Molecular Pharmacology

Drugs affecting the cardiovascular system

16. Antihypertensives
Hypertension Overview
혈압 : 혈액이 혈류로 인해 혈관 ( 단위면적 ) 안쪽에 주는 힘 ,
Pressure exerted by your blood flowing through your arteries

Systolic( 수축기 ) BP Diastolic( 이완기 ) BP

- Dynamic ejection of blood - Cardiac ventricle 이 피를
- Ejecting blood out into the 채우기 위해 relax 할 때의
arteries 혈압
- 심장 수축 시 피크 혈압
Hypertension Overview
원인으로 질환을 분류한다 .

Essential: 내재된 고혈압 .

원인을 알 수 없을 때 분류됨 .

Secondary: 고혈압이 유발한

뚜렷한 이유가 있을 때 .
신장병 , 임신 , 약물 부작용
등.
 Pathophysiology
2.1 Baroreceptors and the autonomous nervous system
Baroreceptor flex: 압력 수용체를 통해 bp maintain 을 rapid 하게 진행함
Aortic arch ( 대동맥궁 ), carotid sinus( 경동맥 부비동 ) 에 존재  medulla oblongata 로 신호전달

If) sympathetic  heart rate up, contractility up

Parasympathetic  heart rate down, contractility down

2.2 Renin – Angiotensin – Aldosterone system (RAAS)

Angiotensinogen(liver) (by Renin, kidney) angiotensin I (by ACE, pulmonary surface / kidney endothe-
lium) angiotensin II (octapeptide)  Adrenal gland cortex, Aldosterone secretion

Angiotensin II  arteriolar vasocontraction, induce ADH secretion(pituitary gland posterior lobe), sympathetic activity. Vaso-
constrictor action on the efferent arterioles of the renal glomerulus: glomerular filtration
Aldosterone  NA+, Cl- reabsorption, K+ secretion, H2O retention, Renal sodium reabsorption & blood volume

Drug Target: Renin, ACE, angiotensin II receptor antagonist, aldosterone receptor antagonist, beta blocker (aldos-
terone)

* Renin 과 ACE 는 peptidase

Pathophysiology
Class MOA (Mechanism of Action) Example
3.1 Diuretics ( 이뇨제 ) Urination up  blood volume down  BP -ide
down
3.2 Beta-blockers Hypertensive patients with heart disease or -olol
heart failure
Beta 1 adrenoreceptors on heart, kidney 
cardiac output & renin release down
3.3 alpha-blockers Relaxation of both arterial / venous smooth Prazocin
muscle
3.4 ACE inhibitor -pril
3.5 Angiotensin II re- -sartan
ceptor blockers
3.6 Renin inhibitor Aliskiren
3.7 Calcium channel Inhibit Ca2+ transport via Ca2+ channel -dipine
blockers  Block muscle contraction
 vasodilation
3.1 Diuretics
Subclass MOA Characteristics Example
Thiazide – sensi- Distal convoluted tubules 에서 Na+ / - Initial drug therapy -thiazide
tive Na+ - Cl- Cl- ion 의 reabsorption 을 막음 - hypokalemia
symporter  Sodium / water excretion 증가 - Not as a single agent
blocker (RAAS 약과 같이 씀 )
- Thiazide diuretics
Loop Na+ - Cl- Loop of Henle 에서 Na+ / Cl- ion 의 - hypokalemia -semide
symporter reabsorption 을 막음 - Not as a single agent
blocker  Sodium / water excretion 증가 - Loop diuretics

Late sodium Epithelial sodium channel 막음 - potassium-sparing diuret- Amiloride

channel blocker  distal, collecting duct 의 Na+ ics Triamterene
재흡수 막음 - K+ 관련 부작용 x
 Sodium, water excretion 증가
Aldosterone re- Aldosterone-mediated epithelial - potassium-sparing diuret- -one
ceptor antagonist sodium channel expression in distal ics Spironolactone
and collecting duct epleronone
Sodium, water excretion 증가

Hypokalemia: NCC(sodium-chloride cotransporter). 혈액 속 K+ 가 감소하게 됨

3.2 beta-Adrenoreceptor blockers
Adrenoreceptor: GPCR

Class MOA Example

3.2 beta- 심장질환 있는 고혈압 환자 -olol

blockers Heart/kidney 의 b1 adrenoreceptor
blocking  Cardiac output, renin re-
lease 억제

B2 antagonist  기관지 확장 차단 , 천식 환자에게 사용 금지

Adverse effects
•  Libido  Sexual dysfunction & erectile dysfunction
• Hypotension (exaggerated pharmacology)
• Bradycardia (exaggerated pharmacology)
• Fatigue, insomnia
• Alterations in lipid profiles: HDL, TG
• In case of drug withdrawl: aggravation of heart conditions
(hypertension,
angina, myocardial infarction)
3.3 Alpha blockers
Class MOA Example

3.3 Alpha blockers Arterial & smooth muscle relaxation prazocin

 Key factors: vascular tone + blood volume

3.4 ACE inhibitor

Class MOA Example
3.4 ACE inhibitor Act on RAAS -pril
Inhibit conversion of angiotensin I to angiotensin II Captopril
(ACE == Zinc metalloenzyme) Enalapril

Hydrogen bonding
cofactor hydrophobic hydrophobic Ionic interaction
Positive charge
Arginine
Histidine
lysine

• Dry cough due to decreased inactivation of

bradykinin and substance P; on-target toxicity in
different tissues
• Hyperkalemia
• Skin rash in captopril use
• Hypotension: exaggerated pharmacology
• No combination with other drugs acting on
RAAS
당뇨병성 신증 환자에게 이득
3.5 Angiotensin II receptor blockers (ARB)
Class MOA Example
3.5 Angiotensin II recep- Act on RAAS -sartan
tor blockers (ARBs) Block binding of angiotensin II to the AT1 receptor Losartan
First-line agents for patients with compelling indication of diabetes, Valsartan
heart failure, or chronic kidney disease Olmesartan

Angiotensin II Type 1 (AT1) receptor

 GPCR
 Gαq/PLC pathway
 Functions: pro-inflammation,
vasoconstriction

Blocking binding of angiotensin II with the AT1 receptor

: similar to ACE inhibitors
arteriolar and venous dilation,
aldosterone secretion,
sodium, water retention
3.6 Renin inhibitors (Aliskiren)
CYP3A4 substrate
No combination with ACE inhibitors or ARBs

3.7 Calcium channel blockers (CCB)

Class MOA Example
3.7 Calcium channel Inhibit calcium transport via calcium channel -dipine
blockers (CCB)  block muscle contraction Amlodipine
 vasodilation Nifedipine

Calcium channel
DHP(dihydropyridine): vascular smooth muscle.
 L-type (long-lasting) voltage-gated calcium
DPA (diphenyl alkylamines, verapamil) : pore blocker
channel
on both cardiac & vascular smooth muscle.( 특히 심장 )
 Composed of α, β, γ, δ subunits
Benzothiazepine (diltiazem): cardiac & vascular smooth
 Calcium rushing into cells causes contraction of
muscle
vascular (arteriole) smooth muscle and
myocardium.
3.8 Others
ATC code •의약품 분류를 위해 WHO 에 의해 관리되는 공통 체계 .
(anatomical therapeutic •장기 > 계통 > 화학적 특성 > 효능 등에 따라 5 개
chemical classification 하위수준으로 분류
system) •알파벳 / 두 자리 숫자 / 알파벳 / 알파벳 / 두 자리 숫자