Pharmacodynamics Lecture Notes PDF

PHARMACODYNAMICS Presenter: Kimberley McKenzie What is Pharmacodynamics? PHARMACOKINETICS: “What the body does to the drug?” PHARMACODYNAMICS : “What the drug does to the body?” Definition: division of pharmacology that studies the effects of drugs and their mechanisms of action in body. Targets For...

PHARMACODYNAMICS Presenter: Kimberley McKenzie What is Pharmacodynamics? PHARMACOKINETICS: “What the body does to the drug?” PHARMACODYNAMICS : “What the drug does to the body?” Definition: division of pharmacology that studies the effects of drugs and their mechanisms of action in body. Targets For Drug Action A drug is a chemical that affects physiological function in a specific way Most drugs are effective because they bind to particular target proteins such as: enzymes carriers ion channels receptors Principles of Drug Action 1. Stimulation- (increase heart rate by epinephrine) 2. Depression- (benzodiazepines depress CNS) 3. Irritation- (bitter increase salivation and gastric irritation) 4. Replacement- (insulin in DM) 5. Cytotoxic- (microorganisms & cancer) Drug Mechanism of Action (MOA) 1. 2. 3. 4. Physical action- (bulk laxative) Chemical action- [antacids, Al(OH)3] Ion Channels- (mimick/block endogenous agents) Enzymes- (inhibition: competitive/non-competitive, neostigmine & AChE/ aspirin & cyclooxygenase 5. Receptors- (epinephrine on beta receptors on heart) HOW DO DRUGS WORK? o Some activate endogenous proteins o Agonists- binds to receptors and elicits tissue response o Some antagonize, block or inhibit endogenous proteins o Antagonists – binds to receptors without producing tissue response and prevents an agonist from binding o A few have unconventional mechanisms of action o Partial agonists (below par response of tissue to drug binding) o Drugs receptor interaction is governed by the drug’s o Affinity o Efficacy Receptors- Affinity Affinity: the degree to which a drug is able to bind and remains bound to a receptor High Affinity: Binds well and remain long enough to activate receptor Low Affinity: Binds less well and may not remain long enough to activate receptor Receptors- Intrinsic Activity Intrinsic Activity/Efficacy: the extent to which the drug activates the receptor. Drug + Receptor = Drug-Receptor Complex --→ Response D + R = D-R --→ Response Drug Classification Drugs acting on receptors may be agonists or antagonists Agonists initiate changes in cell function, producing effects of various types  Antagonists bind to receptors without initiating such changes Drug Classification Agonist: Full agonist: High affinity + high intrinsic activity (maximal efficacy) Partial agonist: High affinity+ low intrinsic activity (less than maximal efficacy) Antagonist: High affinity no intrinsic activity Drug Potency  Potency: amount/dose of drug required to produce an effect of given intensity.  Agonist potency depends on two parameters:  affinity (tendency to bind to receptors) efficacy (ability, once bound, to initiate changes which lead to effects).  A highly potent drug evokes a larger response at low doses, while a drug of lower potency evokes a small response at low doses. Spare Receptors????????????? Very potent agonists can produce the maximum response at concentrations that do not result in occupancy of the full complement of available receptors. The other receptors that are left over (i.e. are not occupied) are called SPARE RECEPTORS. HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS? o Agonists of Cell Surface Receptors (e.g. alpha-agonists, morphine agonists) o Agonists of Nuclear Receptors (e.g. HRT for menopause, steroids for inflammation) o Enzyme Activators e.g. nitroglycerine (guanylyl cyclase), pralidoxime o Ion Channel Openers e.g. minoxidil (K) and alprazolam (Cl) Dose-Response Effects o A series of agonist may bind to the receptor to produce the same maximal response o With such occurrence, the potency is critical. A very potent drug requires a small concentration to elicit maximal effect o Using the concentrations and the response produced, a Dose-Response curve is created o This curve is useful in differentiating between a series of agonist based on their potency, as well as to determine the Emax and ED50 (EC50) of a drug HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Reversible: can be unbound from the receptor Irreversible: cannot be unbound from the receptor Competitive: Competes with other drugs (agonist) for receptor binding sites Non-Competitive: exerts antagonistic effect without competition for occupancy of the receptor Competitive Antagonism o Competitive antagonism – the concentration of the agonist can be increased in the presence of the antagonist, resulting in a response from the tissue 1. The curve progressively shifts to the right without a change in slope 2. Linear increase in dose ratio with the concentration of the antagonist Non-Competitive Antagonism Drug binds to receptor (allosteric binding site) and stays bound Irreversible: cannot be removed (covalent bond) from receptor Produces slight dextral shift in the agonist DR curve in the low concentration range (resembles competitive antagonism) However, as more and more receptors are bound the agonist drug becomes incapable of eliciting a maximal effect Tachyphylaxis and Tolerance o Tachyphylaxis o When a drug is administered continuously and repeatedly, its effect will gradually diminish (within minutes) o Tolerance o Gradual decrease in responsiveness to a drug, which develops over days and weeks o There are many mechanisms giving rise to tachyphylaxis and tolerance: Change in receptor Loss of receptors Exhaustion of mediators Increased metabolic degradation Physiological adaptation Tachyphylaxis and Tolerance o Change in receptors – occurs in receptors directly coupled to ion-channels and second messengers. This change can occur by phosphorylation of regions of the receptor o Loss of receptors – receptors on cell surface become down regulated when they are exposed to agonists for too long. Receptors may also be taken into cells by endocytosis o Exhaustion of mediators – essential immediate substances can become depleted o Increased metabolic degradation – repeated administration of a drug at the same dose can produce progressive lowering of the plasma concentration o Physiological Adaptation – homeostatic responses can nullify a drugs effect Effectiveness, toxicity, lethality ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect LD50 - Median Lethal Dose 50 - dose which kills 50 percent of the subjects Quantification of drug safety Therapeutic Index (TI) = TD50 ED50 Therapeutic Index (TI) = LD50 ED50 The higher the TI the better the drug. Four Types of Receptors 1. Receptors linked to ion channels e.g. Nicotinic receptor 2. Receptors coupled to G-proteins e.g. Beta adrenoceptor 3. Receptors linked to tyrosine kinase e.g. Insulin receptor 4. Intracellular or nuclear receptors e.g. steroid receptor o The rate at which drugs act depends on the type of receptor o Each receptor type is unique, based on its molecular structure, coupling and effector 1. Channellinked Receptors o Also known as ionotropic receptors (have similar structure to ion channels) o They are involved mainly in fast synaptic transmission (ligand binding and channel opening occur on a millisecond timescale) o Found in the extracellular domain (on cell membrane) o Examples include nACh, GABAA, 5-HT3-receptors, Glutamate 1. Channel-linked Receptors o These receptors controls the fastest synaptic events in the nervous system o The receptors convert the binding of neurotransmitters into an electrical signal in the cells of the organ containing the receptor o Once the neurotransmitter binds, it opens a pore for the NA+ or K+ ions to pass into the cells o There is depolarization of the cell which may lead to the generation of a action potential o This is a direct coupling between the receptor and the ion channel 1. Channel-linked Receptors 2. G-protein-coupled Receptors o Also known as metabotropic receptors o All comprise seven membrane-spanning segments (heptahelical) o Membrane receptors coupled to an intracellular effector system through a GProtein o The G-protein is a membrane protein comprising three subunits (), the subunit possessing GTPase activity o Examples include mAChR, adrenoceptors and neuropeptide receptors and Chemokine receptors 2. G-protein-coupled Receptors o Cyclic Adenosine Phosphate (cAMP) and Inositol Triphosphate (IP3) are the principal second messengers cAMP – binding results in activation or inhibition of adenylate cyclase (enzymes which catalyses cAMP to ATP) IP3 - controls the release of Ca2+ from the intracellular stores o Other second messengers cGMP Diacylglycerol (DAG) Calcium ions (Ca2+) 2. G-protein-coupled Receptors 3. Kinase –linked receptors o Receptors for various hormones (e.g. insulin and growth factors) o These receptors have an intracellular domain which binds and activates tyrosine kinase when the receptor is occupied o They are involved mainly in events controlling cell growth and differentiation, and act indirectly by regulating gene transcription o Signal transduction generally involves dimerisation of receptors, followed by auto phosphorylation of tyrosine residues 3. Kinase –linked receptors o Two important pathways: The Ras/Raf/MAP kinase pathway – Important in cell division, growth and differentiation The Jak/Stat pathway – activated by many cytokines and controls the synthesis and release of many inflammatory mediators 3. Insulin receptor o Insulin receptor autophosphorylates o Phosphorylated residues serve as docking sites for other proteins. In this case, IRS-1 binds, becomes phosphorylated, and recruits a kinase o The recruited kinase (PI3 kinase) phosphorylates a lipid-soluble target PIP2, generating PIP3 4. Intracellular / Nuclear Receptors o These receptors are located in the nucleus o Ligands must first enter cells (lipophilic compounds) e.g. steroid hormones, thyroid hormones, vitamin D and retinoic acid o Receptors consist of a conserved DNA binding domain attached to variable ligand-binding and transcriptional control domains DNA-binding domain recognizes specific base sequences, thus promoting or repressing particular genes (controls gene transcription) Effects are produced as a result of altered protein synthesis, and thus are slow in onset 4. Intracellular / Nuclear Receptors o Contains two loops of about 15 residues each (zinc fingers), knotted together by a cluster of 4 cysteine residues surrounding zinc atom o Hormone-binding domain lies downstream of this central region, while upstream lies variable region that is responsible for controlling gene transcription o Thus initiating completely different patterns of protein synthesis and producing different physiological effects Pharmacogenomics The genetic influence of an individual to therapeutic drugs The role of genes on drug response