cardiovascular_agents_(1).pptx

Cardiovascular
agents
pharmacology
DR. MARINA LOTFY
R1 KBA

Objectives
Understand the pharmacology behind the
major classes of cardiovascular agents:
◦ Cholinergic drugs & cholinesterase inhibitors
◦ Adrenergic drugs
◦ Catecholamines.
◦ Sympathomimetics.
◦ Vasodilators.

Cholinergic
agents
DIRECT ACTING :

BETHANECHOL
Not hydrolyzed by acetylcholinesterase but hydrolyzed by other
esterases.
No nicotinic actions.
Has longer duration of action than acetylcholine.
Therapeutic uses: post operative non-obstructive urinary retention &
post-operative ileus.

PILOCARPIN
E
- A natural alkaloid, not hydrolyzed by
acetylcholinesterase.
- Marked muscarinic actions:
◦ Eye: loss of accommodation, miosis and lowering the
intraocular pressure (IOP).
◦ Secretary glands: stimulates sweating, salivation and
lacrimation.
-Therapeutic uses:
◦ Glucoma.
◦ Reverse cycloplagic and mydriatic effect of atropine.
-Side effects: CNS disturbance -----> crosses the BBB,
sweating and salivation.

Indirect acting
Reversible:
◦ water soluble: neostigmine, edrophonium pyridostigmine.
◦ Lipid soluble: physostigmine, donepezil, tacrine, gallantamine
Irreversible: organophosphate compounds, echothiophate,
malathion, parathion, tabun
Reactivation of acetylcholinesterase: pralidoxime

NEOSTIGMIN
E
o Synthetic anticholinergic.
o poorly absorbed.
o Polar compound ----> doesn’t cross BBB/CNS.
o Therapeutic uses:
◦ Antidote for tubocurarine poisoning.
◦ Myasthenia gravis.
◦ In the OT for reversal of NMJ blockers.

PHYSOSTIGMI
NE
o An alkaloid.
o Well absorbed and penetrate the BBB.
o Therapeutic uses:
◦ Glaucoma.
◦ Atropine poisoning.
◦ Alzheimer s disease.
o Side effects:
◦ CNS: convulsions.
◦ Heart: bradycardia.
◦ Paralysis of skeletal muscles (when overdosed).

Edrophonium
The actions of edrophonium are similar to those of neostigmine.
More rapidly absorbed and has a short duration of action.
Used in the diagnosis of myasthenia gravis.
Intravenous injection of edrophonium leads to rapid increase in muscle strength.
Caution: care must be taken, because excess drug may provoke a cholinergic crisis.
Atropine is the antidote.

- TACRINE, -
DONEPEZIL,
-
RIVASTIGMI
NE -
GALANTAMI
NE
Patients with Alzheimer's disease have a deficiency
of cholinergic neurons in the CNS ----> development of
anticholinesterases as possible remedies for the loss
of cognitive function
Tacrine
◦ The first to become available.
◦ Replaced by other agents because of hepatotoxicity.

ORGANOPHOSPHOROUS COMPO
UND
1. Irreversible agents
2. Main components of herbicides, pesticides, and
insecticides
3. Highly lipid soluble compounds ---> cross BBB

ECHOTHIOPHATE
Organophosphate covalently binds via its phosphate group to the serine-oh group
at the active site of acetylcholinesterase.
permanently inactivated
Restoration of acetylcholinesterase activity requires the synthesis of new enzyme
molecules.
The loss of an alkyl group = aging--> impossible for chemical reactivators, such as
pralidoxime, to break the bond between the remaining drug and the enzyme.

Major effects
of agonist
binding at
adrenergic
receptors
Alpha-1 receptor:
◦ Smooth muscle contraction, mydriasis
◦ Gq coupled-receptors
Alpha-2 receptor:
◦ Mixed smooth muscle effects
◦ Gi coupled-receptors
Beta-1 receptor:
◦ Gs coupled-receptors
◦ Increased cardiac chronotropic and inotropic effects
Beta-2 receptor: Gs coupled & Gi + Bronchodilation
Beta-3 receptor: Gs coupled & Gi + Increased lipolysis

Contraindications
Alpha-1 receptor agonists are relatively contraindicated:
hypertension, bradycardia, prostatic hyperplasia
Alpha-2 receptor agonists cautious with hypotension.
Geriatric patients may be at increased risk of falls due to
the sedating and hypotensive effects.
Beta-1 receptor agonists : arrhythmias.
Beta-2 receptor agonists : hypokalemia.
Norepinephrine :. When dosing halothane or
cyclopropane, there is an increased risk of dangerous
arrhythmias.
Epinephrine :angle-closure glaucoma

ALPHA-1
RECEPTOR
AGONISTS
•PHENYLEPHRINE:
•DECONGESTANT AND
VASOPRESSOR.
•IT HAS UTILITY IN CASES OF
HYPOTENSION DUE TO SHOCK,
SUCH AS SEPTIC SHOCK.
•OXYMETAZOLINE: DECONGESTANT
AND TO TREAT ROSACEA.

PHENYLEPHRINE
 Direct-acting sympathomimetic amine
 Related to epinephrine and ephedrine
Short onset of action (1 to 3 minutes)
Short duration of action (5 to 20 minutes)
Phenylephrine dosing can be via weight-based or non-
weight based infusion with typical dose ranges of 0.1 to 1.5
mcg/kg per minute.

ALPHA-2
RECEPTOR
AGONISTS
Methyldopa: hypertension & gestational hypertension.
Clonidine: hypertension & attention deficit hyperactivity
disorder (ADHD).
◦ Non- FDA approved indications : sleep disorders, post-
traumatic stress disorder (PTSD), anxiety, restless leg
syndrome, hot flashes associated with menopause
Dexmedetomidine: sedation in the intensive care unit , no
respiratory depression

Dexmedetomidine
Binding to the presynaptic alpha-2 adrenoceptors
Inhibits the release of norepinephrine ---> terminate the
propagation of pain signals.
Activation of the postsynaptic alpha-2 adrenoceptors ---
> sympathetic activity decreases blood pressure and heart
rate.
Volume of distribution : 118 L
◦ Protein binding :94%
◦ Metabolism: Hepatic
◦ Route of elimination: The majority of metabolites are excreted
in the urine
 Load: 1 mcg/kg IV over 10 minutes
◦ Maintenance 0.6 mcg/kg/hr IV titrate to effect (usually 0.2-1
mcg/kg/hr)

Beta agonists
Cardiac effects : increase contractility (positive
inotropy) & increase relaxation rate (positive lusitropy)
Increase heart rate (positive chronotropy) & increase
conduction velocity (positive dromotropy)
Vascular effects : smooth muscle relaxation (vasodilation)
Other actions:
 Bronchodilation
 hepatic glycogenolysis
 pancreatic release of glucagon
 Renin release by kidneys

BETA-1
RECEPTOR
AGONISTS
Dobutamine:
 Beta-1 adrenergic receptors, with negligible effects on beta-2 or
alpha receptors.
 no release of endogenous norepinephrine, as does dopamine.
 Cardiac Decompensation
◦ 0.5-1 mcg/kg/min IV continuous infusion initially, then 2-20
mcg/kg/min; not to exceed 40 mcg/kg/min
Absorption: Onset: 1-10 min
Duration: 10 min
 Time to peak effect: ~15 min
Distribution : Vd: 0.2 L/kg
Metabolism in tissues and liver by catechol-O-methyl transferase
Excretion: Urine

Beta 2 agonists
Short acting 4-6
hrs
• Albuterol
(Ventolin,
Proventil)
• Salbutamol
Long acting 12
hrs
• Salmeterol
(Serevent)
• Formoterol
(Foradil,
Perforomist)
Ultra long acting
24 hrs
• Fluticasone
Furoate
• Olodaterol

• BETA-3
RECEPTOR
AGONISTS
Mirabegron:
◦ overactive bladder : urinary incontinence & frequency

Catecholamines
Norepinephrine: Shock and hypotension
Epinephrine (adrenaline): Cardiac arrest, anaphylaxis, and
croup
Dopamine: Hypotension, bradycardia, and cardiac arrest.
Isoprenaline: Bradycardia and heart block

Norepinephrine
Alpha-agonist, with some beta-agonism.
Physiology
◦ Increases systemic vascular resistance (SVR)----
> venoconstriction (increasing preload)
◦ Increases blood pressure ----> increase urine output.
◦ Increase cardiac output : (depending on how responsive the
heart is to preload, afterload, and inotropy).

Epinephrine
Lower doses the beta-agonist effects may predominate;
 Ongoing up-titration ---> increasing alpha-agonist effects
as well.
Clinical uses
(1) bradycardia and bradycardic shock (given inotropic effects).
(2) septic shock
(3) Low doses (below 5-10 mcg/kg/min)--> the predominant
effect inotrope, low-output cardiogenic shock.
- Compared to dobutamine/milrinone, low-dose epinephrine has a
touch of alpha-activity ----> prevent hypotension.
4) first-line agent for anaphylaxis.

Midodrine
Oral alpha-1 agonist = pure vasopressor.
Accelerated weaning from vasopressors
◦ According to some experts, may be useful to facilitate
discontinuation of low dose IV vasopressors; prospective data are
limited.
◦ Re-evaluate therapy regularly, at each transition of care.
◦ Dose : starting dose is 10 mg PO q8hr. Dose range is 5-40 mg q8hr
Liver Cirrhosis
 In diuretic resistant patients
 Hypotensive patients.
Hepatorenal syndrome (type 1)
 Alternative to terlipressin
Cleared by the kidney ----> caution in renal impairment.
Caution: reflex bradycardia

inodilators (milrinone,
dobutamine)
◦ Dobutamine stimulates mostly beta-receptors, with very little
stimulation of alpha-receptors.
◦ Milrinone inhibits intracellular adenylyl cyclase, thereby
increasing intracellular cyclic AMP levels.
Physiologic effect :
◦ Primary effect is positive inotropy, with positive
chronotropy as well
◦ Secondary effect is peripheral vasodilation.
◦ Cardiac output is increased due to both inotropic effect
and vasodilation.
◦ Effect on blood pressure is variable
Clinical use
(1) low-output cardiogenic shock = risk of exacerbating
hypotension.
(2) septic shock with inadequate cardiac output (as an add-on
agent)

vasopressin
Stimulates V1 and V2 receptors, causing vasoconstriction
and renal water retention.
Physiologic effects:
◦ Increases systemic vascular resistance (SVR).
◦ Cause venoconstriction, which may increase preload.
◦ Dominant effect on cardiac output is often to cause a reduction (but this
may depend on the heart's ability to tolerate increased afterload
Clinical use:
• Vasodilatory shock (particularly sepsis). low doses (0-0.06
U/min), either as primary or secondary agent.
• Front-line agent for hepatorenal syndrome (HRS) in countries
lacking terlipressin (such as the United States).
• Central diabetes insipidus (only very low doses are needed, e.g.
0.01 units/minute or less).
• Variceal gastrointestinal hemorrhage (theoretically an attractive
agent, but pragmatically it's impossible to titrate adequately).

References
Cv pharmacology
Fundamentals of anesthesia
Stoelting's pahrmacology
Miller

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