Adrenergic Pharmacology
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Adrenergic Pharmacology. Adrenergic receptor agonists Adrenergic recpeotr antagonists. 张纬萍 浙江大学医学院药理 2012.12.3. Brain stem or spinal cord. Pre-ganglionic neuron. Ganglionic transmitter. Post-ganglionic neuron. Neuroeffector transmitter. Effector organ. Efferent neurons of ANS.

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Adrenergic pharmacology

Adrenergic Pharmacology

  • Adrenergic receptor agonists

  • Adrenergic recpeotr antagonists

张纬萍

浙江大学医学院药理

2012.12.3


Adrenergic pharmacology

Brain stem or

spinal cord

Pre-ganglionic

neuron

Ganglionic transmitter

Post-ganglionic

neuron

Neuroeffector transmitter

Effector organ

Efferent neurons of ANS

  • Neurotransmitters

  • Synthesis

  • Storage

  • Release

  • Inactivation

  • Receptors

  • Activation


Adrenergic pharmacology

Tyrosine

tyrosine hydroxylase (TH)*

L-DOPA

DOPA decarboxylase

dopamine (DA)

dopamine beta-hydroxylase (DBH)

norepinephrine (NE)

Noradrenergic Nerve:

Synthesis, storage

and release of NE

  • Uptake

  • neurotransmitter transporters

  • uptake 1: neuronal uptake

  • uptake 2: non-neuronal uptake

  • Enzymatic degradation

  • monoamine oxidase (MAO)

  • catechol-O-methyltransferease (COMT)


Adrenergic pharmacology

Norepinephrine and Epinephrine

Synthesis in the Adrenal Medulla

  • NE is stored in vesicles

  • DBH is located in vesicles

  • PNMT is located in the cytosol .

  • EPI is stored in vesicles

  • - EPI (~80%) and NE (~20%) released into blood

  • - These hormones bind adrenergic receptors on target cells, inducing the same effects as direct sympathetic nervous stimulation.

PNMT

NE

EPI

NE

EPI

PNMT

Chromaffin cell

EPI disposition: metabolism by COMT, MAO,

sulfation, uptake into NE terminals


Adrenergic pharmacology

NE Metabolism

- Within the same cells where the amines are synthesized, and in liver

- Extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism.


Norepinephrine ne release

Norepinephrine (NE) release

Act on adrenergic receptors/adrenoceptors

(2

3)

1

2

1

low affinity for binding NE

G-Protein Coupled Receptors


Adrenoceptors

Adrenoceptors


Adrenergic pharmacology

EP/NE

EP/NE

EP/Iso

q


Adrenergic pharmacology

Adrenergic Receptor Subtypes

& G-Protein Coupled Mechanisms

a1 Adrenergic Receptors:

G protein termed Gqphospholipase C activation, IP3

 mechanism: mobilizes and increases intracellular free Ca2+

 effects: primarily smooth muscle contraction

2 Adrenergic Receptors:

Inhibition of adenylyl cyclase (AC)through Gi proteins

 mechanism: decreases intracellular cAMP levels

effects: decreased protein phosphorylation, decreased cellular

function

b Adrenergic Receptors:

Activation of adenylyl cyclase through Gs proteins

 mechanism: increases intracellular cAMP levels

effects: phosphorylation of intracellular proteins smooth

muscle relaxation (b2), cardiac muscle contraction (b1)


Adrenergic pharmacology

Adrenergic Receptor (adrenoreceptors)

These are receptors activated by NE, EPI, or drugs with similar actions

b3

fat cells

(not NE)


Adrenergic pharmacology

The SNS Plays a Very Important Role in the Regulation of the Cardiovascular System, which, except for the Heart, is not Innervated by the PSNS


Sns regulation of cardiac function

SNS Regulation of Cardiac Function

  • The SNS innervates the entire heart while the PSNS only innervates the S-A and A-V nodes.

  • Neural modulation of heart rate occurs in part through enhancement (NE via b1 ARs) or reduction (ACh via M2R) of pacemaker activity, which is directly stimulated by elevated cAMP levels.

  • The SNS via b1 ARs also increases the force of contraction. Both heart rate and contractile force contribute to cardiac output.


Sns regulation of blood pressure

SNS Regulation of Blood Pressure

  • Acute loss of SNS function lowers blood pressure

  • Chronic loss of SNS function greatly increases blood pressure variability


Adrenergic pharmacology

The SNS EnhancesSmooth Muscle Contraction Primarily by a1 ARs,and Reduces ContractionPrimarily by b2 ARs


Mechanisms of drug actions

Mechanisms of drug actions

1.1 Direct actions on the receptors

  • Agonists

  • Antagonists

    1.2 Indirect actions via affecting transmitters

  • Synthesis (L-dopa)

  • Transport and storage (imipramine, reserpine)

  • Release (ephedrine, amphetamine)

  • Inactivation (MAOI)


Mechanisms of drug actions1

Mechanisms of drug actions

1.3 Mimetics and antagonists

(1) Mimetics

direct-acting: receptor agonists

indirect-acting: increasing amounts and/or

effects of transmitters

(2) Antagonists

direct-acting: receptor antagonists

indirect-acting: decreasing amounts and/or

effects of transmitters


Drug actions and classification

Drug actions and classification

Adrenoceptor agonists

  • ,  receptor agonists

  • epinephrine (adrenaline,肾上腺素),dopamine 多巴胺, ephedrine 麻黄碱

    (2)  receptor agonists

  • 12 receptor agonists:norepinephrine 去甲肾上腺素

  • 1 receptor agonists:phenylephrine苯肾上腺素

  • 2 receptor agonists:clonidine 可乐定

    (3)  receptor agonists:

  • 12 receptor agonists:isoproterenol异丙肾上腺素

  • 1 receptor agonists:dobutamine 多巴酚丁胺

  • 2 receptor agonists:salbutamol 沙丁胺醇


Adrenergic pharmacology

Structure-activity relationship of

catecholamines and related compounds


Adrenergic pharmacology

Sympathomimetic amines

  • Non-catecholamine

  • Indirect-acting by causing the release of stored catecholamine.

  • Not inactivated by COMT; some are poor substrate for MAO

    (orally active, a prolonged duration of action)

  • Greater access to the CNS

  • Catecholamine

  • High potency in activating a or b receptors

  • Rapid inactivation by COMT and by MAO

  • Poor penetration into the CNS


Adrenergic pharmacology

The mode of action

of sympathomimetic drugs

  • Direct mode

  • e.g. Norepinephrine

  • epinephrine

  • isoproterenol

  • Indirect mode

  • Mixed mode

  • e.g. ephedrine

  • Enhances release of stored catecholamines

    e.g. amphetamine

  • Inhibition of reuptake of released catecholamines

    e.g. cocaine

  • Inhibition of MAO

    e.g. pargyline


Adrenergic pharmacology

Epinephrine, Adrenaline: DIRECT

Pharmacological effects

1, 2 , 1 , 2 receptor agonists

(1) Cardiac effects

  • 1: contractility  (positive inotropic),

    HR  (positive chronotropic),

    cardiac output ,

    oxygen consumption ,

    inducing arrhythmia

    (2) Vascular effects (cerebral and renal circulation)

  • 1:vasoconstriction (skin, mucous, viscera),

    especially at larger doses

  • 2:vasodilatation of skeletal muscles

    and coronary vessels


Adrenergic pharmacology

Concentration-dependent response in vascular smooth muscle to epinephrine

Predominant Effects

low [EPI] β2 > α

high [EPI] α > β2


Adrenergic pharmacology

Epinephrine, Adrenaline: DIRECT

(3) Blood pressure

  • Systolic BP , Diastolic BP ↓(slight)

    (4) Respiratory

  • 2:dilatation of bronchial smooth muscles

    (Bronchodilatation)

  • 1:reducing congestion and edema of

    bronchial mucosa

    (5) Metabolic effects

  • blood glucose  (hyperglycemia);

    free fatty acids  (lipolysis)


Adrenergic pharmacology

Effects of epinephrine(therapeutic doses)

systolic pressure due to increased cardiac contractile force and a rise in cardiac output .

diastolic pressure usually falls due to the decrease of peripheral resistance decreasing.

1 in heart, 1 in many microvessels, 2 in the vessels of skeletal muscle


Adrenergic pharmacology

Epinephrine, Adrenaline: DIRECT

(6) Smooth muscle

  • Effects on vascular smooth muscle are of major physiological importance.

  • GI smooth muscle, relax (, )

  • Stomach, relax

  • Pyloric and ileocecal sphincters, contracted (depends on the pre-existing tone of the muscle).

  • Uterine, differ upon the time

  • Detrusor muscle(逼尿肌) of the bladder, contraction


Adrenergic pharmacology

Epinephrine, Adrenaline: DIRECT

Clinical uses

Systematic uses:

Cardiac arrest

Anaphylactic shock

Acute bronchial asthma

Topical uses:

Adjuvant of local anesthesia

Bleeding


Adrenergic pharmacology

Epinephrine, Adrenaline: DIRECT

Adverse effects

(1) Cardiac arrhythmias

(2) Hemorrhage (cerebral or subarachnoid):

reason: a marked elevation of BP

(3) Central excitation:anxiety, headache...

(4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis, hyperthyroidism. Esp. patients receiving nonselective  blockers.


Adrenergic pharmacology

Norepinephrine, Noradrenaline, NE: DIRECT

Pharmacological effect

1, 2 receptor agonists

NE and Epi are similar potent on 1

NE has little action of 2

(1) Vascular effects:

1:vasoconstriction (skin, renal, brain,

hepatic, mesenteric, etc.), blood flow 

2:inhibiting NE release


Adrenergic pharmacology

Actions of norepinephrine on post-synaptic (1) and pre-synaptic (2 ) receptors


Adrenergic pharmacology

Norepinephrine, Noradrenaline: DIRECT

(2) Blood pressure:

  • Systolic BP , Diastolic BP (especially at larger doses)

    (3) Cardiac effects:

  • Weak direct stimulation (1); inhibition via reflex(in vivo)

  • Net result: little cardiac stimulates


Adrenergic pharmacology

Effects of catecholamines(therapeutic doses)

  • Predominant Effects: BP, peripheral resistance, HR

  • 1 receptor: vascular smooth muscle contraction

  • 1 receptor: myocardial contraction


Adrenergic pharmacology

Norepinephrine, Noradrenaline: DIRECT

Clinical uses (limited therapeutic value)

(1) Shock

  • used in early phase of some types of shock: small doses and shorter duration

    (dopamine is better; replaced by Metaraminol,间羟胺)

    (2) Hypotension due to drug poisoning

  • especially for chlorpromazine

    (3) Hemorrhage in upper alimentary tract,上消化道出血

  • orally given after dilution


Adrenergic pharmacology

Norepinephrine, Noradrenaline: DIRECT

Adverse effects

(1) Ischemia and necrosis at the site of iv administrationrelieved by filtrating the area with phentolamine (receptor antagonist)

(2) Acute renal failureavoiding larger doses and longer duration; monitoring urinary volume

(3) Contraindicationhypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders


Adrenergic pharmacology

Dopamine: DIRECT

Pharmacological effects :

,  receptor, dopaminergic receptor agonists

(1) Cardiac effects:1 receptor, weak

(2) Vascular effects:

DA receptor:vasodilatation of renal and mesenteric arteries , blood flow (small doses);

1 receptor:vasoconstriction of skin, mesenteric vessels (larger doses)

(3) Renal effects:renal vasodilatation; natriuretic effects


Adrenergic pharmacology

Dopamine,DIRECT

Clinical uses

(1) Shock, sever congestive failure

  • cardiac and septic shock

    (2) Acute renal failure

  • combined with furosemide

    Adverse effects – short-lived

  • tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction)

L-DOPA but not dopamine can enter brain.


Adrenergic pharmacology

Isoproterenol,

Isoprenaline: DIRECT

异丙肾上腺素

1 , 2 receptor agonists

(1) Cardiac effects (1 receptor)

(2) Vascular effects

2 receptor:dilatation of skeletal muscles and coronary vessels;

SP ,DP  or ,pulse pressure 

(3) Bronchodilatation (2 receptor)

(4) Metabolism

Promoting effects as epinephrine


Adrenergic pharmacology

Effects of catecholamines(therapeutic doses)

Predominant Effects: HR, systolic BP, distolic BP, peripheral resistance 

1, myocardial contraction

2, vascular dialization

, at higher concentrations


Adrenergic pharmacology

Isoproterenol, Isoprenaline

Clinical uses

(1) Cardiac arrest / A-V block: in emergencies

(2) Shock / Bronchial asthma: replaced by

other sympathomimetics

Adverse effects

(1) Heart stimulation, arrhythmia

(2) Contraindications:coronary heart

disease, myocarditis, hyperthyroidism,

pheochromocytoma.


Adrenergic pharmacology

1 receptor agonists

  • Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment)

  • Cardiac stimulation

    (-) isomer of dobutamine is a potent agonist at 1 receptors

    (+)-dobutamine is a potent 1 receptor antagonist

Dobutamine:多巴酚丁胺,DIRECT


Adrenergic pharmacology

2 receptor agonists

Terbutaline:博利康尼,DIRECT

  • Uses:

    Bronchial asthma

    Dilation of bronchial smooth muscle; 2 > 1 agonist (partially selective): preferential activation of pulmonary 2 receptors by inhalation.

    Premature Labor (combine with ritodrine,羟苄羟麻黄碱).

  • Adverse effects:

    headache, cardiac stimulation and skeletal muscle fine tremor (2 receptors on presynaptic motor terminals; their activation enhances ACh release).


Adrenergic pharmacology

Terbutaline:博利康尼

间羟异丁肾上腺素

Metaproterenol

间羟异丙肾上腺

Albuterol

舒喘灵,沙丁胺醇


Adrenergic pharmacology

2 receptor agonists

Isoetharine,N-异丙基乙基降肾上腺素

Pirbuterol,吡舒喘宁吡丁醇

Bitolterol,叔丁肾上腺素双甲苯酸酯

Fenoterol,培罗坦克

Salmeterol,沙美特罗

Ritodrine,羟苄麻黄碱

Procaterol,异丙喹喘宁


Adrenergic pharmacology

1 receptor agonists

Methoxamine(伐沙克新): DIRECT>INDIRECT

Phenylephrine(苯肾上腺素): DIRECT>INDIRECT

  • Induces reflex bradycardia, used in hypotension, paroxysmal supraventricular tachycardia ;

  • Phenylephrine: Mydriasis(瞳孔散大), pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours); act as a nasal decongestant


Adrenergic pharmacology

2 receptor agonists

Clonidine(可乐定):DIRECT

  • Uses: antihypertensive drug; can be administered as transdermal patch (permits continuous administration)

  • Mechanism of action : α2-adrenergic partial agonist; actions predominantly in CNS. Lowers blood pressure by inhibiting sympathetic vasomotor tone (probably on I1 receptor).

  • Adverse effects: (iv administration may result in transient increase in blood pressure (activation of post-synaptic receptors); dry mouth, sedation


Adrenergic pharmacology

Other 2 receptor agonists

Apraclonidine, 阿拉可乐定

Brimonidine, 溴莫尼定

Guanfacine, 氯苯乙胍

Guanabenz, 氯苄氨胍

Methyldopa, 甲多巴

Tizanidine, 替扎尼定


Adrenergic pharmacology

Ephedrine: 麻黄碱,MIXED

Ephedrine

Epinephrine

  • Promoting the release of NE, weak agonist effectson 1、2、1、2 receptors

    Properties:

  • chemically stable, orally effective;

  • less potent but longer action duration;

  • central stimulating: alertness , fatigue ↓, prevents sleep (adverse effects)

  • Tachyphylaxis (快速抗药反应).


Adrenergic pharmacology

Ephedrine

Clinical uses

(1) Prevention of hypotension:anesthetics

(2) Nasal decongestion:nasal drop,如感冒

(3) Bronchial asthma:mild, chronic cases

(4) Relieving allergic disorders:urticaria(荨麻

疹), angioneurotic edema


Adrenergic pharmacology

INDIRECT-acting drugs (summary)


Drug actions and classification1

Drug actions and classification

Adrenoceptor agonists

  •  receptor agonists

  • epinephrine (adrenaline,肾上腺素),dopamine 多巴胺, ephedrine 麻黄碱

    (2)  receptor agonists

  • 12 receptor agonists:norepinephrine 去甲肾上腺素

  • 1 receptor agonists:phenylephrine苯肾上腺素

  • 2 receptor agonists:clonidine 可乐定

    (3)  receptor agonists:

  • 12 receptor agonists:isoproterenol异丙肾上腺素

  • 1 receptor agonists:dobutamine 多巴酚丁胺

  • 2 receptor agonists:salbutamol 沙丁胺醇


Adrenergic pharmacology

Drug actions and classification


Adrenergic receptor antagonists

Adrenergic Receptor Antagonists

  • Antagonist characteristics

  • receptor occupancy (binding affinity)

  • no receptor activation (no efficacy)

  • Antagonists of NE at either a or b receptors

  • - competitiveantagonists (reversible), blocking endogenous norepinephrine

  • - irreversible antagonists

  • nonselective and selective drugs available for both the a or b receptors.


Drug actions and classification2

Drug actions and classification

Adrenoceptor antagonists

(1) receptor antagonists

  • 12 receptor antagonists:

    short-acting: phentolamine,酚妥拉明

    long-acting: phenoxybenzamine,酚苄明

  • 1 receptor antagonists:prazosin,哌唑嗪

  • 2 receptor antagonists:yohimbine,育亨宾


Drug actions and classification3

Drug actions and classification

Adrenoceptor antagonists

(2) receptor antagonists

  • 12 receptor antagonists:propranolol,普萘洛尔

  • 1 receptor antagonists:atenolol,阿替洛尔

  • 2 receptor antagonists:butoxamine,布托沙明

    (3),  receptor antagonists

  • labetalol,拉替洛尔


Adrenergic pharmacology

epinephrine

 antagonist

epinephrine

BP

Epinephrine reversal

(adrenaline reversal)


Adrenergic pharmacology

Phentolamine

  • competitive, nonselective(1, 2 receptor antagonists, block 5-HT release)

Pharmacological effects

(1) Vasodilatation

Blocking 1 receptor: vasodilatation in both arteriolar

resistance vessels and veins

(2) Cardiac Stimulation

Reflex;blocking 2 receptor ~NE release 

(3) Cholinergic and histamine-like effects

Contraction of GI smooth muscles,

Gastric acid secretion 


Adrenergic pharmacology

Phentolamine

Clinical uses

(1) Hypertension from pheochromocytoma (short term use).

  • Pre- and post-operation of pheochromocytoma

    • Diagnostic test for pheochromocytoma

    (2) Peripheral vascular diseases

  • Acrocyanosis, Raynaud’s disease

    (3) Local vasoconstrictor extravasation

    Major Adverse effects– postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions


Adrenergic pharmacology

Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells of the adrenal medulla that produces excess epinephrine.

  • Hypertension & Crises

  • Elevated Metabolic Rate

    -heat intolerance

    -excessive sweating

    -weight loss

  • Temporarily manage with

    -adrenergic antagonists (a1 & ±b)


Adrenergic pharmacology

Phenoxybenzamine

  • Irreversible, nonselective ( 1 and 2 antagonists )

  • Long-acting

  • Similar to phentolamine in actions and clinical uses


Adrenergic pharmacology

1 receptor antagonists

Prazosin(哌唑嗪): treatment for hypertension

Tamsulosin (坦索罗辛): treatment for benign prostatauxe (to relief the difficulty of urination)

Terazosin (特拉唑嗪): less potent than prazosin, but retains high specificity for 1

Doxazosin (多沙唑嗪): similar as prazosin, but has longer duration of action.

Alfuzosin (阿夫唑嗪): structure not related.


Adrenergic pharmacology

Adverse effects of 1 receptor antagonists

First-dose effect, marked hypotension,

Syncope (晕厥)

Clinically,these drug are used for the patient with hypertentsion and benign prostatic hyperplasia (良性前列腺肥大)

2 receptor antagonists

Yohimbine: for research use only


Adrenergic pharmacology

 receptor antagonists

ADME

  • First-pass elimination,

    low bioavailability: propranolol(普萘洛尔)

  • Hepatic metabolism and renal excretion, hepatic and renal functions alter the effects of the drugs and result in large individual variation

  • So, dose individualization is necessary.


Effects of an b ar antagonist

Effects of an b AR Antagonist


Adrenergic pharmacology

 receptor antagonists

Pharmacological effects

(1)  receptor blockade

A. Cardiovascular effects:

Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption

Hypotension: peripheral blood flow , hypertensive effects in hypertensive patients


Adrenergic pharmacology

 receptor antagonists

(1)  receptor blockade

B. Bronchial smooth muscles (2)

Induces bronchial smooth muscle contraction in asthmatic patients

C. Metabolism (2 and 3)

Lipolysis(脂解作用)  , glycogenolysis(糖原分解)  , classical blockers decreasing while novel blockers potentiating insulin effects ~ hypoglycemia(低血糖)。

D. Renin secretion (1)

Decreasing secretion of rennin


Adrenergic pharmacology

 receptor antagonists

(2) Intrinsic sympathomimetic effects

Partial agonists: e.g. pindolol,acebutolol

(3) Membrane-stabilizing effects

Larger doses of some drugs: quinidine-like

effects, Na+ channel block

(4) Others

Lowering intraocular pressure;

Inhibiting platelet aggregation


Adrenergic pharmacology

 receptor antagonists

Clinical uses

(1) Arrhythmia:supraventricular, sympathetic activity 

(2) Hypertension

(3) Angina pectoris and myocardial infarction

不能用于冠脉痉挛引起的心绞痛

(4) Chronic heart failure

(5) Others: hyperthyroidism, migraine, glaucoma(timolol)


The use of beta adrenergic blocking agents in heart failure

The Use of Beta Adrenergic Blocking Agents in Heart Failure

15

10

5

LVEF % change

0

-5

-10

0

6

12

18

24

Time (weeks)

Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF

)


Blockers differ in their long term effects on mortality in hf

-Blockers Differ in Their Long-Term Effects on Mortality in HF

Bisoprolol1

Bucindolol2

Carvedilol3-5

Metoprolol tartrate6

Metoprolol succinate7

Nebivolol8

Xamoterol9

Beneficial

No effect

Beneficial

Not well studied

Beneficial

No effect

Harmful

1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.


Adrenergic pharmacology

 receptor antagonists

Adverse effects

(1) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia

(2) Worsening of asthma: contraindicated in bronchial asthmatic patients

(3) Withdrawal syndrome:up-regulation of the receptors

(4) Worsening of peripheral vascular constriction

(5) Others:central depression, hypoglycemia,etc.


Adrenergic pharmacology

Propranolol

  • 1, 2 receptor blocking

  • no intrinsic activity

  • first-elimination after oral administration, individual variation of bioavailability

Timolol

  • For treatment of glaucoma (wide-angle)


Adrenergic pharmacology

Atenolol, Metoprolol

  • 1receptor antagonists, no intrinsic activity

  • Atenolol : longer t1/2, once daily

  • Usually used for treatment of hypertension


Adrenergic pharmacology

NO, 2 agonist,

1 blocker Ca2+ blocker Antioxidation

1 blocker

NO

受体阻断剂的药理学特性


Adrenergic pharmacology

α,  receptor antagonists

Labetalol

  • α, β receptor blocking, β> α

  • usually used for treatment of

    hypertension


Summary

summary


Summary1

summary


Summary2

summary


Adrenergic pharmacology

Therapeutic Uses of a1 (±b) AR Agonists

1. Hypotension(低血压)

  • Preserve adequate blood perfusion to heart, brain or kidneys in cases of hemorrhage, overdose of antihypertensive drugs or spinal cord injuries.

  • Short duration of treatment: NE, phenylephrine, methoxamine, ephedrine (a1 AR agonists).

2. Shock(休克)

  • Inadequate perfusion to tissues as a consequence of hypovolemia, cardiac failure, or altered vascular resistance.

  • Usually associated with hypotension.

  • Use of a1-adrenergic agonists to increase peripheral vascular resistance, and b1-adrenergic agonists to improve cardiac function.

3. Cardiogenic Shock(心源性休克)

  • Massive myocardial infarction.

  • Stimulation of cardiac b1-adrenergic receptors is needed: isoproterenol, norepinephrine, epinephrine, dobutamine, dopamine.


Adrenergic pharmacology

Therapeutic Uses of a1 (±b) AR Agonists

4. Local Vascular Effects(局部的血管变化)

- Reduction of regional blood flow in surgery (nose, throat, larynx) to improve visualization by limiting hemorrhage.

- Epinephrine retards the absorption of local anesthetics and increases the duration of anesthesia (vasoconstrictor effect of epinephrine)

5. Nasal Decongestion(鼻腔充血)

- a1-Adrenergic agonists are used as nasal decongestants.

- These drugs decrease the volume of the nasal mucosa and therefore reduce the resistance to airflow.

- Oxymetazoline, phenylephrine and ephedrine are commonly used.

6. Allergic Reactions(过敏反应)

- Epinephrine (s.c.) is used in acute hypersensitivity reactions.

- Activation of b-adrenergic receptors on mast cells suppresses the release of histamine and leukotrienes.


Adrenergic pharmacology

Therapeutic Uses of b2 AR Agonists

1. Asthma(哮喘)

- Asthma is a condition of overreactive airways. Asthma attacks can make it very difficult to breath because of excess bronchoconstriction.

- b2 AR agonists such as albuterol, metaproterenol and terbutaline are used.

- The drugs are administered by inhalation and are absorbed slowly, limiting their systemic side effects, and b2 selectivity reduces cardiac stimulation.

2. Premature Labor(早产)

- When labor occurs prematurely (before 37 weeks), it is a risk to the fetus.

- b2 AR agonists relax the smooth muscle of the uterus and help prevent premature delivery. The goal is to reach at least 37 weeks when the fetal lungs have matured.


Adrenergic pharmacology

Therapeutic Uses of a1 & b AR Antagonists

1. Pheochromocytoma(肾上腺嗜铬细胞瘤)

2. Hypertension(高血压)

- While not commonly used anymore, a1 blockers can be use to treat hypertension.

- Somewhat more common is the use of b blockers. These work centrally (the most important effect – the mechanism is not completely understood) and peripherally (decrease heart rate some).

3. Heart Failure(心功能衰竭)

- After a myocardial infarction, the SNS will be activated to increase the cardiac output from the remaining good heart tissue. This is good in the short-term, but long-term changes lead to cardiac hypertrophy and failure.

- Ironically, b blockers reduce the incidence of sudden death from heart failure.


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