atropine produce a decrease in tone, amplitude and frequency of peristalsis, and causes constipation

Large doses decrease secretion of (HCl) mucin and proteolytic enzymes in gastric juice.

The action is non-selective.

Effects on Respiratory & Genitourinary Tract

Respiratory tract:

Inhibition of secretions of upper respiratory tract, prevention of  laryngospasm, induced by excessive secretions due to certain general anesthetics

Inhibition of bronchoconstriction produced by parasympathetic stimulation

Genitourinary Tract:

No Effect on uterus.

Urinary Tract:

Decrease in tone and contraction of urethra and bladder

Sweat Glands

Sweat secretions are decreased, thus hyperthermia blush may occur.

Cutaneous vasodilatation causes atropine flush in neck and upper areas. Hyperthermia may be fatal in children.

Effects on CVS

Heart

Small dose – bradycardia due to blockade of M1 receptors

Larger dose – tachycardia due to blockade of M2 receptors

Ventricles are less affected because less vagal tone has less effect (dilate coronary artery)

Atropine blocks the vasodilatation due to endothelial muscarinic receptors.

Blood Vessels

Majority of blood vessels are not affected.

In toxic doses vasomotor paralysis occurs leading to fall in blood pressure.

Dilatation of cutaneous blood vessels may occur causing flushed skin

Exocrine Secretions

Salivary and bronchial secretions are inhibited – dry mouth

Sweating is inhibited – hot skin.

Antagonists  For Three Types Of Muscarinic Receptors

M1.  Pirenzepine (peptic ulcer, M1 receptor effect), telenzepine

M2.  AF-DX116, methoctramine, himbacine, tripitramine.

Tripitramine is used to block  cholinergic bradycardia.

M3.  Hexa hydro siladifenidiol and darifenacin.

Darifenacin is used for overactive bladder

Atropine is used in the eyes. It is not used in elderly because they are already prone to acute angle glaucoma and bladder actions (urinary retention).

Side Effects (through M2)

1. Blurring of vision
2. Constipation
3. Urinary retention in elderly

Atropine used for moderate tachycardia, may become severe (SA block)

GIT and bladder effects selective drugs are made. Non-selective antimuscarinic drugs block parasympathetic innervation. Thus more adverse effects are seen with non-selective drugs.

Antidepressant, antipsychotic, antihistamine and antimuscarinic effects may be seen so problems might arise when given in combination with these.

Therapeutic classification of Anticholinergics

Mydriatics

Tertiary amines: Homatropine, hydro bromide, eucatropine, cyclopentolate, tropicamide.

Their advantages over atropine are:

They are short acting and produce less cycloplegia.

Anti Spasmodic

Quaternary ammonium compounds:

Propantheline, methantheline, oxyphenonium, glycopyrrolate, hyosine butyl bromide (drug of choice for abdominal cramps)

Tertiary amines:

Dicyclomine (irritable bowel syndrome, bowls of constipation and diarrhea), oxyphencyclimine, piperidolateamprotropine, oxybutynin chloride

Anti-Parkinsonian Agent

These are tertiary amines, e.g. trihexyphenidyl, benztropine, orphenadrine, biperidine, procyclidine, cycrimine, ethopropazine

Anticholinergics were used for Parkinsonism before L dopa.

Anti ulcer

Telenzepine, Pirenzepine

Anti-Asthmatics

Ipratropium, Oxytropium (route of administration is inhalational)

Pre anesthetics

Atropine, Hyosine, Glycopyronium

Motion sickness

Hyosine

Urinary Incontinence

Non- selective: Trospium

Selective M3 antagonists: Darifenacin, Oxybutynin, Solefenacin, Tolterodine

Selective Anti-Muscarinic Drugs

Ipratropium and Oxitropium relieve bronchospasm in asthma/COPD by inhalational route (beta 2 agonists most potent), also given to smokers when cilia are damaged and mucous cannot be removed

Oxybutynin and Tolterodine :

1. Relieve bladder spasm after surgery

2.Urteral spasm due to ureolithiasis

Clinical Uses Of Anticholinergics

Use In GIT

Pirenzepine acts synergistically with H2 blockers in the treatment  of peptic ulcer

Increased tone and motility of GIT

Irritable bowel syndrome

To reduce salivary secretion in heavy metal poisoning, Parkinsonism and esophageal stricture.

Eye

Topical use of mydriatic for fundoscopic examination

Topical use of cycloplegic for iritis, iridocyclitis, choroiditis

Alternating with miotic to prevent or break the adhesions between iris and lens

In open angle glaucoma, trabecular meshwork is broken, to increase the flow, contraction and dilatation breaks adhesions.

Respiratory Tract

Ipratropium inhalation in bronchial asthma and COPD

CVS

To antagonize reflex cardiac slowing

In hyperactive carotid sinus reflex

In patients with inferior or posterior wall infarction having decreased cardiac output, sinus or nodal bradycardia.

In AV block due to digitalis toxicity.

CNS

Benztropine, for treating extra pyramidal disorder due to antipsychotic drugs.

Scopolamine (oral transdermal) for prevention and treatment of motion sickness because of vestibular disturbances. It is taken orally half an hour before journey, thus has prophylactic use

General Anesthesia

Not used any more.

To inhibit excessive salivation and secretion of respiratory tract and to prevent reflex vagal stimulation of the heart

Atropine given with neostigmine to counter its muscarinic effect when given to end the effect of competitive type of neuromuscular blocking agent.

Neostigmine is given for reversal of effects now (anticholine esterase). There are chances of aggravation of bradycardia because of muscarinic effects. Atropine is given for blocking the unwanted blocking actions.

Genitourinary Tract

Atropine with an opioid in the treatment of renal colic to prevent abuse liability. Atropine is not given for antispasmatic actions.

To relieve ureteral spasm and irritability of bladder (urinary urgency) and after urologic surgery (e.g., prostatectomy) and also reducing involuntary voiding in patients with neurological diseases  oxybutynin is used.

Anticholinesterases And Mushroom Poisoning

• Antidote for organophosphate poisoning
•  To antagonize muscarinic effect of neostigmine in myasthenia gravis (symptomatic treatment)
•  Rapid type of muscarinic (inocybe) poisoning

Contraindications Of Atropine(Absolute and Relative)

• Narrow angle glaucoma
•  Enlarged prostate
•  Delayed type of mushroom poisoning
•  Pyloric stenosis
•  Congestive heart failure with tachycardia (blocks intraventricular conduction)
•  Patients over the age of 40 years as it may precipitate an acute attack of congestive glaucoma.
•  Chronic lung disease as this reduces respiratory tract secretions.

Vasodilatation is a diagnostic sign of atropine over dosage.

Blush area is due to hyperthermia, there is redness on cutaneous surface.

Causes of Poisoning

1. occupational poisoning
2. homicidal
3. accidental

In the battle field, soldiers are at risk of poisoning, so they are treated with physostigmine before they are sent.

 Manifestations of Poisoning

Muscarinic:

CNS -CNS stimulant effect leading to tremors, fatigue, drowsiness, confusion,

Eye -Meiosis, blurring of vision, increased lacrimation

GIT -Increased salivation, nausea, vomiting, diarrhea,

Respiratory system -Respiratory distress, increased bronchial secretions

Urinary tract -Excessive urination

Nicotinic:

Skeletal muscle depolarizing blocking type of effect by which fasciculations may occur. The muscle strength decreases.

Management Of Poisoning:

I. General Measures:

The person is quickly removed from the area of contamination. The clothing is removed. Body is washed with sodium bicarbonate. The person is placed in prone position, with mandible elevated. In case of hypotension, IV fluid is administered. If required endotracheal intubation may be performed. Gastric lavage may be done.

II. Specific Treatment;

MANAGEMENT OF CONVULSIONS

Diazepam                          5 – 10 mg I/V

Thiopentone Sodium             2.5%   I/V

MANAGEMENT OF CHOLINERGIC MUSCRINIC EFFECTS:-

Atropine                           2-4  mg I/V or  I/M

MANAGEMENT OF ENZYME INHIBITION:-

Use of oximes.

Oximes
(Acetylcholine Esterase Reactivators)

1. Paralidoxime (1-2 g I/V) (cannot cross BBB)

2. Obidoxime (3.6 mg /kg body weight I/V)

3. Diacetyl monoxime (1.2 g I/V) (DAM)

CNS effects are also reversed by Obidoxime and Diacetyl monoxime.

4. Trimedoxime bromide

Phosphate bond is produced when organophosphate compounds bind active site. Oximes bind anionic site of enzyme and have a high affinity for phosphorus atom, thus enzyme phosphate complex is produced and the active site is free once again. This is only possible if treatment started within 36 hours. Very high doses of oximes have to administered to revert the effects.

Anticholinesterases inhibit the enzymes acting upon acetylcholine.

They are the inhibitors of Cholinesterases:-

• Acetyl cholinesterase (AchE)
• Butyryl cholinesterase (BChE)

Classification:

1. Centrally Acting (Used for the treatment of Alzheimer’s Disease)

Tacrine
Donepezil
Rivastigmine
Galanthamine

2. Peripherally Acting

I.    Reversible 

1.  Carbamates:

a) Tertiary Amines

Physostigmine

b) Quaternary Ammonium Compounds(poor lipid soluble, cannot cross BBB)

Neostigmine

Pyridostigmine

Ambenonium

Distigmine

Demecarium

2. Alcohols:

Edrophonium (short duration of action, limited Vd)

II. Irreversible (organophosphate compounds)

1.  Insecticides:

Dyflos
Diisopropyl fluorophosphates (DFP)
Tetra  methyl pyrophosphate (TMPP)
Octa methyl pyrophosphotetraamide (OMPA)
Parathion (highly dangerous for human race, not converted into non-toxic metabolites)
Malathion (toxic in insects, with vertebrates form non-toxic metabolites but have toxic effects in fish)

2. War gases(banned by Geneva accord)

Sarin
Tabun
Soman

3. Therapeutically useful drugs:

Echothiophate (topical application for glaucoma, chronic use not recommended as after 6 months may cause cataracts, it does not cross BBB)

Mechanism of Action

Acetylcholine is acted upon esterase enzyme. When the ligand binds, only specific region is involved. Acetylcholine esterase has two binding sites:

1. Esteretic site-acetylcholine binds
2. Peripheral anionic site

Once acetylcholine binds, it is acetylated. By addition of water, choline and acetic acid are produced. Hence the active site is available once again.

When alcohols bind the active site, bond produced is weak hydrogen and electrostatic. They are readily washed away. The hydration of bond becomes easy. Thus the duration of action is hardly 2-6 minutes.

Carbamates-like neostigmine and physostigmine have carbamyl group. The carbamyl group is transferred to the active site of the enzyme, thus stronger bond is produced. Their duration of action is 30 minutes to 6 hours. They cannot be rapidly hydrolyzed.

Organophosphates phosphorylate the active site. The bond produced is strong covalent. Thus the duration of action is several days to weeks.

Aging

The binding of organophosphate compounds with enzyme is tighter, so aging might occur due to:

1. loss of alkyl group from this complex
2. loss of oxygen phosphorus may take place

which might lead to stronger bond, producing highly irreversible bonds.

Enzymes known as oximes are used to revert aging in these cases, but within specific time.

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Neostigmine

Physostigmine

Pyridostigmine, Edrophonium and Echothiophate

Neostigmine:

Structure:

Quaternary ammonium compound.

Mode of action:

Neostigmine has dual action:

1. Directly by binding neuromuscular ‘N’ receptors
2. Indirectly by inhibiting cholinesterases

Pharmacokinetics:

CNS effects are not seen. It is an indirectly acting choline esterase having dual mechanism of action. It acts directly on nicotinic receptors, proving to be effective in management of Myasthenia Gravis. Skeletal muscle effects are same as those of directly acting drugs, producing state of depolarization and enhancing the strength of skeletal muscles.

If given orally, it is soluble but leads to toxicity, thus given I/M or subcutaneously.

Mechanism of action:

Carbamate compound

Duration of action is 2 to 8 hours.

Pharmacological Actions:

Pharmacological actions are seen on:-

A) skeletal muscles

B) eye

C) G.I.T.

D) urinary bladder

E) exocrine glands

Effects are same as those of parasympatholytic drugs.

F) C.V.S.-depressant effect, negative ionotropic, chronotropic and dromotropic decreasing heart rate and bradycardia. The contractility of ventricles and atria is decreased. Thus depressant effects are more pronounced.

Effects on blood vessels are minimum or none. There is little decrease or no change in blood pressure.

Neostigmine only acts on those pathways which are cholinergic in nature.

G) CNS- excitatory effects. It is a tertiary compound and does not cross blood brain barrier.

Therapeutic uses:

1.  relief of abdominal distension / paralytic ileus (only if mechanical obstruction is not present)

2. relief of urinary retention.

Orally given in 15 mg dose, subcutaneously 0.5-1 mg

3. Treatment of myasthenia gravis

Myasthenia gravis is an autoimmune disease in which functional nicotinic receptors are destroyed due to production of antibodies in skeletal muscle NMJ leading to decreased nicotinic receptors for normal actions. This produces muscular weakness, diplopia, ptosis, difficulty in swallowing, speech and respiration.

a. Drugs which are used include:

• Neostigmine
• Pyridostigmine
• Ambenonium
• Corticosteroids, immunosuppressants (e.g. Azathioprine, cyclosporine)

Other options include:

• Plasmapheresis / plasma exchange
• Thymectomy

Only those drugs are used which have short duration of action because fluctuations occur and dose needs to be monitored according to the response of patients. Dose needs to be titrated.

Neostigmine is effective because it has dual mechanism of action:

1. More neurotransmitter to act on lesser receptors
2. Direct effects on nicotinic receptors

Drugs Contraindicated in Myasthenia gravis

1. Neuromuscular blocking drugs
2. aminoglycoside  antibiotics,
3. ether
4. phenothiazines
5. Phenytoin

4. post operational anti-curare use

5. reversal of neuromuscular blocking effect.

6. treatment of glaucoma (3% eye drops)

Myasthenic Crisis	Cholinergic Crisis
Under dosage of anticholinesterases	Over dosage of anticholinesterases
No depolarization	Excessive depolarization, thus no impulse can be generated
Flaccidity	Rigidity
Decreased GIT motility	Increased GIT motility
Edrophonium relieves the condition	Edrophonium aggravates the condition

Tensilon Test (trade name of Edrophonium)

This test is used for diagnosis of myasthenia gravis. Edrophonium has a very short duration of action (2-10 minutes). It is rapidly eliminated. Baseline muscle strength is measured then waited for 45 seconds. If no effect is produced, 3 mg is injected IV initially followed by 5 mg after 45 seconds.

If muscle strength is increased, it is indicative of myasthenia gravis.

When drug therapy is started, dose regulation is important otherwise adverse effects might occur.

If 2 mg edrophonium is injected IV and no improvement of muscle strength occurs, or if it worsens, it is indicative of excessive drug therapy. If improvement occurs, then less dose is being administered.

Physostigmine is not recommended in myasthenia gravis because it crosses blood brain barrier and has longer duration of action.

If during course of therapy excessive muscarinic effects occur, anticholinergic agents like atropine may be used (1-2 mg IV). Dose is slightly increased after assessing effects. Reversal of meiosis occurs (anti-muscarinic) if dryness of mouth occurs dose of atropine is halted.

In severe cholinesterase intoxication given on daily basis, 1 mg daily for 1 month.

Neostigmine is also used for skeletal muscle relaxation during surgery

Treatment of Glaucoma

Not first line drug, no longer used, same is true for physostigmine.

Adverse Effects

1. nausea
2. vomiting
3. diarrhea
4. hypotension
5. bradycardia

Physostigmine:

Natural alkaloid obtained from “Physostigma Venenosum”. It is a tertiary amine derivative, crosses blood brain barrier and is highly lipid soluble, penetrating membranes of body.

Use:

1. Treatment in glaucoma, not first line drug.

2. Also effective in atropine poisoning

3. Over dosage of anti depressant drugs

4. As crosses BBB, it is only reserved for special intoxication conditions.

Pyridostigmine, Edrophonium and Echothiophate

Pyridostigmine:

Muscarinic effects are less marked, more nicotinic effects

Duration of action is long (6 hours) than neostigmine

Use:

Myasthenia gravis

Edrophonium:

Alcoholic in nature.

Does not possess carbamyl group

It has shorter duration of action because:

1. Binds only with anionic site

2. Weak hydrogen electrostatic bonds are formed with enzymes.

Muscarinic effects are less marked, more nicotinic effects

Use:

1. Diagnosis of myasthenia gravis

2. Supraventricular tachycardia

3. Post operational anticurare use

Echothiophate:

Mechanism of Action:

It has longer duration of action because:

1. Binds both sites of the enzyme –active and anionic
2. Bond formed is stable

Has both Muscarinic effects and Nicotinic effects

Use:

In the treatment of glaucoma only in refractory cases as can lead to cataract formation.

It is poorly lipid soluble as cannot cross blood brain barrier, thus is only topically effective.

Acetylcholine is the prototype of the group parasympathomimetics. It is NOT USED AS A DRUG

Acetylcholine is rapidly hydrolyzed, if effects are to be observed, very high IV doses are to be administered, while IM and subcutaneous injections produce only local effect.

Pharmacokinetics

Acetylcholine & other choline esters have a permanently charged  quaternary ammonium group in their structure, thus are polar compounds and are poor lipid soluble, resulting in decreased absorption, especially by oral route.

They are rapidly hydrolyzed. Acetylcholine is hydrolyzed more rapidly and produces effects only for 5-20 seconds. Methacholine has beta methyl group, so is more resistant to hydrolysis. It has longer duration of action. Carbachol is more resistant, so has further longer action. All are hydrolyzed in the GIT.

The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. They are lipid soluble thus cross into CNS and bring about stimulant effects on brain. Muscarine, a quaternary amine is less completely absorbed from the GIT and is toxic too.

Nicotine is easily absorbed from skin, lungs, GIT. Among naturally acting, muscarine has quaternary structure and are less absorbed from GIT, when ingested has potential toxic effects involving CNS (exception).

Most of the drugs are excreted by kidney. Acidification promotes their elimination.

True cholinesterase or Acetyl cholinesterase	Pseudocholine esterase or Butyryl cholinesterase
Rapidly acting	Slow acting
Synthesized by neurons and muscles	Synthesized by liver
Found in RBCs, synaptic cleft, nerve endings	Found in plasma, mammary glands, lymph, glial cells, satellite cells, pre and post synaptic terminals.
2 portions; active/esteratic site and anionic site

Pharmacological Actions/ Organ system effects:

a. Muscarinic Actions

b. Nicotinic Actions

Eye (M3):

1. Miosis (constriction of pupil).
2. Spasm of accommodation (ciliary muscles)

These two effects are effective in glaucoma, an increase in intra-ocular due to resistance to flow of aqueous humor which has to be drained by canal of Schema.

3. Decrease in intraocular pressure.

4. Conjunctiva hyperemia (dilatation of vessels)

5. Lacrimation due to stimulation of lacrimal glands

CVS (Heart & Blood Vessels)

a. Heart (M2)

Acetylcholine has depressant effect similar to activation of vagus nerve. It decreases total peripheral resistance and blood flow. In small doses decrease in total peripheral resistance causes reflex increase in heart rate. In high IV doses decrease total peripheral resistance occurs along with hypotension, decreased intraventricular conduction.

Mechanism:

1. Negative ionotropic
2. Negative chronotropic
3. Decrease in AV conduction
4. Little effects on ventricles because cholinergic receptors are more in atria than ventricles.

Acetylcholine has direct effect on SA node (negative ionotropic and negative chronotropic)

b. Blood Vessels (M3)

Acetylcholine has relaxant effect on the smooth muscles in blood vessels through nitric oxide. Endothelial derived relaxant factor (EDRF) is released which causes activation of guanylcyclase activity leading to increased cGMP, producing hyper polarization and smooth muscle relaxation along with vasodilatation.

Pilocarpine has different action. Instead of hypotension, it causes hypertension. Initial hypotension is followed by hypertension. M1 postganglionic receptors are activated through sympathetic ganglion system, K+ channels are closed (instead of opening), causing post-synaptic potentials. Hence hypertension is seen.

M5 receptors in brain release NO which produces vasodilatation.

If endothelium is damaged, acetylcholine directly acts on smooth muscles increasing intracellular calcium (IP3, DAG) producing vasoconstriction.

Respiratory system (M3)

Activation of tracheo-bronchial tree occurs leading to bronchoconstriction and bronchospasm. Excessive bronchial secretion also takes place. Chronic obstructive pulmonary disease may occur.

Gastro intestinal tract

Stimulation of gastric salivary secretions occur which are excessively produced. The sphincters are relaxed and increase in peristaltic movements occur, which may cause diarrhea, by

1. release of calcium from channels
2. depolarization produced through nicotinic receptors

Urinary bladder

Contraction of detrusor muscles and relaxation of sphincters and trigone occurs, which promotes voiding.

Exocrine glands

Acetylcholine causes stimulation of sweat, lacrimal, nasolacrimal and GIT secretions thus profused sweating, excessive salivation and increased lacrimation occurs.

Its effects on adrenal medulla cause increase in catechol secretion while exocrine portion of pancreas has increased secretions as well.

Central Nervous System

Both muscarinic and nicotinic receptors are stimulated. More muscarinic receptors are found in the brain, still nicotinic effects are more prominent. Alkaloid nicotine has more potent CNS effects because is lipid soluble, can cross BBB and has toxic potential. It is obtained from plant source. 40 mg nicotine or one drop of pure nicotine is found in two cigarettes and has toxic effects on CNS. But most of it gets burned in smoke. If alkaloid is ingested in high amounts, vomiting and expulsion occurs. If ingested by small children, toxicity occurs leading to tremors and fatigue. Increased doses cause convulsions, respiratory distress or even coma. Carcinoma might result as well.

Peripheral nervous system

Sympathetic limb effects are more pronounced in CVS, in rest of the systems parasympathetic, effects are more pronounced e.g. respiratory, eye, GIT, urinary and exocrine systems.

N.M Junction

N_M receptors are more activated. Agonists combine with nicotinic receptors having specific structure (4 subunits 2 alpha and 2 beta). Acetylcholine combines with 2 alpha subunits hence conformational change takes place, opening sodium channels (nicotinic receptors), due to which depolarization takes place. As depolarization is due to agonist, it occurs as long as the agonist binds the receptors. If binding is for prolonged duration, muscle fasciculations might result.

Reproductive System

Erection and congestion occurs.

Adverse Effects

CNS

1. Tremors
2. Convulsions
3. Coma
4. Ataxia
5. Confusion

Eye

1. Miosis
2. Hyperthermia
3. Blurring of vision
4. Excessive lacrimation

Respiratory System

1. Increased bronchial secretions
2. Bronchoconstiction/Bronchospasm
3. Respiratory center excitation
4. Asthma
5. Chronic Obstructive pulmonary disease
6. Respiratory distress

CVS

1. Hypotension
2. Cutaneous vasodilatation
3. Bradycardia

GIT

1. Nausea
2. Emesis
3. Abdominal cramps
4. Diarrhoea
5. Peptic Ulcer disease
6. Excessive salivation

Urinary System

Excessive urination

Carbachol:

Carbachol is the ester of carbamic acid, having both muscarinic and nicotinic actions.

Muscarinic actions are prominent on eye, GIT & urinary bladder

Duration of action is more than 30 minutes (longer than acetylcholine)

Mechanism of Action

Carbamoyl group combines with the active site of pseudo cholinesterase, hydrolysis occurs and carbamoylated enzyme is produced, while free choline is regenerated. Then hydration occurs.

Therapeutic uses:

Glaucoma 

Carbachol is not the first line agent because better drug therapies are available like beta blockers, PG analogs, etc. Nicotinic effects are more prominent. It has longer duration of action and receptor non-selectivity.

Adverse Effects

No adverse effects at therapeutic doses because it is a quaternary ammonium compound and lacks systemic penetration.

Methacholine:

Methacholine has methyl group in its structure. It is more resistant to hydrolysis by choline esterase. It has both muscarinic and nicotinic actions (very mild nicotinic actions )

Muscarinic actions are prominent on CVS (M2).

Duration of action is 15-20 minutes. Longer duration of action as compared to acetylcholine

Therapeutic uses:

1. Given subcutaneously for the relief of paroxysmal atrial tachycardia

Previously, it was said to be effective in paroxysmal atrial tachycardia, now better drugs are available like adenosine, Calcium channel blockers, esmolol, etc.

2. Diagnosis of belladonna poisoning

3. Diagnosis of bronchial hyperactivity

4. Glaucoma.

Bethanechol:

Structure related to Acetylcholine, acetate is replaced by carbamate & choline is methylated, thus it is carbomyl beta methyl choline.

It has no nicotinic actions

Muscarinic actions are prominent on eye, GIT & urinary bladder

Prolonged duration of action because is more resistant to hydrolysis.

Duration of action is one hour.

Therapeutic uses:

1. Post operative gastric distension

2. Paralytic ileus

3. Bladder atonia

4. Megacolon

It is given subcutaneously in 5 mg dose. Neostigmine is also given for these conditions (15 mg oral, 0.5-1 mg subcutaneously)

Mechanism of action is like carbamates.

Toxicity includes bronchospasm, it does not enter CNS.

Muscarine and Pilocarpine:

Muscarine

Quaternary amine (Amanita muscaria)

Poorly soluble, less complete absorption from the GIT

Very toxic & can even enter the brain

Treatment of overdosage: Atropine, 1-2 mg parenterally

Pilocarpine

Tertiary amine (plant source; Pilocarpus jaborandi leaves)

Has muscarinic actions

Therapeutic uses:

• Glaucoma
• To reduce the effect of mydriatics
• To break adhesions
• Sjogren’s syndrome (Cevimeline)

Not used for systemic diseases because increased tracheo-bronchial secretions lead to pulmonary edema. It is highly lipid soluble usually given topically.

Nicotine and Lobeline:

Alkaloids liquid in nature, obtained from plant source.

Actions are mainly on nicotinic receptors (CNS, PNS, NMJ)

Effects:

CNS, have important effects on brainstem and cortex.

PNS – autonomic ganglia.

NMJ, immediate depolarization of the end plate – increase in permeability to sodium and potassium ions.

Also known as Cholinergic drugs or Cholinomimetic drugs or Cholinoceptor activating drugs.

Definition:

These are the group of drugs which produce effects resembling those produced by the stimulation of parasympathetic autonomic nervous system on the target organs

Neurotransmitter involved is acetylcholine. Most of the peripheral autonomic nervous system fibers cause synthesis and release of acetylcholine. They activate the parasympathomimetic system, thus called cholinergic fibers.

All preganglionic and most of parasympathomimetic postganglionic and some postganglionic sympathetic fibers, adrenal medulla and skeletal somatic muscle fibers constitute the cholinergic fibers.

Parasympathomimetics were discovered form muscarine alkaloid obtained from natural source, which produces effects by affecting organs similar to parasympathetic system, thus receptors were termed muscarinic receptors.

Nicotine was discovered to act on skeletal muscle NMJ and autonomic ganglia, such receptors were termed nicotinic. They were further discovered by Dale.

Synthesis, storage, Release & inactivation

Already discussed.

Mechanism of Action:

a. G –protein linked (Muscarinic), through transmembrane 2^nd messenger signaling

b. Ligand gated Ion channels (Nicotinic)

Muscarinic receptors act through DAG/IP3 second messenger system.

Cholinergic Receptors

1. Muscarinic

M1 = Nerves, Stomach, Brain

Antagonist:   Pirenzepine

M2 = Heart, Nerves, Smooth Muscle.

Antagonist:    Gallamine

M3 = Glands, Endothelium, Smooth Muscle.

M4 and M5 newly discovered, role not yet known

Muscarinic receptors act through the IP3/DAG cascade. They also cause activation of guanylcyclase activity by increasing cGMP (decrease cAMP in heart and smooth muscles). Calcium is released from sarcoplasmic and endoplasmic reticulum.

M1, M3 and M5 act through IP3/DAG cascade

M2 and M4 act by decreasing the levels of cAMP activating the K+ channels.

2. Nicotinic

a. Present in neuromuscular junction, N_M

Agonist:  Phenyl Trimethyl Ammonium

Antagonist:  Tubocurarine

b. Present in autonomic ganglia, adrenal medulla, N_N

Agonist:   Dimethyl phenyl piperazinium

Antagonist:  Hexamethonium

Classification

A.   Directly Acting –act by causing release of acetyl choline
B.   Indirectly Acting –inactivate enzymes involved like pseudocholine esterase, thus hydrolysis of acetylcholine does not occur

A. Directly Acting Cholinergic Drugs:

I. Choline Esters

Acetylcholine

Carbachol

Methacholine

Bethanechol

II. Cholinomimetic Alkaloids

a.  Mainly Muscarinic Agonists

Natural Alkaloids:

Muscarine

Pilocarpine

Arecholine

Synthetic Alkaloid:                            

Oxotramorine

Selective M3 agonists

Cevimeline

b.  Mainly Nicotinic Agonists     

Natural Alkaloids:

Nicotine

Lobeline

Synthetic Alkaloids:

Dimethyl phenyl piperazinium (DMPP)

Varenicline

Tertiary alkaloids

Pilocarpine

Nicotine

Lobeline

Quaternary amines

Muscarine

B. Indirectly Acting Cholinergic Drugs (Anticholinesterases)

I- Reversible

a. Carbamates

b. Alcohols

II- Irreversible

I- Reversible

a. Carbamates                       

Tertiary amines         

Physostigmine

Quaternary Ammonium compounds

Neostigmine

Pyridostigmine

Distigmine

Ambenonium

Demecarium

b. Alcohols

Edrophonium

c. Miscellaneous

Tacrine

Donepezil

Galantamine

Rivastigmine

II.  Irreversible Anticholinesterases (Organophosphorus Compounds)

1. Therapeutically useful:

Ecothiophate

2. War Gases:

Sarin

Tuban,

Soman

3. Insecticides:-

Parathion

Malathion

DiisopropylFlurophosphate (DFP)

Tetramethyl Pyrophosphate (TMPP)

Octamethyl Pyrophosphotetraamide (OMPA)

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Acetylcholine

Carbachol

Methacholine

Bethanechol

Muscarine and Pilocarpine

Ergot alkaloids are the group of agents or different alkaloid preparations having specific affects on different receptors.

Classification

Derivatives &constituents of ergot

1. Amine alkaloids

• 6-methyl ergoline
•  lysergic acid
•  lysergic acid diethylamide (LSD)‏
• Ergometrine
• methysergide

2. Peptide alkaloids

• ergotamine
•  alpha – ergocryptine
• bromocriptine

3. Non-specific constituents

• Acetylcholine
•  histamine
• tyramine

Source

Natural in a fungus claviceps purpurea (infects grains specially rye).

History

History of ergot alkaloids is 2000 years old. It is usually found on weeds and grains especially in damp and moist storage conditions.

In ancient times, effects of ergot alkaloids were seen and included ergotism, which is poisoning by ergot alkaloids. Another was Saint Anthony’s fire. People used to visit shrine of Anthony because of burning sensation (due to vasoconstriction) and were relieved there. This was due to the fact that they were served uncontaminated weeds and cereals.

This was still reported in 1950s as contaminated grains and cereals were ingested in some parts of the worls. Ergots are also found on the pastures on which animals feed.

If poisoning occurs, it leads to vasoconstriction and gangrenous effects are seen. Acetyl choline, tyramine and histamine may be released.

Receptors

1. alpha receptors
2. dopamine receptors
3. 5-hydroxy tryptophan/serotonin receptors

Chemistry

Derivative of compound 6-methyl ergoline and containing a tetracyclic nucleus.

Pharmacokinetics

Absorption

Absorption is variable. Oral dose of ergotamine is ten times greater than I/M dose Oral absorption is increased with caffeine. 100 mg of caffeine is sufficient for absorption of 1 mg of ergotine.

Oral absorption of ergot alkaloids can be improved with caffeine.

Bioavailability

Less than 1 % after oral administration. Bioavailability is greater after rectal suppositories. It can be given parentally (IV or IM) as well.

Route of Administration

Oral, per rectum, buccal cavity, aerosol inhaler, I/M.

Metabolism

Metabolism occurs in the liver. Ergot alkaloids undergo extensive first pass metabolism, thus rectal route may be used. 90 % metabolites are excreted in bile only traces of unmetabolized drug found in urine & faeces.

Pharmacological Actions

1. CNS

a. Hallucinogenic

LSD and methysergide act on central serotonin receptors having agonist effect.

 b. Parkinsonism

Ergot alkaloids have extra-pyramidal effects especially motor effects e.g. Parkinsonism. Act as agonists on dopamine receptors present in nigrostriatal pathway of basal ganglia to increase motor activity.

 c. Nausea & Vomiting

By affecting the chemoreceptor trigger zone ergot alkaloids act on the dopamine receptors to produce nausea and vomiting.

d. Prolactin secretion

Any tumor or dopamine antagonists when administered can cause hyper-prolactemia resulting in infertility and gynecomastia. Ergot alkaloids acting as dopamine agonists bring about improvement and suppress release of prolactin. Bromocriptine is very effective having high affinity, and

1. inhibits release.
2.  causes regression of tumor size.

2. Vascular smooth muscle

Ergotamine and methysergide act as potent vasoconstrictors increasing TPR and B.P. Blood flow to periphery is decreased. Apart from vasospasm, gangrene also takes place. Red, swollen and severe painful condition occurs. If it is severe, it becomes difficult to revert the condition even with antagonists like alpha and serotonin antagonists. (as effects produced by alpha and serotonin receptors)

3. Uterus

Ergometrine has powerful stimulant effects on uterus. Serotonin and alpha receptors are found in uterine smooth muscles. When given in small doses, contraction and relaxation of smooth muscles is seen. In high doses, sustained contraction occurs which may lead to spontaneous abortion. Thus, the dose needs to be monitored.

Alpha receptors are upregulated with progressing pregnancy, thus during later period, uterus is more sensitive to ergot alkaloids effects.

4. GIT

Serotonin and dopamine receptors produce effects. Serotonin receptors cause an increase in intestinal movement leading to diarrhea and abdominal cramps. Dopamine acts on chemoreceptor trigger zone to cause nausea and vomiting.

5. Eye

Alpha receptors may have agonist and antagonists effects. Ergotamine has alpha antagonist effect, producing miosis (constriction). Ergometrine has alpha agonist effect producing mydriasis (dilatation).

Ergot alkaloids have no role in glaucoma.

6. Metabolic Effects

Metabolic effects are not very much established. They may inhibit hyperglycemia, as seen in administration of adrenaline. This is not understood very well.

Therapeutic Uses

1.  Migraine

Ergot alkaloids are effectively used. During severe attacks, a person may see aura, visual scotoma, hemianopia and even loss of vision, speech abnormality, nausea and vomiting.

Pathophysiology involves the trigeminal division, vasodilator substances are released including calcitonin gene related peptides and substance P. Extravasation within perivascular spaces cause the stimulation of nerves, which leads to classical headache.

Mechanism of action involves agents having vasoconstrictor activity. These include:

1. Serotonin and ergot preparations
2. NSAIDS
3. Beta blockers
4. Anti epileptics
5. Calcium channel blockers

Ergotamine is effective during acute phase of migraine and is not used in prophylaxis. They may be given orally, buccal, inhaler, aerosol, IM, IV or in the form of suppository.

The oral absorption is increased by combining with caffeine. 1 mg ergotamine is used with 50 mg of caffeine. Ergotamine dose is 0.25-0.5 mg given intravenously. Dihydroergotamine is given 0.5-1 mg intravenously.

Dose of ergotamine must never exceed beyond 6 mg per attack or 10 mg /week. This is because of cumulative effects and toxicity might occur.

For prophylaxis, methysergide does not have uncumulative effects. (effect connective tissue, used subendocardial fibrosis and retroperitoneal fibroplasias)

2. Hyperprolactinemia

Increased prolactin may cause enhanced gynecomastia and infertility. Because of dopamine effect regression of tumour size occurs

3. Parkinsonism

Acting through nigrostiatal dopaminergic pathway, improvement in extra pyramidal signs occurs, helpful with dopamine agonists.

4. Post partum hemorrhage

Ergotamine when given after delivery or during delivery of placenta or severe uterine bleeding 2 mg IM dose is effective within 5 minutes. It is not administered before delivery as may cause spontaneous abortion.

5. Diagnosis of variant angina

During angiography administered for vasoconstrictor effects for diagnosis of angina.

6. Senile cerebral insufficiency

Ergot alkaloids have some role. Research is also going on for Alzheimer disease.

7.  Acromegaly

Bromocryptine, by dopamine action, causes decrease in growth hormone in acromegaly. It increases GH in normal person.

Adverse Effects

1. GIT disturbances: (Nausea, Vomiting, Diarrhoea & abdominal cramps.
2. Spontaneous Abortion.
3. Methysergide – central stimulation & hallucination.
4. Drowsiness.
5. Convulsions.
6. Over dosage with ergotamine and ergometrine causes vasospasm ——- gangrene.
7. Bowel infarction —- mesenteric artery vasospasm.
8. Connective tissue proliferation in the retroperitoneal space, pleural cavity and endocardial tissue of heart with chronic therapy of methysergide, leading to:
   a. Hydronephrosis (compression of uterus, urine remains in kidneys)
   b. Heart murmurs

Contraindications

• Obstructive vascular diseases.
• Collagen diseases.
• Early pregnancy
• Renal/liver disease
• Diarrhoea
• Sepsis/infection (delays healing)

Bromocriptine:

Bromocriptine is a semi synthetic ergot derivative, having potent effects on dopamine receptors.

Pharmacokinetics

Rapid but partial absorption from GIT. It is given orally but absorption is variable. This is because of extensive 1^st pass metabolism

Plasma peak levels are observed 1.5 – 3 hrs after oral administration

Half life is 3hrs

It is metabolized in the liver and metabolites excreted in bile

To improve its bioavailability, high doses can be given by oral route.

Pharmacological actions

1. Prolactin release suppressed
2. Growth hormone release increased (unknown mechanism)
3. Extra pyramidal effects; acts directly on postsynaptic receptors in the nigrostriatal system (Parkinsonism)
4. Reticular formation non specific arousal in the CNS
5. Chemoreceptor trigger zone stimulation causes vomiting

Therapeutic uses

1. Parkinsonism
2. For prevention & suppression of lactation
3. Rx of hyperprolactinemia associated with hypogonadism, galactorrhea, infertility
4. Benign breast diseases
5. Acromegaly (decreased GH)
6. Hepatic encephalopathy (hepatic coma, drowsiness occurs, arousal is difficult, it causes arousal or may have role)

Adverse effects

1. GIT – Nausea, Vomiting, constipation, bleeding from peptic ulcer, reflex esophagitis.
2. CNS – headache, dizziness, drowsiness
3. CVS – postural hypotension, cardiac arrhythmias

At higher doses

a. Dry mouth

b. Confusion

c. Hallucination

d. Pleural effusion

e. Leg cramps, digital vasospasm

f. Red painful swollen feet and hands

Ergotamine vs Ergometrine:

Ergotamine	Ergometrine
Peptide alkaloid	Amine alkaloid
Polypeptide chain present	Polypeptide chain absent
Powerful antagonist on alpha receptor and partial agonist	Mild agonist on alpha receptor
No effect on dopamine receptor	Mild effect on dopamine receptor
Partial agonist on serotonin receptor	Partial agonist and antagonist on serotonin receptors
Less effect on uterus	More effect on uterus
Blood vesselsEndothelial damagePotent vasoconstriction	No damageLess vasoconstriction
Miosis (alpha blocked)	Mydriasis (alpha agonist)

Phentolamine is non selective reversible alpha blocker, histamine agonist (H1, H2) and muscarinic agonist. It also has inhibitory effects at serotonin receptors.

Pharmacokinetics:

Oral absorption is unpredictable. Peak plasma levels are observed after 1 hour. Half life is 5-7 hours.

Uses:

Used in pheocytochroma.

Adverse Effects:

Its adverse affects include cardiac stimulation, postural hypertension, reflex tachycardia, headache, arrhythmias, diarrhea and palpitations.

Phenoxy benzamine:

Irreversible alpha blocker, forms covalent bonds. Although being non selective, it is more selective for alpha 1 than alpha 2 receptors. It forms ethylene ammonium metabolite, making strong bond with alpha receptors.

Pharmacokinetics:

It has a very long half life of about 14-48 hours. It is lipid soluble and can cross the blood brain barrier to cause sedation, fatigue, nausea, decreased TPR, postural hypertension, reflex tachycardia. It has lesser intensity than phentolamine. It also inhibits the reuptake of nor adrenaline.

Uses:

It has a role in management of pheochromocytoma.

Phenoxybenzamine	Prazosin
Irreversible antagonism	Reversible antagonism
Alpha 1 and 2 selective	Alpha 1 selective blockers
Decrease TPR and B.P, produce vasodilatation and reflex tachycardia	Veins are less affected, less reflex tachycardia and less decrease in TPR and B.P
May cause sedation, nausea and fatigue	May cause 1st dose phenomenon
Used in pheochromocytoma	Used in HTN and BPH
Can cross blood brain barrier (Antihistamine in nature)	Cannot cross blood brain barrier

Prozasin:

Selective alpha 1 blocker, causing decrease in TPR and venous return. It has no effects on alpha 2 receptors.

Pharmacokinetics:

It has a half life of 3 hours. Its bioavailability is 50%.

Adverse Effects:

Adverse effects include:

1. Postural hypotension
2. Causes first dose response

When administered, causes postural hypotension and the person may collapse. To cope this, first a small dose is administered, which is increased very slowly. It is preferably administered at night, and the patient is advised to stay in bed in lying position. Sudden withdrawal is avoided and other hypertensives are withdrawn. Otherwise severe hypertension might occur. The patient is strictly warned about the side effects.

Phenoxybenzamine	Prazosin
Irreversible antagonism	Reversible antagonism
Alpha 1 and 2 selective	Alpha 1 selective blockers
Decrease TPR and B.P, produce vasodilatation and reflex tachycardia	Veins are less affected, less reflex tachycardia and less decrease in TPR and B.P
May cause sedation, nausea and fatigue	May cause 1st dose phenomenon
Used in pheochromocytoma	Used in HTN and BPH
Can cross blood brain barrier (Antihistamine in nature)	Cannot cross blood brain barrier

Terazosin, Tamsulosin and Yohimbine

Terazosin

Terazosin is useful in prostate diseases.

Tamsulosin

Selective alpha 1 a blocker, useful in benign prostatic hypertrophy, especially in those not having hypertension.

Yohimbine

Selective alpha 2 blocker, obtained from plant source. Its therapeutic importance is not established. Experiments are being done regarding its use in clonidine withdrawal, in which alpha 2 receptors are activated.

In diabetes mellitus, insulin is inhibited. Role is also being investigated in relief in depressive syndromes.