Anti-Anginal Drugs Flashcards by Ibtihal Balubaid

The most COMMON cause of death in the world————

I.H.D

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Transient reversible cardiac

ischemia—————

Angina=

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Presentation: of Angina

3 things

1- Centralized pain (retrosternal pain)
2- Sense of tightness
3- Should not last ˃ 15-20 min

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———– is the first priority and the most important tool for the diagnosis of MI
and can confirm the diagnosis in 80% of cases.

ECG

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Coronary artery contain beta——— adrenoreceptor

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Parienzmetal angina
People with angina have alpha in
coronary artery more than beta,
so once you give beta blocker
the --------- will take the hand and
lead to severe vasospasm
“NEVER EVER GIVE B
BLOCKER”

Alpha

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If u don’t treat stable angina within ——min

Unstable&raquo_space;

15-20

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Angina of effort or
exercise (Chest pain)
Fixed subintimal
Atheroma deposition

Classic Angina
/typical/exertional
or chronic stable
Angina

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subendcardial

myocardial ischemia in

Classic Angina

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Acute coronary syndrome
- Unstable Angina
Rupture ; Partial
coronary obstruction
(-------------)

Sudden chest pain)

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————-: Complete Coronary

obstruction (irreversible)

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Vasospastic or
Variant
(Prinzmetal)
(-----------------angina)
Chest pain
during the ------------------
= Coronary ---------------

Tansmural -rest-VC

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in ————— angina we can use

beta blocker - CCBs - other drugs work on BV

Stable

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In ————–angina we can use Thrombolytics and antiplatelet , coronary vasodilator

Unstable

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in —————- angina we try to make coronary vasodilation and use CCBs and we never never never use Beta blocker

Prinzmetal

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Cardiac work (O2 ------------) α Coronary blood flow (O2---------)
 Contractility x HR α O2 supply

demand-supply

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CAD=I.H.D

——-Cardiac work
——–O2 supply

inc

dec

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Your goal is to restore this balance

———O2 demands (cardiac work)
———-O2 supply (coronary blood flow)

dec

inc

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↓HR & myocardial contractility: 2drugs

Both——–Ve chronotropics and ———Ve inotropics

β-blockers
C.C.Bs
negative

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-↓ Preload (EDV) ( strong venodilatation)

1 drug

Nitrates: venular VD

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-↓Afterload

3 drugs

CCBs: arteriolar VD
βBlockers: ↓BP
Nitrates: arteriolar VD (in higher doses)

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increase O2 supply (coronary blood flow)

3 drugs

A. Nitrates: VD of epicardial
coronary arteries-redistribution
of blood to ischemic areas- VD
of collaterals.
B. CCBs: coronary VD
C. βBs: ↓BP -↑diastolic period
→↑coronary filling (not good).

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First strategy to reduce heart work

• ↓ Preload (EDV) ( strong venodilatation)

A.
 Decrease venous return
 Decrease preload
 Decrease EDV (EDP)
 Blood pooled to periphery
 Decrease the stretch of myocardium
 Decrease contraction
 Decrease O2 demand
 Reduced coronary blood flow (O2 supply)
B.
 Less preload less pressure on deeper myocardial circulation
 better flow to the deeper myocardium
 Less radius less tension less O2 need

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↓ Afterload ( arteriolodilation)

Ca++ channel blockers
 Decrease T.P. resistance
 Decrease PRESSURE
 Decrease TENSION to maintain C.O
 Decrease cardiac work
 Decrease O2 demands

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What is the main arteriolodilator in angina?

Calcium channel blocker

---------- H.R A.------------------------ SA node (Ca++ dependent depolarization) If you block Ca++ channel; Decrease A.P ( - Ve chronotropic) β- blockers SA node ( ----------- receptors) If you block β1- receptors ; Decrease H.R ( - Ve chronotropic) Cardiac cells loaded by Ca++ depend on Voltage gated Ca++ channels (-----------type) + β1- receptors If you block both ; decrease Ca++ loaded ; decrease contractility; decrease O2 demand (- Ve inotropics)

↓ Ca++ channel blockers β1 L

1- decrease the preload by Venodilator (--------- ) 2- decrease the after load by arteriolodilation ( ----------- ) 3- decrease HR which decrease sympathetic activity ( ---------------- )

nitrateCa+ -chanel blocker-Beta 1 blocker

``` Between Attack 1- -------------- blockers 2- ----------- channel blockers (except Nifedipine) ( c. work ) 3- Nitrate (intermediate or long acting) ( c. work ) ( c. work ) 4- Ranolazine 5- Preventive FFA oxidation inhibitors (Trimetazidine) 6- Plaque stabilizers (Statins) 7- Antiplatelete (Aspirin) 8- Thrombolytic drugs ```

β Ca++ Nifedipine

``` Acute attack also (Prophylactic) Short acting ```

Amyl nitrate Nitroglycerin =Glyceryl Trinitrate

Inbetween attack Intermediate acting drug

Isosorbide | dinitrate

What is the dose of Amayl nitrate that patient will have ?and root? onset? duration ?

``` Ampoule 0.3 ml Inhalation 1 min 5 min ```

Prototype is -------

Nitroglycerin (Glyceryl | Trinitrate) ( NTG )

Dose of NTG ?

``` S.L 0.5 mg (Sublingual Plexus) Spray (Buccal Mucosa) I.V µg/ml (Monitoring) Oral SR ```

can we give Beta blockers to a patient with Prinzmetal’s angina?

No if we block beta receptors we are decreasing vasodilation, and the vasoconstriction caused by Alpha receptors will worsen .NEVER EVER GIVE B BLOCKER

What is the main arteriolodilator in angina?

Calcium channel blocker

How to Avoid Nitrate Tolerance ?

Due to prolonged administration Stop give nitrate A.M and P.M ; Give nitrate for 12 h only and substitute other 12 h with another medication in case of angina attack very frequently 12 h with another medication in case of angina attack very frequently

How to avoid the side effect of beta blocker or nitrate?

Nitrate and vise versa

Drug strategies in stable angina?

dec cardiac work 1- decrease the preload by Venodilator ( nitrate) 2- decrease the after load by arteriolodilation ( Ca+ chanel blocker ) 3- decrease HR which decrease sympathetic activity ( Beta 1 blocker )

A 60-year-old man presents to his primary care physician with a complaint of severe chest pain when he walks uphill to his home in cold weather. The pain disappears when he rests. After evaluation and discussion of treatment options, a decision is made to treat him with nitroglycerin. 1. Which of the following is a common direct or reflex effect of nitroglycerin?

(D) Increased cardiac force

In advising the patient about the adverse effects he may notice, you point out that nitroglycerin in moderate doses often produces certain symptoms. Which of the following effects might occur due to the mechanism listed?

(D) Headache due to meningeal vasodilation

One year later, the patient returns complaining that his nitroglycerin works well when he takes it for an acute attack but that he is now having more frequent attacks and would like something to prevent them. Useful drugs for the prophylaxis of angina of effort include

(E) Verapamil - betablocker

4. If a β blocker were to be used for prophylaxis in this patient, what is the most probable mechanism of action in angina?

(A) Block of exercise-induced tachycardia

A 60-year-old man experiencing sudden onset of chest pain radiating to his left shoulder while climbing upstairs. He has past history of angina and his family physician had instructed him to take nitrates sublingually in case of acute pressure or squeezing chest pain. Which of the following nitrate preparation is NOT prescribed for sublingual administration?

B. Isosorbide mononitrate | D. Amyl trinitrate

Nitroglycerin administered sublingually may contribute to the relief of myocardial pain by each of the following mechanisms, except:

Decreased venous pooling resulting in increased cardiac | preload

in Asthma patient has angina can use ------- and -------- because they will decrease HR m.work - Relaxation of coronary s.m and can not use --------- bacause of -----------

``` Nitrate + C.C.B (Verapamil) dec. HR &dec. Contractility m.work Relaxation of coronary s.m Relaxation of Bronchial s.m Beta Blocker - Bronchospasm ```

CHF with angina can use -----------and----------- not -------------or-------------because -------------give them ---------------for long acting

``` Nitrate + C.C.B Verapamil (-ve inotropes) = Myocardial depression NoT Nifedipine: -R. Tachycardia Give Amlodipine (long.A.) ```

HTN can use -------------------and----------------and------------------and------------------and least preferred to use Nitrate

beta-blockers C.C.Bs (long.A.) -VD dec preload+dec afterload -Coronary VD

D.M can use ------------- not ------------and can use --------------- for long action and least preferred to use-----------------

``` Nitrate + C.C.Bs Verapamil (dec insuline release , however not clinically important) Not Nifedipine Give Amlodipine (long.A.) ```

``` 3- Ca++ channel blockers Competitive blocking of--------------- channel.(Ltype) Ca++ dependent cardiac activity: 1- ----+------ nodal depolarization 2- Atrial + ventricular contraction ```

voltage-gated Ca++ | SA +AV

``` drug of CCBs do : dec HR dec Conduction dec Contraction dec velocity decCa++ med. C. myocyte necrosis decC. work ```

Verapamil

``` drug of CCBs do : Vasodilatation ------------ (Short acting; R. Tachycardia; increase the incidence of MI) ```

Nifidipine

Give ------------ (Long acting; does not cause R.tachycardai; DOES NOT affect HR and CO)

Amlodipine

--------- cause Arteriolar smooth m.s (Ca++ channels) dec T.PR ( afterload)dec c.work (D.O.C. in preinzmetal’s angina); ------------ is the best To prevent R.T: + *------------------ (Asthma-D.M) Or give Cardioselective

Nifedipine Amlodipine Beta blockers

S.E of C.C.B:

1- Constipation ( Inhibit Ca++ channels on GIT s.m) | 2- ankle edema ( Decrease B.P; R.T; Activate RAAS)

To avoid side effects of Beta blocker give -------------and vise versa

Nitrate

Propranolol, bisoprolol, metoprolol, atenolol, Carvedilol | are all ---------------------

Beta blockers

Beta Blockers -----Cardiac work --------O2 demands ----------infarct size (post MI mortality) --------- HR & contractility ----------CO and------------ BP----------- SV----------EDV Bradycardia cause -----------diastolic filling time ; --------------------coronary blood flow--------------------coronary filling THIS IS NOT GOOD for angina pts therefore nitrate will cause VD which will reduce EDV.

all dec. except the last one is inc | inc - inc - inc

Block B-2 receptor on coronary artery( -----------of the | blood)

redistribution

Do metabolic switch : switch of the metabolism in infarct size from oxidation of ---------which need more O2 to glucose

FFA

Beta blockers in angina: --------------HR X decrease SV= decrease C.O= decrease cardiac work= decrease need of O2 -B-blockers protect the heart not even at rest but even if person under------------------- . *NB: B1 selective blockers are -----------. - Pindolol (with intrinsic sympathetic activity; ISA) should be------------- .

Decrease -exertional stersses-preferred-avoided

Stable angina (1st choice -----------------; 2nd choice--------- ) Beta-blockers C/I with -------- angina (unopposed alpha effect) Never ever stop Beta-blockers suddenly? Beta in heart upregulation: Precipitate ------

Beta-blockers-C.C.Bs-variant-MI

PKs of NTG 1. Can be given by------,--------,------- (both avoid first pass metabolism). 2. ---------------- have long half lives and are used TO prevent nocturnal angina. 3. Oral bioavailability of nitroglycerine and isosorbide dinitrate is very ----------------(extensive first pass metabolism). 4. Because of its ------action, long established safety and low cost Nitroglycerin is the most useful drug of the organic nitrate given --------------- 5. Isosorbide mononitrate by pass hepatic metabolism and has -------------- bioavailability after oral Admin, delayed onset and long duration (elimination t1/2~ -----------). Therefore has been formulated as Tablet and as a sustained release preparation

``` IV, sublingual & transdermal patches Transdermal patches low rapid sublingually. 100% 4-5 h ```

Why you give NTG S.L in acute attack (stable angina) - To avoid -------------- - If frequent attack; daily - If not frequent attack? - As required (prophylaxis) SR or Transdermal patch or ointment

first pass effect-

- Which one of oral antinational medication does not undergo under first pass effect and therefore has excellent bioavailability after oral administration ?

Isosorbide mononitrate

Organic nitrates: M.O.A They are all have the same M.O.A , the difference only in----------------------- . Nitrate is prodrug of ------------------

PK-nitric oxide

Nitrate - NO (EDRF) - increase ---------------in vein(present in _________and__________) lead to ------------ -------PGE2/I2 lead to VD

cGMP -vascular B.V and smooth muscle -VD | increase

Organic nitrates: Phramacological effects A. Effect of nitrate on blood vessels: 1. ------------ (generalized ) Vein ----- than artery 2. Venular VD -----preload -------cardiac work -----O2 demands 3. Coronary VD Redistribution of the blood (------- infarct size) reduce post MI mortality 4. -------Afterload------ T.PR -------cardiac work -----O2 demands 5.--------- in head and neck blood vessels (Flushing) 6.---------- in meningeal artery in brain (Throbbing headache) B. Effect of nitrate on Heart: 1. ------------- on the heart only on the blood vessels 2. Due to the their VD lead to R. Tachycardia (Not good for angina patients) (----------------)

``` VD more dec dec dec dec dec dec dec dec vd vd does not work high dose ```

Organic nitrates: Phramacological effects A. R.Tachycardia -------------Tachypnia Therefore, You have to monitor the dose which does not cause hypotension. B. Nitrate------------------- NO (Nitric Oxide) - Oxide is a free radical with high dose of nitrate; Oxide oxidation_________ Hemoglobin (F3+) _______MetHb (Cyanosis;---------------------- )

methemoglobinemia

Organic nitrates: Indications 99% in -------------- Not contraindicated in any type of I.H.D, however; more used in --------------- angina with B- blockers. MI : To limit the------------------ and post MI mortality Acute Heart Failure: Nitrate I.V Both (Arteriolodilator + Venular --------------) ---------------- edema : NTG S.L Both (Arteriolodilator + Venular VD) A ---------------- (CN - bind with Hb Hb cannot carry O2 tissue hypoxia ; cyanosis. (Give high dose of 300 mg nitrate; NO; ------------) CNMetHb , then you give Na+ ------------- injection CN- Thiocynate (Kidney)

``` I.H.D-classic infarction size VD Pulmonary cyanide Toxicity MetHb thiosulfate ```

Organic nitrates: S.E 1. B.P : Reflex. T (Not good for ------------)(at high doses) 2. Flushing of the face (VD of the facial blood vessels) 3. ----------- Headache (Good)( Give simple analgesics) 4. Nitrate Tolerance Nitrate show very high tendency to produce tolerance with -------------hr A- NO (oxidizing agent) Oxidation Mitochondrial aldehyde dehydrogense________ Inhibit NO production B. Prolonged VD________ Kidney activate RAAS (Salt,H2O retention) C. Brain; reflex tachycardia -----------------

angina patients Throbbing 12-16 hr VC

How To Avoid Nitrate Tolerance Due to prolonged administration Stop give nitrate A.M and P.M ; Give nitrate for 12 h only and substitute other 12 h like -----with another medication in case of angina attack very frequently

beta blocker

- In exertional angina: Nitrate-free interval (Should be at -----------) - In prinzmetal’s angina: Nitrate-free interval (----------)

night-at noon

Organic nitrates: Precaution | 7 things

1. Do not exceed the recommended dose 2. Keep some nitrate at home (nocturnal chest pain) 3. Patients must consult the doctors if the pain does not disappear with 15 min. 4. Given I.V infusion 5. Check expiry date 6. Photosensitization (Foil) 7. Sildenafil ------inc NO-------inc cGMP----- VD in Corpus cavernosum in penis

Recurrent Attack (Prophylaxis) drugs 5 things

``` 1- B- blockers 2- Ca++ channel blockers( dec c. work) 3- Nitrate (intermediate or long acting) (dec c. work ) 4 - Antiplatelete (Aspirin) 5- Thrombolytic drugs ```

we can us isoprenoid in ----------------attak

acute

What is the dose of Isosorbide | mononitrate that patient will have ?and root? onset? duration ?

``` Oral Ext. R 30 min 30 min ~8 h ~12 h ```

What is the dose of Isosorbide | dinitrate that patient will have ?and root? onset? duration ?

``` S.L Oral SR 5 min 15 min 30 min ~1 h ~5 h ~ 8 h ```

What is the dose of Nitrate that patient will have ?and root? onset? duration ?

~ 2 min 30 min ~15 min ~ 7 h

What is the dose of Amyl nitrate that patient will have ?and root? onset? duration ?

1 min | ~ 5 min

oral Isosorbide dinitrate is-----------------only---------- will reach circulation

oral metabolized by liver | 23%

Angina pectoris is characterized by • Sever, pressing chest pain that occurs when coronary blood flow is ---------- to supply O2 required by the heart.

inadequate

Angina Pectoris - It is the primary symptom of ------------------ caused by accumulation of ------------ in cardiac muscle. • -These transient episodes result from imbalance between myocardial O2 supply and demand.

ischemic heart disease | metabolites

``` Angina Pectoris •----- Demand may be due to: • - ----HR. • - ---- Ventricle wall tension (as in hypertension). • --- ventricular contractility ```

inc inc inc inc

Decreased O2 supply: • Decreased blood coronary flow due to: • -Fixed atherosclerotic narrowing in -----------angina • -Coronary spasm in -----------angina • -Non occlusive thrombus in ------------angina

Stable Paienzemtal Non-Stable

Management of angina pectoris: • I-Reduce --------------: smoking, obesity, treat hypertension, diabetes& dyslipidemia. • II- Decrease incidence of ----------- and increase survival rate

risk factors myocardial infarction

III-Antianginal agents: • 1-Angina of effort: A-acute attack: -------------------- (nitroglycerine) - ------------------------ (sublingual). B- Prophylaxis: -------,------------,--------

glyceryl trinitrate-isosorbide dinitrate- | long acting nitrates- βBs – CCBs

type of Angina ?-------------- • -coronary flow is decreased due to fixed atherosclerotic narrowing of coronary arteries (occurs on exertion &relieved by rest or nitroglycerin).

Typical - angina of effort

type of Angina ?-------------- • - Due to reversible coronary spasm (occurs at rest &unrelated to exercise). • -Relieved by VDs and CCBs not by βBs.

Parinzmetal - Varient -Vasospastic - Alpha mediated syndorme Angina

type of Angina ?-------------- • -Due to episodes of ↑epicardial coronary artery spasm &formation of non-occlusive thrombi resulting from rupture of atherosclerotic plaque (not related to exercise and not relieved by rest or nitroglycerine)

Unstable Angina

type of Angina ?-------------- in patients with advaned coronary artery disease .

Mixed form of Angina

- ↓O2 demand: work done by heart &O2 consumption through dec. HR+ Myocardial contractility -------------------- dec. Preload (venodilation) -------------because it is -------- dec. afterload --------- -because it is --------and---------because it is------------and --------------because at high doses

``` βBs and CCBs Nitrates: mainly venular VD CCBs: arteriolar VD - βBs: ↓BP -nitrates: arteriolar VD (in higher doses) ```

-↑O2 supply: ↑-------------------- (direct)---------------- VD of epicardial coronary arteries-redistribution of blood to ischemic areas- VD of collaterals. coronary VD -:(direct)----------- coronary VD •(indirect) ------------- : ↓BP -↑diastolic period →↑coronary filling

coronary blood flow Nitaite CCBs-βBs

-ORGANIC NITRATES: | • Mechanism of action ?

Nitrates bind to nitrate receptors in vascular endothelial cells and vascular smooth muscle cells → nitrite ions are released then converted to nitric oxide → ↑c-GMP→ dephosphorylation of myosin light chain kinase→ vascular smooth muscle relaxation.

• Pharmacological actions of Organic Nitrate ?

• Relax all segments of vascular system especially veins; it is a potent venodilator( veins responds at the lowest concentrations, arteries at higher ones) → decreasing preload → decreasing work done by the heart and myocardial O2 consumption. • - Vasodilatation of epicardial coronaries → increasing blood supply

Pharmacokinetics: • Can be given by -----------, -------&------------ patches (both avoid first pass metabolism). • Transdermal patches have ----------- half lives and are used TO prevent ---------------angina. • - Oral bioavailability of nitroglycerine and isosorbide dinitrate (metabolized into two mononitrates) is very------------ (extensive first pass metabolism). • - Sublingual→ rapid onset (------to---minutes). • -Isosorbide mononitrate by pass hepatic metabolism and has -------- bioavailability, delayed onset and long duration(more than one hour). • - all Excreted by the -----------

``` oral-sublingual-transdermal long-nocturnal low 1-3 100% kidney ```

Adverse effects of Organic Nitrate :

• -Flushing, throbbing headache, temporal & meningeal pulsations. • - Postural hypotension even syncope and tachycardia. • -Sildenafil (Viagra) potentiates its action (increases c-GMP) → sever hypotension and myocardial infarction have been reported. • Thus an interval of six hours is needed between the ingestion of the two drugs.

using Nitrate with Sildenafil will cause ----------- then--------------then ------------

Reflex Tachy - Ischemia - Death

Organic nitrate -Tolerance: • Nitrate ----------- (--to---- hours) is necessary for drugs with ------ t1/2 and sustained release formulations (24 hours) → overnight or remove the transdermal patch for few hours if tolerance is suspected (for ---------- angina, nitrate free interval should be late in the afternoon as this type of angina worsens early in the morning). • -Dependence so nitrates should not be abruptly withdrawn→ withdrawal symptoms. -Can cause ----------------- at high blood concentration

``` free period 10-12 long few variant methemoglobinemia ```

Beta blockers: • -------------, ------------, ------------,------------ atenolol. • ------O2 demand&↓work done by heart: • - ------- HR& contraction → ↓ CO and BP. • -----------O2 supply: ↑coronary blood flow by ↓HR→----------ED period→ ↑coronary filling • NB: • ---------- selective blockers are preferred. • -------- (with intrinsic sympathetic activity; ISA) should be avoided.

Propranolol(Non selective)-bisoprolol-metoprolol-atenolol ↓ - ↓- ↑-↑ β1 Pindolol

Beta blocker • Best indicated in patients with -----------------→ decrease size of infarction, incidence of attacks & prolong survival. • -Useful in stable & unstable angina but contraindicated in ------------- →↑ spasm

myocardial infarction variant or vasospastic angina

Beta Blocker Contraindicated in ? 4 things

``` asthmatic, diabetics,sever bradycardia& peripheral vascular disease (selectivity is lost within higher doses). • -Should be gradually stopped over 2-3 weeks to avoid infarction or sudden death (up regulation of the receptors) ```

``` Calcium influx is increased in ----------- which depletes energy stores and worsening ischemia. These drugs bind more effectively to channels in ------------ membrane → ↓ the frequency of opening in response to depolarization → marked decrease in transmembrane Ca²+ current in smooth muscle, cardiac muscle→ vasodilatation and reduction in contractility &in SAN pacemaker and AVN conduction velocity ```

hypoxia | depolarized

CCBs Classes 1-Dihydropyridines: • A-Short acting preparations: e.g. -------------- (mainly affects ----------------- than myocardium) → reflex tachycardia, hypotension, flushing, headache and peripheral edema. • Short preparations should be avoided in patients with -------------------- as it increases incidence of infarction. Slow-release and ------------ vasoselective calcium channel blockers are usually well tolerated B- Long acting as amlodipine which does not affect ----------- or ----------------, amlodipine cause --------------

``` nifidepine vascular smooth muscles coronary artery disease long-acting heart rate or cardiac output ankle edema(Swelling) ( lower limb edema) ```

- Non dihydropyridines: • A- Verapamil: • -Mainly affects the ---------------- (directly affects ------- conduction) than smooth muscle (weak VD) → slows HR and 02 demand. • - Extensively metabolized by the liver (dose must be adjusted in ------------------). • -Contraindicated in ---------- conduction abnormalities or depressed cardiac function. • -Verapamil with digoxin →------- level of digoxin as a result of decreased tissue binding and↓ excretion. • - Main adverse effect is -------------------

``` myocardium-AV liver dysfunction AV ↑ constipation ```

Dihydropyridines have NO | effect on ------- conduction

Diltiazem: - -----------in its actions between nifedipine and verapamil. - ------------ AV conduction & decrease the rate of firing of SAN pacemaker →decrease HR and BP. - Extensively metabolized by------------. -Contraindicated in ------------ conduction abnormalities→ heart block -Useful in ----------- angina while βBs are contraindicated. • If response to a single antianginal group is inadequate, a combination of 2-3 drug groups may be used to increase beneficial effects and decrease adverse effects: • -Decrease HR by --------------- can prevent undesirable increase in HR by -----------------

``` Intermediate Slows liver AV variant βBs nitrates ```