Definition of synapse:

• A junctional connection between two neurons, across which asignal can pass

• Pre-synaptic neuron: Where a neurotransmitter issynthesized, stored and released upon cell activation.

• Post-synaptic neuron or effector cell: Where neurotransmitteris detected and its action translated into cellular activities.

The Race Horse and the Cow

Sympathetic Nervous System

Fight or Flight

Rest and Digest

Autonomic Receptor Classification:

1. M1 Receptors. are found mainly in the central nervous systemand peripheral neurons as well as gastric parietal cells(responsible for gastric acid secretion).

2. M2 Receptors. The major location of these receptors is on themyocardium (cardiac muscle) although they can also occur onperipheral neurons. They exert mainly inhibitory effects.

3. M3 receptors: miosis,bronochospasmincrease GI motilitydecrease sphincter tone

Muscarinic receptors

Adrenergic receptors

A. adrenergic receptor : the agonist beingepiniphrine and norephinephrine.

1. 1 Adrenergic receptors,on smooth muscle, all blood vessels (causingconstriction) and causes dilation of pupil of eye onstimulation.

2. 2 Adrenergic receptors,presynaptic are found at adrenergic and cholinergicnerve terminals.

• adrenergic receptors: the agonist beingepiniphrine, and norephinephrine, Antagonist ispropranolol.

• Divided into:

1. 1 adrenergic receptors on heart (some 2 also)increases rate and force of contraction.

2. 2 adrenergic receptors dilation effect on smoothmuscle (some blood vessels), bronchial muscle.

Adrenergic receptors

Autonomic drugs

• Cholinergic agonists

• Cholinergic antagonists

• Adrenergic agonists

• Adrenergic antagonists

Cholinergic agonist

A. Decrease in the heart rate and cardiac output.

B. Decrease in blood pressure (vasodilation).

C. Increase the salivary secretion and stimulate intestinalsecretion and motility.

D. Decrease the Bladder sphincter tone.

E. Contraction of the eye papillary muscles

Bethanecol

Therapeutic uses,• in urologic treatment, Bethanecol is used to stimulate

the atonic bladder,

particularly in or postpartum or postoperative, nonobstructiveurinary retention.

➢ Diabetic autonomic neuropathy➢ Neurogenic bladder

• Paralytic ileus or abdominal distension

Adverse effect, effect of generalized cholinergic stimulation:

• sweating,

• salivation,

• decreased blood pressure,

• bronchospasm.

• Alert- Never give IM or IV – circulatorycollapse, hypotension, cardiac arrest poss.

Bethanecol

Pilocarbine • Pilocarbine exhibits muscurinic activity and is used primarily is

ophthalmology.

• Its major therapeutic indication is the treatment of glaucoma.

• It is one of the most potent stimulators of secretions such assweat, tears, and saliva, but the use is limiting due to its lackof selectivity.

• Xerostomia➢ Head and neck radiation

➢ Sjögren's syndrome.

• Adverse effect: it can enter the brain and cause disturbances.

Contraindications of cholinomimetics

1. Asthma.

2. Hypotension.

3. Peptic ulcer.

Anticholinesterases

• prolonging the lifetime of ACH.

• provoke a response at all cholinoceptors

mascurinic and nicotinic receptors.

Physostigmine

1. This drug is lipophilic enough to cross the blood brain barrier.It is thus useful in treating atropine poisoning.

2. antimuscarinic side effects overdoses,➢ Tricyclic antidepressants

➢ Antihistamines (H1)

3. Physostigmine, instilled as drops into the eye, and iscommonly used in the treatment of glaucoma, but Pilocarbineis more effective.

Remember: cholinergic drugs decrease the visual acuity on thelong run.

• It also produces some what more nicotinic effects thanphysostigmine, and has a greater effect on skeletal muscles.

• The main use of neostigmine is to reverse the effect ofneuromuscular blocking drugs which are used to induce muscleparalysis during surgical procedures.

• Symptomatic treatment of the mysthenia gravis (anautoimmune disease)

• Usually given with atropine to avoid muscarinic adverse effect

Neostigmine

Assessment: Myasthenia Gravis

• Signs and symptoms: muscle weakness, ptosis(droopy eye lid), diplopia (double vision),difficulty chewing and swallowing, decreasedactivity intolerance.

• How do you know medication is working?Increased muscle tone, no droopy eye lid ordouble vision, increased activity tolerance.

Alzheimer’s disease • Donepezil was approved for clinical use. Improved

cognition and global clinical function were seen in the21–81-week intervals studied (Dooley and Lamb, 2000).In long-term studies, the drug delayed symptomaticprogression of the disease for periods up to 55 weeks.Side effects are largely attributable to excessivecholinergic stimulation, with nausea, diarrhea, andvomiting being most frequently reported. The drug iswell tolerated in single daily doses. Usually, 5-mg dosesare administered at night; if this dose is well tolerated,the dose can be increased to 10 mg daily.

Cholinergic Antagonists (Muscarinic

receptor)

• Drugs which bind to cholinergic receptor but do notactivate it

• Prevent acetylcholine from binding

• Opposite clinical effect to agonists –

• lower activity of acetylcholine

• In addition to the inhibition of the muscarinic function, theseagents block the few sympathetic neurons that arecholinergic, such as those innerving sweat glands.

Cholinergic antagonist

Antimuscarinic agents

• Atropine (A) was isolated in 1831. Atropine is a quite highly specificantagonist, with a persistent effect and is still a useful drug today.

• main effects1. increase heart rate, as acetylcholine slows the heart.

2. decreases tone and motility in the gastrointestinal tract, making ituseful in diarrhea treatment.

3. markedly diminish salivary secretion (dry mouth),

4. cause pupil dilation.

5. Atropine relaxes the urinary tract and the airway smooth muscle

Atropine uses

• Dentistry: used to diminish salivation, to produce a dry field

• Bradycardia < 60

administer Atropine .5mg IV

1mg IM every 5 minutes until max dose of 3 mg

Scopolamine (B)

• Produce peripheral effect similar to atropine. However, it hasa greater action on the CNS and longer duration of action, andit is less potent in its effect on the heart, bronchial muscles,and intestine.

• Actions:

a. One of the most effective anti-motion sickness drug available.

b. Also has the unusual effect of blocking short-term memory.

Atropine overdose

• tachycardia, blurred vision, photophobia, dry mouth.

• Can cause marked CNS excitation, with irritation, confusion,and convulsions.

• “red as a beet (flushing), dry as a bone (dry skin), mad as a hatter (delirium,

hallucinations), hot as Hades (hyperthermia), blind as a bat (mydriasis).”

Classification of Neuromuscular Blocking AgentsAGENT CHEMICAL CLASS PHARMACOLOGIC

AL PROPERTIESTIME OF ONSET (MIN)a

CLINICAL DURATION (MIN)a

MODE OF ELIMINATION

Succinyl choline (ANECTINE, others)

Dicholine ester Ultrashort duration; depolarizing

0.8-1.4 6-11 Hydrolysis by plasma cholinesterases

D-Tubocurarineb

Natural alkaloid (cyclic benzyl-isoquinoline)

Long duration; competitive

6 80 Renal and hepatic elimination

Metocurineb Benzylisoquinoline

Long duration; competitive

4 110 Renal elimination

Atracurium (TRACRIUM, others)

Benzylisoquinoline

Intermediate duration; competitive

3 45 Hofmann elimination; hydrolysis by plasma Esterases

Cisatracurium (NIMBEX)

Benzylisoquinoline

Intermediate duration; competitive

2-8 45-90 Hofmann and renal elimination

Doxacuriumb Benzylisoquinoline

Long duration; competitive

4-8 120 Renal elimination

Mivacurium Benzylisoquinoline

Short duration; competitive

2-3 15-21 Hydrolysis plasma by cholinesterases

Pancuronium (generic)

Ammonio steroid Long duration; competitive

3-4 85-100 Renal and hepatic elimination

Pipecuroniumb

Ammonio steroid Long duration; competitive

3-6 30-90 Renal elimination; hepatic

Neuromuscular blocking drugs

• These drugs block the cholinergic transmission between motornerve ending and the nicitonic receptors on the neuromascularend plate of skeletal muscle.

• They are structural analogue of acetylcholine and act eitherantagonist (non-depolarizing type) or agonist (depolarizing type).

• Some of them are useful during surgery for producing completemuscle relaxation, without having to employ higher anestheticdoses.

• Others are useful to control spastic muscle tone.

non-depolarizing blockers Tubocurarine (B)

Tubocurarine is given by i.v. injection.

Mechanism of action

• It binds to the endplate nicotinic cholinoceptors withoutexciting them, acting as a competitive antagonist towardsACh.

• Muscular paralysis develops within about 4 min. d-Tubocurarine does not penetrate into the CNS.

• The patient would thus experience motor paralysis andinability to breathe, while remaining fully conscious butincapable of expressing anything

Depolarizing agents

• Succinylcholine (B)

• Mechanism of action,

- attaches to the nicotinic receptors and act like ACH todepolarize the junction.

Unlike ACH these agents persist at high concentration in thesynaptic cleft remaining attached for a relatively longer timeand providing constant stimulation of the receptors.

- The continue binding of theses agents renders the receptorincapable of transmitting further impulses and the endresult is flaccid paralysis (phase II).

• Therapeutic uses

Depolarizing agents are used

a. as surgical adjuvant to anesthesia for facilitatingendotracheal intubations.

b. with electroconvulsant shock.

Depolarizing agents

Adrenergic agonist

What do these receptors do?

• Alpha 1– Vasoconstriction, ↑ BP, ↑ tonus sphincter muscles

• Alpha 2– Inhibit norepinephrine, insulin release

• Beta 1– Tachycardia, ↑ lipolysis, ↑ myocardial contractility

• Beta 2– Vasodilation, bronchodilation, ↓insulin release

Epinephrine (A) (Adrenalin)

• can stimulate both alpha and beta receptors

i. skin has primarily an alpha response --vasoconstriction

ii. heart primarily beta response –an increased beta response increases (a) rate POSITIVE CHRONOTROPIC (b) force of contraction POSITIVE INOTROPIC (c) cardiac output (d) oxygen utilization

--oxygen utilization is increased tremendously????

uses

1. agent of choice in allergic reactions and asthmatic reactions --counteracts effect of histamine

in such reactions, dose is 0.2-1.0ml of a l:l,000 solution, either SQ or IV

• Adrenaline provides rapid relief of hypersensitivity reactionsto drugs and allergens through physiological antagonism ofthe hypotensive effects of these mediators, and relievingbronchoconstriction which may occur in anaphylactic shock.

uses 2. local anesthetics

Adrenaline is also combined with local anesthetics to prolong their action by virtue of the alpha mediated constrictor effect on blood vessels of the skin and subdermis.

concentration

1:50,000 to 1:250,000

most common: 1:100,000

also reduce the toxicity of the local anesthetic by limiting its systemic absorption. local anesthetic such as Lidocaine in toxic doses can produce cardiac arrthythmias and convulsions.

(cardiopulmonary resuscitation)IV would be 0.1 to 0.25 mg

• 3. It is also used to restore cardiac activity incardiac arrest.

Epinephrine is the best studied and most widelyadministered adrenergic agonist used for thetreatment of cardiac arrest.

Used to jump start the heart.

Adverse effect

• adrenaline may lead to symptoms of fear, anxiety, tenseness,restlessness, headache, tremor, weakness, dizziness orpalpitation.

• As a result of significant blood pressure elevation, cerebralhaemorrhages may occur.

• It may trigger cardiac arrhythmia, particularly if patient isreceiving digitalis.

Contraindications and cautions i. cardiovascular disease –increases workload on the heart in

a very inefficient manner; oxygen is rapidly consumed and patients with cardiovascular disease already have compromised access to adequate oxygen in the heart .

ii. hypertension–vasoconstriction can be throughout the body, including the muscles of the blood vessels.

iii. hyperthyroidism–epinephrine can further stimulate the release of thyroid hormone AND cause an increase in side effects of the hyperthyroid condition!

Phenylephrine (A) (1&2).

• Therapeutic uses:

It is a component of a number of cold medication, where itacts as a nasal decongestant by virtue of its vasoconstrictorability.

Rebound nasal congestion can occur with chronic use as anasal decongestant.

• Mixed with local anaesthetics for the same reason asadrenaline.

• Phenylephrine is used in ophthalmology to produce pupillarydilation (mydriasis) without paralysis of accommodation(cycloplegia). Of course, atropine would produce bothphenomena.

TAC-4 Alternate Dental Gel

• Dental Gel (Prilocaine / Lidocaine / Tetracaine /Phenylephrine)

Phenylephrine helps shrink blood vessels, which in turn may helpwith the prevention of bleeding.

Dopamine (B)

• Dopamine is a naturally occurring catecholamine andneurotransmitter within the CNS.

• Most of the cardiovascular effects of dopamine are producedby its weak effects on 1 receptors and receptors.

• Its effects on renal and mesenteric vasculatures are mediatedthrough stimulation of specific dopaminergic receptors.

• Dopamine has become favoured as a pressor agent tomaintain blood pressure in shock.

• Dopamine has the following advantages over othersympathomimetics

a. It causes cardiac stimulation with little increase in myocardialoxygen consumption .

b. It is less likely to cause cardiac arrhythmias than othersympathomimetics.

c. The increase in renal blood flow which it produces helps tomaintain glomerular filtration, urine production and sodiumexcretion whereas adrenaline and noradrenaline decreaserenal blood flow to the point where renal necrosis is possible.

Dopamine (B)

Dobutamine (B)• 1 Receptors.

• This is a synthetic and relatively new substance. It increasescardiac contractility and cardiac output by selectivelystimulating cardiac 1 receptors.

• Dobutamine appears to have advantages over othercatecholamines forimprovement of myocardial function inheart failure associated with myocardial infarction. Since thethe effects of dobutamine on heart rate and systolic pressureare less than the other catecholamines, there is less oxygendemand by the myocardium compared to othersympathomimetic drugs.

• Dobutamine should be used with caution in atrial fibrillation,as the drug increase atrioventricular conductivity.

Ephedrine (A)

• Is a mix acting sympathomimetic agent, which has both directand indirect action:

• Its primary action is indirect: it cause the release ofnorepinephrine from storage in nerve terminals.

• It also produce direct stimulation of adrenergic receptors.

• Ephedrine increase the blood pressure by vasoconstructionand cardiac stimulation.

• It produces bronchodilation, but it is less potent thanepinephrine and produces its action more slowly.

• Its main therapeutic uses are in the treatment of bronchialasthma, and as a nasal decongestant.

Selective 2 stimulants

• Salbutamol (A)

• These drugs are very widely used in the treatment of asthma.

• Have a relaxant effect on the bronchial smooth muscle andshow little effect on cardiac 1 receptors.

• They are used therapeutically for treatments of bronchialasthma, they chiefly as aerosol inhalants, oral and injection,are available

Salbutamol (A)

• nearly devoid of cardiac effects in the usual human doses, It is as potent as

Isoproterenol in its ability to cause bronchodilation but has only about

1/50th of the cardiac stimulant properties.

• Other examples include mtaproterenol, albuterol, turbutaline, and

bitolterol.

• These agents differ in their onset of action and the duration of their

effects.

54

Sales of Supplements Containing Ephedrine Alkaloids

(Ephedra) Prohibited

On April 12, 2004, a final rule went into effect prohibiting the

sale of dietary supplements containing ephedrine alkaloids

(ephedra).

Ephedra, also called Ma huang, is a naturally occurring

substance derived from plants. Its principal active ingredient is

ephedrine, which when chemically synthesized is regulated as

a drug.

In recent years ephedra products have been

extensively promoted to aid weight loss, enhance sports

performance, and increase energy.

But FDA has determined that ephedra presents an

unreasonable risk of illness or injury. It has been linked to

significant adverse health effects, including heart attack and

stroke. From http://www.fda.gov

2 agonists

– eg, clonidine and Methyldopa (antihypertensive drugs)

– when given orally, reduce sympathetic outflow from CNS and

consequently decrease BP

Central 2 agonists

–hypertension

–menopausal hot flushes

–narcotics, alcohol, smoking withdrawal

2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control Center)

Kidney

Heart

Sympathetic

ganglion

1 Receptors

2 Receptors

1 Receptors

1 Receptors

2-Adrenergic Agonists Reduce Blood Pressure by Reducing Sympathetic Output from the Brain

Brain

Brain Stem (Cardiovascular Control Center)

Kidney

Heart

Sympathetic

ganglion

1 Receptors

2 Receptors

1 Receptors

1 Receptors

Decreased sympathetic tone

• Decr. HR

• Decr. Contractility

• Decr. Renin release

• Decr. Vasoconstriction

58

Adrenoreceptor Antagonists

- Adrenoreceptor Blockadenon-selective

• Non-selective -antagonists have limited beneficial effects onblood pressure reduction, due to associated 2 block whichincreases nor adrenaline effects (remember, block of thenegative feedback 2 receptor will increase noradrenalinerelease).

• This may cause increased 1 stimulation with tachycardia etc -an unwanted additional effect.

Phenetolamine (A)

• Produce a Competitive block of both 1 and 2 receptors.

• Decrease peripheral resistance and increase venous capacity.

• Used to control acute hypertension episodes caused bysympathomimetics.

• Phenetolamine induce reflex cardiac stimulation and tachycardiathrough the baroreceptor reflex and by blocking the 2 receptorsof cardiac sympathetic nerve.

Phenoxybenzamine

• Binds covalently to the receptors, produce an irreversibleblockade.

• The only mechanism to overcome this blockade is to synthesisnew adreno-receptors, which require a day or so.

• phenoxybenzamine induce hypotension due to lack of thesympathetic vasoconstruction.

• It is used to reverse vasoconstruaction in shock, and also inacute hypertension episodes.

• Pheochromocytoma

Selective 1-blockers

• Selectively block 1 receptors

–

–Ie. Alfuzosin, doxazosin, prazosin, terazosin ……..

•Used in the treatment of chronic hypertension

• Also used to treat urinary retention in men with benign

prostatic hyperplasia

Prazosin

• Prazosin, is a selective 1 antagonist, still used in some casesof hypertension, as 1 vasoconstriction effect is blockedwithout an increase in adrenergic effects at -receptor sites.

• Lower blood pressure by causing relaxation of both arterialand venous smooth muscle.

• Importantly, it produce what called “first dose” syncope, byexaggerated hypotensive response that can result fainting.

• First dose effect can be minimize by adjusting the dose to onethird or one fourth, and by giving the drug at bedtime.

• 1 antagonist may cause dizziness, lack of energy, nasalcongestion, headache, and drowsiness.

• Significant orthostatic hypotension is a possibility; monitorpatient when getting out of dental chair.

Prazosin

-adrenoreceptor blockade

• The drugs which block -receptors are very widely used intherapeutics, mostly for their antihypertensive effect, andefficacy in the treatment of angina and some arrhythmias.

• In the 1960's -blockers were developed, and the earliestprototype -blocker was Propanolol, a non-specific receptors antagonist, which is still widely used.

• While -blockers are still widely used for the treatment ofhypertension, exactly how they lower blood pressure hasnever been clarified.

-adrenergic receptor antagonists

• Both non-selective and selective -blockers

• Non-selective

– ie nadolol, pindolol, propranolol, tomilol

– Block both 1 receptors in cardiac tissue and 2 in

smooth muscle, liver and other tissues

• Blockade of 1 reduces sympathetic stimulation of

heart…

Therefore, negative

• Blockade of 2 may cause bronchoconstriction and

limit glycogenolysis Adverse effects

chronotropeinotrope

1-antagonist _____

1-antagonists -- -- --

Selective 1-blockers

• Have greater affinity for 1 than for 2 receptors

– Ie Acebutolol, atenolol, esmolol, metoprolol

CARDIOSELECTIVE BLOCKERS

• Produce fewer adverse effects than non-selective, but their selectivity is not absolute

Clinical uses

• -blockers have a number of clinical applications including treatment of:

• migraines

• Hypertension

• angina pectoris

• cardiac arrhythmia

• glaucoma

Propanolol

• Adverse effects

-Propanolol can induce heart failure, especially in patients withcompromised myocardial function.

-Rash, fever and prolonged use may cause fatigue , depression,sexual dysfunction.

-Rapid withdrawal can lead tosupersensitivity of receptors, which canprovoke anginal attack, arrhythmia, ormyocardial infraction.

Propanolol

• Contraindications:

a. Propanolol must never given to any individual with chronicobstruction pulmonary disease because it causes animmediate contraction of the bronchiolar smooth muscles,which may result in a serious and potential lethal side effect.

b. Propanolol effect the carbohydrate metabolism, and mayincrease the action of insulin, so diabetics treated with insulinshould use it with caution.

Selective 1 blockers

• These include Atenolol, Acebutolol, Esmolol, andMetopropolol.

• These agents enjoy wide use as antihypertensive, althoughless so today than 10 years ago.

• Relatively little effect on the pulmonary function, peripheralresistance, and carbohydrate metabolism.

• They are also useful in diabetic hypertensive patient who arereceiving insulin.

Pindolol and Acebutolol

• Are not pure antagonists, instead, they have the ability to weaklystimulate both 1 and 2 receptors (agonist effect), and producewhat is called intrinsic sympathomemitic activity.

• These partial agonist stimulate the receptors and also inhibit thestimulation by the endogenous neurotransmitters adrenaline andnoradrenalin.

• The intrinsic sympathomemitic activity decreased metaboliceffects that are seen with other blockers, such as carbohydratemetabolism (make them valuable in treatment hypertension indiabetics).

• They used therapeutically to treat hypertension with moderatebradycardia, because a further decrease in the heart rate is lesspronounced with these agents.

Labetalol and carvedilol Antagonist of both and adrenoreceptors

• These two agents are reversible blockers and 1 blocker(producing peripheral vasodilatation).

• So they contrast -blockers in producing peripheralvasodilation, and therefore useful in treating hypertensivepatient whom increased peripheral vascular resistance isundesired, such as elderly and blacks.

• Labetolol may employed as an alternative to hydralazine inthe treatment of pregnancy-induced hypertension.

• Labetolol is also used to treat hypertensive emergenciesbecause it can rapidly lower blood pressure.