1. Sympathomimetic Agents
SYMPATHETIC SYSTEM
Sympathomimetic Agents

2. SYMPATHETIC SYSTEM Mostly activated during stressful situations
Actions can be identified by reactions during
“fright, fight, flight”
Neurotransmitter at most post-ganglionic terminals is Noradrenaline
Others:
Adrenaline (Brain, adrenal)
Adrenaline from adrenal medulla augments
function during sympathetic activation
Dopamine : Basal ganglia, other parts of brain,
? Periphery

3. Synthesis Storage and Release and degradation of NA, DA, Adr

4. Storage and release of Catecholamines
Storage in vesicles along with ATP and other substances
Released by exocytosis
Release is modified by presynaptic autoreceptors & heteroreceptors
α2 ↓
β2 ↑

5. Termination of action of Catecholamines
Re-Uptake
Enzymatic degradation
Diffusion
Extra synaptic uptake

7. Receptors are located PRE and POST-synaptically
Pre-synaptic receptors modify release from the terminal

8. Transduction mechanisms and actions of adrenergic receptor subtypes
Agonist
Alpha 1
1A
1B
1C
1D
Alpha 2
2A
2B
2C
2D
Beta 1 2 3
DA ( 1,2,4,5)
 IP3 ; DAG (common)
+  Ca influx
?  Ca influx
 cAMP (common)
+  K ,  Ca channels
 Ca channels
cAMP (common)
 (D1,5),  cAMP (D2,3,4)
Epi > NE >> Iso
( Phenylephrine, Methoxamine)
( Clonidine )
Iso > Epi > NE
Dobutamine
Terbutaline
Iso = NE > Epi
DA,

9. Organ system effects of sympathetic activation
EYE
Radial muscle
Ciliary muscle
I.O. Pressure
Lacrymal glands
CVS
HEART
SA node; Atria
AV node
Purkinje Ventricles
Blood Vessels 1 2  
1; 2
(& 1)
(1 & 2) D1
Mydriasis
Relaxation &  accomodation
 Aquous outflow
 Increase aquous formation
Secretion +
HR; contractility & CV
 automaticity,
idioventricular pacemakers +++
constriction (Skin, spalnchnic )
relaxation (Skeletal muscle)
relaxation (Renal, coronary, cerebral)

10. Organ system effects of sympathetic activation
BRONCHI (SmM)
GIT
GENITOURINARY
Uterus
Bladder
trigone, sphincter
detrussor
Male sexual organs 2   1
relaxation
relaxation (  ACh release)
relaxation (direct - smooth muscle)
contraction of sphincters
contraction (pregnant)
relaxation (Preg. & Non-preg)
contraction
ejaculation

11. Organ system effects of sympathetic activation
METABOLIC
Fat cells
Liver
Pancreas
J-G cells  2
 (& ) 1
Lipolysis;
Inhibit lipolysis
Glycogenolysis
Insulin secretion
 Insulin secretion
 Renin rsecretion
 Renin secretion

13. Targets for Pharmacological Interference
Tyrosine hyhroxylase  MPT  NA
DOPA decarboxylase  Methyldopa Pseudotransmitter*
Dopamine  hydroxylase Disulfiram
Release of NA Tyramine Sympathomimetic
Amphetamine
Release of NA Guanethidine Sympatholytic
Bretylium
Reuptake Cocaine,  effect of NT
Imipramine  indirect mimetics
Reuptake into granules Reserpine Release Depletion

14. Targets for Pharmacological Interference
Presynaptic 2 Catecholamines  release
Presynaptic 2 Catecholamines  release
Presynaptic M ACh  release
 MAO Several  metabolism
 Extrasynaptic uptake PBZ, Steroids  Effect
 COMT Pyrogallol
Talcapone
Entacapone

15. Sympathomimetic drugs
Directly acting
Mixed
Indirectly acting
Ephedrine
Tyramine
Amphetamine
Catecholamines
Non-Catecholamines
α1 agonists
α2 agonists
β2 agonists
Clonidine
Methyldopa*
Apraclonidine
Guanfacine
Guanabenz
Endogenous
Methoxamine
Phenylephrine
Terbutaline
Albuterol
Fenoterol
Pirbuterol
Long Acting
Procaterol
Salmeterol
DA, NA, Adr
Synthetic
Isoprenaline (β1 & β2)
Dobutamine (β1)
Isoetharine
Prenalterol
Oxymetazoline
Xylometazoline
Naphazoline

16. ENDOGENOUS CATECHOLAMINES
Adrenaline Noradrenaline Dopamine

17. ENDOGENOUS CATECHOLAMINES
ADRENALINE (Epinephrine): Mainly from adrenal medulla (Also some neurons in brain)
Receptor actions : Both  and ; Potency for  > 
All effects of stimulation of  and  receptors; but some are more evident.
Heart:  rate, force, arrhythmias (high dose, rapid
administration)

18. Blood Pressure:
Adrenaline is one of the most potent vasoconstrictors
Pharmacological dose:
↑Force and rate of ventricular contraction (β1) ↑Vascular resistance (skin, mucosa, kidney) (α) +
↑Marked venoconstriction
Lower dose:  B.P. ( 2 more sensitive)
Cutaneous blood flow  ; Skeletal muscle blood flow 
Nett effect:  C.O. & B.P. (systolic ; diastolic ±)

19. Dale’s Reversal Phenomenon
Mean arterial blood pressure
PBZ
Adr

20. Respiratory system:
Bronchodilatation ( specially when constriction +nt)
CNS:
Not marked ( poor BBB penetration)
Large doses: Restlessness, apprehension, headache, tremor
Metabolic:  Blood glucose (  insulin (2); glucose uptake; glycogenolysis)
(glucagon secretion - )
Mast cells : Stabilized

21. Absorption fate and excretion
Orally ineffective (hydrolyzed by liver and gut)
Absorption I.M > S.C. ; Given I.V. in emergencies ;
Inhalation (nebulized)
Toxicity : due to  and  stimulation
Mainly CVS: BP, vasoconstriction, tachycardia, arrhythmia
Therapeutic uses:
Anaphylaxis ( I.M / I.V.) ( 0.3 – 0.5 ml of 1:1000)
Cardiac arrest (May have to be given intra-cardiac )
With local anaesthetics ( 1: )
Topical haemostatic :bleeding from mouth, peptic ulcer, nose
Bronchial asthma – s.c. or inhalation (nebulized)

22. 2.NORADRENALINE (Norepinephrine)
Released from post-ganglionic sympathetic nerves
10-20% of content of adrenal medullary secretion
Receptor action:
α 1 , α 2 & β1
 > 
No effect on β2

23. Comparison of effects of Epinephrine and NE
Receptor action 1 α2 1 2
Heart HR CO
Arrhythmias
Coronary flow
Blood Pressure
Systolic
Mean
Diastolic
Muscle flow
Cutaneous flow
Epinephrine ++ +
+++
++++
+,0,- –
Norepinephrine
++ (slightly less)
0, –
0,+

24. Other effects:
Similar to Epinephrine
Metabolic effects seen with larger doses
Toxicity:
Similar to Epinephrine but greater  in BP
Greater vasoconstriction : sloughing and necrosis can occur at site of administration
Uses : Hardly used now except sometimes in peripheral vascular failure (eg. Septic shock).

25. DOPAMINE Immediate precursor of NE
Neurotransmitter in CNS (? Periphery)
CVS effects:
Low conc. :
D Renal, mesenteric and coronary vasodilatation
 glomerular filteration
renal blood flow, Na excretion
Moderate Conc. :
 Positive inotropic effect on heart
 in systolic BP and pulse pressure,
± on diastolic pressure
High Conc. :
 Generalized vasoconstriction

26. Other effects : Not significant. Therapeutic Uses:-
Severe CHF (sp. with oliguria)
Cardiogenic and septic shock
Major Actions of DA are within the CNS
Five receptor subtypes (D1 to D5)
D1 – excitatory
D2 – inhibitory
Involved in behavioural functions, endocrine regulation

27. Sympathomimetic Catecholamines
DRUG α1 α2 β1 β2 DA
Adrenaline
+++ ++
Noradrenaline
Dopamine +
Dobutamine
+/-
Isoprenaline