DRUGS ACTING ON

AUTONOMIC NERVOUS
SYSTEM
(REVIEW ON ITS ANATOMY AND
PHYSIOLOGY)
(GROUP 2)
AUTONOMIC NERVOUS SYSTEM
Peripheral nervous system located outside the
brain and spinal cord is made of 2 divisions
the autonomic nervous system and somatic.
Autonomic nervous system is also called
visceral system.
Its function include control and regulation of
the heart,respiratory system,GI
tract,bladder,eyes and glands.
Involuntary nervous system.
2 sets of neuron in ANS are: AFFERENT
(sensory neurons) and EFFERENT (motor
neurons).
Afferent neurons send impulses to the
central nervous system where they are
interpreted.
Efferent neurons receives impulses from the
brain and transmit those impulses through
spinal cord to the effectors organ cells.

Efferent pathway is divided into 2 branches :
-Sympathetic
-Parasympathetic
Sympathetic nervous system is also called the
adrenergic system
Adrenaline was the neurotransmitter that
innervated the smooth muscle.
Adrenergic receptor organ cells are:
-Alpha
-Alpha
-Beta
-Beta
Norepinephrine is released from the
terminal nerve ending and stimulate the cell
receptors release response.
Parasympathetic nervous system

Also called the cholinergic system because the
neurotransmitter at the end of the neuron
that innervates the muscle is called
acetylcholine.
Cholinergic receptors are organ cells that are
either nicotinic or muscarinic.

Acetylcholine stimulates the receptor
cells to produce a response ,but the
enzyme acetylcholine sterase may
inactivate acetylcholine before it reaches
the receptor cells.
Drugs that mimic the neurotransmitter
noepinephrine and acetylcholine produce
a response opposite to each other in
same organ.
CHOLINERGIC SYSTEM
and
DRUGS
Cholinergic Transmission
Acetylcholine (Ach) is major neurohumoral transmitter at
autonomic, somatic as well as central sites

SYNTHESIS, STORAGE and DESTRUCTION of Ach

ATP + Acetate + CoEn-A


Acetyl CoEn-A

Choline

Acetylcholine + Co-En-A
Acetate activating reaction

Choline acetyl transferase
CHOLINOCEPTORS

Two types:
1. Muscarinic (G-protein coupled
receptors)

2. Nicotinic (Ligand
gated cation channel)



MUSCARINIC RECEPTORS


Selectively stimulated by muscarine and
blocked by atropine

Located on autonomic effector cells in heart,
blood vessels, eyes, smooth muscles, and glands
of GIT, respiratory and urinary tracts, sweat
glands and in CNS

Subtypes of muscarinic receptors

5 subtypes: M
1
, M
2
, M
3
, M
4
, M
5

M
1
, M
2
, M
3
are present on effector cells, prejunctional
nerve endings
Expressed both in both peripheral organs and in CNS

M
4
, M
5
are present mainly on nerve endings in areas
of brain, ; regulate release of other NTs

Functionally, M
1
, M
3
and M
5
are in one class and M
2
and M
4
in one class

M
1

neuronal receptor located on ganglion cells and central
neurons, esp. in cortex, hippocampus and corpus
striatum

Plays a major role in gastric secretion, relaxation of
esophageal sphincter on vagal stimulation, learning,
memory, motor functions, etc.

Agonist: oxotremorine
Antagonist: pirenzipine, telenzipine
M
2
Are predominantly as cardiac muscarinic receptors and as
autoceptors on cholinergic nerve endings and in smooth
muscles

Mediate vagal bradycardia
Agonist: methacholine antagonist: triptamine,
methoctramine



M
3
Mediate smooth muscle contractions and glandular
secretions
Mediate vasodilation through EDRF release
Agonist: bethanechol antagonist: darifenacin

MOA through M
1
, M
3
. M
5

1. Function through Gq protein


Activate membrane bound phospholipase C (PLc)


Generate inositol triphosphate (IP3) and diacylglycerol (DAG)


Release Ca++ intracellularly


Cause deploarization, glandular secretion, raise smooth muscle tone
Also


2. Also activate phopholipase A2


Enhanced release and synthesis of PGs,
LTs




MOA through M
2
, M
4

1. Function through Gi protein


Open K
+
channel


2. Inhibit adenylyl cyclase


hyperpolarization, reduced pacemaker activity, slowing of
conduction and decreased force of contractions in the heart
Nicotinic receptors
Selectively activated by nicotine
Blocked by tubocurarine or hexamethonium
Enclose ligand activated ion channel: their activation causes
opening of channel

rapid flow of cations

Depolarization

Generation of action potential


Two subtypes: N
M
and N
N
N
N
Present at ganglionic cells (sympathetic and
parasympathetic), adrenal medullary cells and in spinal
cord and certain areas of brain

Selectively stimulated by dimethyl phenyl piperazinium
(DMPP)

Blocked by hexamethonium

mediate primary pathway of transmission in ganglia

CHOLINERGIC DRUGS
or Cholinomimetics
or Parasympathomimetics

Drugs that produce actions similar to ACh

Act either by directly interacting with cholinergic
receptors (cholinergic agonists) or by increasing
availability of ACh at these sites (anticholinesterases)


Cholinergic agonists
CHOLINE ESTERS

Acetylcholine
Methacholine
Carbachol
Bethnechol
ALKALOIDS

Muscarine
Pilocarpine
Arecoline


Actions (of ACh as prototype)


Depending on which receptors Ach is binding to,
peripheral actions can be either muscarinic or nicotinic;
central actions described differently

A. Muscarinic

1. HEART (M2)
ACh hyperpolarizes SA nodal cells; rate of diastolic
depolarization
therefore, rate of impulse generation
bradycardia or even cardiac arrest may occur


HEART
At AV node and His-Purkinje fibres, refractory period;
conduction;
partial AV blockade
force of atrial contraction
- ventricular contractility is reduced


2. BLOOD VESSELS (M3)
All blood vessels are dilated
Fall in B.P. and flushing occur
Reasons
M3 receptors are present on vascular endothelial cells
vasodilatation is mediated through release of EDRF
(NO)
Due to inhibitory action of ACh on NA release from
vasoconstrictor nerve endings


Stimulation of cholinergic nerves to penis cause erection
- by releasing NO
- dilating cavernosal vessels through M3 receptors

3. SMOOTH MUSCLES (M3)
In most organs, are contracted
Tone and peristalsis in GIT
Sphincters relax
Abdominal cramps and evaculation of bowel

peristalsis in ureter
Detruser muscle contracts, sphincter relax
Voiding of bladder

Bronchial muscle constrict
dysponea, precipitation of bronchial asthma


4. GLANDS (M3 and M2)
secretion from all glands
sweating, salivation, lacrimation, gastric secretion



5. EYE
contraction of circular muscles of iris miosis
contraction of ciliary muscles spasm of
accomodation; reduction in intraoccular tension


B. NICOTINIC

1. AUTONOMIC GANGLIA
Both sympathetic and parasympathetic ganglia are
stimulated



2. SKELETAL MUSCLES
contraction of fibre
May cause twitching and fasciculations

C. CNS

Produce a complex pattern of stimulation followed by
depression


USES
Bethanechol is used in post-operative or post-partum
urinary retention
Neurogenic bladder atony, congenital megacolon,
gastroesophageal reflux

Side effects are prominent: belching, colic, involuntary
urination, defecation, flushing, sweating, fall in BP,
bronchospasm

CHOLINOMIMETIC ALKALOIDS

PILOCARPINE
Obtained from leaves of Pilocarpus microphyllus
Has prominent muscarinic actions
Stimulate ganglia
Cause marked sweating, salivation, other body
secretions
Small doses cause fall in BP (through muscarinic
receptors)
Higher doses elicit rise in BP and tachycardia (due to
ganglionic stimulation)
It penetrates cornea; cause miosis, ciliary muscle
contraction, fall in intraocular tension
Used only in the eyes as 0.5-4% drops in open angle
glaucoma

- Side effects: stinging sensation in eye, painful spasm of
accomodation

Used as miotic

MUSCARINE
Occur in poisonous mushroom Amanita muscaria

Mushroom poisoning: 3 types
1. Muscarine type (early mushroom poisoning)
- Symptoms appear within an hour of eating mushroom; promptly reversed
by atropine

2. Anticholinergic/hallucinogenic type
- Central manifestations occur; no specific treatment; atropine is
contraindicated

3. Phalloidin type (late mushroom poisoning)
- Inhibit RNA and protein synthesis
- Symptoms appear after many hours and due to damage to GIT mucosa,
liver, kidney
- Treatment consists of supportive measures, thiotic acid


ANTICHOLINESTERASES (antiChEs)


AntiChEs are agents which inhibit ChE; protect Ach from hydrolysis




REVERSIBLE
Carbamates Acridine
Physostigmine (eserine) Tacrine
Neostigmine
Pyridostimine
Edrophonium
Rivastigmine, Donepezil
IRREVERSIBLE
Carbamates Organophosphates
Carbaryl Dyflos
Propoxur Echothiophate
Parathion, Malathion
Diazinon, tabun,
sarin, soman
MOA
Anti-ChEs (carbamates and phosphates) carbamylate or
phosphorylate the esteratic site of the enzyme

Acetylated enzyme reacts with water rapidly and
esteratic site is freed in few milisec.;

carbamylated enzyme (reversible inhibitors) react
slowly

Phosphorylated enzyme (irreversible inhibitors) react
extremely slowly or not at all
PHARMACOLOGICAL ACTIONS
1. Ganglia
anti-ChEs stimulate ganglia through muscarinic receptors
High doses causes persistent depolarization of nicotinic receptors and
cause transmission blockade

2. CVS
muscarinic action produce bradycardia and hypotension; ganglionic
stimulation heart and B.P.
Overall effects are unpredictable and depend on agent and dose

3. Skeletal muscles
Repetitive firing of muscles twitchings and facsiculations
Higher doses cause persistent depolarization of endplates blockade
of neuromuscular transmission muscle weakness and paralysis

4. Other effects
Stimulation of smooth muscles and glands of GIT, respiratory, urinary
Individual compounds
Physostigmine Neostigmine
1. Natural alkaloid fron Physostigma venonsum 1. synthetic
2. Good oral absorption 2. Poor oral absorption
3. CNS actions present 3. CNS actions absent
4. Penetrate cornea in eye 4. Poor penetration
5. No direct effects on N
M
cholinoceptors 5. direct action on N
M
cholinoceptors
6. Prominent effect on autonomic effectors 6. Prominent effect on skeletal muscles
7. Used as miotic in glaucoma 7. Used in myasthenia gravis
8. Dose: 0.5-1 mg oral/parentral
0.1-1% eye drops
8. dose: 0.5-2.5 mg i.m./s.c.
15-30 mg orally
9. Duration of action: systemic: 4-6 hrs
in eye: 6-24 hrs
9. DOA: 3-4 hrs



** anti-ChEs are to be used cautiously in peptic ulcer,
asthma, COPD and seizure patients

USES
1. As miotic

a) In glaucoma: miotics tone of ciliary muscles and sphincter pupillae
which pull on and improve outflow facility i.o.t. falls in open angle
glaucoma

Pilocarpine is most preferred in glaucoma.
Sideeffects: spasm of accomodation, brow pain;
systemic sideeffects: nausea, diarrhoea, sweating, bronchospasm

Physostigmine is used only to supplement pilocarpine

b) To reverse the effect of mydriatics after refraction testing

c) To prevent formation of adhesions between iris and lens or iris and
cornea in iritis, corneal ulcers etc.

In GLAUCOMA

Group of diseases characterised by a progressive form of optic
nerve damage associated with raised i.o.t. (> 21mmHg)

Therapeutic measure: 1. lower i.o.t. either by reducing aqueous
humor secretion or by promoting its drainage

OPEN ANGLE GLAUCOMA (wide angle, chronic simple)
It is genetically predisposed degenerative disease affecting
patency of the trabecular meshwork which is lost with age
i.o.t. rise progressively,, ocular hypotensive drugs are
used

1. adrenergic blockers: (timolol, betaxolol, levobunolol)
lower i.o.t. by reducing aqueous formation (by downregulation of
adenylyl cyclase)
Doesnot affect pupil size, tone of ciliary muscle or outflow
facility
2. Miotics
They increase tone of ciliary muscles; and pull on and improve
alignment of trabeculae increase outflow facility i.o.t. falls

PILOCARPINE
Preferred as miotic
Therapy is started with lowest effective concentration (0.5%)
Action is rapid and short lasting (4-6 hrs)

3. Adrenergic agonists
Adrenaline, dipivefrine, brimonidine

4. Carbonic anhydrase inhibitors
Acetazolamide, dorzolamide
ANGLE CLOSURE (narrow angle, acute, congestive) glaucoma
Occur in individuals with a narrow iridocorneal angle and
shallow anterior chamber
i.o.t. remains normal (until attack is precipitated)
i.o.t. risese rapidly to very high values
Emergency condition; failure to lower i.o.t. causes loss of sight

Therapy measures
1. Topical blocker: timolol 0.5% is instilled 6-8 hourly
2. Miotic: pilocarpine 1-2%
3. Hypertonic mannitol 20% or glycerol 10%
4. Acetazolamide 0.5 g i.v. or oral twice daily
USES
2. In myasthenia gravis

Autoimmune disorder due to development of antibodies for
nicotinic receptors at muscle end plate

Treatment: 1. Neostigmine (15mg orally 6 hourly;;; dose
adjusted as per response
2. corticosteroids

Anticholinesterase poisoning

Local muscarinic manifestations at site of exposure occur immediately
complex systemic effects due to muscarinic, nicotinic and central
effects
Irritation of eye, lacrymation, salivation, sweating, blurring of vision,
defecation, urination
Fall in B.P., tachycardia, arrythmias, vascular collapse
Muscular weakness, fasciculations, respiratory paralysis
Excitement, ataxia, convulsions, coma, death
Death is due to respiratory failure


Treatment: 1. termination of exposure
2. supportive measures
3. specific antidotes: atropine, cholinesterase
reactivators (pralidoxime (2-PAM))

Anticholinergic Drugs (muscarinic receptor
antagonists, Atropinic, Parasympatholytic)


Anticholinergic drugs are those which block actions of ACh on
autonomic effectors and in CNS exerted through muscarinic
receptors

Generally, called as Neuromuscular blockers

Atropine is prototype of this class
CLASSIFICATION

1. Natural alkaloids: atropine, hyoscine (scopolamine)

2. Semisynthetic derivatives: homatropine , atropine methonitrate,
hyoscine bromide, ipratropium bromide, tiotropium bromide

3. Synthetic compounds:
a) mydriatics: cyclopentolate, tropicamide
b) Antisecretory, antispasmodics:
(i) quaternary compounds eg. Propantheline, oxyphenonium,
clidinium, pipenzolate, isopropamide, glycopyrolate
(ii) tertiary amines eg. Dicyclomine, oxybutynin, flevoxate,
pirenzipine, telenzipine
c) Antiparkinsonians trihexyphenidyl, procyclidine, biperiden,
benztropine, cycrimine, ethopropazine
PHARMACOLOGICAL ACTIONS (of atropine as prototype)

1. CNS: overall stimulant actions

Hyoscine produces central (depressant) effects at low doses

Atropine stimulates medullary centres: vagal, respiratory,
vasomotor
Depresses vestibular excitation; has anti-motion sickness property

By blocking anti-cholinergic activity in basal ganglia, it
suppresses tremor and rigidity in parkinsonism

High doses cause cortical excitation, restlessness, disorientation,
hallucinations, delirium, followed by respiratory depression and
coma


2. CVS: overall stimulant actions

1. HEART : atropine cause tachycardia (due to blockade of M2
receptors on SA node, through which vagal tone heart rate)

Atropine facilatates A-V conduction

2. B.P.: atropine dosenot have any marked effect on B.P.
Tachycardia and vasomotor centre stimulation raise B.P.
Histamine release and direct vasodilator action lower B.P.
Atropine blocks vasodepressor actions of cholinergic agonists
3. EYE
Topical instillation of atropine causes mydriasis, abolition of light
reflex, cycloplegia lasting 7-10 days photophobia, blurring of
near vision
i.o.t. rise




4. SMOOTH MUSCLES
All smooth muscles that receive parasympathetic innervation, are
relaxed by atropine
Tone and amplitude of contractions of stomach, intestine
passage of chyme constipation occur
Atropine cause bronchodilation and airway resistance
Atropine attenuate the action of histamine, PGs, by antagonising
the reflex vagal component
Has relaxant action on ureter and urinary bladder
5. GLANDS
Atropine sweat, salivary, lacrimal secretion
Skin and eyes become dry; talking and swallowing becomes
difficult
Atropine secretion of acid, pepsin and mucus in stomach
Bicarbonate secretino in stomach is ed




4. SMOOTH MUSCLES
All smooth muscles that receive parasympathetic innervation, are
relaxed by atropine
Tone and amplitude of contractions of stomach, intestine
passage of chyme constipation occur
Atropine cause bronchodilation and airway resistance
Atropine attenuate the action of histamine, PGs, by antagonising
the reflex vagal component
Has relaxant action on ureter and urinary bladder
USES
1. As antisecretory
a) Preanaesthetic medication
b) Peptic ulcer (because it reduce gastric secretion)
c) Pulmonary embolism (reducing reflex secretions)
d) To check excess sweating or swelling

2. As spasmodic
a) Intestinal and renal colic, abdominal cramps
b) Nervous and drug induced diarrhoea
c) Spastic constipation, irritable colon
d) Gastric hypermotility, gastritis, nervous dyspepsia
e) To relieve urinary frequency and urgency
f) dynmenorrhoea
USES
3. Bronchial asthma, asthmatic bronchitis, COPD
Reflex vagal activity causes vasoconstriction and
increased secretion

4. As mydriatic and cycloplegic

5. As cardiac vagolytic

6. For central action
i) parkinsonism
ii) motion sickness
iii) hyoscine is used as a lie detector

7. To antagonise muscarinic effects of drugs and poisons
SIDE EFFECTS AND TOXICITY
Dry mouth, difficulty in swallowing and talking
Dry, flushed and hot skin, fever, difficulty in micturition
Dilated pupil, photophobia, blurred vision, palpitation
Excitement, ataxia, delirium, hallucinations
Hypotension, weak and rapid pulse, cardiovascular
collapse with respiratory depression

Treatment: gastric lavage with Tannic acid
supportive measures
Physostigmine 1-3 mg s.c. or i.v.,
repeated 4-6 hourly
Adrenergic blockers (antagonist)
Drugs that block the effect of adrenergic
neurotransmitter

drugs that selectively inhibit specific
receptor sites from sympathetic stimulation.






effects of adrenergic blockers at
receptors
Receptors
Alpha




eta
1

Beta
2


Responses
Vasodilation: decrease blood pressure, reflex
tachycardia might result miosis, occurs;
suppresses ejaculation; reduces contraction
of the smooth muscles in the bladder neck
and prostate gland

Decrease heart rate; reduces force of
contraction.

Constrict bronchioles contract uterus; inhibits
glycogenolysis.
Alpha adrenergic blockers
Drugs that block or inhibit a response at the alpha
adrenergic receptor site.
..eg,. Prazosin and analogs - terazosin,
doxazosin, trimazosin

These are used to treat hypertension by relaxing
arterial and venous smooth muscle, decreasing
vascular resistance and venous return, and
decreasing blood pressure without a significant
increase in heart rate.
Orthostatic hypotension and reflex tachychardia

Beta-adrenergic blockers
Hormones known as catecholamines
(norepinephrine, epinephrine) activate or
stimulate specific receptors on cell surfaces,
known as adrenergic receptors. A receptor has a
specific structure that allows a drug or hormone
to bind to it, similar to a key fitting in a lock.






What Side Effects Can I Expect?

some patients notice muscle fatigue, especially
with vigorous physical activity.
Patients with asthma should not take -blockers
because they can interfere with the passage of air
into the lungs.
In some patients, heart rate and blood pressure
may be reduced too much, causing
lightheadedness and fainting.
The drugs should be used with caution in diabetic
patients taking insulin who have problems with
excessive blood-sugar lowering and
lightheadedness.
The drugs should not be used if a patient has
severe mental depression.


What Precautions Do I Need to Take?

Never stop taking your prescribed -
blockers abruptly without informing your
healthcare provider. Try not to miss any
doses.
If you develop excessive fatigue, mental
depression, lightheadedness, fainting, or
excessive shortness of breath, inform
your healthcare provider.
If you are prescribed new medicines or
herbal remedies, inform your healthcare
provider.

Adrenergic neuron blockers
* Potent drugs that block norepi. form
sympathetic nerve endings a dec. in
norepi. dec. in BP
* Decrease in both cardiac output &
peripheral vascular resistance
* Common SE = Orthostatic Hypotension*

ANTIDIABETIC DRUGS
Diabetes Mellitus
third leading cause of death
antidiabetic drugs are used to control this
Two Groups
Insulin a protein secreted from the beta
cells of pancreas which is necessary for
carbohydrate metabolism and plays an
important role in protein and fat metabolism.
The beta cells make up 75% of the pancreas
and the alpha cells that secrete glucagon, a
hyperglycemic substance, occupy
approximately 20% of pancreas.
Oral hypoglycemic dugs or oral antidiabetic
drugs are synthetic preparations that
stimulate insulin increase otherwise alter the
metabolic response to hyperglycemia.
Diabetes Mellitus
A chronic disease resulting from deficient
glucose metabolism
Caused by insufficient insulin secretion from
the beta cells. This results in high blood sugar
or hyperglycemia
Characterized by 3 ps: Polyuria ( increased
urine output), Polydipsia (increased thirst),
and polyphagia (increased hunger)
Types of Diabetes Mellitus
1. Type 1 DM (Insulin Dependent DM or IDDM)
10%-12%
caused by viral infections, environmental
sanitations, and genetic factors
2. Type 2 DM (Non- Insulin Dependent or NIDDM)
85%-90%
caused by heredity or obesity
some beta cell function with varying amounts
of insulin secretion

3. Gestational DM
< 1% ( 2%-5% of all pregnancies)
during the 2
nd
and 3
rd
trimesters of
pregnancy, the levels of the hormones,
progesterone, cortisol, and human placental
lactogen (HPL), are increased
Glucose is then mabiuzed (?) from the
tissue
Insulin
Released from the beta cells of the islets of
Langerhans in response to an increase in
blood glucose
Promote the uptake of glucose, amino acids,
and fatty acids and converts them to
substances that are stored in the body cells
Normal Range : 60-100mg/dl (blood glucose)
and 70-110mg/dl (serum glucose)
Beta Cells Secretion of Insulin
Beta Cells in the pancreas secrete insulin
approximately 0.2-0.5 units/kg/daily
A client with DM may require 0.2-1.0
units/kg/daily
Commercially Prepared Insulin
Parenteral (injectable) Insulin is obtained from
pork and beef pancreas when the animals re
slaughtered
1. Pork Insulin- related to human insulin having
only one amino acid; weaker allergen
2. Beef Insulin- for different amino acids

Human Insulin (Humulin)
Introduced in 1983 and is produced by two
methods:
1. Changing the direfferent amino acid of prok insulin
2. Using DNA technology


Humulin produced by DNA technology is made
more pure which results in fewer side effects.
It is administered via SubQ and is absorbed
faster and have a shorter duration than animal insulin.

The concentration of insulin is 100 units/ml or
500 U/ml and the insulin is packaged in a 10
ml vial.
Administration of Insulin
Insulin is a protein and cannot be administered daily
because GI secretions destroy the insulin structure.
Administered via SubQ at 45
o
-90
o

Regular insulin is the only type that can administered
IV
Insulin absorption is greater when given in the
deltoid and abdominal areas than when given in the
thigh and buttocks areas. Heat and massage can
increase subQ absorption.



Insulin injection sites should be rotated to
prevent lipodystrophy (tissue atrophy or
hypertrophy) which can interfere with insulin
absorption
Lipoatrophy a depression under the skin
surface that primarily occurs in females & children
caused by the use of animal insulin
(beef &pork)

Lipohypertrophy is a raised lump or knot on
the skin surface that is more common in males
caused by repeated injection
in the SubQ sites
Types of Insulin
A. Rapid Acting Insulins
clear in solution with no added substance to
prolong the insulin action

1. Lispro Insulin (Humalog)
approved for use in 1996
the action begins in 5-15 minutes and the
duration of action is 2-4 hours
Acts faster than regular insulin must not be
administered more than 5 mins before mealtime
formed by reversing 2 amino acids in human
regular insulin



2. Regular Insulin
unmodified , crystalline
any type of insulin that can be administered
IV and SubQ
given 30 minutes before meals

B. Short Acting Insulin
clear in solution with ni added substance to
prolong the insulin action
has an onset of action in 30 minutes to 1
hour
the peak action occurs in 2-4 hours and the
duration of action is 6-8 hours
C. Intermediate Acting Insulins
cloudy and may contain protamine, a protein that
prolongs the action of insulin or zinc which also slows
the onset of action and prolongs the duration of action.

the onset is 1-2 hours, peak action occurs in 6-12
hours and the duration of action 18-24 hours

include neutral protamine-Hagedorn (NPH) , Lerute,
humulinV and Humulin L.

Lerute and humulin L contain zinc which aslo prolongs
the insulin action time

D. Long Acting Insulin
acts in 4-8 hours, peaks in 14-20 hours and lasts for
24-36 hours
1. Humulin V Ultralente
absorbed slower than other insulins because of
its; large crystals which dissolve slowly and prolong the
duration time
2. Lantus
newer long acting insulin
an insulin glargine that is an analogue of human
insulin
first long aching recombinant DNA (rDNA)
human insulin approved by FDA
has 24 hr duration

E. Combination Insulins- commercially premixed
1. Humulin 70/30
its vials or prefilled disposable pens contain 70%
of human isophane (intermediate-acting insulin NPH)
and 30% regular (fast acting) insulin

2. Humulin 50/50
-its vial or pen contains 50% of isophane (NPH)
insulin and 50% insulin

3. Humalog 75/25
- available as a prefilled disposable pen only and
contains 75% Lispro prostamine insulin and 25% Lispro
rapid insulin


- helps prevent hypoglycemia , which could
occur with the 70/30 or 50/50 combinations
insulin and helps control hyperglycemia more
effectively
4. Novalin 70/30
Insulins
DRUG CLASS
Antidiabetic Insulins
Humalog (Lispro) rapid acting
Regular Humulin R short acting
Humulin N- intermediate acting
Glargine (Lantus) long acting
Pregnancy Category B
CONTRAINDICATIONS
Hypersensitivity to beef, prk, zimc, protamine
insulins
Caution: Hypersensitivity

DOSAGE
Varies according to clients blood sugar



DRUG-LAB-FOOD INTERACTIONS
Drugs: Increased hypoglycemic effect with
aspirin, o: Increased oral anticoagulant,
alcohol, oral hypoglycemics, beta-blockers,
tricyclic antidepressants, MAOIs, tetracycline;
Decreased hypoglycemic effect with thiazides,
glucocorticoids, oral contraceptives, thyroid
drugs, smoking

PHARMACOKINETICS
Absorption: Lispro and Humulin R rapidly
absorbed from subQ injection site
Humulin N is absorbed at slower rate
Glargine is absorbed at slow evenly distributed
rate
Distribution PB :UK
Metabolism: t
1
/
2 :
varies with type of insulin
Excretion: Mostly in urine


Pharmacodynamics
Humalog (Lispro)
subQ: Onset 5-15 min
Peak: 30-60 min
Duration: 3-4 h
Regular Humulin R
subQ: Onset 30-60 min
Peak: 2-3 h
Duration: 4-8 h
Humulin N
subQ :Onset 1-2 h
Peak: 4-12 h
Duration: 18-24 h
Glargine (Lantus)
subQ: Onset 1 h
Peak: None
Duration: 24 h

Therapeutics Effects
To control DM; to lower blood sugar

Mode of Action: Insulin promotes use of
glucose by body cells

Side Effects: Confusion, agitation, tremors,
headache, flushing, hunger, weakness,
lethargy, fatigue, urticaria, redness, irritation
or swelling at insulin injection site
Adverse Effects
Tachycardia, palpitations, hypoglycemic
reaction, rebound hypergylcemia (somogyi
effect), lipodystrophy
Life Threatening: Shock, anaphylaxis
Insulin Resistance
antibodies develop over time in persons
taking animal insulin
Antibody development can cause insulin
resistance and insulin allergy. This can slow
the onset of insulin action and extend its
duration action.
Obesity can also be a causative factor of
insulin resistance

Storage of Insulin
Unopened insulin vials are refrigerated until needed
An open insulin vial may be kept at room temperature
for 1 month or in the refrigerator for 3 months
Opened insulin vials lose their strength after
approximately 3 months
Insulin vials should not be put in the freezer or places
in direct sunlight or in high temperature area
Refilled syringes should be stored in the refrigerator
and should be used within 1-2 wks
Sliding Scale Insulin Coverage
Insulin may be administered in adjusted doses
that depend an individual blood glucose test
results
When the diabetic client has extreme
variances in insulin requirements( e.g. stress
from nebulization, surgery illness, infection),
adjusted dosing or sliding scale insulin
coverage provides a more constant.
Insulin Pen Injection

An insulin pen resembles a fountain pen. The
pen contains a disposable needle and
disposable insulin-filled cartridge
The insulin filled pens are considered to
deliver an insulin dose more accurate than the
traditional 100 unit syringe and vial
The capacity of these prefilled and reusable
pens is 150-300 units.

Insulin Pumps
1. Implantable Insulin Pumps


-is surgically implanted in the
abdomen
-it delivers basal insulin
infusion and bolus with
meals, administered either
intraperitoneally or IV
- With use of this, fewer
hypoglycemic reactions
occur and blood glucoses
levels are controlled
2. Portable or External Insulin Pumps a.k.a
Continous SubQ insulin infusion (CSII)
-keeps the blood glucose levels as close to
normal as possible
- insulin pump is a battery-operated device
that uses regular insulin, which is stored in a
reservoir syringe placed inside the device. The
syringe is the size of a pager and weighs about
3.5 oz


Intranasal Insulin
-Administration of this
is in experimental
stage
-causes a rapid onset
and has a short
duration of action
-Its dose is 10 times
greater than a subQ
dose
Insulin Jet Injection
Directly through
the skin in the
fatty tissue
Insulin is
delivered in a
high pressure
Not indicated
for children or
older adults
Oral Antidiabetic Drugs ( Oral
Hypoglycemic Drugs)
A.k.a. hypoglycemics were discovered in 1950s
Persons with type 2 DM are indicated
Sulfonylureas- antidiabetics are chemically related
to sulfonamides but lacking antibacterial activyt
- increases the insulin cell receptors
1. First Generation
- short acting, intermediate-acting and long
acting antidiabetics
2. 2
ND
Generation
- have a greater hypoglycemic potency
- have larger duration and cause fewer side
effects
- have less displacement potential from protein
binding sites by other highly protein-bound
proteins such as salicylates and warfarin
- should not be used when there is liver or
kidney dysfunction

Oral Antidiabetics
Generic Route and Dosage Uses and Considerations
First-Generation: Short
Acting
tobultamide(Orinase)
A: PO: 500-3000 mg/d in 2-
3 divided doses
For managing type 2 Diabetes.
Drug is chemically related to
sulfonamides with no antiinfective
effect. Hypoglycemic reaction may
occur if overdosed.
Pregnancy category: C; PB: >90%;
; 4-7 h
First-Generation:
Intermediate Acting
acetohexamide (Dymelor)


tolazamide (Tolinase)

A: PO: 500-3000 mg/d
before breakfast; max: 1.5
g/d


A: PO: 100-250 mg/d in 1-2
divided doses; max 1 g/d
For managing mild to moderately
severe type 2 DM.
Pregnancy Category : C ; PB:UK ;
t1/2: 5-6 h

Same as acetohexamide. Diet and
exercise should be a part of
diabetic therapy. Duration of action
is 10 to 20 hours.
Pregnancy Category : C ; PB:90% ;
t1/2: 7 h

First Generation: Long Acting
chlorpropamide (Diabinase)
A: PO: Initially :100-250 mg/d
Maint.: 100-500 mg/d in
divided doses; max: 750 mg/d
Second Generation
glipzide (Glucotrol)

glyburide nonmicronized
(Diabeta, Micronase)



A: PO: Initially|: 1.25-5 mg/d;
maint. : 1.25-20 mg
q.i.d./b.i.d.
Max. : 20 mg/d
For managing type 2 DM: May
be given to selected type1
clients for reducing insulin.
Diet and Exercis should be a
part of diabetic therapy.
Duration of action is 24 h. May
cause water and sodium
retention.
Pregnancy Category : C ;
PB:95% ; t1/2: 36h

glyburide micronized
(Glynase)
A: PO: Initially: 1.5-3 mg/d in
AM; maint. : 3-4.5 mg/d
Max. : 12 mg/d in 1 or 2
divided doses
For type 2 Diabetes. Same as
glyburide nonmicronized
glimepiride (Amaryl) A: PO: Initially :1-2 mg a.c.
Maint.: 1-4 mg/d a.c.; max: 8
mg/d a.c.

To treat clients with type 2
DM. Maybe used in
combination with insulin. Can
lower the 2 hour post-prandial
glucose levels significantly. GI
disturbance may occur.
Pregnancy Category : C ;
PB:99.5% ; t1/2: 5-9h

Nonsulfonylurease
Biguanides
metformin (Glucophage)
Inhibitors
acarbose (Precose)
A: PO: Initially :25 mg 1-3x
daily with meals
max: 150 mg/d<60 kg, 300
mg/d if > 60 kg

For managing hyperglycemia
in type 2DM. Used as
monotherapy or in
combination with
sulfonylurea.
Pregnancy category: B;
PB: UK;t; 2 h
Alpha-Glucosidae
Inhibitors
miglitol (Glyset)
A: PO: 25-100 mg t.i.d. with
meals
Maint.: 1-4 mg/d a.c.; max: 8
mg/d a.c.

For managing type 2 diabetes.
Maybe taken with a
sulfonylurea or as with diet
and exercise. GI disturbances
may occur.
Thiazolidinediones (Insulin-
Enhancing Agents)
pioglitazone HCl (Actos)
A: PO: 15-45 mg/d Management of Type 2 DM. It
improves glycemic control and
decreases insulin resistance. It
inhibits gluconeogenesis and
increases sensitivity. Can
increase resumption f
ovulation in premenopausal
women. For monotherapy
use; maybe combined with
metformin. Diet and exercise
and monitoring liver enzymes
are suggested. Replaced
troglitazone (Rezulin), which
was removed from the market
because it caused severe liver
problems.
Pregnancy Category : C ;
PB:99.8% ; t1/2:3-4 h

Meglitinides
repaglinide (Prandin) A: PO: 0.5-4 mg a.c. bid,tid,qid
max: 16 mg/d a.c.

To manage type 2 DM. May be
taken alone or in combination
with metformin. Similar in
action to sulfonylureas but not
in structure. Increases beta-
cell secretion insulin.
Pregnancy Category : C ;
PB:99.8% ; t1/2:3-4 h
nateglinide (Starlix) A: PO:60-120 mg a.c.
bid,tid,qid
max: 540 mg/d a.c.

To treat type 2 DM. It
increases insulin from the beta
cells. This drug may be used
alone or in combination with
metformin.
Pregnancy Category : UK ;
PB:98% ; t1/2:1.5 h

Fixed Combination of Oral Antidiabetic Drugs

glyburide/ metformin
( Glucovance)

A: PO: Initially:1.25/250 mg
(glyburide/ metformin)daily or bid
with meals. Increase dose at 2-wk
intervals; maint: 2.5/500 mg or
5/500mg/d or bid with meals; max:
20/2000 mg/d

For managing type 2 DM. May
be used when glucose or not
controlled with either drug
alone. Contraindicated for
clients with renal insufficiency
because of the risk of
developing lactic acidosis.
Pregnancy Category : B-D ;
PB: UK ; t1/2: UK

Hyperglycemic Drugs
Glucagon
A hyperglycemic hormone secreted by the alpha
cells of the islets of Langerhans
Increases blood sugar by stimulating
glycogenolysis (glycogen breakdown) in the liver
It protects the body cells (esp. in brain and retina),
by providing the nutrients and energy needed to
maintain body function
Available for parenteral use (subQ,IM, and IV)
Used to treat insulin-induced hypoglycemia
Diazoxide
1. Oral Diazoxide (Proglycem)
-increases blood sugar by inhibiting insulin release
from the beta cells and stimulating release of
epinephrine (adrenaline) from adrenal medulla
- not indicated for hypoglycemic reactions
- used to treat chronic hypoglycemia caused by
hyperinsulin because of islet cell cancer or
hyperplasia
-the parenteral form of diazoxide is prescribed for
malignant hypertension
- has a long half life and is highly CHIN bound.
-its onset of action is 1 hr and the duration of action
is 18 hrs
Other Agents
Exenatide (Byetta)
- under new classification of drugs known as
mimetic that improves beta-cell responsiveness,
which improves glucose control in people with
type 2 DM
Enhance insulin secretion, increase beta cell
responsiveness, suppress glucagon secretion, slow
gastric emptying and reduce food intake
A/E: headache, dizziness, nausea, vomiting and
diarrhea
Pramtintide acetate (Symlin)
For adults with type 1 and 2 DM
Improve postprandial glucose control in diabetic
patients who are using insulin but unable to
achieve and maintain glucose control
Suppress glucagon secretion, slow gastric
emptying and modulate appetite by including
satiety
A/E : dizziness, anorexia, nausea, vomiting and
fatigue
Administered via subQ before meals in the
abdomen or thigh.