Parasympatholytics

Drugs which bind with the cholinergic receptors and lock the action of the Ach or Ach like drugs.

It is also called Anticholinergics.

Prototype is Atropine, obtained from natural plant source Atropa belladonna.

This drug was originally used by the women to dilate their pupils to look more beautiful.



Types—

Anti-muscarinic drugs—Atropine, Scopolamine (Datura stromontum), Tropicamide.

Anti-nicotinic drugs—skeletal muscle relaxants, ganglion blockers.



Classification of Anti-muscarinics—

1. Natural source—Atropine, Scopolamine

2. Semisynthetic—Homatropine

3. Synthetic—Ipratropium, Benztropine



Pharmacokinetics of anti-muscarinics—

Atropine and other tertiary drugs are widely distributed after absorption. Scopolamine is fully and rapidly distributed to the CNS. Atropine has half life of 2 hours. About 60% of the dose is excreted in the urine unchanged. Most of the rest appears as conjugates metabolites in the urine.



Anti-muscarinic drugs used in Ophthalmology—
Drug
Duration of action

Atropine
7-10 days

Homatropine
1-3 days

Cyclopentolate
2 day

Tropicamide
<1 day




Indication of use in eye conditions—

§ Accurate measurement of the refractive error, specially in onco-operative patients

§ To facilitate ophthalmological examination of the retina

§ To prevent Synechia (adhesion) formation in Uveitis and Iritis



Pharmacological effects of anti-muscarinic drugs—

On CNS—Atropine causes minimum stimulation, scopolamine causes drowsiness and amnesia. In toxic doses both may cause agitation and hallucination.



On respiratory system—Atropine blocks the muscarinic receptors in bronchial smooth muscle and glands thus producing bronchodilatation and ↓ bronchial secretion.



On GIT—these drugs block muscarinic receptors thuds reducing motility, salivary gland secretion and basal gastric HCl secretion.



On GUT—they block the muscarinic receptor of the urinary bladder and ureter and thus relaxing the bladder wall and shows voiding of urine.



On CVS—these drugs block vagal stimulation of heart (atrium) and cause relative tachycardia. Ventricles are less affected. The drugs cause vasodilatation of the blood vessels of the skeletal muscles by blocking muscarinic receptors.



On Eye—they block the muscarinic receptors of the pupillary constrictor muscle causing Mydriasis. Cycloplegia also occurs because of blocking of the muscarinic receptors of the ciliary body. It also prevents drainage of the aqueous humor and there is ↑ pressure so cannot be given in glaucoma.



Anti-muscarinic drugs used in GIT and GUT conditions—

Tertiary amines—Atropine, Scopolamine, Oxybutynine

Quaternary amines—Propantheline, Glycopyrrolate, Methoscopolamine



Uses—

1. To relief bladder spasm after prostate operation

2. To reduce urinary urgency in inflammatory bladder disease

3. To reduce incontinence, specially in elderly people



*** Ipratropium bromide is used in bronchial asthma.

*** Atropine destructs the ciliary process thus clearing of the bronchial secretion is hampered. So there is a chance of respiratory infection.

*** used for experimental purpose where cholinergic drugs are used, like eye disease –glaucoma, muscle disease –muscular weakness (Ach on the N-M junction can’t work)

*** esters can be used in bladder problem, enhancing the action of the smooth muscle of bladder,

*** tertiary alkaloids are lipid soluble, quaternary alkaloids are water soluble drugs.



Atropine—



Atropine is derived from Atropa belladonna.

It was used for cosmetic purpose for dilating the pupil during the period of renaissance.



Properties of Atropine—

o Tertiary amine compound

o Can cross the BBB

o Sufficiently lipid soluble to be absorbed from the gut and conjunctival sac

o It is a competitive antagonist of the muscarinic receptor



Indication of Atropine—

1. Treatment of OPC poisoning

2. Anti-parkinsonism

3. Anti-motion sickness

4. Premedication for anaesthesia

5. As antispasmodic

6. Infantile pyloric stenosis



Adverse effects of Atropine—

1. Dry mouth

2. Blurred vision

3. Hyperthermia

4. Muscle fasciculation

5. Constipation

6. Urinary retention



Contraindication of Atropine—

1. Acute congestive glaucoma

2. Congestive cardiac failure

3. Prostatic enlargement

4. Gastric outlet obstruction

Parasympathomimetics

Drugs which mimic the action of stimulation of cholinergic receptors.

Also called cholinomimetic or cholinergic drugs.



Classification—

According to the mode of action—

Directly acting—acts exactly like acetyl choline

Indirectly acting (Anti-cholinesterase)—acts by inhibiting the enzyme acetyl-cholinesterase.

Directly acting—

Alkaloid {Muscarine, Nicotine, Pilocarpine} & Esters {Acetyle-choline, Methacholine, Bethanecol, Carbacol}

Indirectly acting—(Anti-cholinesterase)

Reversible {Physostigmine, Neostigmine, Pyridostigmine} & Irreversible {Organo-phosphorous compound-OPC}



Indirectly acting cholinergic drugs are further classified according to chemical structure—

a. Simple alcohol—Edrophonium.

b. Carbamic acid esters of alcohol—Neostigmine, Physostigmine, Pyridostigmine.

c. Organo-phosphates—Parathione, Malathione, Soman (nerve gas), Ecothiophate.



According to the receptor on which they act—

1. Selectively muscarinic—Muscarine, Bethanecol, Pilocarpine, Oxotremorine, methacholine.

2. Selectively nicotinic—Nicotine, Lobeline, DMPP.

3. Non-selective—Ach (major action on M-receptor), Carbacol (major action on N-receptor)



*** Pilocarpine is given in glaucoma to ↓ the intra-ocular pressure. It is given as eye-drop and if it passes into the circulation it can cause ↓ HR.

*** Muscarine = mushroom, when muscarinic receptors are stimulated the sign symptoms are same like eating mushrooms.

***when nicotinic receptors are stimulated the sign symptoms are like taking nicotine.



Synthesis of Acetyl-choline—Acetyl co-A + choline→ Acetyl-choline (by conjugation)

{Acetyl co-A is secreted from nerve body}



Storage of Acetyl-choline—stored in the vesicles along with Ca++, ATP, other proteins, phospholipids etc.



Release of Acetyle-choline—when the parasympathetic system is stimulated due to any reason that develops action potential that travels down to the nerve terminals. If the action potential is strong enough then it causes opening of the calcium channel and calcium enters into the nerve terminal and fusion occurs—them release of acetyl-choline.



Fate of Acetyl-choline—80% is reuptaken by the same nerve terminal.

within milliseconds (flash of time)—major portion of the Ach is degraded by cholinesterase. (true cholinesterase is found in the nerve terminals and pseudo-cholinesterases are found in the liver, skin, brain, GIT and also in plasma in soluble form)



*** pseudo-cholinesterases are Suxamethonium, Butyrylcholine, Procaine, Benzoycholine.

*** if Ach is given IV then it is degraded by the pseudo-cholinesterase. Also all synthetic drugs are destroyed by pseudo-cholinesterase.



Acetyl-choline has no clinical utility—

§ It undergoes rapid hydrolysis (by the pseudo-cholinesterases)

§ It is wide spread, diffuse, non selective pharmacological effect

§ If given orally then rapidly hydrolyzed by the gastric enzymes

*** it is used for the experimental purpose as it is the prototype.



Classification of the cholinergic receptors—







Pharmacological effect of acetyl-choline / cholinomimetic drugs—

Muscarinic action—

On Eye—binds and acts on the muscarinic receptors in the radial, circular and pupillary muscle of the eye. Produces pupillary constriction (myosis) and reduction of the intra-ocular pressure by improving the aqueous humor drainage (opening the angle of Schlem). Can be used in glaucoma.



On CVS—↓ HR, ↓ force of contraction, ↓ A-V conduction. (can be used in shock), ↓ CO



On blood vessels—Ach binding with the muscarinic receptor of the endothelium releases EDRF (endothelium derived releasing factor) that comes back to the smooth muscle and the muscle relaxes. (indirect method)



On Respiratory system—acetyl-choline acting on the smooth muscle of the bronchi causes bronchoconstriction, acting on the glands it also ↑ secretion.



On GIT—acting on the smooth muscle it increases the contraction thus increases the peristalsis. Acting on the glands it causes increase in secretion.



On Genito-urinary system—causes contraction of the visceral smooth muscles. Relaxation of the sphincters of the urinary bladder.



On CNS—inhibitory or excitatory neurotransmitter



Nicotinic action—

On autonomic ganglion—

o On CVS—sympathomimetic effects, ↑ BP

o GIT—parasympathomimetic effect, ↑ motility

o Urinary bladder—parasympathomimetic effect, voiding of urine

o CNS—Parkinsonism



On skeletal neuromuscular junction—when acetyl-choline acts on the nicotinic receptor of the skeletal muscles, it causes contraction (Fasciculation and Twitching). Ex—Neostigmine.



On adrenal medulla—stimulation of the chromaffin cells→ secretion of adrenaline (80%) and noradrenaline (20%)→ vasoconstriction → ↑ BP



Anticholinesterase—Reversible (Neostigmine, Physostigmine) and Irreversible.



§ Quaternary carbamates are poorly absorbed from the skin, conjunctiva, lungs. (neostigmine)

§ Physostigmine is well absorbed from all sites and can be used topically in the eye.

§ Physostigmine is distributed to the CNS and more toxic than polar quaternary carbamates.

§ OPC are well absorbed from the skin, lung, gut thus making them dangerous to human and highly effective as insecticides.



Pharmacological action—

On N-M junction—anti-cholinesterase drugs by inhibiting the acetyl cholinesterase enzyme prolongs and intensifies the action of Ach at skeletal muscle junction. This results in ↑ strength of muscle contraction.

On Eye—it can reduce the intra-ocular pressure by causing contraction of the ciliary body and facilitates the outflow of the aqueous humor.

On GIT and GUT—peristaltic activity is increased by increased contraction of the smooth muscle, it occurs due to depolarization of the smooth muscle. In clinical disorder of depressed muscular activity, without obstruction anti-cholinesterase may be used.

On CNS—in low doses it can cause alertness but at high doses it can cause convulsion.



Difference between neostigmine and physostigmine—
PHYSOSTIGMINE
NEOSTIGMINE

Natural source
Synthetic source

Tertiary amine
Quaternary amine

High lipid solubility
Low lipid solubility

More CNS toxic
Less CNS toxic

Doesn’t have a direct action on skeletal muscle junction (on nicotinic receptor)
Has also direct action on skeletal muscle junction




Mechanism of action of Physostigmine—

Active Acetyl-cholinesterase

↓ ← Physostigmine (stage-I)

Carbamylated enzyme

↓ (stage-II)

Inactivation of the cholinesterase

↓

Inhibition of the hydrolysis of the acetyl choline

↓

Accumulation of increased concentration of acetyl choline

↓

Prolonged action of acetyl-choline



Indications—

1. Glaucoma—Pilocarpine, Physostigmine (↓ the intraocular pressure)

2. Myasthenia gravis (profound muscular weakness)—Neostigmine.

3. Bladder problem (unable to pass urine)—Alkaloids (contracts the smooth muscle)

4. Tachycardia.



OPC—all are insecticides, they are highly lipid soluble and can easily penetrate any organic barrier. It can enter the body from the GIT, Respiratory tract, Skin, Conjunctiva and Mucus membrane.



OPC poisoning—exaggerated function of Ach, they destroy all cholinesterase.



Sign symptom of OPC poisoning—

1. ↓ HR, severe Bradycardia.

2. Severe bronchoconstriction with excessive bronchial secretion causing severe dyspnoea and frothing from the mouth, nostrils. Death is mainly due to respiratory failure.

3. Excessive salivation from the mouth.

4. Excessive sweating and there will be depolarizing block leading to neuromuscular block, causing paralysis.

5. There is CNS involvement, may cause excitement.

6. Myosis.

7. Severe headache due to intense pupillary and ciliary muscle contraction.



Management of OPC poisoning—

Supportive treatment—

1. Decontamination to prevent further absorption

2. Start oxygen after clearing the airway

3. Open IV line and start infusion to maintain fluid and electrolyte balance as well as emergency IV administration.



Specific treatment—

1. Very large and usually repeated doses of Atropine should be given.

0.6mg / ample Atropine in every 2-4 min until the sign symptom of OPC poisoning disappear. {when mouth becomes dry, HR becomes almost normal}. Them the atropine is given every 2-4 hrs accordingly.

2. Pralidoxine

3. Diazepam may be used for relieving the CNS from excitement.



*** a cholinesterase inhibitor may be used to reverse the effects in case of Atropine poisoning.

Sympatholytics

it is also called adrenoceptor blocking drugs or adrenergic receptor blocker

                                                  Adrenergic Receptor Blocker

 

                           α blocker            α + β blocker                     β blocker

α1 (selective) Prazosin Doxazosin α2 (selective) Idazoxan Yohimibine α1 + α2 (non-selective) Phentolamine Phenoxybenzamine

Labetalol

β1 (cardio-selective) Atenolol Acebutolol Metoprolol β2 (selective) Butoxamine β1 + β2 (non-selective) Propranolol Timolol Sotalol

How α₁-blocker reduces BP ?—they occupy the α₁ receptors and prevents the action of adrenaline and nor-adrenaline, thus the smooth muscles of the vessels cannot contract and ↓ PR and ↓ BP.

Adverse effect of α blockers—

1.  Orthostatic / postural hypotension (during sudden change in posture).

2.  Relaxation of the sphincter of the urinary bladder which may cause un-intended dribbling of urine.

3.  α₂ blocking can produce inhibition of platelet aggregation.

4.  Tachycardia due to fall of BP.

Miscellaneous α blockers—Labetalol blocks α₁, β₁, β₂. It has also a little blocking effect on α₂ and can be used in hypertension. Specially hypertension emergencies.

Indications—

1. Moderate degree HTN

2. Raynaud’s phenomenon—in cold vasospasm and pain

3. In prinz metal angina—prazosin might have beneficial effect

4. Benign prostatic hypertrophy

5. Pheo-chromocytoma

β-blockers—now a days extensively used.

Indications—

1.    Hypertension	2.  Anxiety
3.    Angina pectoris	4.  Pheo-chromocytoma
5.    Cardiac arrhythmia	6.  Thyrotoxicosis
7.    Ischaemic heart disease	8.  Post myocardial infarct phases.
9.    Glaucoma	10. Muscle tremor, migraine

Adverse effects of β-blockers—

1.  Bronchoconstriction (no response to Salbutamol)

2.  Cardiac failure

3.  Bradycardia (worsening of heart failure)

4.  Hypotension

5.  Hypoglycaemia

6.  Reduce peripheral blood flow

7.  Fatigue, depression, insomnia, dreaming, gut upset, rash

Contraindications—

1.  Bronchial asthma

2.  Left ventricular failure

3.  Diabetic patients treated with hypoglycemic agents (insulin dependent diabetes)

4.  Peripheral vascular disease (Buerger’s disease)

5.  Hypotension (systolic <90mm of Hg)

6.  Bradycardia (HR <55 /min)

Selective and non-selective β-blockers—β₁ blocker are the cardio selective. Non-selective are (β₁+β₂) blocker. Selectivity is also dose dependant. At high doses they may lose their selectivity.

Water and lipid soluble β-blockers—lipid soluble β-blockers can easily cross the BBB and produce CNS effect. They are easily absorbed from the GIT and enter into the hepatocyte and rapidly metabolized, so half life is less. On the other hand the less lipid soluble β-blockers cannot cross the BBB abundantly and less CNS effect. They are not metabolized significantly in the liver and should largely be excreted unchanged through the kidney.

Intrinsic sympathomimetic activity / partial agonist activity of β-blocker—(drug—Acebutolol)—in normal condition during absolute mental and physical rest, β-blockers with ISA will produce like tachycardia and slight ↑ in cardiac contractility. But the same drug in presence of powerful agonist like adrenaline will blunt the effect of adrenaline because the receptors are occupied by the Acebutolol, which is a partial agonist. Thus Acebutolol will blunt / reduce the intensity of tachycardia, rise of cardiac contractility, palpation, during panic, exercise, anger etc.

*** Name of some ISA—Acebutolol, Pindolol, Labetalol.

*** the relation between the exercise and blocking—if the patient takes β-blocker then cannot exercise for long.

*** Nadolol is excreted through the kidney without being metabolized in the liver.

*** β-blocker used as eye-drop are Timolol, Betaxolol.

Pharmacological effects of β-blocker—

On CVS—negative ionotropic and chronotropic effect on heart. It opposes the β₂ receptor mediated vasodilatation and also antagonizes the release of Renin.

On Respiratory system—they block the β₂ receptors of the bronchial smooth muscle and increases airway resistance by causing bronchoconstriction, specially in asthma. So contraindicated in asthma.

On Eye—↓ the intra-ocular pressure by decreasing the aqueous humor production.

On CNS—Insomnia, Restlessness, Tremor.

Metabolic and endocrine effects of β-blockers—

§    They inhibit sympathetic mediated stimulation of lipolysis.

§    Impair recovery from hypoglycemia specially in diabetic patients on insulin therapy.

Membrane stabilizing effect—

Some β blockers have prominent local anaesthetic action due to blockage of Na-channels.

Propranolol (non-selective β-blockers)—

Indications—

1.   Treatment of HTN (with diuretics)

2.   Cardiac dysrrhythmia

3.   Anginal pain

4.   MI

5.   Glaucoma

6.   Fallot’s tetrallogy

7.   Thyrotoxicosis

8.   Parkinsonism

Antihypertensive

Sympathomimetics

Drugs which mimic the action / effects of stimulation of the adrenergic nerve terminal are called sympathomimetics.

Phenylethylamine can be considered as the parent compound from which sympathomimetic drugs are derived. It consists of a benzene ring with an ethylamine side chain. Addition of OH^- at the carbon 3 & 4 position converts it into Catechol that is Catecholamine.

Catecholamines—compounds that contain Catechol ring. Natural Catecholamines are adrenaline and nor-adrenaline. Catecholamines cannot be given by mouth. Adrenaline, Nor-adrenaline, Dopamin, Isoprenaline etc

Non-catecholamine—can be given by mouth. Dobutamine, Amphetamine, Salbutamol, Ephedrine, Tyramine.

*** Catecholamines cannot be given orally because 2 enzymes are responsible for destruction of these—COMT (Catechol-ortho methyl transferase) and MAO (mono-amine oxidase).

COMT is present in the GIT, which causes degradation of the Catechol ring.

*** Catecholamines cannot cross the BBB

Classification of the sympathomimetic drugs—

Directly acting drugs—

Non-selective—

o  Adrenaline (α, β₁, β₂)

o  Nor-adrenaline (α, β₁)

o  Isoprenaline (β₁, β₂)

o  Dopamine (α, β₁, D₁, D₂)

Selective—

o  α₁—Phenylephrine

o  α₂—Methoxamine

o  β₁—Dobutamine

o  β₂—Salbutamol

Indirectly acting—

Amphetamine

Tyramine

Metaraminol

Mixed acting—

Ephedrine

(directly acts on the β₂ receptor of the bronchial smooth muscle and also releases nor-adrenaline from nerve endings)

Adrenaline—

Pharmacological effects of the Adrenaline—

On the CVS—

On heart—	Heart mainly contains β1 receptors, activation of the β1 receptor causes— ↑ Heart rate ( with the stimulation of the β1 of SA node) ↑ AV conduction (with the stimulation of the β1 of the AV node) ↑ The force of contraction and ↑ CO (with the stimulation of the β1 of the blood vessels)
On blood vessels—	Blood vessels contains α1 and β2 receptors— α1 stimulation causes vasoconstriction and ↑ BP β2 stimulation causes vasodilatation and ↓ BP (so whether the PR will ↑ or ↓ depends upon the number of receptors of each type present in the vessels. In splanchnic nerves PR ↑ as the α1 are more and in skeletal muscle vessels the β2 is more and PR ↓. So as α1 are more in total body ultimately the PR ↑) §    Cerebral blood vessels are not affected by adrenaline §    Pulmonary blood vessels may develop slight vaso-constriction as true arterioles are absent. §    Coronary blood vessels contain α1 and also β2 receptors. Adrenaline indeed causes direct vaso-constriction but it also causes ↑ myocardial contractility, ↑ HR and thus ↑ O2 demand, producing a local hypoxia which, in turn dilates coronary arteries. (via AMP)
On blood pressure—	↑ Chiefly systolic pressure, diastolic pressure is not sharply altered { because diastolic pressure which is due to ↑ PR is subjected to two opposing factors—1.general arteriolar constriction of peripheral vasculature (α1), 2. dilatation of the skeletal muscle arterioles due to vascular smooth muscle relaxation (β2)}

*** Adrenaline is a very potent vasoconstrictor and cardiac stimulant.

*** Adrenaline can act on α, β₁ and β₂ receptors.

*** Nor-adrenaline mainly acts on α₁ but also β₁.

*** Isoprenaline is an extremely potent β-receptor (β₁ and β₂) agonist.

On smooth muscle—

1. smooth muscle of the arterioles relaxes / β₂

2. smooth muscle of the GIT relaxes / β₂

3. Smooth muscle of the bronchial tree relaxes / β₂

4. Detrusor muscle of the bladder relaxes / β₂

5. Smooth muscle of the sphincter of the bladder constricts / α₁

6. Uterine smooth muscle relaxes in the late pregnancy

On eye—

α₁ receptor agonist drugs activates radial pupillary dilator muscle and causes mydriasis, they are also believed to ↑ the outflow of the aqueous humor. β₁ stimulation leads to rise in aqueous humor production.

On Respiratory tract—bronchial smooth muscle contains β₂ receptors. Sympathomimetics stimulate the β receptors and causes bronchodilatation. (Adrenaline, Isoprenaline, Ephedrine)

On Metabolism—

§    Sympathomimetics activate the β₃ receptors in fat cells and causes lipolysis.

§    They activate β₂ receptors in the liver and enhance glycolysis.

§    They activate the β₂ receptors and promote the uptake of K⁺ into the cells.

Adrenaline administration produces hyperglycemia by several mechanism—

a. Adrenaline causes glycogenolysis in both liver and muscle, end product in liver is glucose and in muscle is lactic acid. Adrenaline stimulates the enzyme phosphorylase.

b. It ↓ insulin secretion by stimulating the α₁ receptors of the β cell, it also ↑ the insulin secretion a little bit by stimulating the β₂receptor but α₁ stimulation is stronger.

c.  It ↑ the secretion of glucagon by stimulating the β receptors of the α cells of islets of langerhans.

d.Glucose uptake by the peripheral tissue is inhibited.

On genitor-urinary tract—the human uterus contains α and β₂ receptors. β₂ receptor activation causes uterus relaxation. The bladder base, urethral sphincter contain α receptor, the activation of which promote urinary continence.

It also stimulates the β₁ receptor of the myoepithelial cells of the juxtra-glomerular apparatus and thus ↑ the production of Renin. As a result the rennin-angiotensinogen pathway is activated and ↑ BP.

Selective β₂ agonist—Salbutamol (Albuterol), Terbutalin, Salmeterol.

Nor-adrenaline—

§    They are not used therapeutically.

§    Nor-adrenaline is secreted from the—

a. Postganglionic sympathetic nerve endings

b. From some nor-adrenergic nerves of the brain.

c.  From the supra-renal medulla.

*** normally the ratio between adrenaline and nor-adrenaline secretion is 4:1

Dopamin—it is a catecholamine. Dopaminergic nerves are present in the brain, where they are concerned with certain psychiatric disorders. Beside this in the ANS dopamine may be a neurotransmitter, where it behaves somewhat funnily—

1. in low dose dopamine binds with the dopamin receptors and acts as a agonist of the dopamin receptors.

2. in moderate dose dopamin acts as a agonist of the β₁ receptors.

3. in higher doses dopamin acts as a agonist of the α₁ receptors.

Dopamin has several receptors but dopamin A₁ and A₂ are well known. DA₁ is present in the blood vessels, particularly in the renal, mesenteric and coronary arteries. Stimulation causes vasodilatation.

§    In low doses DA₁ stimulation leads to renal vasodilatation thus improve renal blood flow and ↑ GFR. So dopamin is popularly used in cardio-vascular shock.

§    In moderate dose it stimulates the β₁ receptors of heart muscle leading to ↑ HR, ↑ contraction, ↑ CO and ↑ systolic BP.

§    In higher doses stimulation of the α₁ receptor of the peripheral smooth muscle arterioles and ↑ diastolic BP.

Clinical use of sympathomimetics / Catecholamines—

Adrenaline—

1.  Bronchial asthma—adrenaline working on the β₂ receptors of the smooth muscle of the bronchus activates C-AMP which ↓ the Calcium level→ dilatation of the bronchus (effective in status asthmaticus)

2.  Nasal congestion

3.  Local haemostasis

4.  Combination with the local anesthetics to prolong the action

5.  Anaphylactic shock—in serious type-1 allergic reaction, Adrenaline is used. (penicillin may cause the allergy)

6.  Sudden cardiac shock

    (decreased blood volume)

7.  Hypovolemia(

)