Michaelis-Menten kinetics
Km is inversely related to the affinity of the enzyme for its substrate. Vmax is directly proportional to the enzyme concentration. Most enzymatic reactions follow a hyperbolic curve (ie, Michaelis-Menten kinetics); however, enzymatic reactions that exhibit a sigmoid curve usually indicate cooperative kinetics (eg, hemoglobin).
Lineweaver-Burk plot
↑ y-intercept, ↓ Vmax. The further to the right the x-intercept (ie, closer to zero), the greater the Km and the lower the affinity. Competitive inhibitors cross each other on the y-axis (same Vmax), but is further right on the x-intercept (increase Km). Noncompetitors have the same x-intercept (no change in Km), but have a steeper curve and cross higher on the y-intercept (lower Vmax).
Enzyme inhibitors
Competitive inhibitors, reversible:- Resemble substrate: Yes- Overcome by ↑ [S]: Yes- Bind active site: Yes- Effect on Vmax: Unchanged- Effect on Km: ↑- Pharmacodynamics: ↓ potency Competitive inhibitors, irreversible:- Resemble substrate: Yes- Overcome by ↑ [S]: No- Bind active site: Yes- Effect on Vmax: ↓- Effect on Km: Unchanged- Pharmacodynamics: ↓ efficacy Noncompetitive inhibitors:- Resemble substrate: No- Overcome by ↑ [S]: No- Bind active site: No- Effect on Vmax: ↓- Effect on Km: Unchanged- Pharmacodynamics: ↓ efficacy
Bioavailability (F)
Part of the pharmacokinetics. Fraction of administered drug reaching systemic circulation unchanged. For IV dose, F = 100%.Orally: F typically <100% due to incomplete absorption and first-pass metabolism. F = area under the oral curve/area under the IV curveIf doses arent the same F = (area under the oral curve x IV dose)/(area under the IV curve x oral dose)
Volume of distribution (Vd)
Part of the pharmacokinetics. Theoretical volume occupied by the total amount of drug in the body relative to its plasma concentration. Apparent Vd of plasma protein-bound drugs can be altered by liver and kidney disease (↓ protein binding, ↑ Vd). Drugs may distribute in more than one compartment. Vd = amount of drug in the body/plasma drug concentration Low Vd: Intravascular- Large/charged molecules- Plasma protein boundMedium Vd: Extracellular fluid- Small hydrophilic moleculesHigh Vd: All tissues including fat- Small lipophilic molecules, especially if bound to tissue protein
Clearance (CL)
Part of the pharmacokinetics. The volume of plasma cleared of drug per unit time. Clearance may be impaired with defects in cardiac, hepatic, or renal function. CL = rate of elimination of drug/plasma drug concentration= Vd x Ke (elimination constant)
Half-life (t1/2)
Part of the pharmacokinetics. The time required to change the amount of drug in the body by 1/2 during elimination. In first-order kinetics, a drug infused at a constant rate takes 4-5 half-lives to reach steady state. It takes 3.3 half-lives to reach 90% of the steady-state level. t1/2 = (0.7 x Vd)/CL in first-order elimination 1 half-life: 50% remaining2 half-lives: 25% remaining3 half-lives: 12.5% remaining4 half-lives: 6.25% remaining
Dosage calculations
Loading dose = (Cp x Vd)/F Maintenance dose = (Cp x CL x τ)/F Cp = target plasma concentration at steady stateτ = dosage interval (time between doses), if not administered continuously In renal or liver disease, maintenance dose ↓ and loading dose is usually unchanged. Time to steady state depends primarily on t1/2 and is independent of dose and dosing frequency.
Types of drug interactions
Additive: Effect of substance A and B together is equal to the sum of their individual effects- Example: Aspirin and acetaminophen Permissive: Presence of substance A is required for the full effects of substance B- Example: Cortisol on catecholamine responsiveness Synergistic: Effect of substance A and B together is greater than sum of their individual effects- Example: Clopidogrel with aspirin Tachyphylactic: Acute decrease in response to a drug after initial/repeated administration- Example: Nitrates, niacin, phenylephrine, LSD, MDMA
Receptor binding
Competitive antagonist: Shifts curve right (↓ potency), no change in efficacy. Can be overcome by ↑ the concentration of agonist substrate.- Example: Diazepam (agonist) + flumazenil (competitive antagonist) on GABA receptor. Noncompetitive antagonist: Shifts curve down (↓ efficacy). Cannot be overcome by ↑ agonist substrate concentration.- Example: Norepinephrine (agonist) + phenoxybenzamine (noncompetitive antagonist) on α-receptors. Partial agonist: Acts at same site as full agonist, but with lower maximal effect (↓ efficacy). Potency is an independent variable.- Example: Morphine (full agonist) vs buprenorphine (partial agonist) at opioid μ-receptors.
Zero-order elimination
Capacity-limited elimination. Rate of elimination is constant regardless of Cp (ie, constant amount of drug eliminated per unit time). Cp ↓ linearly with time. Examples of drugs – phenytoin, ethanol, aspirin (at high or toxic concentrations).
First-order elimination
Flow-dependent elimination. Rate of first-order elimination is directly proportional to the drug concentration (ie, constant fraction of drug eliminated per unit time). Cp ↓ exponentially with time. Applies to most drugs.
Urine pH and drug elimination
Ionized species are trapped in urine and cleared quickly. Weak acids: Phenobarbital, methotrexate, aspirin. Trapped in basic environments. - Treat overdose with sodium bicarbonate to alkalinize urine. Weak bases: TCAs, amphetamines. Trapped in acidic environments.- Treat overdose with ammonium chloride to acidify urine. TCA toxicity is generally treated with sodium bicarbonate to overcome the sodium channel-blocking activity of TCAs but not for accelerating drug elimination.
Drug metabolism
Phase I: Reduction, oxidation, hydrolysis with cytochrome P-450 usually yield slightly polar, water-soluble metabolites (often still active).- Geriatric patients lose phase I first. Phase II: Conjugation (methylation, acetylation, glucuronidation, sulfation) usually yiels very polar, inactive metabolites (renally excreted).- Patients who are slow acetylators have ↑ side effects from certain drugs because of ↓ rate of metabolism.
Efficacy vs potency
Efficacy: Maximal effect a drug can produce. ↑ Vmax = ↑ efficacy. Unrelated to potency (ie, efficacious drugs can have high or low potency). Partial agonists have less efficacy than full agonists. Potency: Amount of drug needed for a given effect. Unrelated to efficacy (ie, potent drugs can have high or low efficacy). ↓ EC50 = ↑ potency = ↓ drug needed.
Therapeutic index
Measurement of drug safety. Therapeutic index (TI) = TD50/ED50 = median toxic dose/median effective dose Therapeutic window – dosage range than can safely and effectively treat disease. Safer drugs have higher TI values. Drugs with lower TI values frequently require monitoring (eg, warfarin, theophylline, digoxin, lithium). LD50 (lethal median dose) often replaces TD50 in animal studies.
Acethylcholine receptors
Nicotinic ACh receptors are ligand-gated Na+/K+ channels. - NN (found in autonomic ganglia, adrenal medulla) - NM (found in neuromuscular junction of skeletal muscle) Muscarinic ACh receptors are G-protein-coupled receptors that usually act through 2nd messengers.- M1-5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands (cholinergic sympathetic)
Autonomic drugs
Release of NE from a sympathetic nerve ended is modulated by NE itself, acting on presynaptic α2-autoreceptors → negative feedback. Amphetamines use the NE transporter (NET) to enter the presynaptic terminal, where they utilize the vesicular monoamine transporter (VMAT) to enter neurosecretory vesicles. This displaces NE from the vesicles. Once NE reaches a concentration threshold within the presynaptic terminal, the action of NET is reversed, and NE is expelled into the synaptic cleft, contributing to the effects of ↑ NE observed in patients taking amphetamines.
Bethanechol
Direct cholinomimetic agonist - Activates bowel and bladder smooth muscle- Resistant to AChE- No nicotinic activity Applications:- Postoperative ileus- Neurogenic ileus- Urinary retention
Carbachol
Direct cholinomimetic agonist - Carbon copy of acetylcholine (but resistant to AChE) Application:- Constricts pupil and relieves intraocular pressure in open-angle glaucoma
Methacholine
Direct cholinomimetic agonist - Stimulates muscarinic receptors in airway when inhaled Application:- Challenge test for diagnosis of asthma
Pilocarpine
Direct cholinomimetic agonist - Contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed-angle glaucoma)- Resistant to AChE- Can cross blood-brain barrier (tertiary amine) Application:- Potent stimulator of sweat, tears, and saliva- Open-angle and closed-angle glaucoma- Xerostomia (Sjögren syndrome)
Edrophonium
Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh Application:- Historically used to diagnose myasthenia gravis; replaced by anti-AChR Ab (anti-acetylcholine receptor antibody) test.
Neostigmine
Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh- No CNS penetration (quaternary amine) Application:- Postoperative and neurogenic ileus- Urinary retention- Myasthenia gravis- Reversal of neuromuscular junction blockade (postoperative)
Pyridostigmine
Indirect cholinomimetic agonist (anticholinesterase) ↑ ACh↑ muscle strength Application:- Myasthenia gravis (long acting)- Does not penetrate CNS (quaternary amine)
Cholinesterase inhibitor poisoning
Often due to organophosphages, such as parathion, that irreversible inhibit AChE. - Diarrhea- Urination- Miosis- Bradycardia- Emesis- Lacrimation, salivation- Sweating- BronchospasmMay lead to respiratory failure if untreated. Organophosphates are often components of insecticides; poisoning usually seen in farmers. Antidote – atropine (competitive inhibitor) + pralidoxime (regenerates AChE if given early)
Atopine
Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications. Eye: ↑ pupil dilation, cycloplegiaAirway: Bronchodilation, ↓ secretionsStomach: ↓ acid secretionGut: ↓ motilityBladder: ↓ urgency in cystitis Adverse effects: ↑ body temperature (due to ↓ sweating); rapid pulse; dry mouth; dry, flushed skin; cycloplegia; constipation; disorientationCan cause acute angle-closure glaucoma in elderly (due to mydriasis), urinary retention in men with prostatic hyperplasia, and hyperthermia in infants. - Jimson weed (Datura) → gardener's pupil (mydriasis due to plant alkaloids)
