8-9

Cardiovascular drugs and Non-Steroidal Anti-

inflammatory

،‫اذا فيه شيء مو مفهوم ) بالخط ( كلموني‬

‫بالتوفيق‬

( iir01a ) ‫رنيم‬

‫اللهم صل وسلم على نبينا محمد‬

Department of Pharmacology & Toxicology

College of Pharmacy, UQU, Makkah
 Drugs used to improve CVS function

q Antihypertensive

q Drugs used to treat heart failure

q Antiarrhythmic

q Antianginal
 Antihypertensive agents

Category Systolic/Diastolic pressure

(mm Hg)

Normal < 120/80

Prehypertension 120-129/80
Stage 1 130-139/80-89
Stage 2 ≥ 140/90

BP = CO(cardiac output) × PVR ( peripheral vascular resistance)

 Subclass M/A Effects Application Toxicities

Angiotensin- Inhibits Arteriolar & Chronic heart Cough,

converting ACE venous failure, hyperkalemia,
enzyme (ACE) dilation hypertension angioneurotic
inhibitors: eg edema
§ Captopril

Angiotensin Like ACEI § Like ACEI Like ACEI

receptor § Intolerant to
Blockers (ARBs): ACEI
• Losartan
RENIN INHIBITOR Inhibits Reduces Hypertension Ø Hyperkalemia,
§ Aliskiren enzyme angiotensin I & Ø renal
activity of II and impairment
renin Aldosterone Ø potential
teratogen
BETA BLOCKERS Competiti § Slows heart Chronic heart Bronchospasm,
§ Carvedilol vely blocks rate failure, bradycardia
β1 § reduces hypertension
receptors blood pressure
 Subclass M/A Effects Application Toxicities

Venodilators: Ø Blocks Ca2+ Ø Reduce Hypertension,

§ Verapamil channel cardiac rate angina,
§ Nifedipine and output arrhythmias
Ø Reduce
vascular
resistance
Arteriolar Increases NO Reduces BP Hypertension Tachycardia,
dilators synthesis & afterload fluid
§ Hydralazine retention

Combined Releases NO & Reduces blood Ø Acute cardiac Excessive

arteriolar and activates pressure decompensati hypotension,
venodilator: guanylyl & afterload on thiocyanate
§ Nitroprusside cyclase Ø hypertensive and cyanide
emergencies toxicity
α BLOCKERS Selectively Prevent Hypertension Orthostatic
§ Prazosin block α1 sympathetic hypotension
Adrenoceptors vasoconstrictio
n
 Subclass M/A Effects Application Toxiciti
es

DIURETICS Block Na/Cl Reduce Ø Hypertension,

§ Hydrochloro transporter blood mild heart
thiazide volume Failure
Ø Severe
hypertension,
§ Furosemide heart Failure
§ Spironolactone Block Increase Na Ø hypertension,
aldosterone and heart failure
receptor decrease K
excretion
SYMPATHOPLEGICS, Activate α2 Reduce Hypertension Sedation
CENTRALLY ACTING adrenoceptors ? central
§ Clonidine [bind sympathetic
presynaptically, outflow
so agonism
prevent the
release E/NE]
 Heart Failure (HF)

q Heart failure: heart isn't pumping as well as it should be.

qMost common cause of HF coronary artery disease with

hypertension.

qCardinal symptoms are dyspnea, fatigue, and fluid retention.

 What is heart failure ?
ØIn heart failure, heart's pumping power is weaker than normal.

ØHeart can’t pump enough oxygen and nutrients to the body.

ØHeart respond by stretching to hold more blood to pump through the body or

by becoming stiff and thickened.

ØHeart muscle walls weaken and become unable to pump efficiently.

ØKidneys respond by causing the body to retain fluid (water) and salt in the

arms, legs, ankles, feet, lungs, or other organs.

ØBody becomes congested, and congestive heart failure is the term used to

describe the condition.

 Subclass M/A Effects Application Toxicities

Angiotensin- Inhibits ACE Arteriolar & Chronic heart Cough,

converting venous dilation failure, hyperkalemia,
enzyme (ACE) hypertension angioneurotic
inhibitors: eg edema
§ Captopril
Angiotensin Like ACEI § Like ACEI Like ACEI
§ Intolerant to ACEI
receptor
Blockers (ARBs):
§ Losartan
BETA BLOCKERS Competitively § Slows heart Chronic heart Bronchospasm,
§ Carvedilol blocks β1 rate failure, bradycardia
receptors § reduces hypertension
blood pressure

CARDIAC Reduced Increases Chronic Nausea,

GLYCOSIDE Ca2+ cardiac symptomatic vomiting,
§ Digoxin expulsion contractility heart diarrhea,
& increased failure arrhythmias
Ca2+ stored
 Subclass M/A Effects Application Toxicities

Venodilators: Ø Release reduces Ø Acute and Postural

§ Isosorbide nitric oxide preload & chronic heart hypotension,
dinitrate (NO) ventricular failure tachycardia,
Ø Activate Stretch Ø Angina headache
guanylyl
cyclase

Arteriolar dilators: Increases NO Reduces BP With nitrates Tachycardia,

§ Hydralazine synthesis & afterload reduced mortality fluid retention

Combined Releases NO & Reduces Ø Acute cardiac Excessive

arteriolar and activates blood decompensation hypotension,
venodilator: guanylyl cyclase pressure Ø hypertensive thiocyanate
§ Nitroprusside & afterload emergencies and cyanide
toxicity

BETA- Ø β1selective Increases Acute Arrhythmias

ADRENOCEPTOR agonist cardiac decompensated
AGONISTS Ø Increases contractility, heart failure
§ Dobutamine cAMP output
synthesis
 Arrhythmia
q Irregular heartbeat (also called dysrhythmia).
qHeart rates can also be irregular.

qA normal heart rate is 50-100 beats/min.

qArrhythmias and abnormal heart rates don't necessarily occur together.

qArrhythmias can occur with a normal heart rate, or with heart rates that are
slow (called bradyarrhythmias - <50 beats/min).

qArrhythmias can also occur with rapid heart rates (called tachyarrhythmias
-- >100 beats/min).
 Symptoms of arrhythmia

ØPalpitations (a feeling of skipped heart beats, fluttering or

"flip-flops," or feeling that heart is "running away")

ØPounding in chest

ØDizziness or feeling light-headed

ØFainting

ØShortness of breath

ØChest discomfort

ØWeakness or fatigue (feeling very tired)

 Antiarrhythmic drugs
qUsed to treat disturbances of the normal heart rhythm.

qUnfortunately, many antiarrhythmics are also capable of worsening

or causing the very arrhythmias they’re supposed to treat.

qThe benefits need to be weighed carefully against the risks of

antiarrhythmic therapy.
qAntiarrhythmics are categorized into four classes:

ØClass I (Na+ channel blockers)

ØClass II (β adrenoceptor blockers)

ØClass III (K+ channel blockers)

ØClass IV (Ca2+ channel blockers)

 Subclass M/A Effects Application Toxicities

CLASS 1A Sodium Slows Most atrial and Hypotension

• Procainamide channel conduction ventricular
(INa) blockade velocity arrhythmias
and
pacemaker
rate

CLASS 1B Sodium does Terminate Neurologic

• Lidocaine channel not ventricular symptoms
(INa) blockade prolong tachycardias and
and may prevent
shorten ventricular
action fibrillation
potential after cardioversion
CLASS 1C Sodium Supraventricular Proarrhythmic
• Flecainide channel arrhythmias [precipitate
(INa) blockade in patients with pre-existing
normal arrhythmia]
heart
 Subclass M/A Effects Application Toxicities

CLASS 2 Nonselective Decreased Ø Prophylaxis of Asthma,

• Propranolol competitive heart rate, angina atrioventricular
antagonist at cardiac Ø Atrial Block , acute
β-adrenoceptors output, and arrhythmia heart failure,
blood sedation
pressure

CLASS 3 Blocks IKr, INa, Prolongs Serious Bradycardia

• Amiodarone ICa-L channels, action ventricular and heart block
Β- potential arrhythmias and in diseased
adrenoceptors duration supraventricular heart
and QT arrhythmias
interval
CLASS 4 Ø Blocks Ca2+ channel Ø Reduce Hypertension,
• Verapamil cardiac angina,
rate and arrhythmias
output
Ø Reduce
vascular
resistance
 Antianginal drugs
q Angina occurs when the coronary arteries supply insufficient
oxygen to the myocardium.
q This increases the heart’s
workload by increasing
heart rate, preload, afterload
and force of myocardial
contractility.
qAntianginal drugs
Ø Reduce myocardial oxygen
demand
Ø Increase the supply of
oxygen to the heart
 Subclass M/A Effects Application Toxicities

NITRATES: Ø Release nitric Smooth Ø Acute and Postural

§ Isosorbide oxide (NO) muscle chronic heart hypotension,
dinitrate Ø Activate relaxation failure tachycardia,
guanylyl Ø Angina headache
§ Nitroglycerin cyclase

BETA BLOCKERS Nonselective Decreased Prophylaxis of Asthma,

§ Propranolol competitive heart rate, angina atrioventricular
antagonist at cardiac Block , acute
β-adrenoceptors output, and heart failure,
blood sedation
pressure
Venodilators: Ø Blocks Ca2+ Ø Reduce Hypertension,
channel
§ Verapamil cardiac angina,
§ Nifedipine rate and arrhythmias
output
Ø Reduce
vascular
resistance
 Analgesic, Antipyretic, and
Anti-inflammatory Drugs

= Non-Steroidal Anti-
inflammator y Drugs (= NDAIDs)
(= Aspirin and its Like Drugs)
 Specific Terminology
Anti-inflammatory Drugs:
1. Steroidal anti-inflammatory Drugs (= Glucocorticoids).
2. Non-Steroidal anti-inflammator y Drugs (NSAIDs) = Aspirin &
Aspirin like drugs. 3- Other class of antiinflammatory drugs (anti-TNF-a)

Algesia: pain sensation.

Analgesics: Drugs relief pain sensation (=pain killers).
Examples:
1. Opioid Analgesics (= Narcotic analgesics): = Morphine and
morphine like Drugs.

2. Non-opioid Analgesics (= Non-Narcotic analgesics): = NSAIDs.

Pyresis (hyperpyrexia ): Fever.

Antipyretics: Drugs that decrease fever. Examples: NSAIDs.
NSAIDs Anti-inflammatory, Analgesics, Antipyretics
An Overview of NSAIDs

¨ Inflammation is triggered by the release of chemical mediators from

injured tissues and migrating immune cells.
¨ The most specific inflammatory mediators are prostaglandins (PGs).
¨ T he most Anti-inflammatory Drugs are Steroidal drugs
(=Corticosteroids) and Non-steroidal anti-inflammatory drugs (NSAIDs).
NSAIDs have:
¨ analgesics, antipyretic, and anti-inflammatory activities.
¨ T he main mechanism of action of NSAIDs is reduction of PGs
biosynthesis by inhibition of cyclooxygenase-2 [COX-2]enzyme.
¨ Note: because Paracetamol (acetaminophen) acting mainly centrally, it
hasn’t anti-inflammatory action.
 Characteristics comparison between COX-1 and
COX-2
COX-1 COX-2
Synthesis intrinsic induced
Functions Synthesis of Beneficial 1- Synthesis of harmful
(physiological) PGs that (pathological) PGs that
have: cause:
1. Gastro protection q Inflammation
form HCL q Pain
2. vascular resistance q Fever
regulation q Dysmenorrhea
3. Renal blood flow (painful menstruation)
regulation
 Effects of COX Inhibition by
Most NSAIDS

COX-1 Inhibits Inhibits COX-2

Gastric ulcers Reduce inflammation

Bleeding Reduce pain

Acute renal failure Reduce fever

NSAIDs

Aspirin in child dose also has : anti-platelet—decreases ability of arterial thrombosis

 Classification of NSAIDs
1
Non - Salicylates: e.g. Aspirin
Selective
2
COX aminophenol derivative: Paracetamol = Acetaminophene
Inhibitors
3 Acetic Acid Derivatives: e.g. Indomethacin, Sulindac,

Diclofenac (= Voltaren), * Etodolac

4
Oxicam Derivatives: e.g. Piroxicam & * Meloxicam
5 Propionic acid Derivatives: e.g. Ibuprofen, Fenoprofen,
Ketoprofen, Naproxen
Selective
COX2
Inhibitors 6 Celecoxib, Valdecoxib, Parecoxib, .. Etc.
Differences of Coxibes than traditional NSAIDs (tNSAIDS):
(Coxibes)
1. Less gastric side effects.
2. Should be given with cautions in patients with cardiac diseases
Aspirin
• Mechanism of Action:
• Inhibits synthesis of prostaglandin by cyclooxygenase; inhibits platelet aggregation; has
antipyretic and analgesic activity
• mild to moderate pain are 350 or 650 mg every 4 hours
• Heart attacks are prevented with 75, 81, 162 or 325 mg daily.
• The dose for preventing another stroke is 75 to 100 mg daily.
• Pharmacokinetics
• Bioavailability: 80-100%
• Onset: PO, 5-30 min
• Duration: PO, 4-6 hr
• Uses
• Rheumatoid arthritis
• Pain and Fever
• Ischemic Stroke
• Side effects
• GI pain, ulceration, bleeding,vomiting
Paracetamol = Acetaminophene
• Mechanism of Action:
• Acts on hypothalamus to produce antipyresis
• May work peripherally to block pain impulse generation; may also inhibit prostaglandin
synthesis in CNS
• Pharmacokinetics
• Bioavailability: 80%
• Onset: 1hr
• Duration: PO, 4-6 hr
• Uses
• Analgesia & Fever
• Headache
• Side effects
• Disorientation, Dizziness, Hepatotoxicity
Diclofenac
• Mechanism of Action:
• Inhibits cyclooxygenase (COX)-1 and COX-2, thereby inhibiting prostaglandin synthesis
• Pharmacokinetics
• Bioavailability: 55%
• Onset: 1hr
• Duration: PO, 6-8 hr
• Uses
• Rheumatoid Arthritis
• Osteoarthritis
• Dysmenorrhea
• Acute Pain
• Acute Migraine
• Side effects
• Edema
• Nausea
• Headache