SYMPATHETIC SYSTEM
Sympathomimetic Agents
SYMPATHETIC SYSTEM
Mostly activated during stressful situations
Actions can be identified by reactions during “fright, fight, flight”
Neurotransmitter at most post-ganglionic terminals is NoradrenalineOthers: Adrenaline (Brain, adrenal) Adrenaline from adrenal medulla augments function during sympathetic activation
Dopamine : Basal ganglia, other parts of brain, ? Periphery
Synthesis Storage and Release and degradation of NA, DA, Adr
Storage and release of Catecholamines
• Storage in vesicles along with ATP and other substances
• Released by exocytosis
• Release is modified by presynaptic autoreceptors & heteroreceptorsα2 ↓β2 ↑
Termination of action of Catecholamines
1. Re-Uptake
2. Enzymatic degradation
3. Diffusion
4. Extra synaptic uptake
SUBTYPES OF ADRENERGIC RECEPTORS
ΑLPHA BETA
α1 α2 β1 β2 β3
1A
1B
1C
1D
2A
2B
2C
2D
Receptors are located PRE and POST-synapticallyPre-synaptic receptors modify release from the terminal
Receptor Transduction Agonist
Alpha 1
1A
1B
1C
1D
Alpha 2
2A
2B
2C
2D
Beta1
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)
Epi > NE >> Iso( Clonidine )
Iso > Epi > NE Dobutamine TerbutalineIso = NE > Epi
DA,
Transduction mechanisms and actions of adrenergic receptor subtypes
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)
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)
Organ system effects of sympathetic activation
BRONCHI (SmM)
GIT
GENITOURINARY
Uterus
Bladder
trigone, sphincter
detrussor
Male sexual organs
2
1
1
2
1
2
relaxation
relaxation ( ACh release)
relaxation (direct - smooth muscle)
contraction of sphincters
contraction (pregnant)
relaxation (Preg. & Non-preg)
contraction
relaxation
ejaculation
Organ system effects of sympathetic activation
METABOLIC
Fat cells
Liver
Pancreas
J-G cells
2
(& )
2
1
2
Lipolysis; Inhibit lipolysis
Glycogenolysis
Insulin secretion
Insulin secretion
Renin rsecretion Renin secretion
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 SympatholyticBretylium
Reuptake Cocaine, effect of NTImipramine indirect
mimetics
Reuptake into granules Reserpine Release Depletion
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 ---TalcaponeEntacapone
MethoxaminePhenylephrine
ClonidineMethyldopa*
ApraclonidineGuanfacineGuanabenz
TerbutalineAlbuterolFenoterolPirbuterol
Long ActingProcaterolSalmeterol
Isoprenaline (β1 & β2)Dobutamine (β1)IsoetharinePrenalterol
DA, NA, Adr
OxymetazolineXylometazolineNaphazoline
Sympathomimetic drugs
Indirectly actingDirectly acting
Catecholamines Non-Catecholamines
α1 agonists α2 agonists β2 agonists
Endogenous
Synthetic
TyramineAmphetamine
MixedEphedrine
ENDOGENOUS CATECHOLAMINES
Adrenaline Noradrenaline Dopamine
ENDOGENOUS CATECHOLAMINES
1. 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)
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 ±)
Dale’s Reversal Phenomenon
AdrPBZ
Mea
n a
rter
ial
blo
od
pre
ssu
re
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
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, arrhythmiaTherapeutic 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: 200000)Topical haemostatic :bleeding from mouth,
peptic ulcer, noseBronchial asthma – s.c. or inhalation (nebulized)
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
Receptor action1
α2
1
2
Heart HR CO Arrhythmias Coronary flowBlood Pressure Systolic Mean Diastolic Muscle flow Cutaneous flow
Epinephrine+++
++++
++++
++++++
++++
+,0,-+++–
Norepinephrine ++ (slightly less) ++ + 0
– 0, – ++++ ++
+++ ++ ++ 0,+ –
Comparison of effects of Epinephrine and NE
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).
DOPAMINEImmediate precursor of NENeurotransmitter in CNS (? Periphery)CVS effects:
Low conc. : D1 - Renal, mesenteric and coronary vasodilatation
glomerular filteration renal blood flow, Na excretion
Moderate Conc. : 1 - Positive inotropic effect on heart
in systolic BP and pulse pressure, ± on diastolic pressure
High Conc. : 1 - Generalized vasoconstriction
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
DRUG α1 α2 β1 β2 DA
Adrenaline +++ ++ +++ +++ 0
Noradrenaline +++ +++ ++ 0 0
Dopamine + 0 ++ 0 +++
Dobutamine +/- 0 +++ + 0
Isoprenaline 0 0 +++ +++ 0
Sympathomimetic Catecholamines