Medical brain Notes 3

  Pharmacodynamics   Pharmacodynamics starts where pharmacokinetics left off – it assumes that the drug has managed to reach its target, and looks at the principles that govern the interaction between the two.   Almost all drugs will trigger their effects by binding to a receptor. In physiology, the term `receptor' is limited to the sites of action of hormones, neurotransmitters or cy-tokines. While many drugs do indeed bind to such recep-tors, in pharmacology the term is used in a more inclusive sense and is applied to other targets such as enzymes and cytoskeletal proteins as well.

  Classes of drug receptors Drug receptors are mostly proteins. Most of these fall into one of the following categories:   •       Enzymes   •       Ion channels:   – Ligand-gated channels: Ion channels that open upon binding of a mediator   – Voltage-gated channels: Ion channels that are not normally controlled by ligand binding but by changes to the membrane potential   •       `Metabolic' receptors – hormone and neurotransmitter receptors that are coupled to biochemical secondary messengers and effector mechanisms. Most metabolic receptors that are drug targets belong to the family of G protein-coupled receptors.   •       Cytoskeletal proteins that are involved in cell motility – e.g., actin or tubulin.   Drug target sites that are not proteins include:   •       DNA: This is very common with cytotoxic drugs used in...

  Mechanisms and kinetics of drug receptor interaction   There are several typical mechanisms of action that apply to the different types of receptor proteins. For enzymes, these are   •       Competitive inhibition: The drug occupies the active site and prevents binding of the physiological substrate. Example: The inhibition of angiotensin convertase by enalapril.   •       Irreversible (covalent) inhibition: The drug again binds to the active site of the enzyme and then covalently reacts with it, so that the active site becomes irreversibly blocked. Example: Inhibition of cyclooxygenase by acetylsalicylic acid.   •       Allosteric inhibition: The drug binds outside the active   site but prevents the enzyme from adopting its active conformation. Example: Inhibition of Na + /K + -ATP'ase by digitoxin or digoxin.   The allosteric behaviour seen with many enzymes is also typicall...

  Drug dose-effect relationships in biochemical cascades   We noted the similarity of empirical dose-effect relationships with theoretical plots (Figures 3.5a, 3.3, 3.4). This needs to be qualified in two ways:   1.    While the theoretical plots modeled receptor saturation, the experiment measured muscle tension.   2.    This similarity is by no means perfect.   The two statements are in fact related. In our example, a perfect similarity of theoretical and experimental plots could only be expected if there were a linear relationship between receptor saturation with norepinephrine and mus-cle contraction. Considering that muscle contraction is trig-gered quite a bit downstream of receptor activation, there are numerous possible factors that will `distort' this lineari-ty, and in reality no linear relationship will ever be observed if drug target and drug effect are separated by intervening biochemical cascades. It thus turns out that the shap...

  Spare receptors If, as in the above example, some of the receptors can be in-activated without a decrease in the maximal effect, the dis-pensble receptor fraction is commonly referred to as `spare receptors'. Despite its widespread use in the literature, the term is not very precisely defined, and some argument ex-ists about its proper use. Some authors consider a parallel shift of the dose-effect curve in response to an irreversible inhibitor (as for curves 1 and 2 in Figure 3.9) sufficient evi-dence of spare receptors. Using this interpretation, it would seem that any system with an initial gap between dose-ef-fect and dose-receptor occupancy curves would qualify. Others insist that not only should there be a gap between dose-effect and dose-receptor occupancy curves, but that also the dose-effect curve should be steeper than the dose-receptor occupancy curve. The second position can be summarized as follows: With or without spare receptors, each occupied receptor molecule shou...

  Potency and efficacy Two concepts that at this stage should not present us with any difficulty are the `potency' and `efficacy' of a drug. The potency is a function of the amount of drug required for its specific effect to occur; it is measured simply as the inverse of the EC 50  for that drug. In contrast, the efficacy measures the maximum strength of the effect itself, at saturating drug concentrations. Thus, in Figure 3.10, drug Red exceeds drug Black in potency, while the opposite is true of the efficacy.

  Partial agonism and the two-state model of receptor activation The efficacy will obviously vary for drugs that act on the same physiological parameter by different routes; e.g., morphine is a stronger painkiller than aspirin is. Howev-er, profound differences may even be observed with sub-stances that act on the very same site of the very same tar-get molecule. Figure 3.11 shows an example. The recep-tor in question is a serotonin receptor (subtype 1A) which occurs in the brain and is the target of some psychoactive drugs. Like the adrenergic receptors mentioned above, it is a G protein-coupled receptor. Receptor activation will trig-ger exchange of GDP for GTP in the cognate G proteins. It can therefore be measured by way of incorporation of GTP- γ 35 S, which is both radioactive and resistant to the in-trinsic GTP'ase activity of the G protein. You can see that the effects of the different agonists applied not only arise at different concentrations but also level off at differe...