CLASSIFICATION
OF DRUGS
By: Yasir
Akeel 3rd year PMC.
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]
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
ò It is a potent stimulant of both a and b
adrenoceptors that’s why its effects on different target organs are complex.
ò It is a direct
acting drug and is related to sympathomimetic group of drugs.
SITE OF PRODUCTION.
ò 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.
ò The metabolites of epinephrine appeared in
urine.
òOnly a small amount of epinephrine (unchanged)
appears in urine.
òIn 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
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
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]
-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
-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
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
