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Pharmacodynamics
Drug Receptors and Pharmacodynamics
(how drugs work on the body) The action of a drug on the body, including • interactions, • dose-response phenomena, • mechanisms of therapeutic & toxic action. 2 Pharmacodynamics (how drugs work on the body)
many drugs inhibit enzymes
Enzymes control a number of metabolic processes A very common mode of action of many drugs in the patient (ACE inhibitors) in microbes (sulfas, penicillins) in cancer cells (5-FU, 6-MP)
some drugs bind to:
proteins (in patient, or microbes) the genome (cyclophosphamide) microtubules (vincrne) 3 Pharmacodynamics most drugs act (bind) on receptors in or on cells form tight bonds with the ligand exacting requirements (size, shape, stereospecificity) canbe agonists (salbutamol), or antagonists (propranolol) receptors have signal transduction methods Drug Receptor
A macromolecular component of a cell with which a drug interacts to produce a response Usually - protein Types of Protein Receptors
1. Regulatory – change the activity
of cellular enzymes 2. Enzymes – may be inhibited or activated 3. Transport – e.g. Na+ /K+ ATP’ase 4. Structural – these form cell parts Drug - Receptor Binding
D+R DR Complex
Affinity
Affinity – measure of propensity of a drug to
bind receptor; the attractiveness of drug and receptor Covalent bonds are stable and essentially irreversible Electrostatic bonds may be strong or weak, but are usually reversible Drug Receptor Interaction
DR Complex Effect Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy Definitions Affinity is an ability of drug to bind to receptor, shown by the proximity of the curve to the y axis. ( if the curves are parallel ) . The nearer is axis , the greater is affinity
Potency
Shows relative doses of two ro more agonists to produce same
magnitude of effect , again shown by the proximity of the respective curves to the y axis ( if the curves do not cross) .
Efficacy A measure of how well a drug produces a response ( effectiveness) shown by the maximal height reached by the curve. 2004-2005 Relative Potency
hydromorphone
morphine
Analgesia codeine
aspirin
Dose Agonist Drugs A drug is called agonist when binding to the receptor results in response – in other words: drugs that interact with and activate receptors; they possess both affinity and efficacy two types Full – an agonist with maximal efficacy Partial – an agonist with less then maximal efficacy Agonist Dose Response Curves
Full agonist Partial agonist Response
Dose Antagonist Drug A drug is called an antagonist when binding to the receptor is not associated with a response. The drugs has an effect only by preventing an agonist from binding to the receptor. Antagonists interact with the receptor but do NOT change the receptor they have affinity but NO efficacy two types Competitive
Noncompetitive Competitive Antagonist
competes with agonist for receptor
surmountable with increasing agonist concentration displaces agonist dose response curve to the right (dextral shift) reduces the apparent affinity of the agonist i.e., increases 1/Ke Agonists and antagonists agonist has affinity plus intrinsic activity antagonist has affinity but no intrinsic activity partial agonist has affinity and less intrinsic activity competitive antagonists can be overcome
2004- 2005 Noncompetitive Antagonist drug binds to receptor and stays bound Irreversible – does not let go of receptor produces slight dextral shift in the agonist DR curve in the low concentration range This looks like competitive antagonist As more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect 7 Why are there spare receptors? allow maximal response without total receptor occupancy – increase sensitivity of the system
spare receptors can bind (and
internalize) extra ligand preventing an exaggerated response if too much ligand is present The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC50=kd. Sometimes, full effect is seen at a fractional receptor occupation 6 dose response curves-2
becomes progressively smaller as the dose is increased Eventually, increments in dose produce no further change in effect i.e., maximal effect for that drug is obtained Difficult to analyze mathematically Log Dose Scale
transforms hyperbolic curve to a sigmoid (almost a straight line)
compresses dose scale proportionate doses occur at equal intervals straightens line easier to analyze mathematically
2004-2005 Potency Relative position of the dose-effect curve along the dose axis Has little clinical significance for a given therapeutic effect A more potent of two drugs is not clinically superior Low potency is a disadvantage only if the dose is so large that it is awkward to administer Isolated Muscle Contraction Drug-receptor Arithmetic Scale interaction 100 k1 Drug + Free Receptor Drug-receptor Complex 75 D (100 - DR) m
k-1 DR umi xaM
50 Where: t necreP
25 D = drug concentration 0 DR= concentration 0.00 0.25of drug-receptor 0.50 complex 0.75 1.00
Dose (ug/ml) 2004-
100 - DR = free receptor concentration 2005
11 Desensitization
agonists tend to desensitize receptors
homologous (decreased receptor number) heterologous (decreased signal transduction)
antagonists tend to up regulate
receptors 8 dose response curves-3 quantal dose response curves (used in populations, response is yes/no)
2004- Therapeutic index =Toxic Dose50/Effective Dose50 2005
(TD50/ED50) DR Curve: Whole Animal
Graded – response measured on a
continuous scale Quantal – response is an either/or event relates dose and frequency of response in a population of individuals often derived from frequency distribution of doses required to produce a specified effect DR Curve: Whole Animal Graded – response measured on a continuous scale GRADED (QUANTITATIVE) DOSE RESPONSE (D-R) CURVES Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can reveal information about affinity, potency, and efficacy of these agonists.
PARALLEL AND NONPARALLEL D-R CURVES
Figure I-2-1. D-R Curves for 2 Drugs Acting on Same (left) and When 2 drugs interact with the same receptor (same pharmacologic mechanism), the D-R curves will have parallel slopes. Drugs A and B have the same mechanism; drugs X and Y do not. Affinity can be compared only when 2 drugs bind to the same receptor. Drug A has a greater affinity than drug B. In terms of potency, drug A has greater potency than drug B, and X is more potent than Y. In terms of efficacy, drugs A and B are equivalent. Drug X has greater efficacy than drug Quantal response response is an either/or event relates dose and frequency of response in a population of individuals often derived from frequency distribution of doses required to produce a specified effect QUANTAL (CUMULATIVE) D-R CURVES Quantal D-R curves plot the percentage of a population responding to a specified drug effect versus dose or log dose. Permit estimations of the median effective dose, or effective dose in 50% of a population—ED50. Can reveal the range of inter-subject variability in drug response Steep D-R curve reflects little variability Flat D-R curve indicates great variability in patient sensitivity to the effects of a drug TOXICITY AND THERAPEUTIC INDEX
Comparisons between ED50 and TD50 values permit evaluation of the relative safety of a drug (the therapeutic index, or TI), as would comparison between ED50 and the lethal median dose (LD50) if the latter is known. D-R curves can also show the relationship between dose and toxic effects of a drug. The median toxic dose of a drug (TD50) is the dose that causes toxicity in 50% of a population. From the data above, TI = 10/2 = 5. Such indices are of most value when toxicity represents an extension of the pharmacologic actions of a drug. They do not predict idiosyncratic reactions or drug hypersensitivity.
2004-2005 Effectiveness, toxicity, lethality ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects Quantification of drug safety
TD50 or LD50 Therapeutic Index = ED50 Drug A 100 sleep death
Percent 50 Responding
0 ED50 LD50
dose 2004- 2005 Drug B 100 sleep death
Percent 50 Responding
0 ED50 LD50 dose 2004- 2005 9 The therapeutic index The higher the TI the better the drug.
TI’s vary from: 1.0 (some cancer drugs)
to: >1000 (penicillin)
Drugs acting on the same receptor or enzyme system
often have the same TI: (eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of indapamide) 2004- 2005 SIGNALING MECHANISMS
The binding of an agonist drug to its receptor
activates an effector or signaling mechanism. Several types of drug-responsive signaling mechanisms are known SIGNALING MECHANISMS INTRACELLULAR RECEPTORS Intracellular receptors include receptors for steroids. Binding of hormones or drugs to such receptors releases regulatory proteins which 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 of intracellular receptors: 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. Intracellular receptors
Not all signal receptors are located on the plasma membrane.
Some are proteins located in the cytoplasm or nucleus of target cells. • The signal molecule must be able to pass through plasma membrane.
Examples: ~Nitric oxide (NO) ~Steroid (e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals). Membrane Receptors MEMBRANE RECEPTORS DIRECTLY COUPLED TO ION CHANNELS Many drugs act by : mimicking or antagonizing the actions of endogenous ligands They 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. Similarly, the GABAA receptor in the CNS, which is coupled to a chloride ion channel, can be modulated by anticonvulsants, benzodiazepines, and barbiturates. 2004-2005 RECEPTORS LINKED VIA COUPLING PROTEINS TO INTRACELLULAR EFFECTORS
Many receptor systems are coupled via GTP-binding
proteins (G proteins) to: adenyl cyclase, the enzyme that converts ATP to cAMP, a second messenger which promotes protein phosphorylation by activating protein kinase A These receptors are typically “serpentine,” with 7 transmembrane spanning domains, a third of which is coupled to the G protein effector mechanism
Protein kinase A serves to phosphorylate a set of tissue-
specific substrate enzymes or transcription factors (CREB), thereby affecting their activity 2004-2005 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.
2004-2005 RECEPTORS LINKED VIA COUPLING PROTEINS TO INTRACELLULAR EFFECTORS Gs proteins glucagon, histamine (H2), prostacyclin, and some serotonin subtypes.
2004-2005 4 Signal transduction
1. enzyme linked (multiple actions)
2. ion channel linked
(speedy)
3. G protein linked (amplifier) 4. nuclear (gene) linked (long lasting)
2004- 2005 Structure: 1. G protein-linked receptors •Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices •There’s aG protein attached to the cytoplasmic side of the membrane 2004- (functions as a 2005 switch). 2004- 2005 2. Tyrosine-kinase receptors Structure: •Receptors exist as individual polypeptides •Each has an extracellular signal-binding site •An intracellular tail with a number of tyrosines and a single å helix spanning the membrane 2004- 2005 2004- 2005 3. Ion channel receptors Structure: •Protein pores in the plasma membrane
2004- 2005 B. Second Messengers •Small, nonprotein, water-soluble molecules or ions •Readily spread throughout the cell by diffusion •Two most widely used second messengers are: 1. Cycle AMP 2. Calcium ions Ca2+ 2. Calcium Ions (Ca2+) and Inositol Trisphosphate •Calcium more widely used than cAMP •used in neurotransmitters, growth factors, some hormones •Increases in Ca2+ causes many possible responses: •Muscle cell contraction •Secretion of certain substance •Cell division Two benefits of a signal-transduction pathway 1. Signal amplification 2. Signal specificity
A. Signal amplification •Proteins persist in active form long enough to process numerous molecules of substrate •Eachcatalytic step activates more products then in the proceeding steps 2004- 2005 12 Summary Most drugs act through receptors there are 4 common signal transduction methods the interaction between drug and receptor can be described mathematically and graphically agonists have both affinity (kd) and intrinsic activity () antagonists have affinity only antagonists can be competitive (change kd) or non-competitive (change ) when mixed with agonists agonists desensitize receptors-downregulation antagonists sensitize receptors -upregulation
