High Blood Pressure / Hypertension

Site of action of different classes of antihypertensive drugs

Antihypertensive drugs are directed against a variety of pharmacological targets in various cell types in different organs involved in blood pressure control. The most important targets in the brain, heart, vasculature (vascular smooth muscle cells), and the kidney (nephron) are shown. Some diuretics produce some direct vasodilation; # non-ACE, conversion of angiotensin I (Ang I) to angiotensin II (Ang II) may occur independent from ACE due to the activity of other enzymes in different tissues such as chymase in the heart; DCT, distal convoluted tubule; CCT, cortical collecting duct; TAL, thick ascending limb of the loop of Henle; (-), indicates inhibition. Modified according to reference 3.

Algorithm for the treatment of hypertension

Algorithm for the treatment of hypertension

Unless contraindicated; based on randomized controlled trials;  Evidence suggests that the beneficial effects of ACE inhibitors can be duplicated with AT-1 antagonists (and probably vice versa). Thus, ACE inhibitors could be substituted by AT-1 antagonists in the case of troublesome side effects, such as cough under treatment with ACE inhibitors. Modified according to reference 5.

Effects of anticoagulants on the coagulation cascade

Effects of anticoagulants on the coagulation cascade

Coumarin (Warfarin) and the vitamin K cycle

Coumarin (Warfarin) and the vitamin K cycle

Abbreviations: glu, glutamate; gla, y-carboxyglutamate. (Modified from [2], with permission from Chest.)

Relative effects of UFH, LMWH, and fondaparinux on AT-mediated inhibition of factor Xa and thrombin (lla).

Relative effects of UFH, LMWH, and fondaparinux

AT-mediated inhibition of factor Xa and thrombin (lla). Whereas UFH catalyzes inhibition of Xa and thrombin equally well, only LMWH chains of 18 saccharide units or longer catalyze thrombin inhibition; thus, the anti-Xa/anti-lla ratio of LMWH preparations ranges from 2:1 to 4:1. In contrast, fondaparinux exclusively inhibits Xa. (Modified from [3], with permission from Chest.)

Desensitization, internalization and recycling of β-adrenergic receptors

Desensitization, internalization and recycling of β-adrenergic receptors

Activation of β-adrenergic receptors causes their phosphorylation by members of the GRKs. Cytosolic β-arrestins then bind to the phosphorylated receptors and prevent further interaction with G-proteins. β-Arrestin-bound receptors assemble in clathrin-coated pits, where the complex appears to interact with other proteins, including dynamin and src-kinase. This leads (i) to the activation of non-conventional signalling pathways (raf-kinases, MAP-kinases, JNK-kinases), and (ii) to the internalization of the receptors to endosomes. Endosomal receptors become either dephosphorylated and recycle back to the cell surface; some endosomal receptors undergo lysosomal degradation.

β-Adrenergic signalling in cardiac muscle (predominantly β1) and smooth muscle (predominantly β₂) cells

β-Adrenergic signalling in cardiac muscle

β-Adrenergic signalling in cardiac muscle (predominantly β1) and smooth muscle (predominantly β₂) cells. Proteins that become more active after activation of β-adrenergic receptors are depicted in grey, those which become less active are depicted in white. Both receptors couple to G_s and lead to activation of adenylyl cyclases, generation of cyclic AMP and activation or protein kinase A (protein kinase A). In heart muscle cells, protein kinase A causes phosphorylation of L-type calcium channels (increased Ca²⁺-influx; relevant site of phosphorylation uncertain), troponin I (Tnl; diminishes affinity of troponin C for Ca²⁺ and thus enhances relaxation) and phospholamban (PLB; leads to less inhibition of the sarcoplasmic Ca²⁺ ATPase, SERCA, which pumps Ca²⁺into the sarcoplasmic stores. This in turn enhances relaxation and enhances Ca²⁺-release during the next beat) All this leads to more rapid and forceful contraction as well as relaxation. In smooth muscle cell the signalling pathways are less clear protein kinase A-mediated phosphorylation of myosin light chain kinase (MLCK) causes reduced activity of this kinase, which in turn leads to decreased phosphorylation of myosin light chains and, hence, reduced contraction. A second postulated mechanism for relaxation is hyperpolarization via activation of K⁺-channels; the signalling pathway is unclear and might involve coupling of β₂-receptors to G1.