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