Pharmacology and Physiology, Pharmacology Lectures BIOL243 / BMSC 213

1. Pharmacology and Physiology, Pharmacology Lectures BIOL243 / BMSC 213 Dr Paul Teesdale-Spittle School of Biological Sciences KK713 Phone 6094

2. Case Study: Adrenoceptor agonists and antagonists and control of cardiac function Adrenoceptors The receptors for adrenaline (epinephrine) and noradrenaline (norepinephrine). Also called adrenergic receptors. Widely distributed, being responsible for control of the stimulation and relaxation of muscle, including the heart. Adrenoceptors mediate the control of cardiac function by the sympathetic nervous system; the parasympathetic nervous system control is mediated by muscarinic acetylcholine receptors.

3. Route of the biosynthesis of epinephrine and norepinephrine Don’t panic – I do not expect you to learn the structures!!

4. Adrenoceptors are divided into 5, or possibly 6 types: 1, 2, 1, 2, 3, and potentially 4. • They are all G-protein coupled receptors. • The secondary messengers for the 1 adrenoceptors are inositol triphosphate and diacylglycerol. • All other adrenoceptors have cAMP as their principal secondary messenger. • Remember that cytoplasmic [Ca2+] regulates the development of tension in muscles, such as the heart. • The activation of  and  adrenoceptors usually elicits opposing responses: • receptor activation leads to constriction of veins and arterioles. •  receptor activation leads to dilation of veins and arterioles.

5. Presence and function of adrenoceptors and the heart and vascular system. • Epinephrine administered rapidly intravenously has a number of simultaneous effects that contribute to a rapid rise in blood pressure on its administration. • A rise in the strength of ventricular contraction (a positive inotropic action) • The heart rate is increased (a positive chronotropic action) • Blood vessels become constricted. • Noting the opposing roles of and  receptors, it may be no surprise to discover that administration regimes other than rapidly intravenous injection can have quite different effects.

6. 1-Adrenoceptors:These are less abundant than -adrenoceptors. They couple to phospholipases C and D, to certain Ca2+ channels, and a number of ion channels allowing modification of cellular cation content, including K+ and Na+. Stimulation of 1-adrenoceptors does not lead to elevated cAMP levels within the cell, and may even reduce cAMP levels. 1-Adrenoceptor stimulation leads to formation of 1,4,5-inositoltriphosphate and diacylglycerol. Inositoltriphosphate releases Ca2+ from intracellular stores, and this may explain the observed increase in force of contraction upon 1-adrenoceptor activation. Their activation leads to constriction of vascular smooth muscle.

7. 2-Adrenoceptors: Present in only very low levels in the heart. Their activation leads to constriction of vascular smooth muscle. 1 and 2-Adrenoceptors:The ratio of 1 to 2-Adrenoceptors is about 65:35 in the atria, and around 75:25 in the ventricles. These receptors both lead to increases of [cAMP] following stimulation. This in turn activates protein kinase A, which can phosphorylate, amongst other proteins, certain Ca2+ channels, leading to an influx of Ca2+ ions, and so enhances contraction. -Adrenoceptor agonists also increase heart rate.

8. Only the 1 receptor is thought to be involved in the exercise-induced increase in heart rate bought about by noradrenaline. Adrenaline, on the other hand, may function primarily through the 2-adrenoceptors. 2-adrenoceptor activation also leads to relaxation of vascular smooth muscle. 3, and potentially 4-Adrenoceptors:The presence of these in the heart is not fully established, and their role, if present, is even more uncertain.

9. Adrenoceptor agonists 1-Adrenoceptor agonists: These can be used to treat hypotension through vasoconstriction, leading to increased blood pressure and cardiac arrhythmias through activation of vagal reflexes. Also valuable adjuncts to local anaesthetics, as vasoconstriction can slow the systemic dispersal of the anaesthetic. Drugs in this class include phenylephrine and methoxamine. 2-Adrenoceptor agonists:Despite the tendency of -adrenoceptor agonists to cause vasoconstriction, these can be used to treat hypertension. This unexpected activity occurs through action at the CNS, reducing signal to the heart and so lowering cardiac activity and constriction of the peripheral vasculature. Drugs in this class include methyldopa and clonidine. Clonidine can also be used in protection against migrane.

10. -Adrenoceptor agonists:These can be used to treat hypotension, cardiac arrhythmias and cardiac failure. They stimulate the rate and force of cardiac contraction. Simultaneously, they lead to a drop in peripheral vascular resistance. These combined effects can result in palpitations, sinus tachycardia and serious arrhythmias. Drugs in this class include xamoterol and dobutamine. 2-Adrenoceptor agonists lead to muscle relaxation and so find use in treatment of asthma (salbutamol) and delay in the onset of labour. (ritodrine).

11. Adrenoceptor antagonists 1-Adrenoceptor antgonists:Antagonism (or ‘blockade’) of 1-adrenoceptors inhibits the action of endogenous vasoconstrictors, resulting in vasodilation of both arteries and veins, and thus reduction of blood pressure. These drugs are, therefore, useful in the treatment of hypertension and cardiac failure. Prazosin and indoramin fall into this class of compounds. 2-Adrenoceptor antagonists:Just as 2-adrenoceptor agonists unexpectedly reduce vasoconstriction and lower cardiac activity, their antagonists cause a rise in blood pressure through reversal of these effects. Yohimbine is an 2-adrenoceptor antagonist.

12. -Adrenoceptor antagonists:These can be used to treat hypertension, angina, cardiac arrhythmias and ischemic heart disease. The effects of -adrenoceptor antagonists (‘-blockers’) are only evident when the heart is under stress or increased workload. Under these circumstances, they preclude or attenuate increases in the rate and force of cardiac contraction. They also cause an increase in peripheral resistance to blood flow, although this effect is reversed on prolonged administration. Drugs in this class include propanolol and metoprelol.

13. Introduction • What is pharmacology • History • Drug action • Drug targets • Receptors • Enzymes • Nucleic acids • Mechanisms and Specificity of Drug Binding • Covalent bonds • Van der Waals forces • Electrostatic forces • Hydrogen bonds • The Hydrophobic interaction • Conformation effects • Configuration effects • Dynamics

14. Selectivity, toxicity and therapeutic index • Agonists & antagonists • Activity • Concn vs response curves • Quantised data • Continuous data • Some Physical Chemistry • Agonist binding • Competitive Antagonists • Bioassays • Clinical trials • Drug administration • Enteral administration • Parenteral administration

15. Absorption, distribution & elimination • Bioavailability and crossing membranes • pH effects • Drug distribution • Fat • Plasma proteins • Body fluid compartments • Elimination • Metabolism • Excretion • Pharmacokinetics • Single compartment model • Effect of dosing regimes

16. Case Study:Adrenoceptor agonists and antagonists and control of cardiac function • Adrenoceptors • Presence and function of adrenoceptors and the heart and vascular system • Adrenoceptor agonists • Adrenoceptor antagonists