• (1) Autonomic Nervous System: Sympathetic and parasympathetic
• (2) Renin-Angiotensin System
• (3) Hormones (Epi and Thyroxin) and Autocoids (Histamine, PG)
• (4) Autoregulators: Locally acting metabolites that Ý and ß BV (pH, adenosine, etc.)
• The primary target of the drugs that are considered here, affect the processes involved in the transmission of catecholamines in the sympathetic system from neurons to their end organs
• These processes involve
• Synthesis of norepinephrine
• storage or norepinephrine
• The norepinephrine release process
• Adrenergic receptor binding
• Intracellular events that lead to a physiological response
• norepinephrine reuptake
• norepinephrine metabolism

• Using the chart above, we can determine
• Diastolic Blood Pressure (DBP)
• Systolic BP (SBP)
• Heart Rate (HR)
• Cardiac Output (CO)
• Autonomic Reflexes (Reflex)
• Uses (Uses) of the drug
• Note: a₂ receptors simply function in feedback inhibition, so play a minor role. Also Vagal reflex is parasympathetic ß in HR in response to baroreceptor detection of Ý BP. Conversely, Sympathetic Reflex, is Ý in HR due to a ß in BP. Not all responses can be reasoned out , but the chart gives what is observed in any case.

• Variability of Adrenergic Effects: Contractility in all muscle tissue is seen to be a function of free cytosolic Ca⁺⁺ levels
• Smooth muscle a ₁ adrenregic receptors: are G-proteins coupled to the IP₃ 2^nd messenger system. The SR in SM has IP₃ receptors that release Ca⁺⁺ Þ increased contractility. Vasoconstrictive properties of adrenergic agonists are mediated this way.
• So why does adrenergic binding of b ₁ cause Ý muscle contractility in the heart but b ₂ binding cause ß contractility in smooth muscle? The answer is that the effect of receptor binding is not intrinsic to the receptor but rather substrates for the second messengers within the particular cell.
• Cardiac Myocyte: b receptor results in Ý cAMP which results in the phosphorilation of 3 proteins that ultimately lead to Ý contractility:
• (1) Slow Ca⁺⁺ Channel which lets more Ca⁺⁺ in Þ Ý contractility
• (2) Phospholamban which stimulates Ý in the rate of cycling of Ca⁺⁺ in/out of SR
• (3) TN-I when phosphorylated causes ß Troponin C affinity for Ca⁺⁺, thus allowing for faster contraction cycling.
• Smooth Muscle: The effect of elevated calcium is the activation of the regulatory enzyme myosin light chain kinase (MLCK). MLCK attaches a phosphate onto the myosin light chain (MLC). Phosphorylation activates the actin/myosin contractile cycle. Dephosphorylation of MLC by myosin light chain phosphatase (MLCP) renders the myosin unable to proceed though the contractile cycle, even if actin is present. When cytosolic calcium levels rise, calcium binds to calmodulin. This Ca2+/calmodulin complex in turn binds to MLCK, which activates the MLCK to phosphorylate myosin light chains. If cytosolic calcium is lowered, the Ca2+/calmodulin complex dissociates, and MLCK returns to an inactive state Þ relaxation as MLCP does its thing.

Adrenergic Blockers – a-blockers do not activate receptors, they just prevent agonist binding.

• a Blockers
• (1) Albylating – phenoxybenzamine – mostly used in the lab
• (2) Non selective a₁, a₂ – phentolamine. It actual has the affect of an a -agonist because the a₂ block means there is no feedback inhibition Þ lots of NE being produced in the cleft which can get to a high enough concentration to overcome the competitive inhibition on the a₁ receptor_.
• (3) Selective a ₁ Blockers: (1/1000 have 1^st dose syncope)
• Prazosin- anti HTN agent that can be used if HTN result from Ý sympathetic tone
• Terazosin and Doxasosin – good for urinary retention caused by to BPH.
• Tamsolusin (Flomax) – prostate specific a ₁ Blocker
• b Blockers: Ethanolamines R₁-CH(OH)-CH₂-NH-R₂ ; all are reversible by increased concentration of Androgen
• Effects:
• CV - ß rate, ß Force, ß conduction velocity through the SA node Þ ß CO, ß automaticity (ectopic pace makers) These drugs can be used to reverse left ventricular hypertrophy.
• Vascular - Interferes with b ₂ relaxation of SM
• Pulmonary - Interferes with b ₂ relaxation of SM.
• Partial block the release of rennin from JG cells.
• ß Glycemic response in the liver
• Ý lipids Þ Ý cholesterol, Ý TG, ß HDL
• ß Interoccular pressure in the eye.
• Properties:
• b₁ Selectivity (30-100/1 affinity of b ₁/b ₂)
• Intrinsic Sympathomimetic Activity (ISA) which means it’s a partial agonists. Seen with Pinidol
• T_1/2 = 9min Þ 20h see above chart. Allows to Use drug to achieve therapeutic dose quickly with IV administration (ICU) without overdose, or use once a day regime for maintenance purposes.
• Uses
• Anti- HTN - ß CO, ß rennin
• Anti-anginal - ß hr and O₂ demand
• Anti- arrhythmia, Super Ventricular Tachi (SVT), A Fib, Flutter, Marfans, IHSS
• Post MI
• Peri MI
• Non Cardiac: Glaucoma, Essential Tremor, Speaker’s Phobia, Panic Attack
• Side Effects
• Cardiac: 3^rd degree Heart Block, Bradicardia (<60bpm), CHF
• Vascular: exacerbates claudicaton (leg pain due to Atherosclerosis)
• Hyperlipidemia: small effect compared to HMG CoA inhibitors
• Diabetes: ß liver glycemic response may be too much with insulin meds
• Pulmonary: asthma patients need Epi b ₂ stimulation, Use b ₁ Selectives
• Ý # of b ₁ receptors, so hypersensitive to Epi/NE; Wean off slowly
• Impotence, somnolence, fatigue, depression, vivid dreams