pharmacodynamics.docx

**PHARMACODYNAMICS** **Definition** - **Pharmaco** = drug **Dynamics** = action - [Pharmacodynamics can be defined as:] - **The division of pharmacology that study the effects of drugs and their mechanisms of action in the body; i.e., [What the drug does to the body]**...

**PHARMACODYNAMICS** **Definition** - **Pharmaco** = drug **Dynamics** = action - [Pharmacodynamics can be defined as:] - **The division of pharmacology that study the effects of drugs and their mechanisms of action in the body; i.e., [What the drug does to the body]** - It includes the: - **biochemical and physiological effects of drugs,** - **receptor interactions,** - **dose-response phenomena,** - **mechanisms of therapeutic and toxic action**.  **Modes of Drug Actions** 1. **Through Receptors:** - Most drugs act through receptors - Adrenaline stimulate the heart by acting on receptors on the cardiac muscle 2. **Physical blockade of ion channels** by the drug and prevent passage of ions - local anesthetics act by blocking Na+ channels 3. **Through enzyme: reversible or irreversible** - Aspirin inhibits cyclo-oxygenase enzyme 4. **Drugs acting on metabolic processes within the cells** - 5-flurouracil 5. **Physical action:** drug act through its physical properties - Adsorbent e.g. kaolin and charcoal act as anti- diarrheal agent. 6. **Chemical action:** simple chemical interaction - Antacids neutralize gastric acid 7. **Chelation:** - Chelation is used in the treatment of heavy metal poisoning. A chelating agent holds the toxic metal ion to form a drug-metal complex, which is non-toxic, water-soluble and easily excreted in urine **e.g. EDTA chelates calcium, lead and digitalis** **Definition of [RECEPTOR]** - Macromolecules that drugs, substances or ligands combine with to produce an effect. - These receptors are usually **PROTEINS** - They are located on the cell surface or within the cytoplasm of the cell. - Interaction of the drug with its receptor is similar to the interaction between lock & key. **Terms of drug receptor interactions** - **[LIGANDS] : The substances which combine with and produce the effect.** - Endogenous Ligands -- present naturally in the body - Exogenous Ligands -- supplied in the form of drugs - **[AFFINITY] *:* The ability of a drug to bind to the receptor** - **[INTRINSIC ACTIVITY (IA) or EFFICACY: ]** Ability of the bound drug to change the receptor in a way that produces an effect. **Types of Ligands** They can be of 4 types 1. **Agonist:** - Combine with the receptor and produces an effect - It has affinity and an intrinsic activity which is considered as standard 1 (IA =1) - Example: adrenaline acting on b receptors of the heart increases the heart rate 2. **Partial Agonist:** - The drug which combines with the receptor and produces an effect which is less than that produced by the agonist - Has affinity but intrinsic activity is less than one (\< 1) - Example: Pindolol acts on b adrenoceptors on heart but produced little increase in heart rate 3. **Antagonist:** - Binds with receptors and produces no effect - Has affinity but no intrinsic activity (IA= 0) - Example: Propranolol inhibit the action of agonist by blocking their receptors and decreases the heart rate 4. **Inverse Agonist:** - Combines with the receptor and produces effect in opposite direction - Has affinity but intrinsic activity = -1, because it has an opposite effect **Antagonism** - When two drugs used together and on drug reduces or abolishes the action of the other drug or neurotransmitter **Types of drug antagonism** 1. Pharmacological antagonism - Competitive( reversible) antagonist - Non-competitive (irreversible) antagonist **Differences between competitive and non-competitive antagonist** +-----------------------------------+-----------------------------------+ | **Competitive antagonist** | **Non-competitive (irreversible) | | | antagonist** | +===================================+===================================+ | -Reversibly competes for the same | -irreversibly bind to the same | | binding site as the agonist | receptor at site other than the | | | agonist binding site | | -High concentration of agonist | | | can overcome the inhibition of | \- High concentration of agonist | | the antagonist to produce the | fail to produce the effect | | | | | effect | -Causes non-parallel shift of DRC | | | to the right | | -Causes parallel shift of DRC to | | | the right | -Reduction in maximal response, | | | ED50 | | -No change in maximal efficacy, | | | increase in ED50 | -Example: | | | | | -Examples: | Phenoxybenzamine + noradrenaline | | | for alpha receptors | | b-adrenoceptor antagonists + | | | noradrenaline for beta receptor | | +-----------------------------------+-----------------------------------+ 2. Chemical antagonism - One drug may antagonize the action of other drug by binding to it - E.g., heparin and protamine sulfate 3. Physiological antagonism - One drug may antagonize the action of other drug by acting on different types of receptors and produce opposite physiological action - E.g., adrenal and histamine on bronchial smooth muscle and blood pressure **Classification of Receptors** 1. **Ligand gated ion channel** - Receptor incorporated on ion channel, so stimulation of the receptor causes opening of the channel directly; e.g. stimulation of the Na+ channel associated with nicotine receptors by Ach leading to opening of the channel and influx of sodium → polarization and generation of action → release of calcium and skeletal muscle contraction 2. **G-protein coupled receptors:** - Drug + receptor causes stimulation of G-proteins (Gaunin nucleotides binding regulatory proteins) which are either stimulatory or inhibitory. 3. **Enzyme-linked receptors:** - e.g., Insulin receptor: the receptor has two subunits bound together, the extracellular unit binds with insulin & the intrecellular unit has tyrosine kinase activity that lead to phosphorylation which is necessary for insulin action. 4. **Intracellular receptors -- protein synthesis coupled** - Some lipid soluble drugs can pass through cell membrane ans act on intracellular receptor for drug-receptor complex which migrate into the nucleus to bind with DNA sequences, transcription of gene and synthesis of certain protein that produce the response - E.g., steroids and thyroxine **Receptor regulation** a. **Receptor down regulation:** - Prolonged or repeated exposure of some types of receptors to the agonist → **gradual** **decrease** in the number of receptors which may be the cause of tolerance with some drugs - The process is reversible and receptors number may return to normal after a relatively long period of removing the drug (days or weeks) b. **Receptor up-regulation:** - Prolonged exposure of receptors to an antagonist → increase in the number of receptors - Sudden withdrawal of beta blocker → worsening of angina **Causes of reduction of tissue responsiveness** 1. **Tolerance:** - Gradual decrease in response to a drug on prolonged and repeated administration of a drug - Larger doses of the drug are needed to obtain the same initial response - May cause failure of therapy - May occur to all effect of the drug or some effects only - Loss of responsiveness develops gradually over few days or weeks **Relationship between Drug Dose and Response** - The relationship between a given dose and the observed response is linked by the interaction of the drug with a specific receptor in a phenomenon called **the dose response curve** **Dose-Response Curve (DRC)** - Useful in determining the drug dose that produced the desired therapeutic action - Useful in comparing the potency of different drugs producing the same effect with same mechanism **There are two types of DRCs** - **Graded dose response curve** - Graded response -- **measurable responses** such as blood pressure or blood sugar - DRC obtained by plotting drug effect against the dose of the drug - At low doses, response increases as drug dose increases - Rate of change is rapid at first and becomes progressively smaller as the dose is increased - Eventually, increments in dose produce no further change in effect i.e., maximal effect **(Emax)** for that drug is obtained "**PLATEAU**" - DRC is **Hyperpolic** -- not useful because curve is too steep and difficult to analyze mathematically C:\\Users\\acer\\pharmacodynamics\\dc\_de (Copy 2).gif **Log dose response curve** - The log dose is plotted against the response - Transforms hyperbolic curve to a **SIGMOID** - The mid-portion of the curve is linear and a wide range of doses can be displayed on the graph - Easier to analyze mathematically - Response is a measure of [efficacy] - Drugs that have parallel dose-response curves often have the same mechanism of action  **Advantages of log DRC** - Plotting of more than **one curve** on the same graph paper, since it allows displaying a wide range of doses - This makes **comparison between drugs** more easier - Help in comparing drugs to determine: - **Effective, toxic and lethal doses** - **How safe the drug is at variant doses** **Quantal dose response curve** - **All or none response**, there is response or no response - Examples: prevention of convulsions, arrhythmia, anesthesia, death - **Relates dose and frequency of response in a population of individuals** **Informations obtained from DRC** - **ED0** -- The highest dose which does not produce response - **ED50** --**Median Effective Dose** - The effective dose that produce 50% of maximal response - The dose at which 50% of the population shows a given effect (quantal DRC) - **ED100** -- The lowest dose that produces maximal response - **TD50** -- The dose which produces a particular toxic effect in 50% of animals - **LD50** -- the dose that kills 50 % of animals Figure 3. **Efficacy** - The ability of a drug receptor complex to produce an effect. - Maximal effect (Emax) produced (all receptors are occupied) if a maximal dose is given. - It is determined by the graded DRC - Efficacy is important clinically -- more efficacious have more maximal response and will give better clinical effect  - \- Drug L and N have the same efficacy (same Emax) - \- Drug M has lower efficacy than drug L and N (Emax of drug L and N \> Emax of drug M) **Potency** 1. **The amount of the drug in relation to its response.** 2. **It is determined by ED~50~ which is is defined as the dose required to produce 50% of the maximum effect (the smaller the dose needed means the more potent the drug).** 3. **It is not important clinically** **Quantification of drug safety** - **Therapeutic Index (TI) = Margin of Safety** - A measure of safety of drugs - It is the ratio between TD~50~ or LD~50~ and ED~50~ **TD50 or LD~50~** **ED~50~** - The higher the TI, the safer the drug - Generally drugs with TI \> 3 are considered safe - The lower the TI, the greater the possibility of toxicity e.g. digitalis (TI=3), so death may occur if only 3 mg has been administered because the usual therapeutic dose of cardiac glycoside is 1 mg. \*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*