Pharmacology-Pharmacodynamics

Pharmacodynamics

The actions of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic actions. Simply we can say Pharmacodynamics relates to drugs binding to receptors and their effects.

Agonists

Bind to and activate the receptor in some fashion, bring about the effect. A drug is called an agonist when binding to the receptor results in a response. Full agonists produce a maximal response—they have maximal efficacy.

Partial agonists

Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists. Partial agonists never reach to 100% response even at its maximum doses. Partial agonists are incapable of eliciting a maximal response and are less

effective than full agonists.

Antagonists

bind to a receptor but do not activate them, compete with and prevent binding by other molecules. A drug is called an antagonist when binding to the receptor is not associated with a response. The drug has an effect only by preventing an agonist from binding to the receptor. Antagonists simply block the receptor and block the action of the agonist.

Chemical antagonists, two drugs bind together with zero receptors involved, e.g. heparin and protamine. If we have two drugs and they bind to the same receptor, which one stimulate and the other one block, we call it pharmacologic antagonism. If we have two drugs and binding to 2 different receptors, we can call it physiologic antagonism, for instance nor epinephrine and epinephrine.

Dose-response relations and curves

Affinity

ability of drug to bind to receptor, it is the measures of the propensity of a drug to bind with a given receptor. in the dose-response curve, curve is nearer to the y axis has greater affinity. Note that the curves should be parallel. If the slopes are not parallel, it means that the drugs are working on different receptors.

Potency

Potency denotes the amount of drug needed to produce a specified effect. Potency shows relative doses of two or more agonists to produce the same magnitude of effect, and in the curve, the nearer the y axis, the greater is the potency.

Efficacy

Efficacy—often called maximal efficacy—is the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level. Efficacy is determined mainly by the nature of the drug and the receptor and its associated effector system. a measure of how well a drug produces a response (effective- ness), shown by the maximal height reached by the curve.

In figure 1, between A and B, A is pharmacologically more potent; B has a larger maximal efficacy.

Between B and C, B is pharmacologically more potent; they have same maximal efficacy.

Figure 1. Comparison of D-R Curves

Competitive and non-competitive antagonists

Competitive antagonists bind to the receptor and prevent the binding of agonists to the receptor, but the binding of the competitive antagonists to the receptor is weak and If we have more agonists, competitive antagonists leave the receptor. So, it does change the potency but they don’t change the efficacy of agonists.

Non-competitive antagonists are usually irreversible inhibitors, because they bind covalently to the receptors and is strong binding to break, even there are many agonists it (non-competitive antagonist) won’t be removed from the receptors. So, it will decrease the efficacy of agonists.

Figure 2. Agonist dose-response curves in the presence of competitive and irreversible antagonists

Pharmacologic potency

Refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect.

Depends in part on the affinity (1/Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response.

Median effective dose (ED 50) the dose at which 50% of individuals exhibit the specified quantal effect.

Median toxic dose (TD 50) the dose required to produce a particular toxic effect in 50% of animals.

Median lethal dose (LD 50) the dose required to produce a lethal effect in 50% of animals.

Figure 3. quantal dose-response plots.

Therapeutic index (TI)

In animal studies, the therapeutic index is usually defined as the ratio of the TD50/LD50 to the ED50 for some therapeutically relevant effect, which describes the safety of a drug.

TI= TD50 / ED50 or TI= LD50 / ED50

The larger value of the TI, the wider margin between effective dose and toxic dose shows the drug is safer.

For instance, if the TD50 of the drug is 10 mg/kg and the ED50 of the drug is 2, the TI would be 5, it means that if you take 5 times as much as you supposed to, you will get toxicity, so, it shows this drug is unsafe. Digoxin, warfarin and lithium are kinds of drugs with low TI (less than 2).

Signaling mechanisms

Binding of an agonist drug to its receptor activates an effector or signaling mechanism.

Several different types of drug-responsive signaling mechanisms are known.

Intracellular Receptors

These include receptors for steroids. Binding of hormones or drugs to such receptors releases regulatory proteins that permit activation and in some cases dimerization of the hormone-receptor complex. Such complexes translocate to the nucleus, where they interact with response elements in spacer DNA. This interaction leads to changes in gene expression. For example, drugs interacting with glucocorticoid receptors lead to gene expression of proteins that inhibit the production of inflammatory mediators.

Other examples include intracellular receptors for thyroid hormones, gonadal steroids, and vitamin D.

Pharmacologic responses elicited via modification of gene expression are usually slower in onset but longer in duration than many other drugs.

Figure 4. intracellular receptors

Membrane-spanning receptor- effector enzymes (Receptors That Function as Transmembrane Enzymes) (Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases)

Insulin, epidermal growth factor, and platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor- (TGF-), and many other trophic hormones bind to the extracellular domain of molecules that incorporate tyrosine kinase enzyme activity in their intracellular domains. Most of these receptors dimerize upon activation. The receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, 2 domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane. The cytoplasmic enzyme domain may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase. Binding of the ligand causes conformational changes (e.g., dimerization) so that the tyrosine kinase domains become activated, ultimately leading to phosphorylation of tissue-specific substrate proteins.

Guanylyl cyclase−associated receptors: stimulation of receptors to atrial natriuretic peptide activates the guanylyl cyclase and ↑ cyclic GMP (cGMP)

Imatinib is a specific tyrosine-kinase (TK) inhibitor, while sorafenib is a non-specific TK inhibitor.

Figure 5. Receptors That Function as Transmembrane Enzymes

Cytokine Receptors (Membrane receptors that bind intracellular tyrosine kinase enzymes (JAK-STAT receptors))

Extracellular and intracellular domains and form dimers. Activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated® phosphorylation of signal transducers and activation of transcription molecules (STAT) ® STAT dimers then travel to the nucleus® regulate transcription. These include the receptors for erythropoietin, somatotropin, and interferons.

Their receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (Janus kinases [JAKs]).

JAKs phosphorylate signal transducers and activators of transcription (STAT) molecules.

STATs dimerize and then dissociate, cross the nuclear membrane, and modulate gene transcription.

Figure 6. JAC-STAT receptors

Membrane Receptors Directly Coupled to Ion Channels (Ligand- and Voltage-Gated Channels)

Many drugs act by mimicking or antagonizing the actions of endogenous ligands that regulate flow of ions through excitable membranes via their activation of receptors that are directly coupled (no second messengers) to ion channels.

For example, the nicotinic receptor for ACh (present in autonomic nervous system [ANS] ganglia, the skeletal myoneural junction, and the central nervous system [CNS]) is coupled to a Na+/K+ ion channel. The receptor is a target for many drugs, including nicotine, choline esters, ganglion blockers, and skeletal muscle relaxants. ACh causes the opening of the ion channel in the nicotinic AChR ® allows Na+ to flow down its concentration gradient into cells ® producing a localized excitatory postsynaptic potential— a depolarization.

Similarly, the GABAA receptor in the CNS, which is coupled to a chloride ion channel, can be modulated by anticonvulsants, benzodiazepines, and barbiturates.

acetylcholine, serotonin, GABA, and glutamate are the examples of natural ligands for these receptors.

Figure 7. Membrane Receptors Directly Coupled to Ion

Receptors Linked Via Coupling Proteins to Intracellular Effectors

Many receptor systems are coupled via GTP-binding proteins (G-proteins) to adenylyl cyclase, the enzyme that converts ATP to cAMP, a second messenger that promotes protein phosphorylation by activating protein kinase A. These receptors are typically “serpentine,” with seven transmembrane spanning domains, the third of which is coupled to the G-protein effector mechanism.

GPCRs consist of 7 transmembrane (7-TM) domains and when activated by extracellular ligands, bind trimeric G proteins at the inner membrane surface and cause the release of activated Gα and Gβγ units. These activated units, in turn, modulate cytoplasmic effectors. The effectors commonly synthesize or release second messengers such as cAMP, IP3, and DAG. GPCRs are the most common type of receptors in the body.

Protein kinase A serves to phosphorylate a set of tissue-specific substrate enzymes or transcription factors (CREB), thereby affecting their activity.

Gs proteins

Binding of agonists to receptors linked to Gs proteins increases cAMP production.

Such receptors include those for catecholamines (beta), dopamine (D1), glucagon, histamine (H2), prostacyclin, and some serotonin subtypes.

Gi proteins

Binding of agonists to receptors linked to Gi proteins decreases cAMP production.

Such receptors include adrenoreceptors (alpha2), ACh (M2), dopamine (D2 subtypes), and several opioid and serotonin subtypes.

Gq proteins

Other receptor systems are coupled via GTP-binding proteins (Gq), which activate phospholipase C. Activation of this enzyme releases the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) from the membrane phospholipid phosphatidylinositol bisphosphate (PIP2). The IP3 induces release of Ca2+ from the sarcoplasmic reticulum (SR), which, together with DAG, activates protein kinase C. The protein kinase C serves then to phosphorylate a set of tissue-specific substrate enzymes, usually not phosphorylated by protein kinase A, and thereby affects their activity.

These signaling mechanisms are invoked following activation of receptors for ACh (M1 and M3), norepinephrine (alpha1), angiotensin II, and several serotonin subtypes.

Figure 8. Signaling mechanisms for drug effects

Figure 9. GPCR. Receptors Using Cyclic AMP and IP3, DAG, Ca2+ as Second Messengers

Cyclic GMP and Nitric Oxide Signaling

cGMP is a second messenger in vascular smooth muscle that facilitates dephosphorylation of myosin light chains, preventing their interaction with actin and thus causing vasodilation.

Nitric oxide (NO) is synthesized in endothelial cells and diffuses into smooth muscle.

NO activates guanylyl cyclase, thus increasing cGMP in smooth muscle.

Vasodilators ↑ synthesis of NO by endothelial cells.

Drug development and testing 

The Food and Drug Administration (FDA)

The FDA regulates both the efficacy and safety of drugs but not of foods, nutritional supplements, and herbal remedies.

Teratogenicity

• The FDA has classified drugs into five categories (A, B, C, D, and X).
• Class A has no risks, and Class X designates absolute contraindication. l It is based on animal studies and, when available, human studies.
• In Class D, benefits outweigh the risk.

Figure 10. drug development and testing

Figure 11. FDA classification of drugs and pregnancy