ADRENERGIC AGENTS

Dr. AMIT SHAH

 ADRENOCEPTOR
RECEPTOR SIGNAL TISSUE EFFECTS
Vascular smooth muscle Contraction
Genitourinary smooth mus. Contraction
α1 Gq/Gi Intestinal smooth muscle Relaxation
Heart ↑ Inotropy and excitability
Liver Glycogenolysis and gluconeogenesis
Pancreatic ß-cells ↓ Insulin secretion
Platelets Aggregation
α2 Gi
Nerve ↓ Norepinephrine release
Vascular smooth muscle Contraction
Heart ↑ Chronotropy and inotropy
ß1 Gs Heart ↑ AV-node conduction velocity
Renal juxtaglomerular cells ↑ Renin secretion
Smooth muscle Relaxation
ß2 Gs Liver Glycogenolysis and gluconeogenesis
Skeletal muscle Glycogenolysis and K+ uptake
ß3 Gs Adipose Lipolysis
 CLASSIFICATION
ADRENOCEPTOR AGONISTS

DIRECT ACTING INDIRECT ACTING MIXED ACTING

Selective Non-selective Releasing Uptake MAO COMT

Agents Inhibitors Inhibitors Inhibitors
α1 – α1 α2 –
Phenylephrine Oxymetazoline Entacapone
Ampheta Cocaine Selegine
α2 – Clonidine ß 1 ß2 – mine
ß1 – Isoprenaline Tyramine
Dobutamine α1 α2 ß1 ß2–
ß2 - Epinephrine Ephedrine (α1
Terbutaline α1 α2 ß1 – α2 ß1 ß2 &
Norepinephrine Releasing
Agent)
o Adrenaline: α1, α2, β1, β2 & some β3

o Noradrenaline: α1, α2, β1, β3 but no β2

o Isoprenaline: β1, β2, β3, little α

o Dopamine: D1, D2, α1, β1 but no β2

o Dobutamine: β1
 NORADRENALINE
 Neurotransmitter released from postganglionic adrenergic
nerve endings (80%)
 Agonist at α1, α2 and β1 receptors but no effect on β2
 Orally ineffective & poor SC absorption → give IV
 Metabolized by MAO, COMT
 Short duration of action
 Increases systolic, diastolic B.P, mean pressure, pulse
pressure and stroke volume
 Total peripheral resistance (TPR) increases due to
vasoconstriction
 Decreases blood flow to kidney, liver and skeletal muscles
 Increases coronary blood flow
 NORADRENALINE cont....
 Clinical Uses: Slow IV infusion at the rate of 2-4mg/
minute used as a vasopressor agent in treatment of
hypovolemic shock and other hypotensive states in
order to raise B.P
 ADRs:
 Anxiety, palpitation, respiratory difficulty
 Rise of B.P, headache
 Extravasations causes necrosis, gangrene
 Contracts gravid uterus
 Severe hypertension, violent headache, photophobia,
anginal pain, pallor and sweating
 C/I in hyperthyroid and hypertensive patients
 ISOPRENALINE
 Synthetic β agonist (β1+ β2 agonist)
 Cardiac stimulant & bronchodilator
 Rarely used clinically
 Has been used for bronchial asthma
 Occasionally used to maintain idio ventricular rhythm
till pacemaker is implanted
Epinephrine Norepinephrine Isoprenaline α blocker Epinephrine Norepinephrine Isoprenaline

DALE’S VASOMOTOR REVERSAL PHENOMENON

Property Adrenaline Noradrenaline
Chemistry Catecholamine Catecholamine
On adrenergic Agonist Agonist
receptors
Receptor selectivity Both alpha and beta Predominantly alpha
(α1, α2, β1, β2 & (α1, α2, β1, β3 but no
some β3) β2)
Effect on BP Biphasic Monophasic
Dales’ vasomotor yes no
reversal
Clinical uses many Rarely used in
hypotension
 DOPAMINE
 Immediate metabolic precursor of Noradrenaline
 High concentration in basal ganglia, limbic system and
hypothalamus
 Central neurotransmitter, regulates body movements
 In periphery, synthesized in epithelial cells of the
proximal tubule and exert local diuretic and
natriuretic action
 Substrate for MAO, COMT so Ineffective orally, IV use
only
 Short T 1/2 (3-5minutes)
 Agonists at D1-5, α1 and β1 receptors
 DOPAMINE cont....
Dose Receptor & Site Action
D1-receptors in renal, • Vasodilatation
Small dose
mesenteric and coronary • ↑ renal blood flow,
(2-5 μg/kg/minute)
vessels GFR an natriuresis
Moderate dose • Positive inotropic and
β1-receptors in heart
(5-10 μg/kg/minute) chronotropic actions
High dose vascular adrenergic α1- • Vasoconstriction
(10-30 μg/kg/minute) receptors • ↓ renal blood flow

 Clinical Uses:
 Cardiogenic shock resulting from MI, trauma and surgery
 Congestive heart failure
 ADRs: Nausea, vomiting, tachycardia, ectopic beats,
HT and cardiac arrhythmias
 DOBUTAMINE
 Racemic mixtures of derivatives of Dopamine
 l-form: α1 receptor agonist
 d-form: α1 receptor antagonist; β1 receptor agonist
 Does not act on D1 or D2 receptors
 Increase in force of contraction and cardiac output but
no change total peripheral resistance
 Clinical Uses: Dose of 2-8 mcg/kg/min IV infusion
 Heart failure in cardiac surgery
 Septic and cardiogenic shock
 Congestive Heart failure
 AMPHETAMINE
 Powerful CNS stimulant;
peripheral α and β action
 Indirectly acting
sympathomimetic drug
 Effective after oral ROA and long
acting action
 Mechanism of action:
 Release of biogenic amines from
their storage sites in nerve terminal
 Enhance Release of NE, dopamine,
and 5-HT in CNS
 AMPHETAMINE cont....
 CVS:
 Increase systolic, diastolic BP, HR decrease due to reflex
mechanisms, high doses- arrhythmia

 Smooth muscles:
 Marked contractile response on sphincter of urinary bladder –
used in treatment of enuresis and incontinence
 Other smooth muscles – similar to NE

 Respiration:
 Stimulate respiratory centre, increase rate and depth of
respiration
 AMPHETAMINE cont....
 CNS: (Most potent stimulator)
 Stimulates medullary respiratory centre and RAS
 Wakefulness, decrease sense of fatigue, mood elevation,
increase initiative and self-confidence
 CNS stimulant → Psychoactive performance enhancing drug
 Banned drug (Drug of “Dope Test”)
 Increased alertness, euphoria, talkativeness – thrill or kick
 Increased physical performance without fatigue – short lasting
and mistakes increase
 Anxiety, restlessness, tremor and dysphoria occurs
 Lack of sleep affects quality of performance
 Small analgesic effect: enhance effect of opioids
 AMPHETAMINE cont....
 Anorectic – appetite suppression, reduce food intake
 Repeated use – Behavioural abnormalities

 Clinical Uses: Narcolepsy; Attention Deficit Hyperactive

Disorder (ADHD)

 ADRs: (usually from overdose)

 CNS: restlessness, irritability, dizziness, tremors, confusion,
anxiety, insomnia, panic states, paranoid hallucinations,
suicidal and homicidal tendencies, convulsions, coma – Death
 Fatigue and depression follows central stimulation
 CVS: palpitations, angina, headache, hyper/hypotension,
arrhythmia
 Dependence and tolerance
METHAMPHETAMINE:
 Related to amphetamine, ephidrine
 Release NTs and also inhibit neuronal and vesicular
transporters as well as MAO
 Limited use because of abuse potential

METHYLPHENIDATE, DEXMETHYLPHENIDATE :
 Similar to amphetamine,
 Abuse potential
 Rarely used in treatment of ADHD
 ANORECTIC AGENTS
 Inhibit feeding centre (like amphetamine) but have
little/no CNS stimulant action or abuse liability
 Act by inhibiting the reuptake of NA/DA or 5-HT;
enhancing monoaminergic transmission in the brain
 Noradrenergic agents: Phentermine, phenylpropanolamine
(PPA), diethylpropion, mazindol
 Serotonergic agents: Fenfluramine, dexfenfluramine
 Noradrenergic/serotonergic agent: Sibutramine

 Limited effect- tolerance

 Severe adverse effects, dependence
 All drugs are banned
 EPHEDRINE
 Plant alkaloid having mixed action (agonist at α1,α2,
ß1, ß2 & Releasing Agent)
 Mixed acting sympathomimetic drug
 CVS: increase HR,CO, PVR, BP
 Centrally – Increased alertness, anxiety, insomnia,
tremor and nausea in adults. Sleepiness in children
 Effects appear slowly but lasts longer (t1/2 - 4h); does
not contain catechol moeity – orally effective
 Tachyphylaxis on repeated dosing
 EPHEDRINE cont….

 Therapeutic Uses:
 Used as bronchodilator (ß2 ) in treatment of asthma
 Treatment of complete heart block
 Treatment of common cold as nasal decongestant
 Urinary incontinence treatment – increase resistance to urine
outflow (α)
 PSEUDOEPHEDRINE
 A stereoisomer of ephedrine
 Causes vasoconstriction of mucosa and skin
 Fewer CNS and cardiac effect
 Used orally as a decongestant of upper respiratory
tract, nose and Eustachian tubes
 Combined with antihistaminics, mucolytics,
antitussives and analgesics
 Non selective action on vascular beds ⇒ Rise in BP can
occur, especially in hypertensives
ALPHA ADRENERGIC AGONISTS
 Selective Alpha-1  Selective Alpha-2
Agonists: Agonists:
 Phenylephrine  Clonidine
 Methoxamine  α-methyldopa
 Xylometazoline  Guanfacine
 Oxymetazoline  Guanabenz
 Naphazoline
 PHENYLEPHRINE
 Selective, synthetic and direct α1 –agonist
 Administered parenterally & topically (eye, nose)
 Resistant to MAO and COMT → Long duration of
action
 Does not cross BBB, so no CNS effects
 Produces mydriasis and nasal decongestion
 Sinusitis & Rhinitis as nasal decongestant
 Mydriatics in the form of eye drops and lowers
intraocular pressure
 ADRs: Photosensitivity, conjunctival hyperemia and
hypersensitivity
 NASAL DECONGESTANTS
 XYLOMETAZOLINE, OXYMETAZOLINE, NAPHAZOLINE
 Sympathomimetic vasoconstrictors with α- effects
 Used in allergic rhinitis, colds, coughs and sinusitis as
nasal drops
 Excessive (more often than 3 hrly) or Prolonged
(>3weeks) use → Mucosal ischemic damage
 Rebound congestion leads to overuse
 Longer application reduces ciliiary action
 Failure of antihypertensive therapy
 Fatal hypertensive crisis in patients on MAOIs
 PHENYLPROPANOLAMINE (PPA) → ↑ risk of
hemorrhagic stroke
 CLONIDINE
 α2 agonist agent
 Antihypertensive activity:
 Stimulation of α2 (pre & post synaptic) receptors at vasomotor
centre → ↓ Central sympathetic outflow → ↓ BP & HR
 Imidazoline (I1) receptor mediated modulation of central α2
receptors
 Presynaptic α2 receptors of sympathetic postganglionic
neurons
 Overdose stimulates peripheral postsynaptic α1
adrenoceptors & cause hypertension by vasoconstriction
 Abrupt withdrawal causes rebound hypertension
 CLONIDINE cont.…
 Clinical Uses:
 Moderate Hypertension
 Prophylaxis of Migraine
 Management of Nicotine, Alcohol and Opiate Withdrawal
 Help in reducing sympathetic mediated symptoms and reduce
craving for drug
 Preanaesthetic Medication
 α2 mediated preoperative sedation anxiolysis, drying of
secretions and analgesia; reduce requirement for anaesthetic
agent
 Menopausal Hot Flushes
 CLONIDINE cont.…
 Control Diarrhoea in Diabetic Patients with Autonomic
Neuropathy
 α2 in GIT- increase absorption of NaCl and fluid and inhibit
secretion of bicarbonate
 Diagnosis of Pheochromocytoma
 In primary HT, plasma concentration of NE is markedly
reduced suppress by single dose of clonidine; and response in
absent in pheochromocytoma
 Off label uses:
 Relief of Pain, post herpatic neuralgia, restless leg syndrome
 Atrial fibrillation
 Attention-deficient /hyperactivity disorder
 Constitutional growth delay, pychosis, mania etc.
 CLONIDINE cont.…
 ADRs:
 Sedation
 Dry mouth
 Nasal stuffiness
 Constipation
 Impotence
 Contact dermatitis
 Rebound hypertension on abrupt withdrawal
 TCAs antagonize antihypertensive action & increase
rebound hypertension of abrupt withdrawal
 Newer Imidazolines: Moxonidine, Rilmenidine
 APRACLONIDINE & BRIMONIDINE:
 Selective α2 agonist at ciliary epithelium → ↓ formation of
aqueous humor
 Potent ocular hypotensive agent
 Do not cross BBB
 Treatment of Glaucoma

 DEXMEDETODINE:
 Selective α2A agonist
 Used for Preanaesthetic Medication to provide sedation,
analgesia, antianxiety effects
 GAUNFACINE/GAUNABENZ:
 α2 agonist
 M/A: Reduces BP by activation of brainstem receptors with
resultant suppression of sympathetic activity --- similar to
clonidine
 Efficacy and ADRs – similar to clonidine

 TIZANIDINE:
 α2 agonist; some similar properties with clonidine
 Used as muscle relaxant
 Treatment of spasticity associated with cerebral and spinal
disorders
 α-METHYLDOPA
 α2 agonist agent
 Centrally acting antihypertensive agent
 α-methyldopa → α-methyldopamine → α-
methylnorepinephrine → stimulate central α2 receptors
 Treatment of Hypertension in pregnancy
 ADRs:
 Sedation
 Persistent mental lassitude and impaired mental concentration
(Long-term therapy)
 Nightmares, mental depression, vertigo and extrapyramidal
signs
 Positive Coombs test (Therapy for longer than 12 months)
 Rarely, hemolytic anemia, hepatitis and drug fever
 ΒETA ADRENERGIC AGONISTS
 Selective Βeta-1  Selective Beta-2
Agonists: Agonists:
 Dobutamine  Salbutamol
 Prenaterol  Terbutaline
 Salmeterol
 Selective Βeta-3  Oxiprenaline
Agonists:  Isoxsuprine
 BRL - 37344  Ritodrine
 BRONCHODILATORS
 Selective for β2 receptor subtype
 Short acting : Salbutamol, Metaproterenol,
Terbutaline
 Used for acute inhalational treatment of bronchospasm
 Onset of action within 1 to 5 minutes
 Bronchodilatation lasts for 2 to 6 hours
 Duration of action longer on oral administration
 Directly relax airway smooth muscle
 Relieve dyspnoea of asthmatic bronchoconstriction
 Long acting: Salmeterol, Formoterol
 Prevent night attacks of bronchial asthma
 UTERINE RELAXANTS
 Isoxsuprine, Terbutaline, Ritodrine, Salbutamol
 Selective for β2 receptor subtype
 Used by i.v. infusion to inhibit premature labour
 Tachycardia & hypotension occur
 Use minimum fluid volume using 5% dextrose as
diluents
 Ritodrine: 50 μg/min, increase by 50 μg/min every 10
minutes until contractions stop or maternal heart rate
is 140 beats/minute. Continue for 12-48 hours after
contractions stop
 ADRs of β2 agonist drugs
 Tachycardia (stimulation of heart by β1 )
 Arrhythmia or cardiac ischemia (specially patients with
pre-existing CAD or arrhythmia)
 Tremors
 Increase plasma glucose levels, lactate, FFA (DM patients
should be monitored)
 Decrease plasma potassium concentration (DI: diuretics/
digoxin)
 Tolerance : long term continuous use leads to down
regulation of β2 receptors
 THERAPEUTIC USES
1. VASCULAR USES
a. Hypotensive states (shock, spinal anaesthesia,
hypotensive drugs):
 Neurogenic and haemorrhagic shock
 Pressor agents + volume replacement
 Maintain cerebral circulation
 Should not be used in secondary shock when reflex
vasoconstriction is already marked
 Cardiogenic shock:
 Preessor agents: Rise in BP may also increase cardiac work
 Slow i.v. infusion of dopamine/dobutamine
 Dopamine increases cardiac contractility without causing
significant tachycardia
b. Along with local anaesthetics:
 Adrenaline 1 in 200,000 to 1 in 100,000 for infiltration,
nerve block and spinal anaesthesia
 Duration of anaesthesia is prolonged
 Systemic toxicity of local anaesthetic is reduced
 Local bleeding is minimized

c. Control of local bleeding:

• Epistaxis: Compression with cotton soaked in Adrenaline 1
in 10,000 or phenylephrine/ephedrine 1%
• Bleeding from gastric erosions and stress ulcers: NA 8 mg in
100–200 ml saline put in stomach through a tube
d. Nasal decongestant:
 Colds, rhinitis, sinusitis, blocked nose or eustachian tube
 α-agonists is used as nasal drops
 Shrinkage of mucosa provides relief
 After-congestion, atrophy of mucosa on prolonged use
 Nasal decongestants should be used very cautiously in
hypertensive patients and in elderly males
 Pseudoephedrine and phenylephrine can be used orally
2. CARDIAC USES
a. Cardiac arrest (drowning, electrocution & other
causes):
• IV Adrenaline may be used to stimulate the heart
b. Partial or complete A-V block
• Isoprenaline may be used as temporary measure to
maintain sufficient ventricular rate.
c. Congestive heart failure (CHF)
• As such sympathomometics are contraindicated
• Only dopamine, dobutamine can rarely be used for short
tem mangemnt of acute decompensated state
3. BRONCHIAL ASTHMA & COPD
• β2 agonists for relief of reversible airway obstruction

4. ALLERGIC DISORDERS
• Adrenaline is a physiological antagonist of histamine
(mediator of many acute hypersensitivity reactions)
• Drug of Choice in Anaphylactic shock: Quick relief in
bronchospasm, mucous membrane congestion, angioedema,
and severe hypotension
• Ineffective in delayed, retarded and other types of allergies
5. AS MYDRIATIC
• Phenylephrine: fundus examination; and when cycloplegia is
not required
• Reduce intraocular tension in wide angle glaucoma.
• Dipivefrine (prodrug of Adrenaline): an adjuvant drug for
wide angle glaucoma

6. NOCTURNAL ENURESIS IN CHILDREN AND

URINARY INCONTINENCE
• Amphetamine: central action as well as by increasing tone of
vesical sphincter
7. AS UTERINE RELAXANT
• Isoxsuprine: Threatened abortion and dysmenorrhoea,
• Selective β2 stimulants, especially ritodrine, infused i.v. has
been successfully used to postpone labour
• Adverse cardiac and metabolic actions and increase
incidents of pulmonary edema

8. INSULIN HYPOGLYCAEMIA
• Adrenaline may be used
• Glucose should be given as soon as possible
9. CNS USES
a. Attention deficit hyperkinetic disorder (ADHD):
• Amphetamines have an paradoxical effect to calm down
hyperkinetic children
b. Narcolepsy:
• Sleep episodes can be controlled by amphetamines
c. As Anorectic agent in Obesity:
• No approved sympathomimetic anorectic drug