2021-09-07

DRUGS AFFECTING SANS: ADRENOMIMETICS 5.17 (I)

G. Sakalauskienė
LSMU Institute of physiology and pharmacology

General objects
1. To understand the mechanism and physiological functions of adrenergic
transmission.
2. To analyse the postreceptor (signaling) mechanism caused by
stimulation of adrenergic and dopaminergic receptors.
3. To be able to explain the mechanism of action of adrenoceptors
stimulating (adrenomimetics) and adrenoceptors blocking
(adrenoblockers) agents.
4. To be able to explain the pharmacokinetic and pharmacodynamic
properties of these drugs and agents, also – to compare them within the
appropriate group of medications.
5. To understand the opportunities of clinical use and explain them.
6. To distinguish and identify the side effects and also explain the reasons
of their origins.

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Neurotransmitters in the SANS

⚫ Noradrenaline (norepinephrine, NA)→
▪ major chemical mediator liberated by
mammalian postganglionic sympathetic nerves that acts on the
target organ or tissue;
▪ neurotransmitter in the CNS

⚫ Adrenaline (epinephrine, ADR)→

▪ hormone released from the adrenal medulla;
▪ neurotransmitter in the CNS

⚫ Dopamine (DA) →
▪ central neurotransmitter particularly important in the regulation
of movements;
▪ centrally synthesized in the substantia nigra (SN), the ventral
tegmental area (VTA) and the hypothalamus
▪ in the periphery is synthesized in the epithelial cells of the renal
proximal tubule and is thought to exert local diuretic and
natriuretic effects;
▪ sympathetic postganglionic mediator of the renal beds
(vasodilation);
▪ causes cardiac stimulation.

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Adrenergic synapsis
⚫ DA, NA, ADR are synthesized from tyrosine:
α-methyltyrosine
▪ Oxidation of cytoplasmic tyrosine to dihydroxyphenylalanine (L-DOPA), is
catalyzed by the enzyme tyrosine hydroxylase;
▪ Aromatic L-amino acid decarboxylase converts L-DOPA to DA;
▪ Vesicular monoamine transporter (VMAT) translocates DA (and other
monoamines) into synaptic vesicles;
▪ Intravesicular DA is converted to NA by the dopamine-β-hydroxylase;
▪ NA is then stored in the vesicle until release;
▪ In the adrenal medullary cells, NA returns to the cytosol, where
phenylethanolamine N-methyltransferase (PNMT) converts it to ADR;

▪ ADR is then transported back into the vesicle for storage (not shown);
▪ α-Methyltyrosine inhibits tyrosine hydroxylase, the rate-limiting enzyme in
catecholamine synthesis;
▪ Released NA can stimulate postsynaptic α1-, β1-, or β2-adrenergic receptors or
presynaptic α2-adrenergic autoreceptors;
▪ Released NA can also be taken up into presynaptic terminals by the selective
NE (NA) transporter. NA in the cytoplasm of the presynaptic neuron can be
further taken up into synaptic vesicles by VMAT or degraded to 3,4-
dihydroxyphenylglycoaldehyde (DOPGAL) by mitochondrion-associated
https://meded-lwwhealthlibrary- monoamine oxidase (MAO).
com.ezproxy.dbazes.lsmuni.lt/content.aspx?sectionid=1177976 NE → NA→noradrenaline
06&bookid=1765

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SANS effects – „ fight or flight“

⚫↑ heart rate (β1)

⚫ Bronchodilation (β2)

⚫ Dilated vessels of the skeletal muscles (β2)

⚫ Glycogenolysis/gluconeogenesis (β2, α1)

⚫ Constriction of skin, mucous vessels (α1, α2)

⚫ Mydriasis (α1)

„THE EYES OF FEAR ARE WIDE...“

ORGAN ADRENOCEPTOR TYPE; EFFECT

EYE α1 → PUPIL DILATION; β2→CILIARY MUSCLE RELAXATION (far vision)
SALIVARY GLANDS α, β →THICK, VISCOUS SECRETION
TRACHEA, BRONCHIOLI β2→ DILATION
ADRENAL MEDULLA ADR, NA SECRETION via NICOTINIC RECEPTORS

HEART β1→↑ RATE, ↑ CONTRACTILITY, ↑ AUTOMATICITY

KIDNEY SECRETION OF RENIN (ɑ1→ DECREASES, β1 →INCREASES)

GIT α1, α2, β2→↓ MUSCLE MOTILITY,

URETERS AND BLADDER, UTERUS
SKELETAL MUSCLES/BLOOD VESSELS OF
SKELETAL MUSCLES
BLOOD VESSELS (SKIN, MUCOUS MEMBRANE,
KIDNEYS, SPLANCHNIC AREA, CORONARY)
SPHINCTER CONTRACTION
β2→DETRUSOR RELAXATION
α1→TRIGONE AND SPHINCTER CONTRACTION
β2→RELAXATION OF NON PREGNANT UTERUS, α1→ CONTRACTION OF PREGNANT
UTERUS
β2→TREMOR, ↑ K+ UPTAKE/ DILATION
α1, α2→CONSTRICTION, β2→DILATION

GENITALIA α1 →STIMULATION OF EJACULATION

SWEAT GLANDS STIMULATION via MUSCARINIC RECEPTORS (CHOLINERGIC)
HAIR PILOERECTION

LIVER α1, β2→GLUCONEOGENESIS, GLYCOGENOLYSIS

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Receptor Location
Alpha1 (postsynaptic) Vascular smooth muscle,
Genitourinary smooth muscle,
Intestinal smooth muscle,
Liver
Alpha2 (mainly presynaptic, in Nerve endings,
some sites – postsynaptic) Pancreatic beta cells
Platelets
Vascular smooth muscle
Ciliary body epithelium
Beta1 postsynaptic→cardiac muscle, brain, presynaptic
adrenergic and cholinergic nerve terminals, juxtaglomerular
apparatus, ciliary body epithelium
Beta2 (postsynaptic) smooth muscles,
liver,
skeletal muscle
Beta3 (postsynaptic) adipose cells
Dopamine1 (DA1) smooth muscles of renal
vascular bed
Dopamine2 (DA2) brain, smooth muscles,
presynaptic nerve terminals
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Stimulation of α1 adrenoceptors
Characteristics of METABOTROPIC adrenoceptors
G protein Second messenger
Gαq ↑phospholipase C activation→ ↑
inositol triphosphate (IP3)/diacylglycerol
(DAG)/intracellular Ca2+
Gαi/Gαo adenylyl cyclase inhibition→ ↓ cAMP,
↓neuronal Ca2+, ↑ K+ conductance
Gαs adenylyl cyclase activation→ ↑ cAMP
Gαi adenylyl cyclase inhibition→ ↓ cAMP,
Gβγ ↓neuronal Ca2+, ↑ K+ conductance
Postreceptor mechanisms of catecholamines
Stimulation of α2 and β adrenoceptors
2021-09-07
Major function/biological effect
vascular muscle constriction;
contraction;
relaxation of GIT smooth muscles;
Glycogenolysis/ gluconeogenesis
inhibition of NA release (nerves);
↓insulin release;
platelet aggregation;
vascular smooth muscle contraction;
↓ secretion of eye aqueous humor
↑ cardiac rate and force, ↑AV node
conduction;
↑renin release
relaxation of visceral smooth
muscle; bronchodilation; skeletal
vessels vasodilation; ↑hepatic
glycogenolysis; ↑ glycogenolysis and
K+ uptake in skeletal muscle (muscle
tremor)
lipolysis
relaxation renal vascular smooth
muscle
modulation of neurotransmitter
release in CNS ans SNS
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ADRENERGIC AGONISTS
(SYMPATHOMIMETIC DRUGS, ADRENOMIMETICS)

Origin of adrenergic agonists

CATECHOLAMINES
⚫ natural endogenous agents→ADR, NA, DA;
⚫ synthetic agents→isoproterenol (isoprenalin), dobutamine;

⚫ high potency in direct activation of α and β adrenoceptors;

⚫ duration of action→very short if used parenterally, no effect if used enterally;

⚫ rapid inactivation by COMT and MAO; MAO does not act on isoprenalin;

⚫ poor penetration into the CNS due to polar structure; most drugs can exhibit effects
similar to action on the CNS (tremor, anxiety, headache)
NON CATECHOLAMINES
⚫ synthetic→phenylephrine, amphetamine, and natural→ephedrine,;

⚫ longer half-life, not inactivated by COMT, poor substrate for MAO;

⚫ lipid soluble, penetrate into the CNS;

⚫ could be used enterally

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Classification of adrenergic agonists (sympathomimetic drugs)

DIRECT - ACTING MIXED INDIRECT - ACTING

ACTING
SELECTIVE NONSELECTIVE RELEASING UPTAKE MAO COMT
AGENTS INHIBITORS INHIBITORS* INHIBITORS*

α1 phenylephrine α1, α2, β1, β2 ephedrine amphetamine cocaine selegiline entacapone

adrenaline α1, α2, β1, β2
α2 clonidine α1, α2, β1 noradrenaline tyramine

α2 apraclonidine β1, β2 isoprenalin

β1 dobutamine??? α1, α2 oxymetazoline

β2 terbutaline DA1, DA2, α, β

(salmeterol, dopamine
albuterol)

*- both drugs are used to treat Parkinson disease

Site of actions of direct, indirect and mixed-acting adrenomimetics

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Adrenoceptors agonists (sympathomimetics). Adrenaline (I)

Nonselective catecholamine: α1 =α2 ; β1 = β2 , low C.→β; high C.→α

⬛ Heart (β1)→ + inotropic effect (↑contractility), + chronotropic effect
(↑heart rate):
⬜↑ cardiac output and demand of oxygen;
⬛ low C. →↓ PVR*:
⬜ due to dilation of liver and skeletal muscle vessels (β2)
⬛ high C. →↑ PVR:
⬜ due to constriction of skin, mucous, visceral and renal arterioles (α1);
⬛ BP is increased due to→ + inotropic and + chronotropic effects (β1) and
vasoconstriction (α1):
⬛ usual C. →↑SBP, slightly ↓DBP, the mean BP increases slightly.
⬜ action on CVS is stronger in hyperthyroidism (increased C. of
adrenoceptors) and cocaine use (inhibition of reuptake).
⬤ Respiratory (β2): bronchodilation;
⬤ Hyperglycemia: ↑glycogenolysis/gluconeogenesis in liver (β2),
↓release of insulin (α2);
⬤ Lipolysis (β3)

*- peripheral vascular resistance https://meded-lwwhealthlibrary-com.ezproxy.dbazes.lsmuni.lt/content.aspx?sectionid=197345728&bookid=2486

Direct – acting adrenergic agonists. Adrenaline (II)

⬤ CLINICAL USE:
⬛ anaphylactic shock;
⬛ cardiac arrest;
⬛ reduction of bleeding (surgery);
⬛ prolongs action of LA;
⬛ bronchospasm after the intubation, laryngitis
⬤ ADVERSE EFFECTS:
⬛ anxiety, fear, tension, headache,
⬛ tremor:
⬜ (?) improves transmission in the motor plate→ stimulates rapid release of Ach in the
synapsis of nerve and muscle fiber (α1);
⬜ (?) directly acts on the white (fast glycolytic) muscle fibers and prolongs their activity
(maximal tension) and activates K+ uptake in the muscles, causes hypokalemia (β2).
⬛ cerebral hemorrhage (due to ↑BP);
⬛ arrhythmias;
⬛ pulmonary edema

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Direct – acting adrenergic agonists. Noradrenaline

nonselective catecholamine
α1 = α2 ; β1>>β2
⬛ vasoconstriction (α1)→renal and other vessels;
⬛ no effect on β2 adrenoceptors in the skeletal vessels→no
vasodilation;
⬛↑ PVR →highly ↑ SBP and slightly ↑DBP;
⬛ + inotropic effect (β1);
⬛ induces bradycardia due to high BP (n. vagus stimulation via
baroreceptors).
⬤ CLINICAL USE:

⬜ septic shock (hypotension due to ↓ vascular tone)*:

⬜ IV - ↑ cardiac output, improves microcirculation, perfusion
and prevents from the accumulation of fluids.
⬤ ADVERSE EFFECT:

⬛ vasospasm, extravasation, tissue necrosis;

⬛ excessively ↑ BP;
⬛ arrhythmias, infarction.
* if anaphylactic shock→ADR, if cardiogenic → DA.
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Direct – acting adrenergic agonists. Dopamine (I)

nonselective catecholamine
DA1 = DA2 >> β >> α
⚫ stimulation of DA2 on the presynaptic adrenergic neurons by
DA, inhibits release of NA and on the chromaffin cells of adrenal
Heart rate (beats/min)
medulla – release of ADR
⚫ EFFECTS ON CVS:
⬜ medium doses→CVS (β1): + inotropic and +chronotropic
effect [cardiac stimulation], ↑SBP SBP
(mm/Hg)
⬜ high doses→vessels (α1): vasoconstriction→↑ PVR, ↑SBP
⬜ low doses→dilation of renal, mesenteric, coronary and
brain arterioles (DA1), vasodilation of skeletal muscles (β 2)
dilation: ↓peripheral resistance, little effect on DBP; DBP
(mm/Hg)
⚫ RENAL EFFECT: low doses→ ↑ GFR, improve renal blood flow,
↑natriuresis.
⬛ CLINICAL USE: cardiogenic [symptoms: hypotension, ↓
perfusion, ↓ cardiac output], septic, hypovolemic shock, heart PVR
failure
⬛ ADVERSE EFFECTS: hypertension, arrhythmias, nausea

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What is a low-medium-high dose of dopamine?

Sources Low dose Medium dose High dose

(μg/kg/min) (μg/kg/min) (μg/kg/min)

1. 1-5 From 10 to
20
2. 2-5 5-10 >10
3 5-15 20-50
4. 0,5-2 2-10 >10
5. 0,3-5
Usual dose: 2-5 μg/kg/min;
Titration dose: 2-20 μg/kg/min

Direct – acting adrenergic agonists. Isoprenalin

nonselective, synthetic catecholamine
β1 = β2>>>> α
⚫ CVS (β1):
⬜ + chronotropic and + inotropic effects:
◼ moderately ↑ SBP;
⬜ dilation of skeletal muscle arterioles (β2):
▪ significantly ↓ PVR;
▪ markedly ↓ DBP.
⚫ Respiratory (β2): bronchodilation;
⬛ CLINICAL USE: asthma (rarely), cardiac
stimulation (critical cases)
⬛ ADVERSE EFFECT: as adrenaline
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Direct –acting adrenergic agonists. Dobutamine

selective??? synthetic catecholamine β1 adrenoceptor agonist
β1 > β2>>>> α
⬛Two racemic forms: (+) form acts as agonist on β1 and as antagonist on
α1, (-) form acts as agonist on α1
⚫ CVS (β1):
⚪ + inotropic effect, ↑ cardiac output and stroke volume;

⚪ little effect on the heart rate, does not increase significantly oxygen

demand;
⬛ CLINICAL USE:

⚪ cardiogenic shock;

⚪ acute heart failure;

⚪ imagining diagnostics of IHD;

⬛ ADVERSE EFFECTS: ↑ AV conduction (arrythmias)

Oxymetazoline
Synthetic nonselective α AR agonist: full α1, partial
α2 agonist, non catecholamine
⬤ Vessels (α1)→vasoconstriction:
⬛ CLINICAL USE:
⭕ rhinitis, conjunctivitis→↓ congestion (short-term use

by the ocular drops or intranasal spray).

⬛ ADVERSE EFFECTS:
⭕ reaches the systemic circulation and brain→↑

nervousness, headache, trouble sleeping;

⭕ mucosal irritation;

⭕ long - term use→ rebound congestion.

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Direct –acting adrenergic agonists. Phenylephrine

selective synthetic α1 adrenoceptor agonist, non catecholamine
α1 >α2>>>>>β
⚫ metabolism is not affected by COMT, partially metabolized in the liver and guts by
MAO;
⬛ CVS:
◯ vasoconstriction→↑ DBP, ↑ SBP, ↑ peripheral resistance→reflex bradycardia;
⬛ mucous vasoconstriction ;
⬛ mydriasis;
⬜ CLINICAL USE:
⚪ nasal and ocular congestion;

⚪ pupil dilation (mydriasis);

⚪ hypotension;
⚪ supraventricular tachycardia
⬜ ADVERSE EFFECTS: hypertension, stroke, myocardial infarction.

Direct –acting adrenergic agonists. Clonidine

centrally acting selective α2 adrenoceptor agonist
α2>α1>>>>>β
⬤ not metabolized by COMT; long action;
⬤ if used orally, BA→100%, also could be injected IV or used as the patches;

⭕ ↓ sympathetic outflow from the CNS acting on the α 2 adrenoceptors

in lower brainstem (locus ceruleus)→↓BP;
⭕ ↑ parasympathetic outflow→↓heart rate;
⭕ activates presynaptic α2 adrenoceptors→suppresses release of NA
from the postganglionic sympathetic nerves;
⬛ CLINICAL USE: hypertension, migraine, reduction symptoms of abstinence from
opioids.
⬛ ADVERSE EFFECTS: dry mouth, sedation, sexual dysfunction, bradycardia, after the
long – term therapy→withdrawal and rebound hypertension.

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selective α2 agonist, also acts on the imidazole

receptors
⭕ topical ocular use (eye drops)→glaucoma
and diagnostics of Horner syndrome;
⭕ short action, no penetration through the
BBB, negligible systemic effect.
Apraclonidine
A. Note left ptosis and anisocoria with the
smaller pupil on the left. Both pupils
reacted briskly to light stimulation.
B. Forty-five minutes after topical
instillation of 1% apraclonidine in both
eyes, there is reversal of anisocoria, with
the right pupil now smaller than the left.
Note also improvement in the left-sided
ptosis.

Kanagalingam, S., & Miller, N. R. (2015). Horner syndrome: clinical

perspectives. Eye and Brain, 7, 35–46.
http://doi.org.ezproxy.dbazes.lsmuni.lt:2048/10.2147/EB.S63633

Direct – acting adrenergic agonists. Βeta2 selective agonists

β2 >> β1>>>>α
⬤ Short acting (acute bronchospasm, COPD):
⬛ TERBUTALINE→orally, subcutaneously, inhalation; if inhalation→rapid onset of
action, duration of action - 3 – 6 h;
⬛ ALBUTEROL→orally, inhalation; if inhalation→onset of action within 15 min,
effect for 3 – 4 h.
⬤ Long acting (chronic asthma, COPD):
⬛ SALMETEROL→powder inhalation; longer onset of action, duration >12 h.
⬜ Adverse effects:
⭕ tachycardia (β1), arrhythmias;
⭕ tremor, restlessness, anxiety;
⭕ hyperglycemia

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Mixed – acting adrenergic agonists. Ephedrine

natural agent → from plants of Ephedra (Ma Huang)
⭕↑ NA release from the presynaptic terminals, activates α1, α2, β1, β2 postsynaptic adrenoceptors;
⭕ good absorption in GIT, good lipid solubility→penetrates the BBB;

⭕ constricts vessels, stimulates heart→↑ DBP and ↑ SBP;

⭕ dilates bronchi (was used for BA prophylaxis);
⭕ slightly stimulates CNS→↓ tiredness and sleep, ↑ physical capacity (sport ).
⚫ ADVERSE EFFECT:

⬛ tachycardia (β1), ↑BP;

⬛ urinary retention→ stimulation of sphincter;

⬛ CNS stimulation→ insomnia.

⚫CLINICAL USE:
⬜ PSEUDOEPHEDRINE (racemic form of ephedrine) is more commonly used → ↓nasal, sinus and
Eustachian congestion, urinary incontinence;
⭕ methamphetamine is illegally made from pseudoephedrine 😈

DOPING...DOPING...DOPING 😧

„FIFA listed the five banned

substances in Maradona's test as
ephedrine, phenylpropanolamine,
pseudo-ephedrine, non-pseudo-
ephedrine and
methylephedrine.“ From: The New York
Times. Sports, 01/07/1994

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Indirect – acting adrenoceptors agonists

AGENT EFFECT/RECEPTOR CLINICAL USE ADVERSE EFFECT
Amphetamine ⚫ displaces stored catecholamines anorexiant, high addiction liability,
oral, parenteral from the storage vesicles; attention – deficit disorder, hypertension
⚫ weakly inhibits MAO-A narcolepsy, paranoia,
⚫ competitively inhibits urinary incontinence aggression,
catecholamines reuptake by the arrhythmias,
NAT and DAT→ seizures
⭕ ↑ NA, DA release→,
vasoconstriction (α)→↑BP,
⭕ stimulates CVS (cardiac β1),
⭕ stimulates CNS
⭕ bladder spinchter constriction

Tyramine displaces stored catecholamines, ↑ no clinical use, found in food hypertension,

inactivation by MAO in GIT, liver BP (bananas, cheese, red wine Chianti) arrhythmias,
stroke
Cocaine ⬤ blocks NA reuptake (NAT)→↑ NA was a local anesthetic with intrinsic drug of abuse,
parenteral (topical, IV, local injection) in synaptic hemostatic action→ inhibits neuronal addiction,
cleft→vasoconstriction (α), potential; causes vasoconstriction hypertension,
stimulation of cardiac β→↑ BP; Intranasal use→mucous ischemia and
⬤ blocks DA reuptake (DAT); necrosis,
arrhythmias,
seizures

Indirect – acting adrenoceptors agonists

MAO-A

amphetamine

amphetamine

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Kim ST, Park T. Acute and Chronic Effects of Cocaine on Cardiovascular

Side effects of cocaine (I)
Health. Int J Mol Sci. 2019 Jan 29;20(3). Iš: https://www-ncbi-nlm-nih-gov.ezproxy.dbazes.lsmuni.lt/pubmed/30700023

Side effects of cocaine (II)

Molteni M, et al. Snorting the clivus away: An extreme case of cocaine-induced midline destructive lesion. BMJ Case Reports 2016:bcr2016216393
DOI: 10.1136/bcr-2016-216393

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Adrenomimetics
MAIN CLINICAL USE:
⬤ CVS MAIN ADVERSE EFFECT
Cardiac arrest (ADR)
⚪

⚪ Cardiogenic shock (DA, dobutamine)

⚫Arrhythmias
⬤ Anaphylaxis (ADR)
⚫ Headache
⬤ BA (terbutaline, albuterol, salmeterol)

⬤ Pupil dilation (phenylephrine) ⚫ Hyperactivity

⬤ Nasal congestion (pseudoephedrine)
⚫ Insomnia
⬤ Local anesthesia (ADR)
⚫ Nausea
⬤ BP lowering (clonidine)

⬤ Glaucoma (apraclonidine) ⚫Tremor

⚫ Hypertension

Bring home message

1. Activation of α1 – adrenoceptors mediates smooth muscle contraction, leading to vasoconstriction, dilation
of pupils, and constriction of the bladder sphincter muscle.
2. Activation of α2 – adrenoceptors inhibits release of NA from sympathetic neurons, decreases secretion of
aqueous humor (eye).
3. Activation of β1 – adrenoceptors produces cardiac stimulation, whereas activation of β 2 – adrenoceptors
mediates smooth muscle relaxation.
4. The natural catecholamines are NA, ADR, DA, synthetic - isoprenalin, dobutamine. These drugs are rapidly
metabolized, must be administered parenterally, and are used primarily to treat cardiac disorders and various
type of shock.
5. In addition to activating adrenoceptors, DA activates DA1 – receptors and increases renal blood flow.
6. Noncatecholamines (phenylephrine and albuterol) are resistant to COMT. Phenylephrine activates α1-
adrenoceptors and causes vasoconstriction, albuterol – β2 – adrenoceptors and produces bronchodilation.
7. Oxymetazoline is a topical decongestant, activates α- adrenoceptors. Clonidine is an antihypertensive agent
and apraclonidine is used to control glaucoma.
8. The indirect – acting adrenoceptors agonists (amphetamine and cocaine) increase the synaptic
concentration of NA, DA.
9. Mixed – acting agonists, such as pseudoephedrine have both direct and indirect actions. This drug is used
as a nasal decongestant.

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References / Main readings

1. https://accessmedicine-mhmedical-
com.ezproxy.dbazes.lsmuni.lt/content.aspx?bookid=2988&sectionid=250595038#1176462078
2. https://meded-lwwhealthlibrary-
com.ezproxy.dbazes.lsmuni.lt/content.aspx?sectionid=197345728&bookid=2486

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3. Brunton ll, et al. Goodman & Gilmann:The Pharmacological Basis of Therapeutics, 13 th edition. https://accessmedicine-mhmedical-
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5. Kanagalingam, S., & Miller, N. R. (2015). Horner syndrome: clinical perspectives. Eye and Brain, 7, 35–46.
http://doi.org.ezproxy.dbazes.lsmuni.lt:2048/10.2147/EB.S63633.
6. Molteni M, et al. Snorting the clivus away: An extreme case of cocaine-induced midline destructive lesion. BMJ Case Reports 2016:bcr2016216393
DOI: 10.1136/bcr-2016-216393
7. Goutos I, L. K. Cogswell LK, and H. Giele H. Extravasation injuries: a review . Journal of Hand Surgery (European Volume) Vol 39, Issue 8, pp. 808 –
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8. Velpandian T(ed.). Pharmacology of Ocular Therapeutics. Springer International Publishing Switzerland, 2016.
9. Barrett KE, et al. Ganong's Review of Medical Physiology, 26e. https://accesspharmacy-mhmedical-
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10. Byrne CJ, Khurana S, Kumar A, Tai TC. Inflammatory Signaling in Hypertension: Regulation of Adrenal Catecholamine Biosynthesis. Front Endocrinol
(Lausanne). 2018 Jun 28;9:343. doi: 10.3389/fendo.2018.00343. PMID: 30013513; PMCID: PMC6036303.

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