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Sympathomimetics & Sympatholytics Hazel Anne L. Tabo
Sympathomimetics & Sympatholytics
Sympathomimetics &
Sympatholytics
Sympathomimetics & Sympatholytics Hazel Anne L. Tabo

Hazel Anne L. Tabo

S Sympathetic Outflow P I Paravertebral N sympathetic Depolarization on A post-synaptic chain ganglia
S
Sympathetic Outflow
P
I
Paravertebral
N
sympathetic
Depolarization on
A
post-synaptic
chain ganglia
Adrenoceptor
neuron
L
Na
Na
+
+
N
Ach
NE
NE
NE
E
NE
R
K
+
K
+
V
E
Ganglia
Effector organ
Nicotinic
cholinoceptor
Sympathetic NS
Sympathetic NS

Excitation of preganglionic neurons innervating the adrenal medulla causes a

neurons innervating the adrenal medulla causes a liberation of acetylcholine or nicotine. This, in turn,
neurons innervating the adrenal medulla causes a liberation of acetylcholine or nicotine. This, in turn,
neurons innervating the adrenal medulla causes a liberation of acetylcholine or nicotine. This, in turn,

liberation of acetylcholine or nicotine. This, in turn, elicits a secretion of epinephrine (= adrenaline) into the blood and into body. Liberated norepinephrine

reacts with adrenoceptors:

a) pre-synaptically on the membrane of Varicosities (nerve axons form

enlargements resembling beads on a string.).

b) post-synaptically on the membrane of effector cells or

Activation of presynaptic α2-receptors inhibits NE release. By this negative feedback, release can be regulated.

METABOLISM: The effect of released norepinephrine wanes quickly, because approx. 90 % is actively transported back into the axoplasm then back to storage

vesicles (neuronal re-uptake). Small portions of norepinephrine are inactivated by the enzyme catechol-O-methyltransferase (COMT, present in the cytoplasm of

postjunctional cells, to yield normetanephrine), and Monoamine oxidase (MAO,

present in mitochondria of nerve cells and postjunctional cells, to yield 3,4-

dihydroxymandelic acid).

• The liver is richly endowed with COMT and MAO; it contributes significantly to the
• The liver is richly endowed with COMT and MAO; it contributes significantly to the
• The liver is richly endowed with COMT and MAO; it contributes significantly to the

The liver is richly

endowed with COMT and

MAO; it contributes significantly to the degradation of circulating

norepinephrine and

epinephrine.

The end product of the combined actions of MAO and COMT is

vanillylmandelic acid.

Distribution of Adrenergic Receptors: Tissue (Actions)
Distribution of Adrenergic
Receptors: Tissue (Actions)
Distribution of Adrenergic Receptors: Tissue (Actions) • α 1 - Vascular smooth muscles (constriction) - Pupillary
Distribution of Adrenergic Receptors: Tissue (Actions) • α 1 - Vascular smooth muscles (constriction) - Pupillary
Distribution of Adrenergic Receptors: Tissue (Actions) • α 1 - Vascular smooth muscles (constriction) - Pupillary

α1

- Vascular smooth muscles (constriction)

- Pupillary dilator muscle (dilates pupil)

- Arrector pili / pilimotor smooth muscle (erects hair)

- Rat liver (glycogenolysis)

α2

- Postsynaptic CNS adrenoceptors (mutiple effects)

- Adrenergic & cholinergic nerve terminals (inhibition of transmitter release)

- Platelets (aggregation)

β1

- Heart, Adipocytes, CNS (activates Adenylyl cyclase, stimulates fast cardiac activity)

β2

- Respiratory, Uterine & Vascular smooth muscle (activates adenylyl cyclase, relaxation of

smooth muscles or bronchodilation)

Β3 urinary bladder (relaxation) - controls frequency & urgency

Dopa1 Renal vessels, CNS - activates A-cyclase

Dopa2 Nerve terminals, CNS - Inhibition of A-cyclase

• Activation of α 1 receptors by catecholamines
• Activation of α 1 receptors by catecholamines
• Activation of α 1 receptors by catecholamines
• Activation of α 1 receptors by catecholamines

Activation of α1 receptors by catecholamines

Adrenoceptors and Catecholamine Actions

Adrenoceptors and Catecholamine Actions • Three major groups: α1, α2, and β 1. Smooth muscle effects
Adrenoceptors and Catecholamine Actions • Three major groups: α1, α2, and β 1. Smooth muscle effects
Adrenoceptors and Catecholamine Actions • Three major groups: α1, α2, and β 1. Smooth muscle effects
Adrenoceptors and Catecholamine Actions • Three major groups: α1, α2, and β 1. Smooth muscle effects

Three major groups: α1, α2, and β
1. Smooth muscle effects Figure A
2. Vasoconstriction Local α-sympathomimetics -Nasal decongestion (naphazoline, tetrahydrozoline, xylometazoline). Systemic sympathomimetic - Epinephrine- tx:anaphylactic shock (allergies) for combating hypotension

3. Bronchodilation - β2-Adrenoceptor, tx of bronchial asthma (Ex: terbutaline, fenoterol,

or salbutamol)

4. Tocolysis - The uterine relaxant effect of β2-adrenoceptor agonists can be used to

prevent premature labor, such asterbutaline or fenoterol. Vasodilation with a resultant

drop in systemic blood pressure results in reflex tachycardia (partial effect of drug to β1-

receptors)

5. Cardiostimulation – β1 -receptors by Ad-cyclase and cAMP production, catecholamines augment all heart functions
5. Cardiostimulation – β1 -receptors by Ad-cyclase and cAMP production, catecholamines augment all heart functions
5. Cardiostimulation – β1 -receptors by Ad-cyclase and cAMP production, catecholamines augment all heart functions

5. Cardiostimulation – β1-receptors by Ad-cyclase and cAMP production,

catecholamines augment all heart functions systolic force (positive inotropism),

velocity of shortening (clinotropism), sinoatrial rate (chronotropism), conduction

velocity (p. dromotropism), and excitability (bathmotropism). In pacemaker fibers,

diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostimulant

effect of β-sympathomimetics such as epinephrine, for tx. Of cardiac arrest. Use of β- sympathomimetics in heart failure carries the risk of cardiac arrhythmias.

6. Metabolic effects - β-Receptors mediate (glycogenolysis) in both liver and skeletal muscle. In adipose tissue, triglycerides are hydrolyzed to fatty acids (lipolysis, mediated by β3-receptors). The metabolic effects of catecholamines are not

amenable to therapeutic use.

The CATECHOLAMINES Classification of Drugs • Catechol –presence of OH- at phenyl ring (trivial name
The CATECHOLAMINES
Classification of Drugs
Catechol –presence of OH- at phenyl ring (trivial name for O-
hydroxyphenol)
Amino group – species of drugs
1. Catecholamines – endogenous and non-endogenous
2. Non-catecholamines – non-endogenous
OH
-CATECHOL, phenyl ring
(aromatic)
OH
CH 2 – CH 2 – NH 2
- AMINO GROUP., ethylamine
Direct sympathomimetics (agonists) mimic the actions of the naturally-occurring catecholamines, norepinephrine and
Direct sympathomimetics (agonists) mimic the actions of the naturally-occurring catecholamines, norepinephrine and
Direct sympathomimetics (agonists) mimic the actions of the naturally-occurring catecholamines, norepinephrine and
Direct sympathomimetics (agonists) mimic the actions of the naturally-occurring catecholamines, norepinephrine and
Direct sympathomimetics (agonists) mimic the actions of the naturally-occurring catecholamines, norepinephrine and

Direct sympathomimetics (agonists) mimic the actions of the naturally-occurring catecholamines, norepinephrine and epinephrine, and are used for various therapeutic effects:

epinephrine, and are used for various therapeutic effects: Catecholamines • 1. Endogenous (adrenal medullary

Catecholamines

1. Endogenous (adrenal medullary hormones) E, NE,

Dopamine

2. Non-endogenous Isoproterenol, Dobutamine

Non-catecholamines (non-endogenous)

Amphetamine resists COMT: high adrenergic effect

Phenylephrine

Ephedrine

Albuterol

Terbutaline

Ritodrine

Mechanism of Action Direct-acting Indirect-acting Mixed - Directly reacts with adrenergic receptors as Selective or
Mechanism of Action Direct-acting Indirect-acting Mixed - Directly reacts with adrenergic receptors as Selective or
Mechanism of Action Direct-acting Indirect-acting Mixed - Directly reacts with adrenergic receptors as Selective or
Mechanism of Action
Mechanism of Action
Direct-acting Indirect-acting Mixed
Direct-acting
Indirect-acting
Mixed

- Directly reacts with adrenergic receptors as Selective or Non- selective drugs

- Bring the effect but does not directly react with receptors

(Amphetamine); resistant to COMT/MAO or enzyme inhibitors (e,g. MAO-Inhibitors)

- Mimics an endogenous drug and at the same time release the

endogenous forms (Ephedrine)

I. Direct-acting: Selective Drugs • Specific receptor – alpha 1, alpha 2, beta 1, beta
I. Direct-acting: Selective Drugs • Specific receptor – alpha 1, alpha 2, beta 1, beta
I. Direct-acting: Selective Drugs • Specific receptor – alpha 1, alpha 2, beta 1, beta
I. Direct-acting: Selective Drugs
I. Direct-acting: Selective Drugs

Specific receptor alpha 1, alpha 2, beta 1, beta 2, dopa1, dopa2

EPINEPHRINE: Due to its equally high affinity for all α-and β-receptors, epinephrine

does not permit selective activation of a particular receptor subtype. Like most

catecholamines, it is also unsuitable for oral administration. NOREPINEPHRINE: differs from epinephrine by its high affinity for α-receptors and low affinity for β2-receptors. In contrast, ISOPROTERENOL - has high affinity for β- receptors, but virtually none for α-receptors

DOPAMINE is the immediate precursor in the synthesis of NE (regulates Na+ & renal

fxn.); CNS neurotransmitter; Vasodilator; reward stimulus relevant to addiction; Low

levels – Parkinson’s Dse; Anti-psychotic drugs (dopa receptors)

Norepinephrine α, β1

Epinephrine α, β1, β2

Isoproterenol β1, β2

Direct Sympathomimetics
Direct
Sympathomimetics
Direct Sympathomimetics MOA: affected by their structure affinity relationship; typically share a phenylethylamine
Direct Sympathomimetics MOA: affected by their structure affinity relationship; typically share a phenylethylamine
Direct Sympathomimetics MOA: affected by their structure affinity relationship; typically share a phenylethylamine

MOA: affected by their structure

affinity relationship; typically

share a phenylethylamine

structure.

The side chain β-hydroxyl group

confers affinity for α- and β-

receptors. Substitution on the

amino group reduces affinity for

α-receptors, but increases it for β-

receptors (exception: α-agonist

phenylephrine)

group reduces affinity for α - receptors, but increases it for β - receptors (exception: α

II. Indirect-acting:

II. Indirect-acting: MAO inhibitors • Apart from receptors, adrenergic neurotransmission involves mechanisms for the
II. Indirect-acting: MAO inhibitors • Apart from receptors, adrenergic neurotransmission involves mechanisms for the
II. Indirect-acting: MAO inhibitors • Apart from receptors, adrenergic neurotransmission involves mechanisms for the
MAO inhibitors
MAO inhibitors

Apart from receptors, adrenergic neurotransmission involves mechanisms for the active re-uptake and re-storage of released amine, as well as enzymatic

breakdown by monoamine oxidase (MAO). Norepinephrine (NE) displays

affinity for receptors, transport systems, and degradative enzymes. Chemical

alterations of the catecholamine differentially affect these properties and result in

substances with selective actions.

Inhibitors of MAO enzyme MAO is abundant at mitochondria and serves to

scavenge axoplasmic free NE (norepinephrine). Inhibition of the enzyme causes

free NE concentrations to rise. Likewise, dopamine catabolism is impaired,

making more of it available for NE synthesis the amount of NE stored in

granular vesicles will increase high amine release per impulse

Indirect-acting Sympathomimetics on CNS effect
Indirect-acting Sympathomimetics on
CNS effect
Indirect-acting Sympathomimetics on CNS effect • In the CNS, inhibition of MAO affects neuronal storage not
Indirect-acting Sympathomimetics on CNS effect • In the CNS, inhibition of MAO affects neuronal storage not
Indirect-acting Sympathomimetics on CNS effect • In the CNS, inhibition of MAO affects neuronal storage not

In the CNS, inhibition of MAO affects neuronal storage not only of NE but also of dopamine and serotonin stimulant effects in mood and psychomotor drive, and

used as anti-depressants.

Ex: Tranylcypromine - for depressive illness; as a covalently bound suicide

substrate, it causes long lasting inhibition of both MAO isozymes, (MAOA, MAOB).

Moclobemide - reversibly inhibits MAO-A; used as antidepressant.

Selegiline (deprenyl) MAO-B inhibitor retards the catabolism of dopamine; used in the treatment of parkinsonism

Cocaine indirect-acting; NE uptake inhibitor (more NE at the synapse)

• Amphetamine – high adrenergic stimulation (sympathomimetic) -blocks MAO & NE transport • Cocaine –
• Amphetamine – high adrenergic stimulation (sympathomimetic) -blocks MAO & NE transport • Cocaine –
• Amphetamine – high adrenergic stimulation (sympathomimetic) -blocks MAO & NE transport • Cocaine –

Amphetamine high adrenergic stimulation

(sympathomimetic)

-blocks MAO & NE

transport

Cocaine blocks

the transport

system, lower

adrenergic stimulation (local

anesthetics); blocks NE

transport

Indirect Sympathomimetics : MOA • Agents that elevate the concentration of NE at neuroeffector junctions,
Indirect Sympathomimetics : MOA • Agents that elevate the concentration of NE at neuroeffector junctions,
Indirect Sympathomimetics : MOA • Agents that elevate the concentration of NE at neuroeffector junctions,
Indirect Sympathomimetics : MOA
Indirect Sympathomimetics : MOA

Agents that elevate the concentration of NE at neuroeffector

junctions, because they either inhibit re-uptake (cocaine), facilitate

release, or slow breakdown by MAO, or exert all three of these

effects (amphetamine, methamphetamine).

Tachyphylaxis effectiveness of these sympathomimetics diminishes

when vesicular NE becomes depleted at axolemma.

Effects of Indirect Sympathomimetics • Penetrate the blood-brain barrier and evoke such CNS effects as
Effects of Indirect Sympathomimetics • Penetrate the blood-brain barrier and evoke such CNS effects as
Effects of Indirect Sympathomimetics • Penetrate the blood-brain barrier and evoke such CNS effects as
Effects of Indirect Sympathomimetics
Effects of Indirect
Sympathomimetics

Penetrate the blood-brain barrier and evoke such CNS effects as a feeling of well-being, enhanced physical activity and mood (euphoria), and decreased sense of hunger or fatigue. Subsequently, the user may feel tired and depressed.

These after effects are partly responsible for the urge to re-administer the drug (high abuse potential).

To prevent their misuse, these substances are subject to governmental

regulations (e.g., Food and Drugs Act: Canada; Controlled Drugs Act:

USA) restricting their Rx and distribution.

Amphetamines
Amphetamines

Amphetamine-like substances are misused to enhance athletic performance (doping) Risk: Dangerous physical overexertion.

Because of the absence of a sense of fatigue, a drugged athlete

may be able to mobilize ultimate energy reserves. In extreme situations, cardiovascular failure may result.

Closely related to amphetamine are “appetite

suppressants or anorexiants” (fenfluramine, mazindole, and

sibutramine). These may also cause dependence and their therapeutic value and safety are questionable.

mazindole, and sibutramine). These may also cause dependence and their therapeutic value and safety are questionable.
mazindole, and sibutramine). These may also cause dependence and their therapeutic value and safety are questionable.
mazindole, and sibutramine). These may also cause dependence and their therapeutic value and safety are questionable.
• α1 – vascular smooth tone (local bld vessels) • α2 - nerve terminals’ CNS
• α1 – vascular smooth tone (local bld vessels) • α2 - nerve terminals’ CNS
• α1 – vascular smooth tone (local bld vessels) • α2 - nerve terminals’ CNS

α1 – vascular smooth

tone (local bld

vessels)

α2- nerve terminals’

CNS blood vessels

1 reflex

vasoconstriction

(heart)

Take home Quiz: (ELGA Grouping)

Take home Quiz: (ELGA Grouping) Discuss the general mechanism of action of: (give example of drugs
Take home Quiz: (ELGA Grouping) Discuss the general mechanism of action of: (give example of drugs
Take home Quiz: (ELGA Grouping) Discuss the general mechanism of action of: (give example of drugs
Take home Quiz: (ELGA Grouping) Discuss the general mechanism of action of: (give example of drugs

Discuss the general mechanism of action

of: (give example of drugs at least 2)

alpha and beta sympathomimetics

alpha and beta sympatholytics

beta blockers? Why are they called such.

adrenergic drugs

SYMPATHOLYTICS
SYMPATHOLYTICS

α-Sympatholytics . The interaction of NE with α-adrenoceptors can be inhibited by α-sympatholytics -adrenoceptor antagonists, α-blockers). This inhibition

can be put to therapeutic use in antihypertensive treatment (vasodilation

peripheral resistance ↓, blood pressure ↓).

peripheral resistance ↓, blood pressure ↓). Non- selective α - blockers /sympatholytics:
peripheral resistance ↓, blood pressure ↓). Non- selective α - blockers /sympatholytics:
peripheral resistance ↓, blood pressure ↓). Non- selective α - blockers /sympatholytics:

Non-selective α- blockers/sympatholytics: Phenoxybenzamine, Phentolamine -

inhibit the NE action at both post- and pre-synaptic α-adrenoceptors. Presynaptic

α2-adrenoceptors are sensors of NE release concentration outside the

axolemma, its regulation is through local feedback mechanism. When presynaptic

α2-receptors are stimulated, further release of NE is inhibited (negative feedback

mechanism). Conversely, blockade of α2-adrenoceptors leads to overt

enhancement of sympathetic effects, at β1-adrenoceptor-mediated myocardial neuroeffector junctions (since it receives uncontrolled NE release) tachycardia

and tachyarrhythmia.

• α1 – vascular smooth tone (local bld vessels) • α2 - nerve terminals’ CNS
• α1 – vascular smooth tone (local bld vessels) • α2 - nerve terminals’ CNS
• α1 – vascular smooth tone (local bld vessels) • α2 - nerve terminals’ CNS

α1 – vascular smooth

tone (local bld

vessels)

α2- nerve terminals’

CNS blood vessels

1 reflex

vasoconstriction

(heart)

Selective α-Sympatholytics or α- blockers
Selective α-Sympatholytics or α-
blockers
Selective α-Sympatholytics or α- blockers • Prazosin; Terazosin and Doxazosin (longer-acting) • Suppress α1
Selective α-Sympatholytics or α- blockers • Prazosin; Terazosin and Doxazosin (longer-acting) • Suppress α1
Selective α-Sympatholytics or α- blockers • Prazosin; Terazosin and Doxazosin (longer-acting) • Suppress α1

Prazosin; Terazosin and Doxazosin (longer-acting)

Suppress α1-receptors activation w/o associated NE release; Lack affinity for presynaptic α2-adrenoceptors.

TX: Used in HPN (prevent reflex vasoconstriction); Can cause postural

hypotension with pooling of blood in lower limb capacitance veins during

change from the supine to the erect position (orthostatic collapse: ↓ venous

return, ↓ cardiac output, fall in systemic pressure, ↓ blood supply to CNS,

syncope).

For benign hyperplasia of the prostate, α-blockers (terazosin, alfuzosin)

may serve to lower tonus of smooth musculature in the prostatic region

and thereby facilitate micturition (urination).

• Reversible – Phentolamine & Prazosin Irreversible • – Phenoxybenzamine

Reversible

Phentolamine &

Prazosin

Irreversible

Phenoxybenzamine

β-Sympatholytics / β-blockers • Antagonists of NE and E at β -adrenoceptors ; no affinity
β-Sympatholytics / β-blockers • Antagonists of NE and E at β -adrenoceptors ; no affinity
β-Sympatholytics / β-blockers • Antagonists of NE and E at β -adrenoceptors ; no affinity
β-Sympatholytics / β-blockers
β-Sympatholytics / β-blockers

Antagonists of NE and E at β-adrenoceptors; no affinity for α-receptors.

Therapeutics: Protects the heart from the O 2 - wasting

effect of sympathetic inotropism by blocking cardiac β-receptors; thus, cardiac

work can no longer be augmented above basal levels (the heart is

“coasting/gliding”). This effect is utilized prophylactically in angina pectoris to

prevent myocardial stress that could trigger an ischemic attack.

Lower cardiac rate (sinus tachycardia) and elevated BP due to high cardiac

output. The mechanism underlying their antihypertensive action via reduction

of peripheral resistance is unclear.

Applied topically to the eye, β-blockers are used in the management of

glaucoma; they lower production of aqueous humor without affecting its

drainage (enhanced parasympathetic resp.)

Undesirable effects / Side effects

Undesirable effects / Side effects

The hazards of treatment with β-blockers become apparent

The hazards of treatment with β -blockers become apparent particularly when continuous activation of β -receptors
The hazards of treatment with β -blockers become apparent particularly when continuous activation of β -receptors
The hazards of treatment with β -blockers become apparent particularly when continuous activation of β -receptors

particularly when continuous activation of β-receptors is needed

in order to maintain the function of an organ.

1. Congestive heart failure (CHF) - In myocardial insufficiency,

the heart depends on a tonic sympathetic drive to maintain

adequate cardiac output, ↑HR and systole tension. Β-blockers

eliminate β-receptor sympathetic drive leading to stroke volume

and cardiac rate decline, a latent/covert myocardial insufficiency

is exposed, and overt insufficiency is exacerbated or intensified.

2. Bradycardia, A-V block: Decline of sympathetic drive can

lead to a marked fall in cardiac rate and lead to A-V d/o of

impulse conduction.

Undesirable effects of β-blockers • 3. Bronchial asthma: Increased sympathetic activity prevents bronchospasm in
Undesirable effects of β-blockers • 3. Bronchial asthma: Increased sympathetic activity prevents bronchospasm in
Undesirable effects of β-blockers • 3. Bronchial asthma: Increased sympathetic activity prevents bronchospasm in
Undesirable effects of β-blockers
Undesirable effects of β-blockers

3. Bronchial asthma: Increased sympathetic activity prevents bronchospasm in patients disposed to paroxysmal (spastic) constriction of the bronchial tree

(bronchial asthma, bronchitis in smokers). In this condition, β2-receptor blockade

will precipitate acute respiratory distress (ARDs).

Undesirable effects… • 4. Hypoglycemia in D. mellitus: Insulin or oral hypoglycemics in the diabetic
Undesirable effects… • 4. Hypoglycemia in D. mellitus: Insulin or oral hypoglycemics in the diabetic
Undesirable effects… • 4. Hypoglycemia in D. mellitus: Insulin or oral hypoglycemics in the diabetic
Undesirable effects…
Undesirable effects…

4. Hypoglycemia in D. mellitus: Insulin or oral hypoglycemics in the diabetic patient lowers blood glucose below a critical level, epinephrine is

released, which then stimulates hepatic glucose release via activation of β2-

receptors. β-Blockers suppress this counter-regulation; in addition, they

mask other epinephrine-mediated warning signs of imminent hypoglycemia,

such as tachycardia and anxiety, thereby enhancing the risk of hypoglycemic

shock.

5. Altered vascular responses: When β2-receptors are blocked, the

bronchodilating effect of epinephrine is abolished, leaving the α-receptor-

mediated vasoconstriction unaffected: peripheral blood flow ↓ – “cold hands

and feet”.

• 6. β -Blockers exert an “anxiolytic“ action that may be due to the suppression
• 6. β -Blockers exert an “anxiolytic“ action that may be due to the suppression
• 6. β -Blockers exert an “anxiolytic“ action that may be due to the suppression
• 6. β -Blockers exert an “anxiolytic“ action that may be due to the suppression

6. β-Blockers exert an “anxiolytic“ action that may be due to the suppression of somatic responses (palpitations, trembling) caused by sympathetic epinephrine release and induce emotional stress; in turn, these would exacerbate “anxiety” or “stage fright”. Because alertness is not impaired by β-blockers, these agents are occasionally taken by orators and musicians before a major performance. Stage fright, however, is not a

disease requiring drug therapy.

Types of β-blockers
Types of β-blockers

Isoproterenol (sympathomimetic) vs.

Propanolol (β-blocker)

(sympathomimetic) vs. • Propanolol ( β -blocker) • Propanolol – 1 s t β -blocker introduced
(sympathomimetic) vs. • Propanolol ( β -blocker) • Propanolol – 1 s t β -blocker introduced
(sympathomimetic) vs. • Propanolol ( β -blocker) • Propanolol – 1 s t β -blocker introduced

Propanolol 1 st β-blocker introduced in therapy (1965)

Pindolol is a partial agonist in full agonist e.g. isoprenaline,

thus binds to β receptors and effect of full agonist becomes

impeded.

Metoprolol, Acebutolol, Bisoprolol cardioselective (affinity for cardiac β1 > β2)

These β- blockers can exert a membrane-stabilizing

effect, as evidenced by the ability of the more lipophilic

congeners to inhibit Na+-channel function and impulse

conduction in cardiac tissues.

Anti-Adrenergics • Drugs capable of lowering transmitter output from sympathetic neurons, i.e., “sympathetic tone”.
Anti-Adrenergics • Drugs capable of lowering transmitter output from sympathetic neurons, i.e., “sympathetic tone”.
Anti-Adrenergics • Drugs capable of lowering transmitter output from sympathetic neurons, i.e., “sympathetic tone”.
Anti-Adrenergics
Anti-Adrenergics

Drugs capable of lowering transmitter output from

sympathetic neurons, i.e., “sympathetic tone”. Their

action is hypotensive (indication: Hypertension);

however, being poorly tolerated, they enjoy only

limited therapeutic use.

Inhibitors of sympathetic tone: Clonidine, Methyldopa, Reserpine, Guanethidine

• Other Anti-adrenergics or Sympatholytics 1. Clonidine is an α2 -agonist with high lipophilicity (dichlorophenyl
• Other Anti-adrenergics or Sympatholytics 1. Clonidine is an α2 -agonist with high lipophilicity (dichlorophenyl
• Other Anti-adrenergics or Sympatholytics 1. Clonidine is an α2 -agonist with high lipophilicity (dichlorophenyl

Other Anti-adrenergics or Sympatholytics

• Other Anti-adrenergics or Sympatholytics 1. Clonidine is an α2 -agonist with high lipophilicity (dichlorophenyl

1. Clonidine is an α2-agonist with high lipophilicity

(dichlorophenyl ring), permits rapid penetration through the blood-

brain barrier. The activation of postsynaptic α2-receptors reduces

the activity of vasomotor neurons in the medulla oblongata,

resulting in a resetting decrease of systemic arterial pressure. In

addition, activation of presynaptic α2-receptors in the Peripheral

NS leads to a decreased release of both NE and Ach.

Side effects (SE). Lassitude (tiredness), dry mouth; rebound hypertension after abrupt cessation of clonidine therapy

(withdrawal syndrome).

2. Methyldopa (dopa = d ihydr o xy p henyl a lanine ), an amino

2. Methyldopa (dopa = dihydroxyphenylalanine), an amino acid, is transported across the BBB, decarboxylated in the brain to α-methyldopamine, and then hydroxylated to α-methyl-

NE. Rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter α-

methyl-NE can be stored. However, unlike the endogenous dopamine, methyldopa has a

higher affinity for α2- than α1-receptors and produce SE similar to those of clonidine.

Inhibition of dopa-decarboxylase non-conversion of Dopa to Dopamine

Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkinson-like symptoms, cutaneous reactions, hepatic damage, immune-hemolytic anemia

• 3. Guanethidine. (+) high affinity for axolemmal and vesicular amine transporters. It is stored

3. Guanethidine. (+) high affinity for axolemmal and vesicular amine transporters.

It is stored instead of NE, but unable to mimic NE fxns. It stabilizes the axonal membrane impeding the propagation of impulses in the sympathetic nerve terminals. Storage and release of epinephrine from the adrenal medulla are not affected, owing to the absence of a re-uptake process. The drug is impermeable in BBB.

Adverse effects. Risk of Cardiovascular crises : emotional stress of the patient

may cause sympathoadrenal activation with E release. It can increase BP and can

be more marked because persistent depression of sympathetic nerve activity

induces supersensitivity of effector organs to circulating catecholamines.

depression of sympathetic nerve activity induces supersensitivity of effector organs to circulating catecholamines.
depression of sympathetic nerve activity induces supersensitivity of effector organs to circulating catecholamines.
depression of sympathetic nerve activity induces supersensitivity of effector organs to circulating catecholamines.
• 4. Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic

4. Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular

alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopamine (DA), serotonin
alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopamine (DA), serotonin
alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopamine (DA), serotonin

storage of biogenic amines (NE, dopamine (DA), serotonin (5-HT) ) by inhibiting ATPase required for the vesicular amine pump. Low NE release per nerve impulse, impaired E release from the adrenal medulla, and higher reserpine dose irreversible damage to storage vesicles or “pharmacological sympathectomy”, days to weeks being required for transmitter re-synthesis. It is permeable to brain impaired vesicular storage of biogenic amines.

Adverse effects. Extrapyramidal motor function D/O with pseudo-Parkinsonism,

sedation, depression, stuffy nose, impaired libido, and impotence; increased

appetite. These adverse effects have rendered the drug practically obsolete.