Pharm Unit 2 More Review PDF

 Phase 1 : catabolic , more reactive and Sometimes toxic. - if you see CP450-phase Phase 11 : anabolic , less reactive, P more20 soluble , drug Clearance...

 Phase 1 : catabolic , more reactive and Sometimes toxic. - if you see CP450-phase Phase 11 : anabolic , less reactive, P more20 soluble , drug Clearance Phase II is If insufficient , the reactive intermediates from Phase I can accumulate and potentially cause toxicity. - Pharmacokinetics : Time course of ADME of drugs in patients. - Pharmacodynamics : Biochemical and Physiological effects of drug, the mechanism of action including and dose-response relationships. - Pharmacokinetics - plasma [I vs Time - Pharmacodynamics-dose response cure At the active site  Response is proportional (directly related) At the Active Site. to dose - easier to measure [7 in plasma. - Dose (amount) at active site is Proportional to plasma [J. - Plasma [3 time curve is directly related to response. curve shape depends upon how drug - is administered and how ADME affects drug. [] time curve is the Net result of ADME. - Clearance : The rate of drug elimination from the body. - disease can alter clearance. - Half life (t12) : time for plasma drug Is to ↓ by. half - Bioavailability (F) : amount of drug that ultimately reaches the blood. F for IV = 1 F2) for all other routes. Rate : Speedor velocity at which a process occurs. - consider a metabolic n by which drug A is metabolized by metabolite M. A - >X1 - Rate of rxn can be determined rate Of: by measuring - Disappearance of A - Appearance of M - order of the run depends upon relationship but rate and [A - - zero order n : rate is onstant and does not of [A] depend - First order rxn : rate On depends [A] As [A] + Over time , rate b.  Zero Order half life changes ul time. + y2 = [0 540/k]. 0 5+, -. First Order half life doesn't time change wh + 112 = 0. 693 - enteric-coated capsules protect drugs from stomach acid and release them in intestines I leading to delayed but effective absorption , - Time-release capsules provide sustained druplevealong forconsistent of period time who frequent dosing. - Disease State : - distribution : diseases like liver or Kidney affect blood flow and issues protein binding , I drug levels and toxicity risk. - elimination : Liver/Kidney diseases I risk of Slow drugClearance , accumulation and prolonged effects. - Age : - childern : immature metabolism and renal function lead to slower clearance requiring dose , adjustments Reduced livery kidney. Elderly : -  function and altered body composition slow drug metabolism and elimination , I half lives. - Food : - Absorption : food can enhance delay, , reduce drug absorption depending , on the drug. ex fatty mealsa - : lipophilic drug absorption , while calcium t absorption of certain antibiotics. - Drug-drug interaction : - Absorption some drug : bind in the gut, I absorption - metabolism : drugs can inhibit or induce CYP450 enzymes , altering drug levels. All thesefactors help adjust dosing to improve drug efficacy and safety. Protein targets for drug interaction - Receptors - Enzymes Transporters (Carrier molecules - - Transmission of info across a biological membrane (cell or intracellular membrane). - example Nerve impulse : transmission. - Nt is released from a nerve  - Nt interacts wa receptor on another cell - initiates a sequence of events in target cell - Nerve Cell initiation of AP - muscle cell-contraction or relaxation. Receptors areProteins Types of Receptors : 1. Ion channels - ionotropic receptors Gen fast no targets - 2. G-protein Coupled Receptors (GPCRs) - Thetransmembranespan is - largest family for ; target many hormones and slow transmitters.. Kinase-linked 3 and related receptors -extracellular-binding domain and intracellular domain enzymatic. 4. Nuclear Receptors Regulate gene expression - Ion Channels as drug targets : Ions cannot penetrate lipid - bilayer of cell membrane wion channels or transporters. - Ion Channels Control ion Auxes Across membrane - Ion channels are H20-filled pores surrounded protein molecules by that span the mem. - Direction of movement of ions depends upon - ion [b on either side of mem - Net electrical charge of mem (mem. potential). - Ion Channels are characterized : -Selectivity for a particular ion C Gating properties - - molecular structure cation or anion selective Ligand-gated Ion Channels - - open when one or more agonist is bound - voltage gated Ion channels - Gated by changes in the transmembrane potential. - Many drugs and toxins exert their effects by altering behavior of ion Channels. direct indirectly or. Ligand gated channels : Receptors of this control the - type fastest synaptic events of nervous system Lacetylcholine). P Nat Excitatory nt : -  and+ permeability (Sometimes (a2 ) + - Speed : fraction of millisecond - implies intermediate biochemical no steps involved in transduction. uni G-Protein-coupled Receptors (GPCRs) : -very family of receptors. abundant - common target for drugs - Many NTs can interactwl both GPCRs and ligand gated iOn Channels same molecule to produce - fast (lrgand-gated) and relatively Slow (GPCRs) effects. GPCR components : Receptor - Located in tell mem M transmem - alpha helicies - Ligand binding domain : - Small molecules (noradrenaline, acetylcholine) : buried in Cleft but alpha helical segments - Larger molecules (peptide ligands) in extracellular loop - Intracellular G-protein binding domain - selective binding to G Proteins. GPCR Components : G-Protein - Function : recognize activated GPCRs and pass on the "message" to effector systems that generate a cellular response. - on cytoplasmic side of cell mem , - G Protein Activation results in Amplification - dissociation of G-protein from activated agonist-receptor complex allows another G-protein to be activated. - Activation can continue as long as agonist-receptor complex remains intact GPCR components : Target - Enzymes & Ion Channels -mult targets possible GPCR Cycle 1. Un-stimulated GPCR - GPCR and G-protein aren't associated. 2 Agonist binds to GPCR - Activates receptor - G-protein binds to activated recept. via its a-subunit - GTP replaces GDP on asubunit. G-protein dissociates from receptor 3 splits into Alpha and betagamma - subunits 4. fragments G-protein effectors interact w/ stimulate or inhibit may target -. 5 Return to un-stimulated state and is ready for another Cycle  CAMP = Classical Secondary Messenger - Regulates many functions cellular - channels ion , energy metab , etc. - All regulation sharesCommon mechanism : - Activation of Protein Kinases by CAMP - Protein Kinases phosphorylate proteins - Protein Phosphorylation inactivates or activates enzymes - CAMP inactivated by hydrolysis to 5"-AMP by phosphodiesterases CAMP , secondary messenger in GPCRs : - GPCRs activate G-proteins - G-proteins activateadenyly) Cyclase - Adenylyl Cyclase produce CAMP CAMP activates downstream Signaling - (like protein Kinase A) to generate a cellular response. why does pharmacology care?abt GPCRs andIndary messengers They affect cellular activity - - Allows therapeutic intervention. - Kinase Kinase-linked Receptors activity - Large proteins - - extracellular Single ligand Transmem binding domain Alpha. helix domain - & - Large intracellular , protein Catalytic , domain - Receptors for various hormones and growth factors and cytokines , -Generally affect cell division , cell growth, differentiation , etc. 1. Ligand associates wl binding domain. Activated 2 receptor dimerize. 3 Autophosphorylation of Catalytic domains 4. Adapter Protein is phosphorylated by kinases and detaches. Affects 5 gene transcription via several mechanisms including kinase cascade. Types of Receptor Kinases : - Serine/Threonine Kinases Tyrosine Kinases - - Cytokine receptors Phosphylation in Signal Tranduct Protein - Phosphorylation Controls function and binding properties of intracellular Proteins - Protein phosphorylation is Catalyzed by protein Kinases - Many wi different substrates Kinases allows specificity in pathway activation. - some GPCRs are inactivated by Phosphorylation catalyzed by receptor Kinases - Phosphatases phosphate group cleave from phosphorylated effect of proteins, Kinases reversing. ~ Nuclear Receptors - Present in Cytoplasm or win nucleus - Translocated to nucleus after activation - unlike other receptors , can directly interact W/ DNA Affects gene transcription , - ultimately protein synthesis - Ligands include: steroid hormones , Thyroid hormones Vit D , etc. , - Receptor-mediated regulation of DNA transcription - Receptors are intracellular so , ligands must first enter cell to interac wy them. are lipophilic , easily cross Ligands - tell membrane Basic structure of Nuclear Receptors : Binding domain (interacts w/ ligand - and DNA binding domain - When nuclear receptor binds wl ligand : - Receptor changes conformation - Receptor dimer forms - Dimerbinds to Specific DNA Sea Chormone-responsive element) - Pin RNA polymerase - Produces Specific mRNA Coccurs in minutes) - Protein Synthesis begins Physiological take response to protein - synthesis may hours-days to occur. - Many xenobiotics affect activity of Xenobiotic metabolizing enzymes. - Exposure metabolism , ↑ clearance - PXR(SXR) class of nuclear recept respond to wide range of xenobiotics. - Peroxisome proliferation activated nuclear receptors (PPARs) are key control of lipid metab. in the players and pathogenesisof metabolic and cardiovascular diseases  - Molecular details of receptor function revealed diseases directly linked to receptor function or malfunction. m Pharmacogenomics : study of how diff genes affect drug response. variation due to age : - Less efficient elimination in neonates apiver)more - metabolism notthe same can result in and intense prolonged drug effects.I half life. CP450 enzyme activity cassociated w/ phase 1) decreases steadily but , unpredictably wi age, Drug metabolizing enzyme lower in neonates activities - Takes at least 8 weeks to reach adult levels. During Pregnancy Kidney not effective. , elimination  Polymorphism variation : in DNA sequence of coded which alters AA sequence Protein If alteration produces a deleterious. - effect mutation dies out. , - If ambiguous effect occurs, advant or disadvant. may occur. GGPD is the first step of Pentose Phosphate pathway(shunt) - helps produce NADPH Which Produces GSH. - protect RBC's NADPH and GSH against Oxidative damage and subsequent hemolysis. GGPD deficiency can be protective malaria due to against vulnerability of RBCs under oxidative stress , but it can also lead to serious problems like hemolytic anemia (a condition where the body doesn't have enough RBC to Carry 02) When exposed to certain triggers like medications (primaquine) and fava beans. Rxns (Type B ADR) Idiosyncratic - unpredictablexns, not dose related - unrelated to the main effect of the drug. - Qualitatively abnormal and usually , serious rXnS.  - ex : Malignant hyperthermia : Severe and rapid rise in body temp upon exposure to some muscle relaxants and anesthetic gases Life threatening , if left untreated - caused by an inherited - abnormality in cast release in muscle. Pharmacokinetic's alterations in : - Absorption : GI stasis / diarrhea, malabsorption from SI. - Distribution : Altered protein binding, impaired BBB - Metabolism : impaired hepatic function - Excretion : impaired renal function Pharmacodynamics alterations - Receptors. ex : myasthenia gravis = alteration in Nicotinic receptors - signal transduction. Ex : mutant GPCRs remain "turned On" in absence of hormone agonist Administration of one drug may alter the action of another drug - may effect pharmacodynamics and or pharmacokinetic's interactions  - Risk of drug interaction PWI : polypharmacy - concurrent : treatment mult wh , drugs - use of dietary or her bel supplements. Pharmacodynamic drug-drug interactions where , affect each drugs other's action in the body : - Antagonism : 2 drugs w opposite effects - EX : Aspirin (inhibits clotting) combined w/ warfarin (a blood thinner) will actuallyI bleeding risk. - EX : Alcohol enhances the drowsiness caused by antihistamines. Drug-drug interactions can also affect Pharmacokinetics ADME : - A : One drug slows gastric emptying or inhibits absorption of another - D: Changes in Plasma protein [J. affect drug binding and free drug levels - M : One drug induces or inhibits enzymes, altering the metabolism of another. Cardiac drugs can change hepatic - blood flow , affecting metabolism. - E : Altered protein binding free drug filtration (Kidney); P and glomerular tubular excretion /absorption untary PH can be affected  Adverse Drug rxns (ADR) : harmful affects of drugs iChangeovertime.Frtmedyi - effects I 4th time use, intolerable CADR). Adverse drug rxns (ADR) occur blc While would only affect the an ideal drug target tissue in , mostreality , drugs also impact other tissues. - This happens blc the drug's target. Tissues often exists in mult the body. throughout All drugs have side effects Tolerable dependant on - - intolerable (ADR)> person Diagnosis of ADR is difficult Type A ADR Augmented : , expected but exaggerated responses, - , either pharmacological Predictable and or toxicological involve the - typically known mechanism of action. can occur in target or Indary tissues - Often caused by in ADME due Changes - - Todisesordrug interactioners le if the dose reduced. is  Type B APR , Bizarre - unexpected responses, unrelated to Pharmacological effect dose - unpredictable, idiosyncratic ,. independent - TypeC : Chronic xns Type D: delayed rxns - Type E : effects from wldrawl of drug. - Pharmaceutial : interaction occurs prior to administration (mixing acidic drug WI basic drug) ; can cause inactivation. Post-marketing Surveillance is necessary ADR that weren't detected to identify during Clinical trials especially rare or , term effects in diverse pop long larger include ,. of - Limitations underreporting , difficulty detecting delayed ADRs in effects and , Challenges in linking ADRs to specific drugs due to concurrent drug use. Gen mechanisms of toxic damage to cells Oxidative destruction : - Lipid peroxidation : of lipids causing cell mem damage. - Protein modification : Disruption of enzyme function or structural proteins  - DNA damage Mutations of covalent : binding to DNA that can lead to Cancer - Impaired metabolism Interference : ul cellular respiration or energy production. Mutagenesis process of inducing : genetic mutations typically involving , in DNA sequence. Changes carcinogenesis : multi-step process that results in the formation of cancer. - ANS : 2 efferent neurons pre and - post ganglionic neuron Somatic nervous system : I efferent neuron Sympathetic thoracolumbar : - short preganglia neuron Long postganglia neuron - Parasymphatic Craniosacral : Enteric nervous system : can function independently of ANS. Synpase : Junction bH 2 neurons or a neuron and its target cell.  Types of synapses in ANS: Adrenergic - - N+= norepinephrine ; occurs at the of symphatic post-ganglionic Synapse - cholinegric - N = a cetylcholine (nic and mus) ; present Synapseota sympatheticganglionic at pre Chic) and post (mus) ganglionic synapses of the parasympathetic Gen scheme of Neurohumoral Transmission : 1. NT Synthesis and storage in vesicles. 2 Nerve impulse reaches axon terminal. 3 vesicles move to cell membrane 4. NT is released into synapse (exocytosis). NT diffuses across synapse 5. NT binds to receptor 6 4.. Response is generated terminated 8 is Signal Neg Feedback inhibition : - Further norepinephrine release is inhibited by norepinephrine in synapse. -serves to limit amount norepinephrine released.  Adrenergic Transmission is - Termination : Norepinephrine reabsorbed or broken down by enzymes - Modulation :Receptor activity can be regulated by Feedback mechanisms cholinergic Termination : Ach is broken down - by the enzyme acetylcholinesterase in the synapse. sympathetic: Prate , P force Parasympathetic : I rate , ↓ force - 2 types of cholinergic receptors -muscarinic - Nicotinic effect I heart rate mus : sweating, an anomaly (part of symphatetic) Nicotinic : Ligand-Gated Ion Channel (nAChR) MUS : G Protein Coupled receptors (GPCRs) - 5 subtypes (M, - Ms) - M2 and My inhibit adenyly ! cyclase - intracellular CAMP  Muscarini Dagonists : - agents producing muscarinic effects Muscarinic Antagonists : agents blocking muscarinic effects - Ganglion-stimulating agents Nicotinic : - receptor agonists neuromuscular blocking agents, Depolarizingactivate nicotini Dreceptors agonists but then , keep them in a depolarized State preventing further muscle , contraction Non-depolarizing agents entirely antagonists, , block these receptors , contractions by stopping muscle Ach No mus contraction competing wh. Muscarinic Agonists Effects : - SLUDDE : salivation , Lacrimation , Urination Diarrhea , emesis , Muscarinic effects - Antagonists Anti-SLUDDE : NiCOtmic Agonists' sites of 2 possible action - - Ans ganglia - Neuromuscular junction  muscle-twitches Indirect - : Agonists don't directly activate receptor but i the activity of + such as Ach in Other ways such as : - Preventing Ach breakdown , (metabol) - Pach release - In the case of anti-cholinesterases, they Ach's action by indirectly 1 enhance of the enzyme that would inhibitingbreak normally Ach in it down , leading to more synapase 2.types of cholinesterases : - AcetylcholineSterase CAChE) Butyrylcholinesterase (BUChE) = - pseudocholinesterase Inhibition of Ach Synthesis : preventing the production of Ach a NT , Inhibition of Ach release : blocking release of Ach into the synapse , it from preventing transmitting signals neurons or neurons to muscles ↓ It. -  Adrenergic NT - Norepinephrine (NE) - Epinephrine - Dopamine NE is stored in vesicles until needed NE release involves exocytosis triggered eazt influx during depolarization by - Regulated by : - Autonhibitory Feedback via presynaptic a2 receptors - cast influx is promoted by CAMP , produced by adenylate cyclase - receptors inhibit adenylate a2 Cyclase reducing CAMP , cart influx, , and thus NE exocytosis. cAMP is a Indary messenger that is produced by adenylate cyclase When a neuron is depolarized. CAMP helps relay Signal transduction : - from NT receptors (a 2 Signals adrenergic receptors) on the neuron to intracellular presynaptic processes - Regulating Ca2+ influx : Promotes Cart influx (movement of ca2t) through ion channels which trigger release (exocytosis) Of NT (NE)  Feedback mechanism : When - a2 receptors are activated , they presynaptic inhibit adenylate cyclase activity, to↓ CAMP production. leading - This reduction ↓ cast influx which ↓ NE exocytosis. All Adrenergic Receptors are GPCRs a2 receptors : inhibit NE release into synapse Bi receptors : ↑ Cardiac rate and force B2 receptors : Bronchodilation, relaxation of visceral smooth muscle 4 Ways to affect NE release 1. Direct block 2 NE release. WI nerve AP. 3 Pre-synaptic receptor agonism that inhibits release or stimulates extra-normal release 4 Por ↓ available intracellular NE. stores Specific Adrenergic Antagonists : - specifically blocks either a or B ( adrenergic receptors for specific. more targeted allowing - , selectively  effects wi reduced risk of therapeutic unwanted side effects. Nonspecific Adrenergic Antagonists - Blocks both a and beta adrenegic receptors. ranlead torangeofphysiologia are receptor types. - may cause side effects related to both a and B inhibition. Specific Adrenergic Agonists : - Activate both a and B adrenergic receptors , Produce a wide range of physiological - responses due to activation of mult. receptortypes P. - can lead to both heart rate and vasocontriction , etc. Specific Adrenergic Agonists : foror -targetParticularreceptors a