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