Textbook:

MCQ Matrix: General Pharmacology 15%

Pharmacodynamics 1.2.1 Mechanisms of action 1 1.2.2 Receptors and their regulation 1 1.2.3 Second messengers/G protein [see physiology week 2] 1 1.2.4 Dose response 1 1.2.5 Dosing issues

Pharmacodynamics: what the drug does to the body

Pharmacokinetics: what the body does to the drug

Definitions

Drug: any substance that brings about a change in biologic function through its chemical action                     

Receptor: the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drugs observed effects. Receptor affinity and total number of receptors determines the pharmacologic effects of a drug. Most receptors are proteins e.g. the enzyme HMG-CoA reductase is the receptor target for statins and structural proteins like tubulin are the receptor targets for colchicine.

Agonist: drugs which bind to and activate the receptor in some fashion, working indirectly or directly

  • Inverse agonist: Antagonists block receptors but don’t change their baseline/constitutive or ‘basal’ activity. Inverse agonists decrease receptor activity BELOW their normal baseline level of activity/activation e.g. propranolol
  • Partial agonists bind and activate the receptor in the same way as a full agonist but don’t evoke as great a response, no matter how high the concentration. Partial agonists competitively inhibit the responses produced by full agonists. e.g. buprenorphine is a partial u opioid agonist, which means it is effectively anti-analgesic when administered with more efficacious opioid drugs such as fentanyl (full agonist).

Antagonist: drugs which, by binding to a receptor, compete with and prevent binding with other molecules.

  • Non-competitive antagonists often form an irreversible (covalent) bond with the receptor and increasing agonist concentration will not surmount the antagonists inhibitory effect. This means duration of action of irreversible antagonists are more dependent on the rate of turnover of receptor molecules than its own rate of elimination.
  • Competitive antagonist: in the presence of a fixed concentration of agonist, competitive antagonists progressively inhibit the agonist response. Conversely, sufficiently high concentrations of agonist can surmount the effect of a given concentration of antagonist. Implications:
    • The degree of inhibition produced depends on the concentration of the antagonist, which is affected by how much each individual clears the drug (so effect varies in each individual, may need to adjust dose)
    • Clinical response depends on concentration of agonist. e.g. propranolol drops HR by blocking basal levels of norepinephrine(NE) but this is overcome when more norepinephrine is released by the body in times of stress/exercise, or when patients have higher basal concentrations of NE/E

Kd: equilibrium dissociation constant. If Kd is low, binding affinity is high.

Potency: the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drugs maximum effect, which depends on the affinity (Kd) of receptors for binding the drug, and the efficacy of response. Potency should be stated in dosage units, in terms of a particular therapeutic endpoint e.g. '50mg for mild sedation'

Efficacy: the maximum effect a drug can bring about, independent of potency. Is determined by the drugs mode of interaction with receptors or by characteristics of the receptor-effector system involved.

EC50 vs ED50: the half-maximal effective concentration (EC50) is the concentration of drug required to reach 50% of its maximal possible biologic response, measure in moles. Whereas ED50 is the dose at which 50% of individuals exhibit the specific quantal effect, measured in mg/kg E.g. if the ED50’s of two drugs are 5mg and 500mg, then the first drug can be said to be 100x more potent

TD50: median toxic dose: the dose required to produce toxic effects in 50% of people on the drug

LD50: median lethal dose: the dose required to kill 50% of people on the drug

Therapeutic index: relates the dose of a drug required to produce a desired effect to that which produces an undesired effect ie. ratio of TD50:ED50

Therapeutic window: the range between the minimum toxic dose and the minimum therapeutic dose. Obviously the clinically acceptable risk of toxicity depends on the severity of disease. For treatment of lethal diseases such as Hodgkins lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller

Graded dose-response curve: indicates the maximal efficacy of a drug

Quantal: an ‘either-or’ response

Quantal dose-effect curve: indicates the potential variability of drug response amongst individuals

 

 

What is allosteric binding?

Allosteric binding: when drugs bind to the same receptor molecule but do not prevent the agonist from binding (which can enhance or inhibit the action of the agonist). Note that allosteric inhibition is NOT usually overcome by increasing the dose of the agonist. E.g. Diazepam binds to allosteric site on ion channels that are physiologically activated by GABA, potentiating the ability of the agonist GABA to increase channel conductance. This means benzos have little activating effect on their own and are safer in overdose unless combined with other sedating drugs. Another example of a positive allosteric modulator is Ivacaftor which binds to CFTR (cystic fibrosis transmembrane regulator) that is mutated in CF, rescuing some channels which are hypoactive in the disease.

Name some factors which affect the amount of drug which reaches its target receptor?
  • Variations in; age, weight, sex, disease state, liver and kidney function and active transport of drug from the cytoplasm (which is mediated by MDR/multidrug-resistance genes).
  • Hormones which can alter receptor numbers (e.g thyroid hormones increase beta adrenoreceptors in rat heart muscle).
  • The agonist ligand inducing a decrease (downregulation) or coupling efficiency (desensitisation) of its receptors
  • Inert binding sites: binding of a drug to a non-regulatory molecule e.g. albumin. Relevant because this binding affects the distribution of drug within the body and the amount of free drug in circulation

Describe tachyphylaxis, withdrawal and other idiosyncratic drug responses

Idiosyncratic drug responses are usually caused by genetic differences in metabolism of the drug, or by immunologic mechanisms.

  • Hyporeactive or hyperreactive: when the intensity of effect of a given dose of drug is diminished or increased compared to the effect seen in most individuals
  • Tachyphylaxis: when responsiveness diminishes rapidly after administration of a drug
  • Tolerance: when drug responsiveness decreases as a consequence of continued drug administration
  • Withdrawal: An antagonist may increase the number of receptors in a critical cell or tissue by preventing down-regulation caused by an endogenous ligand. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiologic concentrations of agonist. Potentially disastrous withdrawal symptoms can result for the opposite reason when administration of an agonist drug is discontinued. In this situation, the number of receptors which has been reduced by drug-induced downregulation, is too low for endogenous agonist to produce effective stimulation. e.g. the withdrawal of clonidine (a drug whose alpha-adrenoreceptor agonist activity reduces BP), can produce a hypertensive crisis, probably because clonidine down-regulates alpha2 adrenoreceptors.

Explain chemical and physical antagonism with examples

Chemical antagonist: doesn’t involve interaction of drug at single receptor e.g. protamine, a positively charged protein at physiologic pH counteracts the effects of heparin (a non-protein) that is negatively charged, by ionic bonding that makes the other drug unavailable to interact with proteins involved in blood clotting.

Physiologic antagonism: drugs which act between endogenous regulatory pathways mediated by different receptors e.g. catabolic actions of glucocorticoid hormones lead to increased BGLs that is physiologically opposed by insulin. These drugs are less specific and less easy to control compared to receptor-specific antagonists.

Explain the difference between efficacy and potency using dose-response curves

Explain the difference between agonist, partial agonist, competitive and non-competitive agonist using dose-response curves

Give examples of the different methods of drug signalling 

Intracellular receptors for lipid-soluble agents e.g. ‘gene-active’ drugs such as steroids and thyroid hormone whose receptors stimulate gene transcription. This leads to a characteristic lag in the time required to synthesis new proteins (why steroids don’t immediately relieve asthma) and the effects of these agents persists for hours/days due to the relatively slow turnover of most enzymes and proteins (which result from their transcription)

Ligand-regulated transmembrane receptors e.g. Tyrosine kinase. This intensity and duration of action of agents that act via receptor tyrosine kinases are often limited by downregulation, which is when receptors are endocytosed from the cell surface and degraded in lysosomes at a rate faster than de novo synthesis of receptors e.g. EGF’s rate of internalisation is accelerated after activation by EGF itself, which, if gene-mutations interfere with, can cause excessive and prolonged responses implicated in many forms of cancer

Cytokine receptors e.g. JAK. Similar to TK receptors, involves dimerization and phosphorylation

Ion Channels e.g. Verapamil binds to a region in the pore of voltage gated ion channels in the heart and vascular smooth muscle, inhibiting ion conductance separately from the “voltage sensor” domain of the channel that is opened by membrane potential. This means it produced anti-arrhythmic effects and reduces BP without mimicking any known endogenous transmitter. Local anaesthetics work by inhibiting voltage-gated sodium channels expressed in sensory neurons.

What are the types of diffusion? What role does ionisation and pH partitioning play in the ability of a drug to cross membranes?

Types of diffusion

  • Aqueous diffusion: usually driven by the concentration gradient of the permeating drug. Ficks law of passive diffusion determines how readily the drug enters the lipid membrane from aqueous medium.
  • Lipid diffusion: most important limiting factor for drug penetration (because the body has so many lipid barriers). Because lipid barriers separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how readily it will move between lipid and aqueous media. The ability of drugs (many of which are weak acids/bases) to move between these compartments is impacted by pH, because charged molecules attract water molecules, resulting in a water-soluble lipid-insoluble complex, reducing a drugs ability to permeate membranes. Because the uncharged form is more lipid-soluble, more of a weak acid will be in the lipid-soluble form at acid pH, whereas more of a basic drug will be in the lipid-soluble form at an alkaline pH. This is why we give sodium bicarbonate in aspirin(weak acid) overdose, as it causes alkalosis (increase in pH of the urine), trapping the drug in its ionised form in the urine, so it can’t be re-absorbed by the kidney, and is thus excreted. Conversely, drugs which are weak bases will be excreted faster in acidic urine.
  • Special carriers: many drugs resemble peptides/sugars etc. and can use their carriers to cross membranes. The ABC family of transporters (e.g. MDR1) are less selective membrane carriers that specialise in expelling foreign molecules. These play an important role in excreting some drugs.
  • Endocytosis and exocytosis: substance bound by cell surface receptor>engulfed by cell membrane>carried in vesicle>released into cytosol. This is how vitamin B12 complexed with the binding protein known as intrinsic factor gets across the wall of the gut.