Antihypertensive Drugs Definition: Systolic BP≥140mmHg or Diastolic BP≥90mmHg Diagnosis is based on multiple(>3)measurements,on different days For patients having diabetes or chronic kidney disease(high-risk group), diagnosis of hypertension is made with BP 130/80 mmHg 1
1 Antihypertensive Drugs Definition: Systolic BP ≥ 140 mm Hg or Diastolic BP ≥ 90 mm Hg • Diagnosis is based on multiple (≥ 3) measurements, on different days • For patients having diabetes or chronic kidney disease (high-risk group), diagnosis of hypertension is made with BP ≥ 130/80 mmHg
Classification and management of BP for adults Category Systolic Diastolic Lifestyle Initial drug modification therapy Normal <120 and <80 Encourage Not needed No,or treat Pre-hypertension 120-139 or 80-89 Yes Compelling indications Stage 1 hypertension 140-1590r 90-99 Yes Diuretic,ACEl,ARB.B-blocker.CCB. Combination;+compelling indications Stage 2 hypertension ≥160 or 2100 Yes Two-drug combo (diuretic and ACEl. or ARB or B-blocker or CCB: Also treat compelling indications Based on 7th Report of the Joint National Committee on Detection,Evaluation,and Treatment of High BP(JNC 7) Diuretic here means thiazide-type;ACEl,ACE inhibitor;ARB,angiotensin receptor blocker;B-blocker,B-adrenergic receptor blocker,CCB,calcium channel blocker Hypertension is a leading global risk factor for mortality 8000- 7000 High-mortality,developing region Lower-mortality.developing region 6000- ▣Developed region 5000 4000 3000 2000 1000 0- LO* The Lancet,360:1347(2002) 2
2 Normal Pre-hypertension Stage 1 hypertension Stage 2 hypertension Category Systolic Diastolic < 120 120-139 140-159 ≥ 160 and or or or < 80 80-89 90-99 ≥ 100 Classification and management of BP for adults Based on 7th Report of the Joint National Committee on Detection, Evaluation, and Treatment of High BP (JNC 7) Lifestyle modification Encourage Yes Yes Yes Initial drug therapy Not needed No, or treat Compelling indications Diuretic, ACEI, ARB, β-blocker, CCB, Combination; + compelling indications Two-drug combo (diuretic and ACEI, or ARB or β-blocker or CCB; Also treat compelling indications Diuretic here means thiazide-type; ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; β-blocker, β-adrenergic receptor blocker; CCB, calcium channel blocker Hypertension is a leading global risk factor for mortality The Lancet, 360:1347 (2002)
BP=CO×PVR CNS/sympathetic nerves Baroreceptor reflex arc Heart rate Aortic arch contractility carotid sinuses 81-AR Peripheral a1-AR Arterial Cardiac Blood output resistance Pressure Stroke Na'/Ca2 volume exchange Renin- angiotensin- Venules aldosterone Sodium/ capacitance volume Factors affecting drug treatment of hypertension: Accuracy of diagnosis;severity of hypertension Etiology:Primary(essential hypertension)vs.secondary(10-15%patients) Identifiable causes of hypertension:Pheochromocytoma,renal artery constriction,Cushing's syndrome(hypercorticism)and Cushing's disease (over-production of ACTH).primary aldosteronism,thyroid or parathyroid disease,coarctation of the aorta Pre-existing risk factors and medical conditions(smoking,hyperlipidemia, diabetes,congestive heart failure,asthma,current medications) Individualization(age,gender,ethnicity);patient compliance Single drug(monotherapy)vs.multiple drug(polypharmacy) 3
3 Peripheral resistance Baroreceptor reflex arc Sodium/ volume Venules capacitance Stroke volume Heart rate contractility Na+/Ca2+ exchange Reninangiotensinaldosterone Cardiac output Arterial Blood Pressure CNS / sympathetic nerves BP = CO × PVR Aortic arch carotid sinuses β1-AR α1-AR Baroreceptors Factors affecting drug treatment of hypertension: • Accuracy of diagnosis; severity of hypertension • Etiology: Primary (essential hypertension) vs. secondary (10-15% patients) • Identifiable causes of hypertension: Pheochromocytoma, renal artery constriction, Cushing’s syndrome (hypercorticism) and Cushing’s disease (over-production of ACTH), primary aldosteronism, thyroid or parathyroid disease, coarctation of the aorta • Pre-existing risk factors and medical conditions (smoking, hyperlipidemia, diabetes, congestive heart failure, asthma, current medications) • Individualization (age, gender, ethnicity); patient compliance • Single drug (monotherapy) vs. multiple drug (polypharmacy)
Pharmacological mechanism-based classification Diuretics: Thiazide-Hydrochlorothiazide Loop-furosemide,torsemide,ethacrynic acid Potassium-sparing-amiloride,spironolactone,triamterene Sympathoplegic agents Adrenergic synthesis/release blockers-reserpine,granethidine Central a-adrenergic agonists-a-methodopa,clonidine a-blockers-prazosin,tetrazosin,doxazosin B-blockers-propranolol,nadolol,timolol,metoprolol,acebutolol,penbutolol,pindolol Ganglion blocker-Trimethaphan Direct vasodilators:hydralazine,minoxidil,sodium nitroprusside,diazoxide Calcium channel blockers:nifedipine,amlodipine,felodipine,diltiazem,verapamil AT-lI antagonists ACE inhibitors: ACE inhbitors-captopril,enalapril,enalaprilat,lisinopril,benazepril AT-lI receptor antagonists-losartan DIURETICS First-line drug for hypertension.Relatively safe and effective. Suitable for older adults.Can be given orally.Use alone or with other antihypertensive agents.Low cost and mostly available in 3rd world countries. Mechanism of action: Diuretics lower BP by depleting body sodium stores.Full effects take 2 steps:(1)initial reduction of total blood volume and hence cardiac output;peripheral vascular resistance may increase;(2) when CO returns to normal(takes 6-8 weeks),PVR declines. 4
4 Pharmacological mechanism-based classification Diuretics: Thiazide - Hydrochlorothiazide Loop - furosemide, torsemide, ethacrynic acid Potassium-sparing - amiloride, spironolactone, triamterene Sympathoplegic agents : Adrenergic synthesis / release blockers - reserpine, granethidine Central α-adrenergic agonists – α-methodopa, clonidine α−blockers - prazosin, tetrazosin, doxazosin β−blockers - propranolol, nadolol, timolol, metoprolol, acebutolol, penbutolol, pindolol Ganglion blocker - Trimethaphan Direct vasodilators: hydralazine, minoxidil, sodium nitroprusside, diazoxide Calcium channel blockers: nifedipine, amlodipine, felodipine, diltiazem, verapamil AT-II antagonists & ACE inhibitors: ACE inhbitors – captopril, enalapril, enalaprilat, lisinopril, benazepril AT-II receptor antagonists - losartan I. DIURETICS First-line drug for hypertension. Relatively safe and effective. Suitable for older adults. Can be given orally. Use alone or with other antihypertensive agents. Low cost and mostly available in 3rd world countries. Mechanism of action: Diuretics lower BP by depleting body sodium stores. Full effects take 2 steps: (1) initial reduction of total blood volume and hence cardiac output; peripheral vascular resistance may increase; (2) when CO returns to normal (takes 6-8 weeks), PVR declines
Therapeutic use: Thiazide diuretics噻嗪类利尿剂，such as hydrochlorothiazide氢氯 噻嗪，act on distal convoluted tubule and inhibit Nat-Cl-symport..Can counteract the Na+and H2O retention effect of direct vasodilators such as hydralazine and therefore are beneficial for combined use Particularly useful for elderly patients,but not effective when kidney function is inadequate. Thiazides reduce blood K+and Mg2+levels,and induce hypokalemia. It also retains Ca2+and decreases urine Ca2+content.It is necessary to monitor serum K+level in patients with cardiac arrhythmias and when digitalis is in use. Loop diuretics亨利氏环类利尿剂，including furosemidei速尿， torsemide:托拉赛米，and ethacrynic acid:利尿酸，are more powerful than thiazides.They are often used for treatment of severe hypertension when direct vasodilators are administered and Na+and H2O retention becomes a problem.Can be used in patients not responding to thiazides.Increase urine Ca2+content. K-sparing diuretics include triamterene氨苯蝶呤，amiloride阿米洛利 (both are Na+channel inhibitors),and spironolactone安体舒通 (aldosterone antagonist).Used for treating hypertension in patients who also take digitalis.This class of drugs enhance the natriuretic effects of other diuretics(e.g.,thiazides)and counteract the K+ depleting effect of these diuretics
5 Therapeutic use: Thiazide diuretics 噻嗪类利尿剂, such as hydrochlorothiazide 氢氯 噻嗪, act on distal convoluted tubule and inhibit Na+-Cl- symport. Can counteract the Na+ and H2O retention effect of direct vasodilators such as hydralazine and therefore are beneficial for combined use. Particularly useful for elderly patients, but not effective when kidney function is inadequate. Thiazides reduce blood K+ and Mg2+ levels, and induce hypokalemia. It also retains Ca2+ and decreases urine Ca2+ content. It is necessary to monitor serum K+ level in patients with cardiac arrhythmias and when digitalis is in use. Loop diuretics 亨利氏环类利尿剂, including furosemide速尿, torsemide托拉赛米, and ethacrynic acid利尿酸, are more powerful than thiazides. They are often used for treatment of severe hypertension when direct vasodilators are administered and Na+ and H2O retention becomes a problem. Can be used in patients not responding to thiazides. Increase urine Ca2+ content. K-sparing diuretics include triamterene氨苯蝶呤, amiloride阿米洛利 (both are Na+ channel inhibitors), and spironolactone安体舒通 (aldosterone antagonist). Used for treating hypertension in patients who also take digitalis. This class of drugs enhance the natriuretic effects of other diuretics (e.g., thiazides) and counteract the K+ depleting effect of these diuretics
Adverse effects and toxicity: (1)Depletion of K+(except K+-sparing diuretics),leading to hypo- kalemia. (2)Increase uric acid concentration and precipitate gout. (3)Increase serum lipid concentrations.Diuretics are not used for treating hypertension in patients with hyperlipidemia or diabetes. (4)Gynecomastia with spironolactone. II. SYMPATHOPLEGIC AGENTS Centrally acting (on vasomotor center): a-methyldopa,clonidine,guanabenz,guanfacine acting as a2 agonists Blocking synthesis and/or release of NE: reserpine,guanethidine,granadrel Blocking B-adrenoceptors: propranolol,metoprolol,labetalol,etc. Blocking sympathetic ganglia: trimethaphan Blocking a1-adrenoceptors in vessels: prazosin,doxazosin,tetrazosin Blocking renin release: propranolol and other B-blockers 6
6 Adverse effects and toxicity: (1) Depletion of K+ (except K+-sparing diuretics), leading to hypokalemia. (2) Increase uric acid concentration and precipitate gout. (3) Increase serum lipid concentrations. Diuretics are not used for treating hypertension in patients with hyperlipidemia or diabetes. (4) Gynecomastia with spironolactone. II. SYMPATHOPLEGIC AGENTS Centrally acting (on vasomotor center): α-methyldopa, clonidine, guanabenz, guanfacine acting as α2 agonists Blocking synthesis and/or release of NE: reserpine, guanethidine, granadrel Blocking β-adrenoceptors: propranolol, metoprolol, labetalol, etc. Blocking sympathetic ganglia: trimethaphan Blocking α1-adrenoceptors in vessels: prazosin, doxazosin, tetrazosin Blocking renin release: propranolol and other β-blockers
CNS Pre-ganglionic Ganglion Post-ganglionic Parasympathetic Ach Ach lelueJo Cardiac smooth muscles,gland cells. Nicotinic Muscarinic nerve terminals Sympathetic Cardiac smooth muscles,gland cells, alpha,beta nerve terminals Sympathetic ....Ach Sweat glands Muscarinic Sympathetic D Renal vascular D: smooth muscle Sympathetic(adrenal medulla) Ach Epi bebgeadno Motor(somatic) Ach Skeletal muscle Nicotinic D=dopamine Epi=epinephrine NE=norepinephrine Distribution and functions of AR relating to antihypertensive drug treatment: a1:postsynaptic effector cells,especially smooth muscle Vasoconstriction,relaxation of gastrointestinal smooth muscle,hepatic glycogenolysis a2 presynaptic adrenergic nerve terminals,platelets,lipocytes,smooth muscle Inhibition of transmitter release,platelet aggregation,contraction of smooth muscle B1 postsynaptic effector cells:heart,lipocytes,brain,presynaptic ad./ch nerve term. Increased cardiac rate force,relaxation of gastrointestinal smooth muscle B2 postsynaptic effector cells:smooth muscle,cardiac muscle Bronchodilation,vasodilation,relaxation of visceral smooth muscle,hepatic glycogenolysis B3 postsynaptic effector cells:lipocytes Lipolysis 7
7 Thoracolumbar Cranial Sacral CNS Pre-ganglionic Ganglion Post-ganglionic Parasympathetic Ach Nicotinic Ach Nicotinic Ach Nicotinic Ach Nicotinic Ach Nicotinic Epi Sympathetic Sympathetic Sympathetic Sympathetic (adrenal medulla) Motor (somatic) Ach Ach Muscarinic Muscarinic NE alpha,beta D D1 Ach Nicotinic Cardiac & smooth muscles, gland cells, nerve terminals Cardiac & smooth muscles, gland cells, nerve terminals Sweat glands Renal vascular smooth muscle Released into blood Skeletal muscle Ach = acetylcholine D = dopamine Epi = epinephrine NE = norepinephrine α1: postsynaptic effector cells, especially smooth muscle Vasoconstriction, relaxation of gastrointestinal smooth muscle, hepatic glycogenolysis α2 presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of transmitter release, platelet aggregation, contraction of smooth muscle β1 postsynaptic effector cells: heart, lipocytes, brain, presynaptic ad./ ch nerve term. Increased cardiac rate & force, relaxation of gastrointestinal smooth muscle β2 postsynaptic effector cells: smooth muscle, cardiac muscle Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis β3 postsynaptic effector cells: lipocytes Lipolysis Distribution and functions of AR relating to antihypertensive drug treatment:
Centrally-acting adrenergic drugs: Clonidine可乐定 A 2-imidazoline derivative that reduces sympathetic and increases parasympathetic tone,leading to BP lowering and bradycardia. Mechanism of action:Clonidine binds a2-AR with higher affinity than a-AR. The a-agonistic activity contributes to its BP lowering effect due to negative feedback at the presynaptic neurons.When given i.v.,clonidine induces a brief rise of BP,which is followed by proloned hypotension. In addition,clonidine is thought to bind imidazoline receptors(IR)that have not been fully characterized at molecular level. Similar drugs:guanabenz胍那苄and guanfacine胍法辛 Therapeutic use:Clonidine reduces CO due to decreased heart rate and relaxation of capacitance vessels.Used for treatment of mild to moderate hypertension,often together with diuretics.Because it decreases renal vascular resistance,it maintains renal blood flow and glomerular filtration and therefore can be used in patients with renal diseases.Clonidine is lipid-soluble and enters brain readily.Half-life is about 8-12 h. Adverse effects and toxicity:Sedation,dry mouth.Clonidine also causes Nat and H2O retention.Abrupt withdrawal may induce hypertensive crisis. Do not give to patients who are at risk of mental depression,or are taking tricyclic antidepressants. 8
8 Centrally-acting adrenergic drugs: A 2-imidazoline derivative that reduces sympathetic and increases parasympathetic tone, leading to BP lowering and bradycardia. Mechanism of action: Clonidine binds α2-AR with higher affinity than α1-AR. The α2-agonistic activity contributes to its BP lowering effect due to negative feedback at the presynaptic neurons. When given i.v., clonidine induces a brief rise of BP, which is followed by proloned hypotension. In addition, clonidine is thought to bind imidazoline receptors (IR) that have not been fully characterized at molecular level. Similar drugs: guanabenz 胍那苄 and guanfacine 胍法辛 Clonidine 可乐定 Therapeutic use: Clonidine reduces CO due to decreased heart rate and relaxation of capacitance vessels. Used for treatment of mild to moderate hypertension, often together with diuretics. Because it decreases renal vascular resistance, it maintains renal blood flow and glomerular filtration and therefore can be used in patients with renal diseases. Clonidine is lipid-soluble and enters brain readily. Half-life is about 8-12 h. Adverse effects and toxicity: Sedation, dry mouth. Clonidine also causes Na+ and H2O retention. Abrupt withdrawal may induce hypertensive crisis. Do not give to patients who are at risk of mental depression, or are taking tricyclic antidepressants
-methyldopa a-甲基多巴 a-methyldopa is a prodrug.It enters into adrenergic neurons and is converted by two enzymes to a-methylnorepinephrine,which has the antihypertensive effect. Mechanism of action:The metabolite,a-methylnorepinephrine,is stored in neurosecretory vesicle in place of NE.When released,a-methyl-NE is a potent a-AR agonist and in PNS is a vasoconstrictor.Its CNS effect is mediated by a2- AR(an autoreceptor),resulting in reduced adrenergic outflow from the CNS and an overall reduced total peripheral resistance. Therapeutic use:This drug does not alter most of the cardiovascular reflexes Cardiac output and blood flow to vital organs are maintained.It reduces renal vascular resistance and can be used in patients with renal insufficiency.Given orally:effect reaches max.in 4-6 h and continues to 24 h.Not used as first drug in monotherapy,but effective when used with diuretics. Adverse effects and toxicity:Sedation,lassitude,nightmares,lactation(due to inhibition of dopaminergic neuron in hypothalamus).Long-term use may cause development of autoantibodies against Rh locus and give positive Coomb's test. 9
9 α-methyldopa α-甲基多巴 α-methyldopa is a prodrug. It enters into adrenergic neurons and is converted by two enzymes to α-methylnorepinephrine, which has the antihypertensive effect. HO HO CH3 NH2 C COOH H H C HO HO CH3 NH2 C NH2 H H C HO HO CH3 NH2 C NH2 OH H C Aromatic L-amino acid α-methyldopamine α-methylnorepinephrine decarboxylase Dopamine β-oxidase α-methyldopa Mechanism of action: The metabolite, α-methylnorepinephrine, is stored in neurosecretory vesicle in place of NE. When released, α-methyl-NE is a potent α-AR agonist and in PNS is a vasoconstrictor. Its CNS effect is mediated by α2- AR (an autoreceptor), resulting in reduced adrenergic outflow from the CNS and an overall reduced total peripheral resistance. Therapeutic use: This drug does not alter most of the cardiovascular reflexes. Cardiac output and blood flow to vital organs are maintained. It reduces renal vascular resistance and can be used in patients with renal insufficiency. Given orally; effect reaches max. in 4-6 h and continues to 24 h. Not used as first drug in monotherapy, but effective when used with diuretics. Adverse effects and toxicity: Sedation, lassitude, nightmares, lactation (due to inhibition of dopaminergic neuron in hypothalamus). Long-term use may cause development of autoantibodies against Rh locus and give positive Coomb’s test
Antihypertensive agents that act on PNS 1.Beta blockers(B受体阻断剂) Mechanism of action:(1)Reduce cardiac output;(2)inhibit renin release, AT-lI and aldosterone production,and lower peripheral resistance;(3)may decrease adrenergic outflow from the CNS. Therapeutic use:Recommended as first-line antihypertensive agents. Combined use with diuretics are common.More effective in treating hyper- tension in white than in black patients,and in young patients than elderly (due to high occurrence of chronic lung and heart diseases in the elderly). Especially useful in treating hypertension with preexisting conditions such as previous myocardia infarction,angina pectoris,migraine headache. Propranolol普蓁洛尔：A prototypic B-blocker that antagonizes B,andB2AR.t inhibits renin production(due to B,-antagonistic activity)and can be used in patients with high renin level.It causes no prominent postural hypotension in mild to moderate hypertension patients.This class of drugs also include timolol. Nadolol纳多洛尔 ↑balf-life Metoprolol獎托涪尔 Pindolol引哚洛尔 B2 antagonistic effeet BI antagonistic Partial 82 agonistic B1 and B2 antagonistic Propranolol普装洛尔 Acebutolol醋丁洛尔 Atenolol安替洛尔 Bl antagonistic Bl antagonistic Partial B2 agonistic half-life CH 10
10 Antihypertensive agents that act on PNS 1. Beta blockers (β 受体阻断剂) Mechanism of action: (1) Reduce cardiac output; (2) inhibit renin release, AT-II and aldosterone production, and lower peripheral resistance; (3) may decrease adrenergic outflow from the CNS. Therapeutic use: Recommended as first-line antihypertensive agents. Combined use with diuretics are common. More effective in treating hypertension in white than in black patients, and in young patients than elderly (due to high occurrence of chronic lung and heart diseases in the elderly). Especially useful in treating hypertension with preexisting conditions such as previous myocardia infarction, angina pectoris, migraine headache. Propranolol 普萘洛尔: A prototypic β-blocker that antagonizes β1 and β2 AR. It inhibits renin production (due to β1-antagonistic activity) and can be used in patients with high renin level. It causes no prominent postural hypotension in mild to moderate hypertension patients. This class of drugs also include timolol. O OH NH CH3 CH3 Propranolol 普萘洛尔 N H O OH NH CH3 CH3 Pindolol 吲哚洛尔 O OH NH CH3 CH3 NH O CH3 H3C Acebutolol 醋丁洛尔 O OH NH CH3 CH3 HO HO Nadolol 纳多洛尔 O OH NH CH3 CH3 O H3C Metoprolol 美托洛尔 O OH NH CH3 CH3 NH2 O Atenolol 安替洛尔 β1 antagonistic ↑ half-life β1 and β2 antagonistic ↑ half-life ↓ β2 antagonistic effect β1 antagonistic Partial β2 agonistic β1 antagonistic Partial β2 agonistic