cardiovascular agents

1. Cardiovascular
agents
pharmacology
DR. MARINA LOTFY
R1 KBA

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

3. Adrenergic vs
cholinergic

6. Cholinergic
agents
DIRECT ACTING :

7. 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.

8. 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.

9. 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

10. 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.

11. 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).

12. 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.

13. - 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.

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

15. 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.

16. Adrenergic
drugs

17. 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

18. 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

19. 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.

20. 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.

21. 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

22. 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)

23. 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

24. 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

25. 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

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

27. Beta
blockers

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

30. 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).

31. Let's compare

32. 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.

33. 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

34. 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)

35. 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).

37. Levosimendan

39. Vasodilators

41. Diuretics :

42. References
Cv pharmacology
Fundamentals of anesthesia
Stoelting's pahrmacology
Miller

43. Thank you