MIXED ACTING

ADRENERGIC
AGONIST
 Drugs that cause;

 Activation of adrenergic receptors direct binding

 Release of endogenously-stored norepinephrine from presynaptic terminals

 Ephedrine is the prototype mixed-acting agonist

 Action somewhat diminished but not eliminated by reserpine or guanethidine

pretreatment

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THIS IS A SLIDE TITLE

Indirect “Tyra mine-like”

sympathomimetic
mechanism
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Examples of Mixed Acting Drugs

▰ Ephedrine
▰ Pseudoephedrine
▰ Metaraminol
▰ Me phentermine
▰ Dopamine

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 Ephedrine-A natural alkaloid
“
▰ Obtained from ephedra species like
ephedra sinica and ephedra officialis
▰ It is now made synthetically
▰ Contains two asymmetrical carbon atoms
▰ only l-ephedrine and racemic ephedrine are
used clinically.

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PHARMACOLOGICAL ACTIONS

▰ Various actions mediated by alpha-1 receptors are;

 Vasoconstriction leading to rise in blood pressure
 Nasal decongestion
▰ Similarly action on beta receptors produce;
 Increase in rate and force of contraction of heart-beta1
 Increase in cardiac output-beta1
 Broncho dilatation=beta2
 Increased renin release-beta 1
 Increase in blood glucose levels-beta 2
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 INDICATIONS

▰ Diet suppressant
▰ Bronchodilator
▰ Decongestant
▰ As a mydriatic
▰ CNS stimulant / energy supplement
▰ Narcolepsy and depressive states
▰ prophylactically in chronic asthma
▰ myasthenia gravis in conjunction with anticholinesterases
▰ In Stokes-Adams syndrome
▰ presser agent during spinal anesthesia
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PHARMACOKINETICS

▰ Absorbed when taken orally

▰ It exhibits tachyphylaxis (acute tolerance) when
administered repeatedly.
▰ Resistant to COMT and MAO, therefore long lasting
action
▰ Ephedrine is eliminated largely unchanged in the
urine
▰ Response occurs more slowly and lasts longer

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 SIDE EFFECTS

▰ Higher than normal incidence of ▰ Tachycardia

myocardial infarction, stroke ▰ Palpitations
and sudden death
▰ Anxiety
▰ Hypertension
▰ Tremor
▰ Nervousness
▰ paranoid schizophrenia
▰ Anorexia
▰ Addiction
▰ Painful urination
▰ Insomnia
▰ Euphoria
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 CONTRAINDICATIONS

▰ Hypersensitivity to sympathomimetic amines.

▰ Prostatic hypertrophy
▰ Diabetes mellitus
▰ Angina, cardiac arrhythmias, cardiac disease, coronary artery
disease, hypertension
▰ Closed-angle glaucoma
▰ Hyperthyroidism, thyrotoxicosis
▰ Labor, obstetric delivery, pregnancy Metabolic acidosis (umbilical
artery pH of <= 7.2) has been reported in newborns.
▰ Geriatric
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 DRUG INTERACTIONS

▰ oxytocin:
▰ Antidiabetic ▰ Sympathomimetic potentiation of the
▰ CNS stimulants agents pressor effect.
▰ Cardiac glycosides- ▰ Ergot alkaloids ▰ Urinary
arrhythmias. (dopaminergic Alkalinizers, such
action) as acetazolamide,
▰ Guanethidine,
Reserpine ▰ NRSI(minalcipran, sodium
venlafaxine) bicarbonate
▰ Hydrocarbon
inhalation ▰ Tricyclic ▰ Theophylline: CNS
anaesthetics, antidepressants and GI side effects
Methyldopa (TCAs) ▰ Antiepileptics
▰ Monoamine Oxidase
(MAO) inhibitors

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“ ▰ PSEUDO EPHEDRINE

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DIFFERENCE FROM EPHEDRINE

▰ Stereoisomer of ephedrine
▰ Both are controlled substances-methamphetamine precursors
▰ Both are banned in dietary supplements
▰ Less potent than ephedrine for promoting weight loss
▰ Both use for off-label reasons such as increasing energy, enhancing
concentration and boosting weight loss.
▰ Pseudoephedrine is slightly less effective as a stimulant compared to
ephedrine
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 PHARMACOLOGY

▰ INDICATIONS
▻ Nasal and sinus congestion
▻ congestion of the Eustachian tubes.
▻ Lesser effect in the peripheral blood vessels
▻ temporary relief of stuffy nose and sinus pain
▻ infection (such as the common cold, flu)

▻ stress incontinence.
▰ Side Effects
▻ Less potent than ephedrine in producing tachycardia, hypertension, C.N.S. stimulation
▰ Pharmacokinetics:
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▻ incomplete hepatic metabolism before elimination in the urine
 METARAMINOL

“▰
▰ The pressor effect of metaraminol begins in 1 to
2 minutes after intravenous infusion,
In about 10 minutes
after intramuscular injection
▰ In 5 to 20 minutes after subcutaneous injection
▰ The effect lasts from about 20 minutes to one
hour.

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 METARAMINOL

▰ MECHANISM OF ACTION class of

phenylethanolamines
▻ alpha-1 adrenergic receptor agonist

▻ inhibition of adenyl cyclase which leads to an inhibition of the production of cAMP.

▻ Releases norepinephrine from its storage sites indirectly.

▰ EFFECTS
▻ increase systolic and diastolic blood pressure by increasing total peripheral resistance

▻ Minor positive inotropic action on the heart via beta1 effect

▰ INDICATIONS
▻ Acute or severe hypotension as in;

▻ Spinal anaesthesia

▻ Trauma/head injury/Reaction to medication

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▻ Cardiogenic or septic shock
CAUTIONS

▰ ADVERSE EFFECTS: ▰ INTERACTIONS

▻ sinus or ventricular tachycardia
▻ Atropine

▻ Arrhythmias
▻ Furazolidone

▻ Malaria relapse
▻ Halothane

▻ Abscess formation
▻ Dopamine

▻ Tissue necrosis
▻ Monoamine oxidase inhibitors

▻ Hypersensitivity reactions (sulfite)

▻ tricyclic antidepressants

▻ Tissue necrosis, abscess formation

▻ Digitalis
with extravasation

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 MEPHENTERMINE

▰ MECHANISM
▻ Mephentermine is an alpha adrenergic receptor agonist
▻ Acts indirectly by releasing endogenous norepinephrine.
▰ ACTIONS
▻ Cardiac output and systolic and diastolic pressures are usually increased.
▻ It has a positive inotropic effect on the myocardium.
▻ AV conduction and refractory period of AV node is shortened with an increase in
ventricular conduction velocity.
▻ It dilates arteries and arterioles in the skeletal muscle and mesenteric vascular beds,
leading to an increase in venous return
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 MEPHENTERMINE
▰ USES
▻ It is used to maintain blood pressure in hypotensive states(spinal anesthesia)
▻ Muscle relaxant. Antidote to strychnine poisoning
▻ High blood pressure after heart attack
▰ OVER DOSE
▻ Large doses may depress the myocardium or produce central nervous system
(CNS) effects.
▻ its use may lead to amphetamine-type dependence
▰ METABOLISM
▻ Hepatic, by N-demethylation and then p-hydroxylation.
▻ Half life is 17 to 18 hours. 20
 CAUTIONS

▰ ADVERSE EFFECTS ▰ INTERACTIONS ▰ CONTRAINDICATIONS

▻ Arrhythmias ▻ Cyclopropane ▻ Hypotension caused by
phenothiazines
▻ Extrasystoles/AV block ▻ Isocarboxazid
▻ Hypertension
▻ Fear/restlessness/anxiety ▻ Pargyline
▻ Phaeochromocytoma
▻ Insomnia ▻ Phenelzine
▻ cardiovascular disease
▻ Tremors ▻ Tranylcypromine
▻ pregnancy, lactation
▻ Confusion/psychosis ▻ Ergot alkaloids
▻ Nausea/vomiting/reduced ▻ Halothane
appetite
▻ Oxytocin
▻ urinary retention/dyspnea
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DOPAMINE

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 DOPAMINE

▰ Endogenous catecholamine
▰ Immediate metabolic precursor of Noradrenaline
▰ A nonselective direct and indirect adrenergic agonist
▰ Clinical effects vary markedly with the dose
▰ Short T 1/2 (3-5minutes)
▰ USES
▻ Shock to improve cardiac output, support blood pressure, and maintain renal function
▻ Refractory CHF and CCF
▻ Combination therapy dopamine with dobutamine to increase cardiac output &
coronary perfusion Dosage
▻ Great Clinical benefit in CVS shock
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 DOPAMINE

▰ In small doses 2-5 μg/kg/minute

▻ It stimulates D1- kidney-leading to vasodilatation (Increase in cAMP)
▻ Interaction with D2 receptors (present in presynaptic adrenergic neurones) – suppression of NA
release (no alpha effect)
▻ Activate emetic center in medulla- nausea & vomiting , suppress secretion &function of ant.
Pitutatary harmone
▰ Moderate dose (5-10 μg/kg/minute)
▻ stimulates β1- receptors in heart producing positive inotropic and chronotropic actions actions
▻ Releases Noradrenaline from nerves by β1- stimulation
▰ High dose (10-30 μg/kg/minute)
▻ Stimulates vascular adrenergic α1-receptors (NA release)
▻ vasoconstriction and decreased renal blood flow
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 References
▰ http://www.pathwaymedicine.org/mixed-adrenergic-agonist
▰ https://www.pharmacology2000.com/Autonomics/Adrenergics1/Adr
energic-1.htm#Adrenergic_Drug_Classification
▰ Lippincott Pharmacology, Direct acting adrenergic agonist Page 71
▰ http://n-pharmacology.blogspot.com/2013/06/chapter-6-adrenergic-
agonists-i.html
▰ http://web.med.u-szeged.hu/phcol/notes/sympshort.pdf
▰ https://egpat.com/tutorials/adrenergic-agonists/mixed-acting-
adrenergic-agonists
▰ http://tmedweb.tulane.edu/pharmwiki/doku.php/ephedrine
▰ https://egpat.com/tutorials/adrenergic-agonists/mixed-acting-
adrenergic-agonists
▰ http://www.angelfire.com/art2/sensony/cldrugs.html
▰ http://ephedrineweb.com/ephedrine-vs-pseudoephedrine/
▰ http://www.differencebetween.net/science/health/drugs-
health/difference-between-ephedrine-and-pseudoephedrine
▰ https://www.slideshare.net/drdhriti/adrenergic-drugs
▰ https://www.rxlist.com/ephedrine-drug.htm#interactions
▰ https://www.pdr.net/drug-summary/Akovaz-ephedrine-sulfate-23927
▰ https://www.drugs.com/pseudoephedrine.html
▰ https://pubchem.ncbi.nlm.nih.gov/compound/metaraminol#section=NLM-
Curated-PubMed-Citations
▰ https://www.rxlist.com/aramine-drug.htm#clinpharm
▰ https://www.aci.health.nsw.gov.au/__data/assets/pdf_file/0019/334126/meta
raminol.pdf
▰ https://www.rxwiki.com/mephentermine#drug-interactions
▰ https://www.lybrate.com/medicine/mephentermine
▰ https://pubchem.ncbi.nlm.nih.gov/compound/mephentermine#section=Drug-
Warning
▰ https://www.drugbank.ca/drugs/DB01365
▰ https://www.slideshare.net/KailashMittal/adrenergic-agonist-antagonist
▰ https://www.tabletwise.com/mephentermine-injection
▰ https://slideplayer.com/slide/8346536/
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