SYMPATHETIC SYSTEM Sympathomimetic Agents. SYMPATHETIC SYSTEM Mostly activated during stressful...
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Transcript of SYMPATHETIC SYSTEM Sympathomimetic Agents. SYMPATHETIC SYSTEM Mostly activated during stressful...
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SYMPATHETIC SYSTEM
Sympathomimetic Agents
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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
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Synthesis Storage and Release and degradation of NA, DA, Adr
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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 ↑
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Termination of action of Catecholamines
1. Re-Uptake
2. Enzymatic degradation
3. Diffusion
4. Extra synaptic uptake
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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
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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
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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)
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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
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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
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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
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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
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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
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ENDOGENOUS CATECHOLAMINES
Adrenaline Noradrenaline Dopamine
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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)
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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 ±)
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Dale’s Reversal Phenomenon
AdrPBZ
Mea
n a
rter
ial
blo
od
pre
ssu
re
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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
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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)
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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
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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
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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).
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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
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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
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DRUG α1 α2 β1 β2 DA
Adrenaline +++ ++ +++ +++ 0
Noradrenaline +++ +++ ++ 0 0
Dopamine + 0 ++ 0 +++
Dobutamine +/- 0 +++ + 0
Isoprenaline 0 0 +++ +++ 0
Sympathomimetic Catecholamines
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