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![Protein Binding
Reversible and rapid
Depends on [free drug], affinity for binding sites, [protein]65PATKI](https://image.slidesharecdn.com/pharmacokinetics1-190725042518/85/Pharmacokinetics-1-65-320.jpg)
![High protein binding, low clearance
• [Free drug] depends on clearance of free drug
• [Total drug] depends on protein binding
0
10
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1 2
patient
drugplasmaconcentration
free
bound
Birkett et al., 1979
Same drug
Same dose
Same clearance
68PATKI](https://image.slidesharecdn.com/pharmacokinetics1-190725042518/85/Pharmacokinetics-1-68-320.jpg)
![Comparison
• First Order Elimination
– [drug] decreases
exponentially w/ time
– Rate of elimination is
proportional to [drug]
– Plot of log [drug] or
ln[drug] vs. time are
linear
– t 1/2 is constant regardless
of [drug]
• Zero Order Elimination
– [drug] decreases linearly
with time
– Rate of elimination is
constant
– Rate of elimination is
independent of [drug]
– No true t 1/2
86PATKI](https://image.slidesharecdn.com/pharmacokinetics1-190725042518/85/Pharmacokinetics-1-86-320.jpg)
![Law of Mass Action
(a model to explain ligand-receptor binding)
• When a drug combines with a receptor, it does so at a rate which
is dependent on the concentration of the drug and of the
receptor
• Assumes it’s a reversible reaction
• Equilibrium dissociation (Kd) and association/affinity (Ka)
constants
– Kd = Kon/Koff = [D][R]/[DR]
– Ka = 1/Kd = Koff/Kon = [DR]/[D][R]
108PATKI](https://image.slidesharecdn.com/pharmacokinetics1-190725042518/85/Pharmacokinetics-1-108-320.jpg)
Uploaded byDr Pralhad Patki
Pharmacokinetics 1
The document provides an overview of pharmacology, defining drugs and their classifications, as well as the branches of pharmacology such as pharmacokinetics and pharmacodynamics. It discusses various drug sources, routes of administration, and the impact of metabolism on drug bioavailability, including the first-pass effect. Additionally, it elaborates on drug absorption mechanisms and factors affecting the distribution and efficacy of drugs in the body.
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Pharmacokinetics 1
- 1. . 1IMS PATKI Superworld of PHARMACOLOGY welcomes you
- 2. After attending thissession, students will be able to • Define drug with two examples • Define Pharmacology and name at least three of its sub branches • Enumerate different nomenclatures of drug with one example each. • Discuss three different sources of drugs with one example each • Discuss at least four different routes of drug administrations with their advantages and disadvantages. PATKI 2
- 3. Pharmacology • Pharmacon, logos.Science of drugs. • What is drug ? • Any substance used or intended to be used to modify or explore physiological systems or pathological state. • Treatment, cure, diagnosis, prevention of a disease. PATKI 3
- 5. Branches • Pharmacokinetics • Pharmacodynamics •Pharmacy • Pharmacognosy • Pharmacogenetics • Therapeutics • Chemotherapy • Toxicology • Clinical pharmacology • Posology PATKI 5
- 6. Sources of drugs •Plants , Alkaloids, Glycosides, Oils, • Animal sources • Microorganisms • Chemicals , Organic, Inorganics, • DNA technology • Radioisotpes • Monoclonal antibodies. PATKI 6
- 7. Nomenclatures • Chemical name •Generic name, Pharmacological name. Non proprietary name • Brand name PATKI 7
- 8.
- 9. At the endof the session, student will be able to • Define Pharmacokinetics with example of movement of a drug across membranes. • Enumerates three routes of drug administrations with two advantages and two disadvantages. • Defines First pass effect with suitable examples. • Explains the importance of Bioavailability of a drug with examples. • Defines bioequivalence, area under curve , onset and duration of activity of a drug using kinetic graphs. 9PATKI
- 10. Definitions • Pharmacokinetics – Theprocess by which a drug is absorbed, distributed, metabolized and eliminated by the body – Quantitative study of drug movement in, through and out of the body. – It determines – the route of administration, dose, onset, time to peak, duration of action, and frequency of drug administration. – Absorption, Distribution, Metabolism and Excretion of a drug. – Transport mechanism- Pass through biological barriers – Intestinal epithelium, Renal filtration mechanism, Capillary barriers 10PATKI
- 11. The Life Cycleof a Drug (pharmacokinetics) • Absorption • Distribution • Degradation • Excretion 11PATKI
- 12. Movement of drugsacross cell membranes 12PATKI
- 13. Is the passageof drug through cell membranes to reach its site of action. Mechanisms of drug absorption 1. Simple diffusion = passive diffusion. 2. Active transport. 3. Facilitated diffusion. 4. Pinocytosis (Endocytosis). Patki
- 14.
- 15.
- 16. water soluble drug(ionized or polar) is readily absorbed via aqueous channels or pores in cell membrane. Lipid soluble drug (nonionized or non polar) is readily absorbed via cell membrane itself. Patki
- 17.
- 18. Characters common. Occurs alongconcentration gradient. Non selective Not saturable Requires no energy No carrier is needed Depends on lipid solubility. Depends pka of drug - pH of medium. Patki
- 19. PKa of thedrug (Dissociation or ionization constant): pH at which half of the substance is ionized & half is unionized. pH of the medium Affects ionization of drugs. – Weak acids → best absorbed in stomach. – Weak bases → best absorbed in intestine. Patki
- 20. Drugs exist intwo forms ionized (water soluble & nonionized forms (lipid soluble) in equilibrium. Drug ionized + nonionized • Only nonionized form is absorbable. • Nonionized / ionized fraction is determined by pH and pKa according to Henderson- Hasselbach pKa- pH= log protonated / non-protonated Patki
- 21. Relatively unusual. Occursagainst concentration gradient. Requires carrier and energy. Specific Saturable. Iron absorption. Uptake of levodopa by brain. Patki
- 22.
- 23. Occurs alongconcentration gradient. Requires carriers Selective. Saturable. No energy is required. Patki
- 24.
- 25. Active transport Carrier-mediated facilitateddiffusion Against concentrationAgainst concentration gradientgradient (From low to high)(From low to high) along concentrationalong concentration gradientgradient (From high to low)(From high to low) Needs carriersNeeds carriers Needs carriersNeeds carriers Selective, saturableSelective, saturable Selective, saturableSelective, saturable Energy is requiredEnergy is required No energy is requiredNo energy is required Patki
- 26. Endocytosis: uptake ofmembrane-bound particles. Exocytosis: expulsion of membrane-bound particles. High molecular weight drugs or Highly lipid insoluble drugs Patki
- 27.
- 28. Routes of Administration ©2006Twentieth Century Fox Film Corporation 28PATKI
- 29.
- 30. Oral Absorption • Passivenon-ionic diffusion – Majority of drugs • Specialised transporters – Large neutral amino acid transporter • L-dopa, Methyldopa, Baclofen – Oligopeptide transporter (PEPT-1) • Amino beta lactams, ACE inhibitors – Monocarboxylic acid transporter • Salicylic acid, pravastatin 30PATKI
- 31. Oral (enteral): absorptionfrom mouth, stomach and small intestine • Stomach: minority • Small Intestine: majority – Passive > Active – Rate ~ 75% in 1-3 hours. Depends on: • Motility eg diarrhoea decreases absorption • Blood flow • Food – enhance or impair • Particle size and formulation • Physico-chemical factors – Unionised – Lipid soluble • Rate of gastric emptying rate limiting step 31PATKI
- 32. Gastric Emptying RateAffects Paracetamol Absorption Nimmo et al., Br Med J, 1973 Gastric emptying is: -Delayed by propantheline -Stimulated by metaclopramide 32PATKI
- 33. Effects of Foodon Oral Drug Absorption • Poor acid stability: prolonged gastric exposure → degradation – eg erythromycin, azithromycin, isoniazid • Require acid environment – eg itraconazole, ketoconazole • Fat or bile acids enhance absorption – eg tacrolimus, carbamazepine • Bind to fibre, reducing absorption – eg digoxin • Bind to calcium (chelate), reducing absorption – eg tetracyclines, quinolones 33PATKI
- 34. Formulation • Rate ofdisintegration of tablet – Tablet compression – Bulk excipients • Rate of dissolution of drug particles in intestinal fluid – Particle size: smaller dissolve quicker • Modified Release – Reduce frequency of oral administration • eg morphine, nifedipine, paracetamol extend – Deliver contents to site of action • eg mesalazine: pH sensitive coating – 5-ASA released in distal small bowel and colon 34PATKI
- 35. Advantages Disadvantages EasyEasy Self useSelfuse SafeSafe ConvenientConvenient cheapcheap No need forNo need for sterilizationsterilization Slow effectSlow effect No complete absorptionNo complete absorption (Low bioavailability).(Low bioavailability). Destruction by GITDestruction by GIT First pass effectFirst pass effect GIT irritationGIT irritation Food–Drug interactionsFood–Drug interactions Drug-Drug interactionsDrug-Drug interactions Not suitableNot suitable for vomiting,for vomiting, unconscious, emergency.unconscious, emergency. Patki
- 36. Sublingual Administration • Fromblood vessels at base of tongue • Lipid soluble drugs only – nitroglycerin • Small surface area – potent drugs only • Avoids first pass metabolism • Rapid absorption: minutes 36PATKI
- 37. Rectal Formulations • Avoidfirst pass metabolism • Erratic absorption because of rectal contents • Acceptable to patients? • Useful if unable to take oral medications – eg paracetamol, oxycodone, NSAIDS • Useful if unable to get IV access – eg diazepam in status epilepticus • Direct effect on large bowel – eg corticosteroids in Inflammatory Bowel Disease 37PATKI
- 38. Inhaled Medications • Formulations: –Powders – Aerosol solutions – Nebulised solutions • Delivery to bronchioles – ~10% – Depends on type of inhaler and how used • Local effects – eg oral candida • Some systemic absorption – Salbutamol: tremor – Corticosteroids: osteoporosis – Ipratropium bromide: anticholinergic ‘dry mouth’ in 15% patients 38PATKI
- 39. Topical: Intranasal Formulations •Direct therapeutic effect – Sodium chromoglycate for rhinitis • Systemic effect – Sumatriptan in migraine (vomiting) • Local toxicity – Cocaine – necrosis of nasal septum Saddle-nose deformity Villa, J Can Dent Assoc, 199939PATKI
- 40. Routes of Administration ©2006Twentieth Century Fox Film Corporation 40PATKI
- 41. Topical: Eye Drops •Absorption through conjunctival sac epithelium • Local effects in eyes with minimal systemic effects • Some systemic absorption – eg timolol for glaucoma may precipitate bronchospasm in asthma 41PATKI
- 42. Routes of Administration ©2006Twentieth Century Fox Film Corporation 42PATKI
- 43. Topical: Cutaneous Administration •Local effect on skin – Steroids • Slow systemic absorption (patch) – Lipid soluble drugs only • Oestrogen • Opioids – Fentanyl, Buprenorphine 43PATKI
- 44.
- 45. • 77 yearold woman found dead • Applied heating pad over fentanyl patch, which was also site of her pain • Increased fentanyl absorption due to heat • Possible application of 2nd patch without removing 1st 45PATKI
- 46. First pass metabolismof oral drugs Gu t Liver 46PATKI
- 47. First Pass Metabolismin Gut Lumen – Gastric acid inactivates benzylpenicillin – Proteolytic enzymes inactivate insulin 47PATKI
- 48. First Pass Metabolismin Gut Wall – Monoamine oxidase – metabolises monoamines • Irreversible MAO inhibitors + amine-containing foods – Tyramine not metabolised by MAO in gut wall » enters systemic circulation » releases NAd from stores in nerve endings causing hypertensive crisis Microsoft Clip Art 48PATKI
- 49. First Pass Metabolismin Gut Wall • CYP 3A4 • Blocked by grapefruit juice • Many drugs inducers, inhibitors, substrates PlasmaSimvastatinConcentration(ng/ml) Water Grapefruit juice Administration of 40mg Simvastatin with Lilja et al., Br J Clin Pharmacology, 1994 49PATKI
- 50. First Pass Metabolismin Gut Wall • P-glycoprotein (enterocytes to gut lumen) – Interactions b/w inhibitors (eg verapamil, macrolides) and substrates (eg digoxin) Administration of 0.75mg digoxin withplacebo clarithromycin Rengelshausen et al., Br J Clin Pharmacol, 2003 50PATKI
- 51. Hepatic First PassMetabolism • Reduced amount of parent drug • Metabolites – More water soluble - facilitates excretion – Activity • Decreased • Increased: Pro-drugs – Inactive precursors, metabolised to active metabolites – eg cyclophosphamide, simvastatin, ramipril, perindopril – Reduced first pass metabolism – reduced bioavailability of pro- drugs 51PATKI
- 52. Oral availability Bioavailability: the% of an ingested dose of a drug that enters systemic circulation www.icp.org.nz 52PATKI
- 53. Bioavailability: implications fororal and parenteral dosing • High bioavailability, dose same for IV and po routes – eg metronidazole, fluconazole, amoxicillin • Low bioavailability, lower dose for parenteral than po routes – eg morphine: 10 mg s/c or IM = 30 mg po 53PATKI
- 54.
- 55. Bioavailability after oraladministration of different formulations Burkitt, Australian Prescriber, 2003 55PATKI
- 56. Factors Affecting Bioavailability: Molecular weight of drug. Drug Formulation (ease of dissolution). (solution > suspension > capsule > tablet) Drug solubility of the drug Chemical instability in gastric pH (Penicillin & insulin ) First pass metabolism reduces bioavai Patki
- 57. Factors Affecting Bioavailability(BAV): Blood flow to absorptive site • Greater blood flow increases bioavailability • Intestine has greater blood flow than stomach Surface area available for absorption. • Intestinal microvilli increases it Rate of gastric emptying • rapid gastric emptying fast transit to intestine pH of gut Patki
- 58. Intestinal motility (TransitTime) • Diarrhea reduce absorption Drug interactions Food • slow gastric emptying • generally slow absorption • Tetracycline, aspirin, penicillin V Patki
- 59. Bioequivalence • Pharmaceutically equivalentand equal systemic bioavailability • Generics – must be bioequivalent to innovator (80-125%) • Phenytoin toxicity outbreak (Australia 1968) – ‘Inert’ excipient changed: CaSO4 to lactose – Increased solubility and systemic availability 59PATKI
- 60. Change in phenytoinexcipients results in epidemic toxicity F Bochner, Proc Aust Assoc Neurol, 1973 60PATKI
- 61. AUC A >B: Therapeutic Significance? 0 1 2 3 4 5 6 7 8 9 0 5 10 15 20 25 Time after drug administered (hours) serumconcentration Drug A Drug B 61PATKI
- 62. AUC A >B: B Ineffective MEC MEC = Minimum Effective Concentration 0 1 2 3 4 5 6 7 8 9 0 5 10 15 20 25 Time after drug administered (hours) serumconcentration Drug A Drug B 62PATKI
- 63. AUC A >B: Equally Effective MEC MEC = Minimum Effective Concentration 0 1 2 3 4 5 6 7 8 9 0 5 10 15 20 25 Time after drug administered (hours) serumconcentration Drug A Drug B 63PATKI
- 64. Drug Binding andDistribution 64PATKI
- 65. Protein Binding Reversible andrapid Depends on [free drug], affinity for binding sites, [protein]65PATKI
- 66. Protein binding • Manydrugs bind to plasma proteins – Albumin (acidic drugs, eg warfarin, NSAIDs) – Alpha-1 acid glycoprotein (basic drugs, eg quinine) – Lipoproteins (basic drugs) – Globulins (hormones) • Only free drug can bind to receptors 66PATKI
- 67. Clinical implications ofchanges in protein binding • Changes in protein binding – Disease and nutrition – Protein binding displacement interactions • eg valproate displaces phenytoin – increases free phenytoin, compensate with increased clearance • Clinically relevant effects if – >90% of drug is protein bound • eg phenytoin, warfarin – Small volume of distribution 67PATKI
- 68. High protein binding,low clearance • [Free drug] depends on clearance of free drug • [Total drug] depends on protein binding 0 10 20 30 40 50 60 70 80 90 100 1 2 patient drugplasmaconcentration free bound Birkett et al., 1979 Same drug Same dose Same clearance 68PATKI
- 69. Tissue Binding • BodyFat – Lipid soluble drugs – Stable reservoir – eg anaesthetics • Bone – Adsorption onto bone-crystal surface – Reservoir – slow release – eg tetracyclines, heavy metals 69PATKI
- 70. Distribution: body fluidcompartments Plasma Water 5% Interstitial Water 16% Fat 20% Intracellular Water 35% Transcellular Water 2% Free drug can move between compartments. Depends on: - permeability - binding - pH partition 70PATKI
- 71. Apparent distribution volumesof some common drugs Volume (L/kg body weight) Compartment Vd (L/kg body weight) Examples 0.05 Plasma 0.05-0.1 0.1-0.2 Heparin Insulin Warfarin Atenolol 0.2 Extracellular fluid 0.4-0.7 Theophylline 0.55 Total body water 1-2 2-5 Ethanol Phenytoin Methotrexate Paracetamol Diazepam Morphine Digoxin 71PATKI
- 72. Apparent Volume ofDistribution (Vd) • Vd: volume of fluid required to contain the total amount of drug in the body at the same concentration as that in the plasma • Vd = amount of drug in body plasma concentration • Loading dose = Vd x desired plasma concentration 72PATKI
- 73. Gentamicin • Absorption – Oral:<1% - highly polar cation, ↑ disease – Topical: ↑ large wound/burn/ulcer – IMI: rapid, peak 30-90 mins, ↓ shock • Distribution – Apparent Vd 25% lean body weight (~ECF) – Loading dose = Vd x desired plasma concentration = 0.25 L/kg x 12-20 mg/L = 3-5 mg/kg Apparent Vd increases in sepsis – ? higher loading dose Adjust interval or maintenance dose in renal impairment – clearance next lecture! – High concentrations in renal cortex and endolymph/perilymph inner ear – toxicity 73PATKI
- 74. Barriers to DrugDistribution • Blood brain barrier – Only lipid soluble drugs can enter brain and CSF – ‘Leaky’ in disease – eg penicillin in meningitis • Placenta – Allows passage of lipid and some water soluble drugs - eg opioids, antiepileptics – Enzymes in placenta inactivate some drugs 74PATKI
- 75. Faster Absorption • Parenterally(injection) – Intravenous (IV) – Intramuscular (IM) – Subcutaneous (SC) – Intraperitoneal (IP) • Inhaled (through lungs) 75PATKI
- 76. Fastest Absorption • Directlyinto brain – Intracerebral (into brain tissue) – Intracerebroventricular (into brain ventricles) General Principle: The faster the absorption, the quicker the onset, the higher the addictiveness, but the shorter the duration 76PATKI
- 77.
- 78. Distribution: Depends onBlood Flow and Blood Brain Barrier 78PATKI
- 79. Bioavailability • The fractionof an administered dose of drug that reaches the blood stream. • What determines bioavailability? – Physical properties of the drug (hydrophobicity, pKa, solubility) – The drug formulation (immediate release, delayed release, etc.) – If the drug is administered in a fed or fasted state – Gastric emptying rate – Circadian differences – Interactions with other drugs – Age – Diet – Gender – Disease state 79PATKI
- 80. Depot Binding (accumulation infatty tissue) • Drugs bind to “depot sites” or “silent receptors” (fat, muscle, organs, bones, etc) • Depot binding reduces bioavailability, slows elimination, can increase drug detection window • Depot-bound drugs can be released during sudden weight loss – may account for flashback experiences? 80PATKI
- 81. Degradation & Excretion •Kidneys – Traps water-soluble (ionized) compounds for elimination via urine (primarily), feces, air, sweat • Liver – Enzymes(cytochrome P-450) transform drugs into more water- soluble metabolites – Repeated drug exposure increases efficiency tolerance 81PATKI
- 82. Excretion: Other routes •Lungs alcohol breath • Breast milk acidic ---> ion traps alkaloids alcohol: same concentration as blood antibiotics • Also bile, skin, saliva ~~ 82PATKI
- 83. Metabolism and Elimination(cont.) • Half-lives and Kinetics – Half-life: • Plasma half-life: Time it takes for plasma concentration of a drug to drop to 50% of initial level. • Whole body half-life: Time it takes to eliminate half of the body content of a drug. – Factors affecting half-life • age • renal excretion • liver metabolism • protein binding 83PATKI
- 84. First order kinetics Aconstant fraction of drug is eliminated per unit of time. When drug concentration is high, rate of disappearance is high. 84PATKI
- 85. Zero order kinetics Rateof elimination is constant. Rate of elimination is independent of drug concentration. Constant amount eliminated per unit of time. Example: Alcohol 85PATKI
- 86. Comparison • First OrderElimination – [drug] decreases exponentially w/ time – Rate of elimination is proportional to [drug] – Plot of log [drug] or ln[drug] vs. time are linear – t 1/2 is constant regardless of [drug] • Zero Order Elimination – [drug] decreases linearly with time – Rate of elimination is constant – Rate of elimination is independent of [drug] – No true t 1/2 86PATKI
- 87. Drug Effectiveness • Dose-response(DR) curve – Depicts the relation between drug dose and magnitude of drug effect • Drugs can have more than one effect • Drugs vary in effectiveness – Different sites of action – Different affinities for receptors • The effectiveness of a drug is considered relative to its safety (therapeutic index) 87PATKI
- 88. ED50 = effectivedose in 50% of population 100 50 0 DRUG DOSE 0 X ED50 % subjects 88PATKI
- 89. Therapeutic Index • Effectivedose (ED50) = dose at which 50% population shows response • Lethal dose (LD50) =dose at which 50% population dies • TI = LD50/ED50, an indication of safety of a drug (higher is better) ED50 LD50 89PATKI
- 90. Potency • Relative strengthof response for a given dose – Effective concentration (EC50) is the concentration of an agonist needed to elicit half of the maximum biological response of the agonist – The potency of an agonist is inversely related to its EC50 value • D-R curve shifts left with greater potency 90PATKI
- 91. Efficacy • Maximum possibleeffect relative to other agents • Indicated by peak of D-R curve • Full agonist = 100% efficacy • Partial agonist = 50% efficacy • Antagonist = 0% efficacy • Inverse agonist = -100% efficacy 91PATKI
- 92.
- 93. Tolerance (desensitization) • Decreased responseto same dose with repeated (constant) exposure • or more drug needed to achieve same effect • Right-ward shift of D-R curve • Sometimes occurs in an acute dose (e.g. alcohol) • Can develop across drugs (cross- tolerance) • Caused by compensatory mechanisms that oppose the effects of the drug 93PATKI
- 94. Sensitization • Increased responseto same dose with repeated (binge-like) exposure • or less drug needed to achieve same effect • Left-ward shift in D-R curve • Sometimes occurs in an acute dose (e.g. amphetamine) • Can develop across drugs (cross- sensitization) It is possible to develop tolerance to some side effects AND sensitization to other side effects of the same drug 94PATKI
- 95. Mechanisms of Toleranceand Sensitization • Pharmacokinetic – changes in drug availability at site of action (decreased bioavailability) – Decreased absorption – Increased binding to depot sites • Pharmacodynamic – changes in drug-receptor interaction – G-protein uncoupling – Down regulation of receptors 95PATKI
- 96. Other Mechanisms of Toleranceand Sensitization • Psychological As the user becomes familiar with the drug’s effects, s/he learns tricks to hide or counteract the effects. Set (expectations) and setting (environment) Motivational Habituation Classical and instrumental conditioning (automatic physiological change in response to cues) • Metabolic The user is able to break down and/or excrete the drug more quickly due to repeated exposure. Increased excretion 96PATKI
- 97. • Pharmacokinetic andpharmacodynamic – With pharmacokinetic drug interactions, one drug affects the absorption, distribution, metabolism, or excretion of another. – With pharmacodynamic drug interactions, two drugs have interactive effects in the brain. – Either type of drug interaction can result in adverse effects in some individuals. – In terms of efficacy, there can be several types of interactions between medications: cumulative, additive, synergistic, and antagonistic. Drug-drug Interactions 97PATKI
- 98. Response Hi Lo Time Cumulative Effects Drug A DrugB The condition in which repeated administration of a drug may produce effects that are more pronounced than those produced by the first dose. 98PATKI
- 99. Response Hi Lo Time A B Additive Effects A+ B The effect of two chemicals is equal to the sum of the effect of the two chemicals taken separately, eg., aspirin and motrin. 99PATKI
- 100. Response Hi Lo Time A B A +B Synergistic Effects The effect of two chemicals taken together is greater than the sum of their separate effect at the same doses, e.g., alcohol and other drugs 100PATKI
- 101. Response Hi Lo Time A B A +B Antagonistic Effects The effect of two chemicals taken together is less than the sum of their separate effect at the same doses 101PATKI
- 102. Pharmacodynamics • Receptor – target/siteof drug action (e.g. genetically-coded proteins embedded in neural membrane) • Lock and key or induced-fit models – drug acts as key, receptor as lock, combination yields response – dynamic and flexible interaction 102PATKI
- 103. Pharmacodynamics (cont.) • Affinity –propensity of a drug to bind with a receptor • Selectivity – specific affinity for certain receptors (vs. others) 103PATKI
- 104. Agonism and Antagonism Agonistsfacilitate receptor response Antagonists inhibit receptor response (direct ant/agonists) 104PATKI
- 105. Modes of Action •Agonism – A compound that does the job of a natural substance. – Does not effect the rate of an enzyme catalyzed reaction. • Up/down regulation – Tolerance/sensitivity at the cellular level may be due to a change in # of receptors (without the appropriate subunit) due to changes in stimulation • Antagonism – A compound inhibits an enzyme from doing its job. – Slows down an enzymatically catalyzed reaction. 105PATKI
- 106. Agonists/Antagonists • Full • Partial •Direct/Competitive • Indirect/Noncompetitive • Inverse A single drug can bind to a single receptor and cause a mix of effects (agonist, partial agonist, inverse agonist, antagonist) Functional Selectivity Hypothesis: Conformational change induced by a ligand-receptor interaction may cause differential functional activation depending on the G-protein and other proteins associated with the target receptor 106PATKI
- 107. Important implications of drug-receptorinteraction • drugs can potentially alter rate of any bodily/brain function • drugs cannot impart entirely new functions to cells • drugs do not create effects, only modify ongoing ones • drugs can allow for effects outside of normal physiological range 107PATKI
- 108. Law of MassAction (a model to explain ligand-receptor binding) • When a drug combines with a receptor, it does so at a rate which is dependent on the concentration of the drug and of the receptor • Assumes it’s a reversible reaction • Equilibrium dissociation (Kd) and association/affinity (Ka) constants – Kd = Kon/Koff = [D][R]/[DR] – Ka = 1/Kd = Koff/Kon = [DR]/[D][R] 108PATKI