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Enzymes Jason Ryan, MD, MPH Www.Medicalstudyzone.com.
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www.medicalstudyzone.com Www.Medicalstudyzone.com This PDF was created and uploaded by which is one the biggest free resources platform for medical students and healthcare professionals. You can access all medical Video Lectures, Books in PDF Format or kindle Edition, Paid Medical Apps and Softwares, Qbanks, Audio Lectures And Much More Absolutely for Free By visiting our Website https://medicalstudyzone.com all stuff are free with no cost at all. Furthermore You can also request a specific Book In PDF Format OR Medical Video Lectures..
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Enzymatic Reactions S E P S + E ⇄ ES ⇄ E + P Www.Medicalstudyzone.com.
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Enzymatic Reactions Image courtesy of Wikipedia/U+003F S + E ⇄ ES ⇄ E + P Www.Medicalstudyzone.com.
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Michaelis-Menten Kinetics V [S] V = Reaction velocity Rate of P formation Vmax V = Vm* [S] Km + [S] Www.Medicalstudyzone.com.
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Michaelis-Menten Kinetics • Adding S → More P formation → Faster V • Eventually, reach Vmax Www.Medicalstudyzone.com.
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Michaelis-Menten Kinetics • At Vmax, enzymes saturated (doing all they can) • Only way to increase Vmax is to add enzyme Www.Medicalstudyzone.com.
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Enzyme Kinetics [S] Vmax Vmax More Enzyme Www.Medicalstudyzone.com.
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Michaelis-Menten Kinetics V [S] V = Reaction velocity Rate of P formation Vmax V = Vm* [S] Km + [S] Www.Medicalstudyzone.com.
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Michaelis Constant (Km) V = Vm * [S] Km + [S] Key Points: 1. Km has same units as [S] 2. At some point on graph, Km must equal [S] Www.Medicalstudyzone.com.
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[S] + [S] 2 [S] 2 Michaelis Constant (Km) V = Vm * [S] = Vm * [S] = Vm When V = Vm/2 [S] = Km Www.Medicalstudyzone.com.
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[S] Vmax V = Vm* [S] Km + [S] Michaelis Constant (Km) Vmax/2 Km Www.Medicalstudyzone.com.
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V = Vm* [S] Km + [S] • Small Km → Vm reached at low concentration [S] • Large Km → Vm reached at high concentration [S] Michaelis Constant (Km) [S] Vmax Vmax/2 Km Www.Medicalstudyzone.com.
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V = Vm* [S] Km + [S] Michaelis Constant (Km) • Small Km → Substrate binds easily at low [S] • High affinity substrate for enzyme • Large Km → Low affinity substrate for enzyme [S] Vmax Vmax/2 Km Www.Medicalstudyzone.com.
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Key Points • Km is characteristic of each substrate/enzyme • Vm depends on amount of enzyme present • Can determine Vm/Km from • Michaelis Menten plot V vs. [S] • Lineweaver Burk plot 1/V vs. 1/[S] Www.Medicalstudyzone.com.
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Lineweaver Burk Plot V = Vm* [S] Km + [S] 1 = Km + [S] = Km + [S] V Vm [S] Vm [S] Vm[S] 1 = C * 1 + 1 V [S] Vm Www.Medicalstudyzone.com.
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Lineweaver Burk Plot 1 V 1 S 1 Vm -1 Km Km Vm Www.Medicalstudyzone.com.
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Enzyme Inhibitors Jason Ryan, MD, MPH Www.Medicalstudyzone.com.
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Enzyme Inhibitors • Many drugs work through enzyme inhibition • Two types of inhibitors: • Competitive • Non-competitive Www.Medicalstudyzone.com.
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Enzymatic Reactions S E P S + E ⇄ ES ⇄ E + P Www.Medicalstudyzone.com.
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Enzyme Inhibitors S E I Competitive Competes for same site as S Lots of S will overcome this S E P Non-competitive Binds different site S Changes S binding site S cannot overcome this Effect similar to no enzyme I Www.Medicalstudyzone.com.
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Competitive Inhibitor [S] Vmax Vmax/2 Km Normal Km Same Vm Higher Km Inhibitor Www.Medicalstudyzone.com.
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Non-competitive Inhibitor [S] Vmax Vmax With inhibitor Vmax/2 Vmax/2 Lower Vm Same Km Km Www.Medicalstudyzone.com.
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Competitive Inhibitor 1 V 1 S 1 Vm -1 Km Normal Www.Medicalstudyzone.com.
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Competitive Inhibitor 1 V 1 S 1 Vm -1 Km -1 Km Normal Inhibitor Www.Medicalstudyzone.com.
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Non-competitive Inhibitor 1 V 1 S 1 Vm -1 Km Normal Inhibitor 1 Vm Www.Medicalstudyzone.com.
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Inhibitors Competitive • Similar to S • Bind active site • Overcome by more S • Vm unchanged • Km higher Non-competitive • Different from S • Bind different site • Cannot be overcome • Vm decreased • Km unchanged Www.Medicalstudyzone.com.
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Dose-Response Jason Ryan, MD, MPH Www.Medicalstudyzone.com.
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Efficacy • Maximal effect a drug can produce • Morphine is more efficacious than aspirin for pain control Www.Medicalstudyzone.com.
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Potency • Amount of drug needed for given effect • Drug A produces effect with 5mg • Drug B produces same effect with 50mg • Drug A is 10x more potent than drug B • More potent not necessarily superior • Low potency only bad if dose is so high it’s hard to administer Www.Medicalstudyzone.com.
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Pain Control Analgesia Dose (mg) Morphine Aspirin Www.Medicalstudyzone.com.
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Dose-Response • For many drugs we can measure response as we increase the dose • Can plot dose (x-axis) versus response (y-axis) Www.Medicalstudyzone.com.
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Dose-Response • Graded or quantal responses • Graded response • Example: Blood pressure • Can measure “graded” effect with different dosages • Quantal response • Drug produces therapeutic effect: Yes/No • Example: Number of patients achieving SBP<140mmHg • Can measure “quantal” effect by % patients responding to dose Www.Medicalstudyzone.com.
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Graded Dose Response Curve Dose Effect Emax E50 10 20 30 40 50 60 Www.Medicalstudyzone.com.
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Graded Dose Response Curve Log [Dose] Effect Emax E50 1 10 100 ↓EC50 = ↑Potency Www.Medicalstudyzone.com.
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Graded Dose Response Curve Log [Dose] Effect Emax E50 EC50/Potency A > B > C A B C Potency Www.Medicalstudyzone.com.
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Graded Dose Response Curve Log [Dose] Effect Emax E50 EMax/Efficacy B>A A B Efficacy Emax Www.Medicalstudyzone.com.
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Competitive Antagonists Log [Dose] Effect Emax E50 Receptor Agonist Receptor Agonist + Competitive Antagonist Www.Medicalstudyzone.com.
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Non-competitive Antagonists Log [Dose] Effect Emax E50 Receptor Agonist Receptor Agonist + Non-Competitive Antagonist E50 EC50 Max Effect Www.Medicalstudyzone.com.
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Spare Receptors • “Spare” receptors: Activate when others blocked • Maximal response can occur even in setting of blocked receptors • Experimentally, spare receptors demonstrated by using irreversible antagonists • Prevents binding of agonist to portion of receptors • High concentrations of agonist still produce max response Www.Medicalstudyzone.com.
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Spare Receptors Log [Dose] Effect Agonist + Low Dose Non-Competitive Antagonist Agonist + High Dose Non-Competitive Antagonist Emax Source: Basic and Clinical Pharmacology, Katzung Www.Medicalstudyzone.com.
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Partial Agonists • Similar structure to agonists • Produce less than full effect Www.Medicalstudyzone.com.
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Partial Agonists Agonist or Partial Agonist Given Alone Log [Dose] Effect Emax Full Agonist Partial Agonist Max Effect Effect similar to agonist plus NC antagonist Www.Medicalstudyzone.com.
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Partial Agonist Single Dose Agonist With Increasing Partial Agonist Log [Dose Partial Agonist] % Binding 100% Agonist Partial Agonist 0% Www.Medicalstudyzone.com.
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Partial Agonist Single Dose Agonist With Increasing Partial Agonist Log [Dose Partial Agonist] Response 100% Agonist Response Partial Agonist Response 0% Total Response Www.Medicalstudyzone.com.
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Partial Agonists • Pindolol/Acebutolol • Old antihypertensives • Activate beta receptors but to less degree that norepinephrine • “Intrinsic sympathomimetic activity” (IMA) • Lower BP in hypertensive patients • Can cause angina through vasoconstriction • Buprenorphine • Partial mu-opioid agonist • Treatment of opioid dependence • Clomiphene • Partial agonist of estrogen receptors hypothalamus • Blocks (-) feedback; ↑LH/FSH • Infertility/PCOS Www.Medicalstudyzone.com.
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Quantal Dose Response Curve Log [Dose] % Patients Therapeutic Response Adverse Response 100% 50% ED50 LD50/ TD50 Www.Medicalstudyzone.com.
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Therapeutic Index • Measurement of drug safety Therapeutic Index = LD50 ED50 Www.Medicalstudyzone.com.
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Therapeutic Window Therapeutic Window Log [Dose] % Patients 100% 50% LD50 Minimum Effective Dose Minimum Toxic Dose Www.Medicalstudyzone.com.
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Low TI Drugs • Often require measurement of levels to avoid toxicity • Warfarin • Digoxin • Lithium • Theophylline Www.Medicalstudyzone.com.