Basic Pharmacology Slides 2023 PDF

Enzymes Jason Ryan, MD, MPH Www.Medicalstudyzone.com This PDF was created and uploaded by www.medicalstudyzone.com 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...

Enzymes Jason Ryan, MD, MPH Www.Medicalstudyzone.com This PDF was created and uploaded by www.medicalstudyzone.com 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 Www.Medicalstudyzone.com 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. Enzymatic Reactions P S E S + E ⇄ ES ⇄ E + P Www.Medicalstudyzone.com Enzymatic Reactions S + E ⇄ ES ⇄ E + P Image courtesy of Wikipedia/U+003F Www.Medicalstudyzone.com Michaelis-Menten Kinetics V = Reaction velocity Rate of P formation Vmax V = Vm* [S] Km + [S] V [S] Www.Medicalstudyzone.com Michaelis-Menten Kinetics Adding S → More P formation → Faster V Eventually, reach Vmax Www.Medicalstudyzone.com Michaelis-Menten Kinetics At Vmax, enzymes saturated (doing all they can) Only way to increase Vmax is to add enzyme Www.Medicalstudyzone.com Enzyme Kinetics Vmax More Enzyme Vmax [S] Www.Medicalstudyzone.com Michaelis-Menten Kinetics V = Reaction velocity Rate of P formation Vmax V = Vm* [S] Km + [S] V [S] Www.Medicalstudyzone.com 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 Michaelis Constant (Km) V = Vm * [S] = Vm * [S] = Vm [S] + [S] 2 [S] 2 When V = Vm/2 [S] = Km Www.Medicalstudyzone.com Michaelis Constant (Km) Vmax V = Vm* [S] Vmax/2 Km + [S] Km [S] Www.Medicalstudyzone.com Michaelis Constant (Km) Small Km → Vm reached at low concentration [S] Large Km → Vm reached at high concentration [S] Vmax V = Vm* [S] Vmax/2 Km + [S] Km [S] Www.Medicalstudyzone.com Michaelis Constant (Km) Small Km → Substrate binds easily at low [S] High affinity substrate for enzyme Large Km → Low affinity substrate for enzyme Vmax V = Vm* [S] Vmax/2 Km + [S] Km [S] Www.Medicalstudyzone.com 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 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 Lineweaver Burk Plot 1 V Km Vm 1 Vm 1 S -1 Km Www.Medicalstudyzone.com Enzyme Inhibitors Jason Ryan, MD, MPH Www.Medicalstudyzone.com Enzyme Inhibitors Many drugs work through enzyme inhibition Two types of inhibitors: Competitive Non-competitive Www.Medicalstudyzone.com Enzymatic Reactions P S E S + E ⇄ ES ⇄ E + P Www.Medicalstudyzone.com Enzyme Inhibitors P S S I E E I Competitive Non-competitive Competes for same site as S Binds different site S Lots of S will overcome this Changes S binding site S cannot overcome this Effect similar to no enzyme Www.Medicalstudyzone.com Competitive Inhibitor Same Vm Higher Km Normal Inhibitor Vmax Vmax/2 Km Km [S] Www.Medicalstudyzone.com Non-competitive Inhibitor Lower Vm Same Km Vmax With inhibitor Vmax Vmax/2 Vmax/2 Km [S] Www.Medicalstudyzone.com Competitive Inhibitor 1 Normal V 1 Vm 1 S -1 Km Www.Medicalstudyzone.com Competitive Inhibitor Inhibitor 1 Normal V -1 Km 1 Vm 1 S -1 Km Www.Medicalstudyzone.com Non-competitive Inhibitor Inhibitor 1 1 Vm Normal V 1 Vm 1 S -1 Km Www.Medicalstudyzone.com Inhibitors Competitive Non-competitive Similar to S Different from S Bind active site Bind different site Overcome by more S Cannot be overcome Vm unchanged Vm decreased Km higher Km unchanged Www.Medicalstudyzone.com Dose-Response Jason Ryan, MD, MPH Www.Medicalstudyzone.com Efficacy Maximal effect a drug can produce Morphine is more efficacious than aspirin for pain control Www.Medicalstudyzone.com 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 Pain Control Morphine Analgesia Aspirin Dose (mg) Www.Medicalstudyzone.com 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 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 SBPB>C Emax A B C Effect E50 Potency Log [Dose] Www.Medicalstudyzone.com  Graded Dose Response Curve EMax/Efficacy Emax B>A Emax A B Efficacy Effect E 50 Log [Dose] Www.Medicalstudyzone.com  Competitive Antagonists Emax Receptor Agonist Receptor Agonist + Competitive Antagonist Effect E50 Log [Dose] Www.Medicalstudyzone.com  Non-competitive Antagonists Emax Receptor Agonist Receptor Agonist + Max Effect Effect Non-Competitive Antagonist E50 E50 EC50 Log [Dose] Www.Medicalstudyzone.com 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  Spare Receptors Agonist + Low Dose Non-Competitive Antagonist Emax Agonist + High Dose Non-Competitive Effect Antagonist Log [Dose] Www.Medicalstudyzone.comSource: Basic and Clinical Pharmacology, Katzung Partial Agonists Similar structure to agonists Produce less than full effect Www.Medicalstudyzone.com Partial Agonists Agonist or Partial Agonist Given Alone Effect similar to agonist plus NC antagonist Emax Full Agonist Max Effect Effect Partial Agonist Log [Dose] Www.Medicalstudyzone.com  Partial Agonist Single Dose Agonist With Increasing Partial Agonist 100% Agonist Partial Agonist % Binding 0% Log [Dose Partial Agonist] Www.Medicalstudyzone.com  Partial Agonist Single Dose Agonist With Increasing Partial Agonist 100% Agonist Response Total Response Response Partial Agonist Response 0% Log [Dose Partial Agonist] Www.Medicalstudyzone.com 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  Quantal Dose Response Curve 100% Therapeutic Response Adverse Response % Patients 50% ED50 LD50/ TD50 Log [Dose] Www.Medicalstudyzone.com Therapeutic Index Measurement of drug safety Therapeutic Index = LD50 ED50 Www.Medicalstudyzone.com  Therapeutic Window 100% % Patients 50% Therapeutic Window Minimum Minimum Effective Toxic Dose Dose LD50 Log [Dose] Www.Medicalstudyzone.com Low TI Drugs Often require measurement of levels to avoid toxicity Warfarin Digoxin Lithium Theophylline Www.Medicalstudyzone.com Drug Elimination Jason Ryan, MD, MPH Www.Medicalstudyzone.com  Elimination Zero Order First Order Plasma Concentration Plasma Concentration Time Time Www.Medicalstudyzone.com  Zero Order Elimination Constant rate of elimination per time No dependence/variation with [drug] No constant half life Rate = 5 * [Drug]0 5units Plasma Concentration 5units Ethanol 5units Phenytoin Aspirin Time Www.Medicalstudyzone.com First Order Elimination Rate varies with concentration of drug Percent (%) change with time is constant (half life) Most drugs 1st order elimination Rate = C * [Drug]1 4units Plasma Concentration 2units 1units Time Www.Medicalstudyzone.com Zero Order Elimination Time (hr) Amount (g) Change (g) % 0 20 100 1 15 5 75% 2 10 5 50% 3 5 5 25% Www.Medicalstudyzone.com First Order Elimination Time (hr) Amount (g) Change (g) % 0 10 100 1 5 5 50 2 2.5 2.5 25 3 1.25 1.25 12.5 Www.Medicalstudyzone.com This PDF was created and uploaded by www.medicalstudyzone.com 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 Www.Medicalstudyzone.com 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. Special Types of Elimination Flow-dependent Capacity-dependent Www.Medicalstudyzone.com Flow-dependent Elimination Some drugs metabolized so quickly that blood flow to organ (usually liver) determines elimination These drugs are “high extraction” drugs Example: Morphine Patients with heart failure will have ↓ clearance Www.Medicalstudyzone.com Capacity-dependent Elimination Follows Michaelis-Menten kinetics Rate of elimination = Vmax · C / (Km + C) “Saturatable” → High C leads to Vmax rate When this happens zero order elimination occurs Three classic drugs: Ethanol Phenytoin Aspirin Www.Medicalstudyzone.com Urine pH Many drugs are weak acids or weak bases Weak Acid: HA A- + H+ Weak Base: BOH B+ + OH- Www.Medicalstudyzone.com Urine pH Drugs filtered by glomerulus Ionized form gets “trapped” in urine after filtration Cannot diffuse back into circulation Weak Acid: HA A- + H+ Weak Base: BOH B+ + OH- Www.Medicalstudyzone.com Urine pH Urine pH affects drug excretion Weak acids: Alkalinize urine to excrete more drug Weak bases: Acidify urine to excrete more drug Weak Acid: HA A- + H+ Weak Base: BOH B+ + OH- Www.Medicalstudyzone.com Examples Weak acid drugs Phenobarbital, aspirin Sodium bicarbonate to alkalinize urine in overdose Weak base drugs Amphetamines, quinidine, or phencyclidine Ammonia chloride (NH4Cl) to acidify urine in overdose Historical: Efficacy not established, toxicity severe acidosis Www.Medicalstudyzone.com Drug Metabolism Many, many liver reactions that metabolize drugs Liver “biotransforms” drug Usually converts lipophilic drugs to hydrophilic products Creates water-soluble metabolites for excretion Reactions classified as Phase I or Phase II Www.Medicalstudyzone.com Phase I Metabolism Reduction, oxidation, or hydrolysis reactions Often creates active metabolites Two key facts to know: Phase I metabolism can slow in elderly patients Phase I includes cytochrome P450 system Www.Medicalstudyzone.com Cytochrome P450 Intracellular enzymes Metabolize many drugs (Phase I) If inhibited → drug levels rise If induced → drug levels fall Www.Medicalstudyzone.com Cytochrome P450 Inhibitors are more dangerous Can cause drug levels to rise Cyclosporine, some macrolides, azole antifungals Luckily, many P450 metabolized drugs rarely used Theophylline, Cisapride, Terfenadine Some clinically relevant possibilities Some statins + Inhibitor → Rhabdomyolysis Warfarin Www.Medicalstudyzone.com P450 Drugs Some Examples Inducers Inhibitors Chronic alcohol Isoniazid Rifampin Erythromycin Phenobarbital Cimetidine Carbamazepine Azoles Griseofulvin Grapefruit juice Phenytoin Ritonavir (HIV) Www.Medicalstudyzone.com Phase II Metabolism Conjugation reactions Glucuronidation, acetylation, sulfation Makes very polar inactive metabolites Www.Medicalstudyzone.com Slow Acetylators Genetically-mediated ↓ hepatic N-acetyltransferase Acetylation is main route isoniazid (INH) metabolism Also important sulfasalazine (anti-inflammatory) Procainamide and hydralazine Can cause drug-induced lupus Both drugs metabolized by acetylation More likely among slow acetylators Www.Medicalstudyzone.com Pharmacokinetics Jason Ryan, MD, MPH Www.Medicalstudyzone.com Pharmacokinetics Absorption Distribution Metabolism Excretion All impact drug’s ability to achieve desired result Www.Medicalstudyzone.com Drug Administration Enteral Uses the GI tract Oral, sublingual, rectal Parenteral Does not use GI tract IV, IM, SQ Other Inhalation, intranasal, intrathecal Topical Www.Medicalstudyzone.com Bioavailability (F) Fraction (%) of drug that reaches systemic circulation unchanged Suppose 100mg drug given orally 50mg absorbed unchanged Bioavailability = 50% Www.Medicalstudyzone.com Bioavailability (F) Intravenous dosing F = 100% Entire dose available to body Oral dosing F < 100% Incomplete absorption First pass metabolism Www.Medicalstudyzone.com First Pass Metabolism Oral drugs absorbed → liver Some drugs rapidly metabolized on 1st pass Decreases amount that reaches circulation Can be reduced in liver disease patients Www.Medicalstudyzone.com  Bioavailability (F) Bioavailability = AUC oral x 100 IV AUC IV Plasma Concentration Oral Time Www.Medicalstudyzone.com Volume of Distribution (Vd) Theoretical volume a drug occupies Determined by injecting known dose and measuring concentration Www.Medicalstudyzone.com Volume of Distribution (Vd) Vd = Total Amount In Body Plasma Concentration Vd = 10g = 20L 0.5g/L Www.Medicalstudyzone.com  Volume of Distribution (Vd) Vd = Amount Injected C0 C0 Plasma Concentration Extrapolate C0 Time Www.Medicalstudyzone.com Volume of Distribution (Vd) Useful for determining dosages Example: Effective [drug]=10mg/L Vd for drug = 10L Dose = 10mg/L * 10L = 100mg Www.Medicalstudyzone.com Fluid Compartments 3L Plasma 12L Total Body Extracellular Water 9L 36L 24L Interstitial Intracellular Vd ↑ when drug distributes to more fluid compartments (blood, ECF, tissues) Www.Medicalstudyzone.com Volume of Distribution (Vd) Drugs restricted to vascular compartment: ↓Vd Large, charged molecules Often protein bound Warfarin: Vd = 9.8L Drugs that accumulate in tissues: ↑↑Vd Small, lipophilic molecules Often uneven distribution in body Chloroquine: Vd = 13000L Www.Medicalstudyzone.com Protein Binding Many drugs bind to plasma proteins (usually albumin) This may hold them in the vascular space Lowers Vd Www.Medicalstudyzone.com Hypoalbuminemia Liver disease Nephrotic syndrome Less plasma protein binding More unbound drug → moves to peripheral compartments ↑Vd Required dose of drug may change Www.Medicalstudyzone.com Clearance Volume of blood “cleared” of drug Volume of blood that contained amount of drug Number in liters/min (volume flow) Cx = Excretion Rate Px Www.Medicalstudyzone.com Clearance Mostly occurs via liver or kidneys Liver clearance Biotransformation of drug to metabolites Excretion of drug into bile Renal clearance Excretion of drug into urine Www.Medicalstudyzone.com Clearance In liver or kidney disease clearance may fall Drug concentration may rise Toxicity may occur Dose may need to be decreased Www.Medicalstudyzone.com Clearance Can also calculate from Vd Need elimination constant (Ke) Implications: Higher Vd, higher clearance Supposed 10g/hour removed from body Higher Vd → Higher volume holding 10g → Higher clearance Cx = Vd * Ke Www.Medicalstudyzone.com Clearance Cx = Vd * Ke Ke = Cx Vd Www.Medicalstudyzone.com Clearance Cl (l/min) = Dose (g) AUC (g*min/l) Plasma Concentration Area Under Curve (AUC) Time Www.Medicalstudyzone.com Half-Life Time required to change amount of drug in the body by one-half Usually time for [drug] to fall 50% Depends on Vd and Clearance (CL) t1/2 = 0.7 * Vd CL Www.Medicalstudyzone.com Half-life Www.Medicalstudyzone.com Steady State Dose administered = amount drug eliminated Takes 4-5 half lives to reach steady state 25 20 15 Dose 10 5 0 0 1 2 3 4 5 6 7 Half-Lives Www.Medicalstudyzone.com Calculating Doses Maintenance dose Just enough drug to replace what was eliminated Loading dose Given when time to steady state is very high Get to steady state more quickly When t1/2 is very high In kidney/liver disease, maintenance dose may fall Less eliminated per unit time Less needs to be replaced with each dose Loading dose will be unchanged Www.Medicalstudyzone.com Maintenance Dose Dose Rate = Elimination Rate = [Drug] * Clearance Dose Rate = [5g/l] * 5L/min = 25 g/min Www.Medicalstudyzone.com Maintenance Dose * If Bioavailability is