CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

CARDIO-NOTES

Part II: CVS Drugs (the clinical use of cardiovascular drugs)

Dr. Ahmed Abdelmageed Alfarra, MSc

National Heart Institute

Physiological review for CVS drugs

This chapter is an introduction for CARDIO-NOTES Part II (CVS Drugs) book to read before each
corresponding drug class, it is written to facilitate our understanding of CVS drugs.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Inotropes and beta blockers

There are multiple cardiovascular regulatory mechanisms that affect the cardiac output,
arteriolar diameters (resistance vessels) or the amount of blood pooled in the veins (capacitance
vessels), these mechanisms include the neural system (autonomic system), hormonal system
(renin-angiotensin-aldosterone system), and locally produced vasodilator metabolites.

Autonomic nervous system (ANS): the autonomic nervous system is formed of and control
the cardiovascular system by two arms; sympathetic and parasympathetic nervous system. It is
the part of the nervous system that is responsible for homeostasis, it innervates smooth muscle,
cardiac muscle and glands, some target organs are innervated by both divisions and others are
controlled by only one.
- Sympathetic parasympathetic
Origin Thoracolumbar(T1-12 &L1-3) Craniosacral (CN2,7,9,10
&S2-4)
Mediators Norepinephrine(or ACh) Acetylcholine (ACh)
Receptors Adrenergic( beta &alpha) Muscarinic(M)
&Nicotinic(N)
Effects Heart ↑ HR, ↑ contractility, ↑ conduction ↓ HR, ↓ contractility, ↓
on the (through beta1) conduction
CVS Arterioles Constriction of skin and splanchnic No innervation
arterioles(α1), dilation of skeletal muscle
arterioles(β2)
Veins Constriction /dilation (α1/β2) No innervation
Other effects (to Bronchodilation(β2), ↓gut motility(α2&β2) Bronchoconstriction, ↑
know the side effects contraction of sphincters (α1), relaxation gut motility, relaxation of
of the drugs) of UB wall(β2), mydriasis (α1), sphincters, contraction of
ejaculation(α1), thick salivary secretion UB wall, miosis, erection,
(α1), uterine relaxation(β1), watery salivary
sweating(M!!) secretions.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

*All preganglionic neurons secret acetylcholine (ACH), the postganglionic parasympathetic neurons secret
also ACH while the postganglionic sympathetic neurons secret norepinephrine (or ACH).

*The peripheral motor portions of the ANS are made up of two neurons; preganglionic and postganglionic
neurons, the cell bodies of the preganglionic neurons are located in the spinal cord and motor nuclei of
some cranial nerves and a preganglionic axon diverges to an average of 8-9 postganglionic neurons which
terminates on the target organ.

As beta blockers act through beta receptors, we will discuss beta receptors in some important
details, we have 5 known beta receptors (β1-5), and we need to remember 2 of them; β1&β2:

Beta1
Location(common Cardiac muscle, kidney
important sites) (JGC)
G-protein Gs
Actions (by agonist) ↑ all cardiac properties ,
stimulates renin release
Agonist (stimulator) Adrenaline, noradrenaline,
dopamine, dobutamine
Antagonist bisoprolol, metoprolol,
(blockers) atenolol, nebivolol
Beta 2
Smooth muscle( blood vessel, bronchi,
GIT, UB, uterus)
Gs
Relaxation (VD, BD, uterine relaxation)
Albuterol, sameterol
Carvidolol (β1&β2) , labetalol (β1&β2),
Propranolol (β1&β2)

There are at least two important alpha receptors:

Alpha 1 Alpha2
Location (important sites) Vascular smooth muscle. CNS.
G-protein linked Gq Gi
Actions (by agonist) Vasoconstriction Autoregulation of sympathetic
system (↓), sedation & analgesia.
Agonist (stimulator) Adrenaline & Adrenaline & Noradrenaline
Noradrenaline
Antagonist (blockers) Phentolamine, Prazosin, Yohimbine.
Tamsulosin (used in BPH)
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

There are at least 5 known dopamine receptors, the most important two receptors are:
D1 D2
Location CNS, GIT & kidney. CNS.
G-protein Gs Gi
Actions (by Vasodilation of renal and mesenteric Decreases pituitary hormones and
agonist) vasculature, modulates extrapyramidal noradrenaline release.
activity.
Agonist Dopamine. Dopamine.
Antagonist Antipsychotics (e.g; haloperidol). Antiemetic (e.g; metoclopramide)

To summarize
Receptor Action
Alpha-1 Vasoconstriction.
Beta-1 + Ve inotropy and chronotropy action.
Beta-2 Vasodilation.
D1 Vasodilation.
D2 Vasoconstriction (↑noradrenaline release).

G-proteins coupled receptors

There are 3 common types of heterotrimeric G-proteins; Gs (stimulatory), Gi (inhibitory), Gq
(stimulatory).

 Stimulation of Gs coupled receptors (by an agonist/ligand) will stimulate adenylyl

cyclase enzyme which will convert ATP to c AMP (stimulates protein kinas A)
 Stimulation of Gi coupled receptors (by an agonist/ligand) will inhibit adenylyl cyclase
enzyme which will decrease cyclic adenosine monophosphate (cAMP) from ATP.
 Stimulation of Gq coupled receptors (by an agonist/ligand) will stimulate phospholipase
C (PLC) which will stimulate conversion of PIP2 to DAG (stimulate protein kinase C) and
IP3 (increases the intracellular calcium by binding the IP3 receptors)
 Protein kinases cause phosphorylation of some proteins→ physiological effects

Sympathomimetic drugs are classified into catecholamines and non catecholamines:

 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Catecholamines Non catecholamines

Contain catechol group, so:
 They are rapidly metabolized by MAO and
COMT in the CNS or the gut and so they did
not given orally and have a very short half-
life.
 No CNS penetration.
EX: adrenaline, noradrenaline, dopamine,
dobutamine & isoprenaline.
Contain no catechol group, so:
They are not metabolized by MAO and COMT
in the CNS or the gut and so they can be given
orally and have longer half-life.
 Good CNS penetration.
EX: phenylephrine & ephedrine.

Receptor selectivity of vasopressors and inotropes*:

Drug Alpha-1 Beta-1 Beta-2 D1 Clinical effect
Adrenaline +++ +++ ++ 0 ↑COP & ↑SVR.
Noradrenaline +++ ++ 0 0 ↑SVR (↑MAP).
Dobutamine 0/+ +++ ++ 0 ↑COP & ↓SVR.
Isoprenaline 0 +++ +++ 0 ↑COP & ↓SVR.
Phenylephrine +++ 0 0 0 ↑SVR (↑MAP).
Dopamine Selectivity differs according to doses (mcg/kg/min).
0.5-2 (< 5) 0 + 0 ++ ↑COP.
5-10 + ++ 0 ++ ↑COP & ↑SVR.
10-20 ++ ++ 0 ++ ↑SVR (↑MAP).
*Adapted from uptodate.com.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Angiotensin converting enzyme inhibitors (ACEIs)

Renin-angiotensin-aldosterone system (RAAS)

 Renin is released from juxtaglomerular cells (JGCs) in renal afferent arterioles (in response
to diminished renal perfusion pressure or ↓ Na+ or stimulation of β1 receptors).
 Renin release is stimulated by activation of β1 receptors in (JGCs).
 Renin (protease enzyme) converts angiotensinogen (released from the liver) to angiotensin I
 Angiotensin I (Ang I) is converted to angiotensin II by ACE (and also by non-ACE pathways).
 Angiotensin II is broken down in the kidney and liver to inactive metabolites and angiotensin
III, which retains some activity.
 Angiotensin II acts on angiotensin receptors (AT) which are of 2 types; AT1 and AT2.
 AT1 receptors stimulation by angiotensin II cause vasoconstriction, myocytes proliferation,
↑aldosterone release which causes salt and water retention and cardiac remodeling, ↑NE
release, and↑ ADH release.
 Angiotensin II also↑ sympathetic outflow and causes modest vagal inhibition (so we find no
tachycardia despite vasodilation by ACEIs)
 ACE also converts bradykinin to inactive form.
 Bradykinin causes vasodilation (by increasing NO and prostacyclin).
 So, ACEIs cause vasodilation (↓ angiotensin II, ↑ bradykinin ↓ NE, and ↓ sympathetic
activity), Na+ and water loss and K+ retention (↓ aldosterone and ADH) and prevents cardiac
remodeling (↓ angiotensin II and ↓aldosterone).

 ACEIs have antioxidant properties (SH containing ACEIs) (angiotensin II ↑superoxide; a

major source of H2O2).

Vasoconstriction caused by angiotensin II is 5-40 times more intense than that caused by NE
and occurs predominantly in arterioles and to a lesser degree in veins and is more
pronounced in the skin and kidney with some sparing of vessels in the brain and muscle.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Calcium channels blockers (CCBs)

 There are two common types of calcium channels in CVS; L-Type and T-Type Ca2+ channels:
1. L-Type (long lasting): in cardiac cells (+ve inotropy) and vascular smooth muscle
(contraction).
2. T-Type (transient): in cardiac cells only (SA node and AV node cells).
 The intracellular concentration of calcium plays an important role in smooth muscle
contraction and myocardial contractility, influx of calcium into muscle cells stimulates
smooth muscle contraction and cardiac myocyte contraction. Calcium movement into the
cytosol is mediated by several mechanisms, the most important are:
1. Voltage gated calcium channels (blocked by CCBs).
2. Receptor gated calcium channels (blocked by BBs)

CCBs available for clinical use are only of L-Type channel blockers. Other types of Ca2+ channels
are N (nerve) - and P-type.

Smooth muscle contraction:

Calcium enters the cells >>>binds to calmodulin >>>calcium-calmodulin complex >>>
activates myosin light chain kinas (MLCK)>>> phosphorylation of myosin>>>actin-myosin
interaction>>> muscle contraction, cAMP >>> inhibits MLCK >>> inhibits muscle
contraction. BBs decrease formation of cAMP >>> promote smooth muscle contraction
(that is what explains why BBs may cause bronchospasm or increased peripheral resistance
at the starting).
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Diuretics
Nephrons are the site of action of most diuretics, the nephrons are formed of proximal
convoluted tubule, loop of henle, and distal convoluted tubule and collecting ducts.
 In the proximal convoluted tubules (PT): about 60-70% of filtered Na+ is reabsorbed
through Na+/H+ exchange (in the luminal side) which is followed by passive H2o
reabsorption, then Na+ is pumped out through Na+/K+ ATPase pump (in the basolateral side)
which is diffused into blood vessels, hydrogen ions that is exchanged with Na+ are formed by
carbonic anhydrase enzyme.
NaHCO3 filtered by glomeruli is dissociated into Na+ and HCO3 (in the lumen), Na+ is
reabsorbed in exchange with H+, HCO3 is combined with Hydrogen ions to form H2CO3 (in the
lumen) which spontaneously dissociated into H2O and CO2, both of them are reabsorbed into
PT cells, inside the cells, they form H2CO3 again which is dissociated into H+ and HCO3, H+ is
exchanged with Na+ while HCO3 is diffused into blood vessels, H2CO3 is formed by the help of
carbonic anhydrase (CA) enzyme (in the lumen and inside the cells), so, inhibition of CA lead
to loss of Na+ and HCO3 in the urine (diuresis).

Diuretics acting on PT are carbonic anhydrase inhibitors (e.g, acetazolamide).

 In loop of henle (LH): about 20-30% of filtered Na+ is reabsorbed through Na+/K+/2Cl- co-
transporter driven by the Na+ gradient produced by Na+/K+ ATPase pump in the basolateral
membrane.
Diuretics acting on LH are loop diuretics (furosemide, torsemide and bumetanide).

 In early distal convoluted tubules: about 5–10% of filtered Na+ is reabsorbed in distal
tubules through Na+/Cl- symporter.
Diuretics acting on distal tubules are thiazides and thiazide like (hydrochlorothiazide,
chlorthalidone, metolazone and indapamide).

 In late distal tubule, collecting tubules and duct: Na+ is reabsorbed from the collecting
duct through epithelial sodium channels. Water reabsorption in this region is occurred
under effect of antidiuretic hormone (ADH).
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Epithelial Na+ channels are activated by aldosterone, K+ or H+ is secreted into the tubule
in exchange for Na+ in this distal region, Na+ passes from tubular fluid through sodium
channels in the apical membrane down the electrochemical gradient created by the
Na+/K+ ATPase; a lumen-negative potential difference across the cell results, increasing
the driving force for K+ secretion into the lumen. Thus K+ secretion is coupled to Na+
reabsorption.

Diuretics acting in late distal tubules and collecting duct are potassium sparing diuretics
(spironolactone, eplerenone and amiloride).

Potassium clearance
Potassium is the major cation of intracellular fluid, about 98% of body potassium are located
intracellular, total amount of K in the body is about 50 mEq/kg with intracellular concentration is
about 150 mEq/L and intracellular concentration about 3.5-5 mEq/L. Normal daily intake in adult
is about 50-100 mEq absorbed in the intestine with excess K is secreted through the urine (90%)
or feces (10%). 70% of K reabsorbed in the proximal tubule (passively), 20% in the ascending
limb of loop of henle (through NKCC) and 10% is secreted or reabsorbed in the collecting duct, K
secretion depends on amount of K reaching collecting duct, elevated serum K stimulates
aldosterone secretion which enhances Na reabsorption and K secretion.

Nitrodilators (nitrates and nitroprusside)

Nitric oxide (NO) is produced by endothelial cells to induce vasodilatation of veins, arterioles
and coronary arteries. NO is synthesized from arginine in many body cells by nitric oxide
synthase (NOS) enzyme. Three forms of NOS are present; constitutive or type III (cNOS),
inducible or type II (iNOS) and both are present in endothelial cells and neural or type I (nNOS).
NO stimulates guanylyl cyclase >>> forms cGMP from GTP, cGMP >>> stimulates proteins kinase
I and inhibits calcium release/entry >>>> smooth muscle relaxation and inhibits platelets
aggregation. In case of endothelial dysfunction (e.g; atherosclerosis) NO synthesis and release is
impaired. Nitrates interact with sulfhydryl groups and forms NO, depletion of intracellular
sulfhydryl groups may explain nitrate tolerance. Nitroprusside releases NO directly.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Dyslipidemia
 Lipids include fats (fatty acids & triglycerides), sterols (cholesterol), phospholipids,
sphingolipids, waxes and eicosanoids.
 Lipids functions include energy storage, important for cell membranes formation and
integrity and have cellular signaling function. Cholesterol is important for cell membranes,
synthesis of steroid hormones and bile acids.
 Excess cholesterol leads to atherosclerosis and atherothrombotic complications.
 Our cells obtain cholesterol either from blood (by food intake or hepatic product) or from
intracellular synthesis.
 Cholesterol absorption occurs through receptors called Niemann-Pick C1-Like1 (NPC1L1) on
the enterocytes (blocking of theses receptors decrease cholesterol absorption).
 Intracellular synthesis is regulated by many enzymes, the key enzyme is the HMG CoA
reductase enzyme (inhibition of this enzyme decreases cholesterol synthesis).
 Once synthesized or absorbed, cholesterol is esterified to cholesteryl esters (storage form)
by the lecithin-cholesterol acyltransferase (LCAT) enzyme in the blood or by acetyl CoA
acetyl transferase (ACAT). ACAT II is important for esterification of intestinal (dietary) and
hepatic (synthetic) cholesterol in the cytoplasm. And
 Triglycerides (TGs): 3 fatty acids + glycerol.
 Phospholipids = 2 fatty acids + glycerol + phosphate. PLs are essential for transport of lipids
as they form the hydrophilic surface (amphipathic) of lipoproteins and have many other
important functions.
 Lipids are water insoluble and to move in the aqueous medium of the blood, they form an
outer hydrophilic layer of PLs and unesterified cholesterol (free) and bind to Apo proteins in
the hepatocyte and enterocytes. These Apo proteins represent ligands for the interaction
with receptors. Lipids with Apo proteins are called lipoproteins.
 Lipoproteins are classified into chylomicrons, VLDL, LDL and HDL.
 Chylomicrons: formed mainly of TGs and less cholesterol in the enterocytes (transport TGs
and cholesterol from diet or synthesized in enterocytes to the liver), as the chylomicrons
pass in the circulation, they lose TGs under the action of lipoprotein lipase (LPL) in the form
of FFA (used by the liver for VLDL or by the cells for energy production) and forms
chylomicrons remnants that are removed by the liver through chylomicrons scavenger
receptors (CSR). LPL is activated by Apo C-II and inhibited by Apo C-III (inhibition of Apo C-II
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

or stimulation of Apo C-III decreases FFA production and delivery to the liver and so
decreases VLDL).
 VLDL: formed mainly of TGs and less cholesterol (about 20% of blood cholesterol) in the
liver and secreted in blood stream. Important enzymes for VLDL formation are the diglycerol
acyltransferase (DGAT) which forms TGs from FFAs and the microsomal triglyceride transfer
protein (MTP) which transfer TGs to phospholipids and cholesterol ester transfer protein
(CETP) (see below). Of practical importance, VLDLs by themselves are large particles and
cannot migrate in arterial wall and has no important role in atherogenesis. As VLDLs pass in
the blood, they lose TGs (under the effect of LPL enzyme) and form VLDL remnants (IDL)
taken up by the liver or form LDL particles.
 LDL: formed mainly of cholesterol from VLDL/IDL (in the blood). About 50% of LDL is taken
up by hepatocytes and the remaining is deposited in the arterial wall.
 HDL: formed in the liver (80%) and intestine (20%). Contains mainly cholesterol which is
taken from peripheral tissues, then cholesterol in HDL is taken up by hepatocytes or
transferred (in exchange with TGs) to VLDL remnants and LDL under the effect of CETP
which transfers TGs from VLDL & CM to HDL and transfers cholesterol in the opposite
direction (reverse cholesterol transport pathway). Cholesterol transfer from peripheral
tissues to HDL is mediated by transporters called ABCA1 and ABCG1.
 LDL receptors: also called B-E receptors, they bind to lipoproteins that contain Apo B-100
(LDL) or Apo E (VLDL, VLDL remnants and HDL). Once bind to lipoproteins undergo
internalization then dissociated intracellular. Then LDL receptors recycled to be reused by
the cell or degraded by the action of proprotein convertase subtilisin/kexin type 9 (PCSK9)
(inhibition of PCSK9 leads to recycling and increases surface LDL receptors. LDL receptors
expression on cells surface (hepatocytes and other tissues) regulated by intracellular
synthesis of cholesterol, where increased cholesterol synthesis will decrease surface LDL
receptors and vice visa. Macrophages contain special receptors called macrophage
scavenger receptors (MSRs) that mediate uptake of oxidized lipoproteins (LDL) to form foam
cells (high cellular cholesterol does not suppress MSRs). Endothelial cells also contain
specialized receptors that mediate uptake of oxidized LDL called LDL-R LOX1.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

 From the above review, what are our targets to control dyslipidemia?

Target Drugs Notes

HMG co A reductase Statins The most powerful drugs
enzyme decrease LDL (apart from
PCSK9Is).
LPL enzyme Fibrates Control TG
MTP enzyme MTP inhibitors
CETP enzyme CETP inhibitors Clinical trials showed higher
mortality or no benefits (only
one exception under trial).
PCSK9 PCSK9 inhibitors
NPC1L1 NPC1L1 blockers
Apo C-II & Apo C-III Volanesorsen ↓ TG
Apo B-100 Apo B-100 synthesis
inhibitors (Mipomersen)
HSL Niacin
Others Resins

Antiplatelets
When an injury occurs, three mechanisms try to stop bleeding; vascular constriction, platelet
activation and aggregation and clotting factors activation this ends with plug formation that stop
blood loss (the same steps are involved in the formation of an unwanted intravascular thrombus
except that the triggering stimulus is a pathological condition in the vascular system).

Mechanism of platelet activation and aggregation:

In absence of vascular insult, platelets circulate freely with no aggregation due to: 1: release of
chemical mediators such as prostacyclin (PGI2) and nitric oxide (NO) by intact endothelium, 2:
low level of circulating thrombin and thromboxane. While in the presence of vascular insult,
platelets adhere to the exposed collagen with release of chemical mediators such as ADP, TXA2,
PAF, serotonin and thrombin which bind to and activate the resting platelets to release their
stored chemical mediators and lead to expression of glycoprotein receptors (GPIIb/IIIa) on
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

platelets surface, simultaneously, fibrinogen binds to GPIIb/IIIa on two separate platelets

causing platelets cross-linking and aggregation. ADP, TXA2, thrombin and other chemical
mediators cause increase of intracellular (platelets) calcium, increased intracellular calcium
causes release of platelet granules, ↑TXA2 synthesis and activation of GPIIb/IIIa.

How can we inhibit platelets aggregation? By:

1- Inhibition of release of aggregating factors from platelets (this is achieved by low dose
aspirin and P2Y12 inhibitors).
2- Prevention of binging of fibrinogen to platelets (this is achieved by GPIIb/IIIa inhibitors)

Anticoagulants
Mechanism of coagulation (clot formation): at the same time of platelets aggregation,
coagulation cascade is stimulated by tissue factors released from the inured tissue and by
mediators on the surface of platelets, coagulation cascade ends by formation of thrombin which
converts fibrinogen (bound to platelets) to fibrin which add more stabilization to platelet- fibrin
plug and clot formation.

Why there is no clotting formation in normal persons (the absence of insult)? Because:
1- Smooth intact endothelium releases PGI2 and nitric oxide.
2- The clotting factors are present in inactive state.

The aim of the coagulation process is to form thrombin which converts fibrinogen to fibrin to
add more stability for platelet-fibrin plug, and this is achieved by activation of clotting factors
from inactive state to the active form by 2 interrelated pathways; intrinsic and extrinsic
pathways.

 The extrinsic pathway initiated by activation of factor VII by tissue factor released
from vascular endothelium (thromboplastin), then factor VII → factor X → factor II.
 The Intrinsic pathway initiated by contact of blood with the exposed collagen and
starts by activation of factor XII, then factor XII → factor XI → factor IX → factor X →
factor II.

Normally, there are several inhibitors of coagulation factors such as protein C, protein S and
antithrombin III (AT III), and our anticoagulants act on these proteins.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Antiarrhythmic drugs (AADs)

Antiarrhythmic drugs block sodium channels, potassium channels, calcium channels or beta
adrenergic receptors (beside other antiarrhythmic drugs of different mechanisms). To understand
the mechanism and electrical effects of these drugs, we need to know the electrical activity of the
heart and action potentials (AP).

 Action potential of non-pacemaker cells (Fig. 1), atrial, ventricular myocytes and purkinje
cells), it is a fast response AP as very rapid depolarization occurs by fast Na+ channels:

 Phase 4 (resting membrane potential): there is an equilibrium potential for potassium, during
which potassium channels are open (potassium efflux) but fast sodium channels and slow calcium
channels are closed.

 Phase 0 (depolarization phase): upon arrival of an action potential from the adjacent cells, fast
sodium channels open (Na+ influx) and potassium channels close causing rapid depolarization
moving the cell membrane toward the equilibrium potential for Na+.

The slope of phase 0 (Vmax = conduction velocity) represents the maximum rate of
depolarization.
 Sodium channels are present in 3 states: 1) open or active (during phase 0), 2) inactive (during
phase 1, 2 ,3 and early phase 4, during which Na+ channels cannot be stimulated, absolute
refractory period), 3) closed or resting or excitable state (during late phase 4, during which Na+
channels can be stimulated by a strong stimulus, relative refractory period).

 Phase 1 (initial repolarization): represents initial repolarization caused by opening of special

type of transient potassium channels.

 Phase 2 (plateau): occurs due to opening of calcium channels (Ca+2 influx) that antagonize the
efflux of potassium.

 Phase 3 (repolarization): opening of potassium channels causing repolarization due to

increased potassium conductance along with inactivation of calcium channels.

 Therefore, the action potential in non-pacemaker cells is primarily determined by relative

changes in fast Na+, slow Ca+2 and K+ conductance and currents.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

 As regard the antiarrhythmics, these fast-response action potentials in non-nodal tissue are
altered by antiarrhythmic drugs that block specific ions channels; sodium-channel
blockers such as quinidine inactivate fast-sodium channels and reduce the rate of
depolarization (↓ the slope of phase 0), calcium-channel blockers such as verapamil and
diltiazem affect the plateau phase (phase 2) and potassium-channel blockers that delay
repolarization (phase 3) by blocking potassium channels that are responsible for this phase.

 Action potential of pacemaker cells (Fig.1): (SA node and AV node), it is a slow response
AP as slow depolarization occurs by slow Ca+2 channels. Pacemaker cells are characterized by
having no true resting potential, instead they generate regular, spontaneous action potentials
(automaticity).

It differs from action potential of non-pacemaker cells in:

 Phase 4: is called spontaneous depolarizing phase (not resting membrane potential), during
which potassium conductance decreases and sodium channels open conducting slow, inward
(depolarizing) Na+ currents. These currents are called "funny" currents” that cause the membrane
potential begins to depolarize spontaneously, thereby initiating Phase 4. As the membrane
potential reaches about -50 mV, another type of channel opens, this channel is called transient
or T-type Ca+2 channel. Then, when the membrane depolarizes to about -40 mV by inward Ca+2
current, a second type of Ca+2 channel opens, these are the so-called long-lasting or L-type
Ca+2 channels. Opening of these channels cause more Ca+2 to enter the cell and to further
depolarize the cell until an action potential threshold is reached.

 Phase 0: is caused by calcium influx due to opening of slow L-type calcium channels (fast
Na+ channels operating in non-nodal cells).

 Phase 1 & 2: are absent, no plateau phase.

 Phase 3: the same.

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During depolarization, the membrane potential moves toward the equilibrium potential for
Na+ or Ca+2.
During repolarization, the membrane potential moves toward the equilibrium potential for K+.
 Therefore, the action potential in SA nodal cells is primarily dependent on changes in
Ca+2 and K+ conductance while the action potential in non-pacemaker cells is primarily
dependent on changes in Na+, Ca+2 and K+ conductance.
 As regard antiarrhythmics, we have drugs that affect Na+ and Ca+2 channels and affect
funny currents.

Fig (1): ventricular and SA node action potentials.

Important terms with antiarrhythmics:
 Action potential duration (APD): the whole length of AP from the start of phase 4 till the end of
phase 3.
 Absolute refractory period (ARP) or effective refractory period (ERP): from the start of phase 0 till
early phase 4 during which a new action potential cannot be initiated, The ERP acts as a protective
mechanism, it limits the frequency of depolarization and therefore heart rate. Drugs that block K+
channels and delay phase 3 will prolong ERP.
 Relative refractory period (RRP): immediately following the absolute refractory period during
which initiation of a second action potential is inhibited, but is not impossible (can be initiated by a
strong stimulus).
 Conduction velocity (Vmax): reflected by slope of phase 0 (dependent on Na+ or Ca+2 influx) and is
controlled by the autonomic nervous system which is most apparent at the AV node. Drugs that
antagonize the sympathetic actions (e.g; beta blockers) or that block Ca+2 channels (e.g; CCBs) or that
increase vagal activity (e.g; digoxin) will decrease the Vmax.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Solutions
 Body fluids (water and its dissolved solutes, solute is a substance dissolved in another
substance {water}): in an adult man, fluids make up 60% of body weight (bout 42 L), in an
adult woman, fluids make up 55% of body weight, heavy individuals and women have less
water proportion than slim individuals and men as fats contain no water. Body fluids
decrease with age.
 Homeostasis (maintaining body fluid balance): body fluids are distributed as 2/3 in the
intracellular compartment (40% of BW, about 28 L) and 1/3 in the extracellular
compartment (20% of BW, about 14 L); extracellular fluids (ECF) are divided into ¾ (15% of
BW, about 9-10 L ) in the interstitial compartment and ¼ (5% of BW, about 4-5 L) in the
intravascular compartment and very small amounts in the third spaces. Movement of fluids
between different compartments is a dynamic process, movements of fluids between
intravascular compartment and interstitial compartment is determined by the hydrostatic
and oncotic pressures of these two compartments. This homeostasis in maintained by
interplay of the nervous and endocrine systems including the kidney that regulates fluids
intake and loss. The oncotic pressure (26 mmHg) is produced by albumin (75%), hemoglobin
(20%) and globulins (5%). Fluids output includes (500-1000 ml insensible {differs according
to the climate} + 100-150 ml in feces + UOP) and fluid input includes (1200 ml ingested
water + 1000 ml water in food + 300 ml water from oxidation).
 Osmolarity: it is the main determinant of fluids movement across a permeable membrane
where fluid moves from area with relatively high water and low solutes (low osmolarity) to
area with low water high solutes (high osmolarity). Plasma osmolality (280-290 mOsm/kg) is
the solute concentration in the body fluids per weight of solvent (mOsm/kg), plasma
osmolarity is the solutes concentration in the body fluids per volume of solutions
(mOsm/liter), and both terms are interchangeable in practice. Sodium and its balancing
anions (Cl- and HCO3-) are the principal determinant of ECF osmolarity while potassium and
its balancing anions (proteins and glycogen) are the mainstay of ICF osmolarity.
 After fluids administration water will distribute in different compartments according to the
osmolarity, and solutes in any solution will distribute according to their major area of
location, for example K + will go to intracellular while Na+ will remain in the extracellular
compartment and glucose will be taken up by cells.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

 According to molecular weight, solutions are classified into colloid and crystalloid, and
according to their osmolarity (tonicity), crystalloids are classified into isotonic, hypotonic
and hypertonic solutions.
Crystalloid solutions Colloid solutions
 Contain low molecular weight particles  Contain high molecular weight particles that
that can pass the cell membrane (the cannot pass the cell membranes and retained in the
principal component of crystalloids is the intravascular space and pull water (high oncotic
NaCl). They diffuse rapidly in extracellular pressure) from extravascular spaces increasing blood
spaces (25% in plasma and 75% in IS), and volume.
so large amounts of this solution are  Have longer duration of action than hypertonic
required for resuscitation or replacement crystalloids.
that may cause dilution of plasma  Ex: albumin, hetastarch (blood products act as a
proteins and ↓tonicity. colloid).
 EX: 0.9% NaCl, Hartmann’s solution  Indications: volume expansion, specific indication
and 5% glucose. (such as blood in hemorrhage & albumin in
 Indications: volume replacement and hypoalbuminaemia).
resuscitation & drug preparation.

Isotonic solutions Hypotonic solutions Hypertonic solutions

(solutes concentration is (solutes concentration is lower (solutes concentration is
similar to that of plasma) than that of plasma) higher than that of plasma)
 Have the same osmolarity  Have osmolarity less than  The opposite of hypotonic
as plasma. that of plasma. solutions.
 When administered will  When administered, it will  Used as volume expanders.
produce no change in decrease intravascular  They behave as colloids but
plasma osmolarity. osmolarity leading to escape of have shorter duration of
 EX: 0.9% sodium chloride, water to extravascular to re- action.
Ringer, Hartmann’s solutions establish osmotic equilibrium.  EX: 25% mannitol, 10%
& D5W.  EX: 0.45% NaCl, D5W glucose & 20% albumin.
 Glucose in glucose solutions is rapidly taken up by cells leaving hypotonic solution.
 D5W: initially, is isotonic and after glucose uptake by cells, it becomes hypotonic (water only).
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Composition of solutions
You may find different quantities of solutes in different preparations, revise the product label.
Solution Osmolarity Na+ Cl- K+ Ca+2 Glucose pH
Normal level 275-295 135 - 95 -105 3.5 - 2.2 -2.6 3.5 - 5.5 7.35-
mOsm/l 145 mEq/l 5.3 mmol/l mmol/l 7.45
mEq/l mEq/l
0.9% NaCl 308 154 154 0 0 0 4.5-7
0.45% NaCl 154 77 77 0 0 0 5.6
3% NaCl 1026 513 513 0 0 0 5
Ringer solution 308 147 111 4 2.25 0 5-7.5
Ringer lactate* 278 130 109 5 1.4 (or 2) 0 5-7
Ringer acetate * 276 130 112 5 1 0 6-8
D5W 278 0 0 0 0 50 g/l 5
D10W 505 0 0 0 0 100 g/l 4.3
5% albumin** 309 145 145 0 0 0
6% Hetastarch** 286-308 137-154 110-154 0 0 0
*Ringer acetate and lactate contain about 28 mEq/l of HCO3, ringer acetate contains Mg (1
mmol/l).
**Half-life of albumin is about 20 days with oncotic pressure 20 mmHg and half-life of 6%
hydroxyethyl starch is about 12 hours with oncotic pressure 36 mmHg.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Anti-diabetics
Insulin
 Insulin is a polypeptide hormone synthesized and released from beta cells of pancreatic islets;
synthesized in the form of pre-proinsulin that is processed to proinsulin then cleaved into insulin
and C-peptide.

 Insulin secretion is regulated by nutrients, GI hormones (incretins), pancreatic hormones and

autonomic nervous system (α2 ↓ its release while β2 and vagal nerve stimulation ↑ its release).

 Insulin release is greater when glucose is administrated orally than intravenously due to the
effect of incretins in GI tract (incretin effect).

 Insulin produces its action by binding to insulin receptors (tyrosine kinase linked) which are
found on all mammalian cells, it stimulates or inhibits many enzymatic reactions or gene
transcription.

 Actions of insulin:

1. Insulin is an anabolic hormone; stimulates uptake, use and storage of glucose (through
GLUT4), lipids and amino acids (stimulates glycogenesis, lipogensis and protein
synthesis).
2. Inhibits glycogenolysis, lipolysis and protein catabolism.

Glucagon like peptide-1 receptors agonists (GLP-1 RAs) and DDP-4 inhibitors

GLP-1 is a peptide secreted with glucagon from alpha cells of pancreas in the form of
preproglucagon that cleaved into glucagon and GLP-1 and GLP-2, GLP-1 acts on GLP-1 receptors
(heart, vasculature, lung, GIT, kidney, nervous system) leading to:

1. Increased insulin release

2. Decreased glucagon release
3. Delayed gastric emptying
4. Decreased food intake.
 CARDIO-NOTES, Part II (CVS drugs) Physiological review for CVS drugs

Then, GLP-1 are metabolized and inactivated by dipeptidyl peptidase 4 (DPP-4) enzyme. So, two
groups of drugs for management of DM are developed; GLP-1 receptors agonists (injectable)
and DPP-4 inhibitors (oral), both groups produce actions similar to GLP-1 peptide.

Sodium glucose cotransporter-2 inhibitors (SGLT2Is)

Sodium glucose cotransporter-1 (SGLT1) and 2 (SGLT2) are responsible for glucose reabsorption
in the kidney, SGLT2 is located in the proximal part of the proximal tubules and enables 90% of
glucose reabsorption (also present in alpha pancreatic cells) and SGLT1 is located in the distal
part of proximal tubules and enables the other 10% of glucose reabsorption form the urine.
Inhibition of SGLT2 lead to loss of about 50 g/d glucose. Also SGLT2Is may decrease ROS,
inflammatory cytokines and endothelial dysfunction. The observed benefits of SGLT2Is are
reduction of blood glucose, blood pressure, weight loss, and reduction of cardiovascular events
and mortality in diabetic and non-diabetic patients.