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                                   CLASSIFICATION OF DRUGS   

                                                       By: Yasir Akeel 3rd year PMC.

                                                           

                                    yasirakeel@hotmail.com

                                                                             

         AUTONOMIC NERVOUS SYSTEM

  We can classify drugs related to nervous system under 4 headings

    1-Sympathomimetics.

    2-Sympatholytics.

    3-Parasympathomimetics.

    4-Parasympatholytics.

        

                   SYMPATHOMIMETICS

                        These can be classifieds on following basis!

     A-ACCORDING TO MECHANISM OF ACTION

1-      DIRECT ACTING ADRENERGIC A GONISTS

                          They bind to adrenergic receptors without interacting with the presynaptic neurons and activate them. After their activation the 2nd messenger system begins to produce their pharmacological actions.

                  Examples   1-Epinephrine.

                                     2-Norepinephrine.

                                     3-Dopamine.

                                     4-Isoprotrenol.

                                     5-Dobutamine.

                                     6-Clonidine.

                                     7-Phenylephrine.

         2-INDIRECT ACTING ADRENERGIC AGONISTS

                          They do not act directly by binding to receptors but cause the                release of nor-epinephrine from presynaptic terminals thus potentiating the effect of nor-epinephrine on the presynaptic receptors.

                  Examples   1-Amphetamine.

                                     2-Tyramine.

                                     3-Methylamphetamine.

                                     4-Hydroxyamphetamine.

3-MIXED ACTION ADRENERGIC AGONISTS

                           They release nor-epinephrine from presynaptic terminals and activate postsynaptic adrenergic receptors.

                  Examples   1-Ephidrine.

                                     2-metaraminol.

      B-ACCORDING TO CHEMICAL NATURE.

        1-CATECHOLAMINES

                           Examples   1-Epinephrine.

                                              2-Norepinephrine.

                                              3-Dopamine.

                                              4-Isoproterinol.

                                              5-Dobutamine.

         2-NONCATACHOLAMINES

                           Examples   1-Amphetamine.

                                              2-Tyramine.

                                              3-Methylamphetamine.

                                              4-Hydroxyamphetamine.

                                              5-Ehidrine.

                                              6-Phenylephrine.

      C-ACCORDING TO RECEPTORS ON WHICH DRUG ACTS

         1-ALPHA-1 SELECTIVE

                           Examples   1-Phenylephrine.

                                              2-Methoxamine.

                                              3-Cirazoline.

                                              4-Metazoline.

         2-ALPHA-2 SELECTIVE

                           Examples   1-Clonidine.

                                              2-Guanabenz.

                                              3-Oxymetazoline.

                                              4-Methylepinephrine.

         3-BETA-1 SELECTIVE

                           Examples   1-Dobutamine.

                                              2-Prenalterol.

         4-BETA-2 SELECTIVE

                           Examples   1-Salbutamol.

                                              2-Turbutaline.

                                              3-Ritodrine.

                                              4-Fenoterol.

         5-ALPHA AND BETA NON-SELECTIVE

                           Examples   1-Epinephrine.

                                              2-Norepinephrine.

                                              3-Dobutamine.

                                              4-Ephedrine.

                                              5-amphetamine.

         6-DOPAMINE RECEPTOR STIMULANTS

                           Examples   1-Dopamine

                                              2-Bromocryptine.

 

 

                                 SYMPATHOLYTICS

 

    1-ALPHA RECEPTOR ANTAGONIST

                         These can be classified on following basis

      A-ACCORDING TO ALPHA RECEPTOR SELECTIVITY

         1-ALPHA-1 SELECTIVE ANTAGONISTS 

                           Examples   1-Prazosin.

                                              2-Terazosin.

                                              3-Doxazosin.

                                              4-Urapidil.

         2-ALPHA-2 SELECTIVE ANTAGONIST

                           Example     1-Yohimbine.

         3-ALPHA 1 AND 2 NON SELECTIVE

                           Examples   1-Phenoxybenzamine.

                                              2-Phentolamine.

                                              3-Tolazoline.

                                              4-Ergotamine[ergot derivative]

 

       2-ACCORDING TO DURATION OF ACTION

 

         1-REVRSIBLE ALPHA BLOCKERS

                            Examples   1-Phentolamine.

                                               2-Prazosin.

                                               3-Ergot derivative.

 

         2-IREVERSIBLE ALPHA BLOCKERS

                           Examples   1- Phenoxybenzamine[It is a nitrogen mustard and links both 

                                                                                   a-1(postsynaptically) and a-2(post-

                                                                                  synaptically)This bond is irreversible

                                                                                  and noncompetitive and new a

                                                                                  receptor must be synthesized to revive

                                                                                  the functions]

           B-BETA RECEPTOR ANTAGONIST

 

         1-BETA-1 SELECTIVE ANTAGONIST

                           Examples   1-Metoprolol.

                                              2-Alebutolol.

                                              3-Atenolol.

                                              4-Esmolol.

         2-BETA-2 SELECTIVE ANTAGONIST

                           Examples   1-Butoxamine.

        3-BETA 1 AND 2 NON SELECTIVE ANTAGONIST

                           Examples   1-propanolol.

                                              2-Pindolol.

                                              3-Alprenolol.

                                              4-Sotalol.

                                              5-Timolol.

                                              6-Nadolol.

            C-ALPHA AND BETA NON SELECTIVE ANTAGONIST

                           Examples   1-Lobetalol.

           D-CENTRALLY ACTING SYMPATHOLYTICS

                           Examples   1-Methyldopa.

                                              2-Clonidine.

                                     3-Guanabenz.

   E-ADRENERGIC NEURON BLOCKER

                  Examples   1-Reserpine.

                                     2-Guanithidine

                                     3-Guanadrel.

                               

 

                 PARASYPATHOMIMETICS

 

 

  DIRECT ACTING

  1-CHOLINE ESTERS

                  Examples   1-acetylcholine.

                                     2-Methacholine.

                                     3-Carbachol.

                                     4-Bethanechol.

  2-CHOLINERGIC ALKALOIDS

                  Examples   1-Muscarine.

                                     2-Pilocarpine.

                                     3-Arecholine.

                                     4-Oxotremorine.

               They mimic the effects of acetyl choline by binding directly to                                      

               Cholinoreceptors.

  INDIRECT ACTING

  A-REVERSIBLE

      1-ALCOHOLS

                        Examples   1-Edrophonium.

                                          

      2-CARBAMATES

                        Examples   1-Tertiary amines[can cross blood brain barier]

                                                     They include Physostigmine.

                                           2-Quaternary amines[can not cross blood brain barier]

                                                      They include  1-Neostigmine.

                                                                             2-Pyridostigmine.

                                                                             3-Distigmine.

                                                                             4-Tecrine.

 B-IRREVERSIBLE

     ORGANOPHOSPHORUS COMPOUND

                        Examples   1-Disopropyl flouro phosphate.

                                           2-Sarin.

                                           3-Parathion.

                                           4-Tabun.

                                           5-Samon.

                                           6-Eicothiopate.

                                           7-TEPP.

                     The irreversible anticholinesterases bind covalently to acetylcholinesterase.

                                          

                 PARASYMPATHOLYTICS

ANTIMUSCRINIC AGENTS

            THEY ARE CLASSIFIED INTO TWO SUB TYPES

A-NATURAL

                  Examples   1-Atropine.

                                    2-Scopolamine.

                                    3-Hyoscine.

B-SYNTHATIC

                  Examples  1-Homotropine.

                                    2-Tropicamide.

                                    3-Piorenzipine.

                                    4-Isopropamide.

                                    5-Benztropene

                                    6-Benzhexone.

GANGLIONIC BLOCKERS[ANTI NICOTINIC]

                  Examples  1-Mecamylamine.

                                    2-Nicotine.

                                    3-Pempidine.

                                    4-Hexamethonium.

N-M BLOCKER[ANTI NICOTINIC]

                    They can be further subdivided as follows

A-DEPOLARIZERS

                  Examples   1-Suxamethonium.

                                    2-Decamethonium.

B-COMPETITIVE

                  Examples   1-Atracurium.

                                    2-Doxacurium.

                                    3-Metocurium.

                                    4-Vecurium.

                                    5-Tubocurarine.

CHOLINEESTERASE REACTIVATOR

                  Examples   1-Pralidoxamine.

                                    2-Obidoxime.

 

                        OPHTHALMOLOGICAL DRUGS

 

THESE CAN BE CLASSIFIED UNDER 3 MAIM HEADINGS

  1-ANTI GLAUCOMA DRUGS.

  2-MIOTICS.

  3-MYDRIATICS.

 

             ANTI GLAUCOMA DRUGS

They can be further sub- classified as follows

DRUGS FOR CLOSED GLAUCOMA

                     Examples   1-Pilocarpine.

                                        2-Manitol.

                                        3-Physostigmine.

                                        4-Acetazolamide.

DRUGS FOR OPEN GLAUCOMA

                     Examples   1-Pilocarpine[Parasympathomimetics].

                                        2-Eicothiopate[Parasympathomimetics]..

                                        3-Physostigmine[Parasympathomimetics]..

                                        4-Carbachol[Parasympathomimetics]..           

                                        5-Epinephrine.

                                        6-Timolol. 

 

                                                MIOTICS

These can be further sub divided as follows.

PARASYMPATHMIMETICS

                     Examples   1-Pilocarpine.

                                        2-Carbachol.

                                        3-Neostigmine.

                                        4-Physostigmine.

                                        5-Eicothiopate.

SYMPATHOLYTICS

                     Examples   1-Tolazoline.

                                        2-Phentolamine.

                                        3-Reserpine.

                                           

                                                MYDRIATICS

These can be further classified as below

 SYMPATHOMIMETICS

                     Examples   1-Epinephrine.

                                        2-Norepinephrine.

                                        3-Phenylephrine.

                                        4-Ephidrine.

PARASYMPATHOLYTICS

                     Examples   1-Atropine.

                                        2-Scopolamine.

                                        3-Homatropine.

 

 

 SKELETAL MUSCLE RELAXANT

 

N-M BLOCKERS OR PEREPHERAL MUSCLE RELAXANT

These can be classified as follows

DRUGS INHIBITING ACETYLCHOLINE OUT PUT

                     Examples   1-Neomycine[Dec. calcium]

                                        2-Gentamycine[Inc. magnecium]

                                        3-Botulinium toxin[local anesthetic]

DRUGS INHIBITING STORAGE AND SYNTHESIS OF ACETYLCHOLINE

                    Examples   1-Hemicholinium.

                                       2-Triethylcholine.

DRUGS INHIBITING ACTION OF RELEASED ACETYLCHOLINE

 These can be further classified as follows

 A-NON DEPOLARISERS[COMPETITIVE N-M RELAXANTS]

                    Examples   1-d-tubocurarine.

                                       2-Gallamine.

                                       3-Atracurium.

                                       4-Pancuronium.

                                      5-Mivacurium.

B-DEPOLARISERS[NON COMPETITIVE]

                   Examples   1-Succinylcholine.

                                      2-Suxamethonium.

                                      3-Decamethonium.

CENTRAL MUSCLE RELAXANTS

They can be further classified as follows

 BENZODIAZIPINES

                      Examples   1-Diazepam.

                                         2-Medazepam.

BENZOXAZOLE  DERIVATIVE

                     Examples   1-Chlorzoxazone.

                                        2-Benzimidazole.

PROPANEDIOLE DERIVATIVE

                    Examples   1-Styramate.

                                       2-Meprobamate.

GABA ANALOGUE

                    Examples   1-Baclofen.

DIRECT  ACTING MUSCLE RELAXANT

                    Example    1-Dantrolene

 

REFERENCES:  R &Dale pharmacology of autonomic nervous system, Goodman, Gillman pharmacology.

 

 

 

                AUTONOMIC NERVOUS SYSTEM

             By, yasir akeel 3rd year pmc.

 

    EPINEPHRINE

̣ It is a potent stimulant of both a and b adrenoceptors that’s why its effects on different target organs are complex.

̣ It is a direct acting drug and is related to sympathomimetic group of drugs.

   SITE OF PRODUCTION.

̣ It is produced mainly in adrenal medulla by chromaffin tissue.

 Its response varies in different organs

 

 It constricts blood vessels in the skin -- because of a1 receptors

 

 It dilate - muscular arterioles – because of  b2 activation

 

It reacts with a1 , a2 , b1 , b2 adrenoceptors.

 

at low concentration b2-predominates – dilation occurs

at high conc. a1 predominates - constriction occurs

 

a. Blood pressure

- large doses increases BP due to vasoconstriction mediated through a1 activation.

increase HR, increase contraction of heart - b1 action

 

- low doses decreases BP, or no change

 

increase HR, increase contraction

potent bronchodilator

b. Metabolic effects

 

1. increase glucose production - energy - b2 - fight or flight (ie. increase glucagon, glycogen to glucose)

2. Inhibition of insulin secretion - a2

3. Increase in oxygen consumption

4. increased renin from juxtaglomerular- b1- renin- angiotensin (vasoconstriction) - aldosterone -Na retention

c. Pharmacologic effect of NOREPINEPHRINE

 

1. equal to Epin. in b1 action -- ie.) heart

2. slightly less a (ie. constriction)

3. no b2 activity -therefore, no dilation, no bronchodilation

Norepinephrine-  acts at a1, a2, b1 adrenocepters

d. Pharmacokinetics of Epinephrine and Norepinephrine

   ABSORPTION

1. Absorption is poor with oral administration because drugs are rapidly conjugated and oxidized in intestinal mucosa and in liver (first pass metabolism).

2. Absorption is slow with subcutaneous administration because drugs cause local vasoconstriction.

3. Inhaled solution can be used for their action on respiratory tract (b2 - epinephrine)

4. Drugs IV administration must be careful so that heart does not fibrillate

5.It may be applied topically at mucous membrane to produce local effects.

  METABOLISM.

. Liver is important in degradation- COMT, MAO enzymatic systems are involved in their degradation.

  EXCRETION.

̣ The metabolites of epinephrine appeared in urine.

̣Only a small amount of epinephrine (unchanged) appears in urine.

̣In pheochromocytoma large amounts of epinephrine and norepinephrine along with their metabolites appear in urine

e. Therapeutic uses

 

1. Epinephrine

 

a) Treat bronchospasm b2

 

b) Primary treatment for anaphylactic shock (allergy- exposure to antigen- bee venom -powerful antibody response Ig E. --- mast cells produce histamine and PG, get leakage of fluid and dilation of blood vessels, also bronchoconstricton ****- can't breath (often injected SC - there is some rapid absorption)

 

c) Restore cardiac activity in cardiac arrest (in physiology lab--give to animals to restore heart activity

 

2. Norepinephrine - treating hypotension during anesthesia- not used much (given IV)

 

f. Untoward effects (troubling)

 

1. anxiety - stimulus of CNS- later

2. headaches - increase blood flow to brain - b1 (increase heart rate and increase contraction)

3. cerebral hemorrhage- vasopressor effect

4. pulmonary edema- pulmonary hypertension

above are due to alterations in blood flow

 

g. Prolonged exposure can lead to receptor downregulation -- true for all receptors -- desensitization -- this has been studied for adrenoceptors -- ie. internalization of receptors -- or for b receptors ---bARK - badrenergic receptor kinase -- phosphorylates/disrupts G protein so no adenylyl cyclase to produce cAMP

 

B. Other Sympathomimetic Drugs----Isoproterenol b1, b2

 

 

 

1. Pharmacologic effects

 

a. mostly b effect

 

b. IV- decreases peripheral resistance- b2 - decreases BP

 

c. Blood pressure falls slightly- vasodilation, but also increased heart rate, increased contractility b1, thus there is an increased CO

 

d. Relaxation of bronchial smooth muscle

 

e. less hyperglycemia (glycogen-glucose) than epinephrine (b2) because isoproterenol directly stimulates insulin secretion from pancreatic islet cells (glucose - to glycogen)

 

2. Pharmacokinetics

 

a. oral unreliable

b. good parenteral absorption - bypass GI (ie. SC no vasoconstriction)

c. metabolized by COMT- little by MAO

3. Therapeutic uses

 

a. bronchodilator

b. cardiac stimulant

4. Untoward effects

 

similar to epin.

 

- if take too much, increase rate of sudden heart failure -- OD of inhalation (aerosol) - fatal ventricular arrhythmias

 

C. Dopamine (intermediate of NE synthesis) a (high doses), b1

 

1. Pharmacologic effects

 

a. important NT of CNS, also has b1 effect, and causes release of NE from nerve terminals

b. receptors for dopamine in kidney D1 (decrease kidney arterial resistance- (vasodilation via increased cAMP) - increase pressure in kidneys - increase glomerular filtration. also D2 receptors - discuss later

c. at high doses it has an a effect -- vasoconstriction

2. Pharmacokinetics

 

a. similar to Epinephrine

 

3.Therapeutic uses

 

a. shock, cardiogenic- loss of contraction

b. congestive heart failure

4. Untoward effects

 

a. Heart pain, arrhythmias, hypertension, short lived - because of rapid metabolism

 

D. Phenylephrine a

 

 

 

 

1. Pharmacologic effects

 

a. Direct stimulant of a receptors, less potent than NE but longer lasting because not broken down by COMT

 

- vasoconstriction

- increased AP (arterial pressure)

- reflex decrease in the heart rate

2. Therapeutic usage

 

a. nasal decongestant

b. increases blood pressure

c. to provide local vasoconstriction (As a 10% opthalmic solution for eyes "gets the red out")

3. Untoward effects

 

a. cardiac irregularities

b. administration to eyes and nose - can be systemically absorbed

E. Ephedrine-occurs in various plants--used in China for 2000 years- in US 70 years ago- first orally active sympathomimetic drug

1. Pharmacologic effects

 

a. mixed-acting agent - that is both indirect and direct

 

1) Primary effect is indirect, it causes the release of NE from storage terminals. This is accomplished by displacing NE from storage granules inducing release

 

2) The direct effect - adrenergic receptors (a, b1, and b2)

 

b. When administered IV- action similar to Epin. - but less potent, longer lasting.

 

It does cause central nervous system stimulation- which can result in insomnia, nervousness, nausea, agitation

 

2. Pharmacokinetics

 

a. Ephedrine- absorbed when taken orally

b. resistant to COMT and MAO, therefore long lasting.

3. Therapeutic uses

 

a. Treatment for bronchial asthma

b. nasal decongestant [similar drug pseudoephedrine---Sudafed]

F. Amphetamine

 

-CNS stimulant-talk about later

 

-but also sympathomimetic -- mimics the action of the sympathetic nervous system

 

1. Pharmacologic effects

 

a. Acts indirectly by releasing norepinephrine

b. amphetamine also CNS stimulant --enters CNS easily

 

1) stimulates respiratory center-medulla

2) wakefulness

3) alertness

4) decreased sense of fatigue

5) elevation of mood

6) physical activity of athletes is improved

7) depresses appetite center in lateral hypothalamus (dextroamphetamine, Dexedrine- you buy dexatrim)

 

 

 

. a2 agonists [decreased cAMP]

 

-used for treating hypertension

 

Clonidine and methyl dopa prevent NE release

 

 

 

VII. Sympathetic Antagonists

 

-Block adrenergic receptors

-called sympatholytics

-antiadrenergic

A. a Adrenergic blocking agents

 

-agonists- NE, phenylephrine

 

1. Phenoxybenzamine - orally - not used much anymore

 

a. Mechanism of action

 

1) Binds covalently to the a receptor, producing irreversible blockade (not permanent--14-48 hours)

 

-also blocks Histamine (H1), Ach. and serotonin receptors, role of these actions is not known.

 

 It is Non Competitive Inhibitor

 

 

b. Pharmacologic effects

 

-antagonizes sympathetic responses mediated by a adrenergic receptors

 

1) Cardiovascular

 

A) increases cardiac output - result of decreased TPR

 

            DP

CO = ---------

            TPR

B) postural hypotension - lack of compensatory symp. vasoconstriction

 

 

 

PA in brain falls - normally sensed by baroreceptors- if phenoxybenzamine, no norepinephrine a receptor response- thus no increased TPR - called orthostatic hypotension

 

drugs that block both a and b1 would produce even more orthostatic hypotension

 

2) CNS- stimulates CNS --direct effect -- nausea, hyperventilation

 

c. Therapeutic uses

 

1) For acute hypertensive episodes---due to sympathomimetics or MAO inhibitors i.e. tranylcypromine (a MAO inhibitor- derivative of amphetamine)

 

was once used to reverse vasoconstriction in shock but not anymore -- ie. constriction in gut and kidney- irreversible shock

 

--Must be careful so that BP does not fall too much

 

2) To relieve vasospasm in Raynaud's Phenomenon- contraction of blood vessels to digits- results from great increase in sympathetic activity

 

3) Pheochromocytoma- tumor of adrenal medulla- get excess NE and E

 

d. Untoward effects

 

1) Hypotension- reflex tachycardia

 

2. Phentolamine and tolazoline- slowly absorbed orally reversible a1, a2 adrenergic blockade.

 

a. Pharmacologic effects

 

-lowers blood pressure, reflex cardiac stimulation

-used for acute hypertensive episodes

B. b-adrenergic blocking agents (agonists -- Isoproterenol, Epinephrine)

 

1. Propranolol- b1 and b2 competitive antagonist

 

a. Pharmacologic effects

 

1) Propranolol decreases heart rate, CO

 

2) Decreases blood flow to most tissues except brain

 

3) Decreases oxygen consumption in coronary

 

4) Propranolol inhibits renin secretion (kidney) renin- angiotensinogen- angiotensin I - angiotensin II - aldosterone- (angiotensin is a potent vasoconstrictor - decrease in resistance) b1

 

5) Increase airway resistance- b2 blockade

 

b. Pharmacokinetics

 

1) Completely absorbed from GI tract, but large portion is metabolized by liver

2) 90% is bound to plasma proteins

3) Elimination half-time ~ 3 hours - but is much longer in cirrhosis

c. Therapeutic uses

 

1) Treatment of hypertension

 

2) Prevention of angina pectoris (heart doesn't work so hard)

 

3) Prevention of ventricular arrhythmias

 

4) Long term prevention of sudden death in patients with myocardial infarction

 

5) Prevention of migraine headaches--excessive pulsation of temporal arteries propranolol decreases HR and BP.

 

6) Reduces intraoccular pressure (ie. glaucoma)

 

Other examples

 

a. Timolol- blocks b1 and b2

b. Metoprolol- blocks b1

c. dozens of others in testing phase

All three are important anti-hypertensive and antiarrhythmic

 

C. Agents that inhibit action of adrenergic nerves

 

1) reserpine- depletes stores of NE (MAO destroys NE) in nerve terminal- hypertension treatment

 

2) Guanethidine- inhibits release from presynaptic terminal- long term antihypertensive - but get orthostatic hypotension because no a1 or b1 -stand up pass out)

 

3) Bretylium- blocks release of NE -- it also inhibits reuptake of NE into nerve terminal -initially used as antiarrythmic and antihypertension - via local anesthetic effect, same with guanethidine