Lecture 1 - Drug - Receptor PDF

What is Pharmacology? Pharmacology - science investigating the mechanisms by which drugs act on the functions of living things. - Concerned with the study of “drug” action on the body your owrody Dr...

What is Pharmacology? Pharmacology - science investigating the mechanisms by which drugs act on the functions of living things. - Concerned with the study of “drug” action on the body your owrody Drug = man made, natural, or endogenous molecule that ↓ drugs produced by ⑳ exerts a biochemical or physiological effect on the cell, tissue, organ, or organism Neuropharmacology – study of drug-induced changes on the central and peripheral nervous system Psychopharmacology – behavioral pharmacology, the study of effect of medication on psyche. Study of psychoactive drugs Pharmacology – Ligand/Receptor Interactions Pharmacology – Advances in the treatment of disease Ine facture Paul EhrlichTourmandy a ver +O ~1900; one of the main founders of chemotherapy Nobel Prize in Physiology or Medicine 1908 Goal: to find chemical substances which have special affinities for pathogenic organisms Linked these chemicals with arsenic sidechains ↑ “Magic Bullets” dyes something : link a A affinity with for toxic, specific bacteria dyes (syphilis have Treatment for Syphilis Salvarsan – Introduced in 1910 totion kills Syphilis Salvarsan Drugs Affect the Nervous System at a Variety of Sites a membrane easiest-druginterac ↳ transmembranethe · crosses Membea 7. pump art ↳ - Schematic diagram of potential drug targets. Kenakin, 2004. A Pharmacology Primer. Elsevier. pg 3. Drug - Receptor Interactions minase activity showa & - · Structural basis of specific enzyme inhibition have don't Geo prote e most Example: Imatinib interaction with the BCR-Abl kinase = genexe mutao amemia Drug - Receptor Interactions a (irreversible)ifadrugbin, Major Types of Drug - Receptor Interactions SITE OF DRUG–RECEPTOR SITE OF RESULTANT RECEPTOR TYPE INTERACTION ACTION Transmembrane ion channel (A) Extracellular, intrachannel, or Cytoplasm intracellular Transmembrane linked to GPC-R Extracellular or intramembrane Cytoplasm intracellular G protein (B) Transmembrane with enzymatic Extracellular Cytoplasm cytosolic domain (C) Intracellular (D) Cytoplasm or nucleus Cytoplasm or nucleus Transmembrane Ion Channels CHANNEL MECHANISM OF FUNCTION TYPE ACTIVATION Ligand- Binding of ligand to Altered ion gated channel (Confirmational change conductance Change in Voltage- Altered ion transmembrane gated conductance voltage gradient Binding of ligand to transmembrane Second receptor with G Second messenger protein-coupled messenger- regulates ion cytosolic domain, regulated conductance of leading to second (Gpar) channel messenger generation Ligand-gated nicotinic acetylcholine receptor Transmembrane G-protein coupled receptors (GPCRs) sensesa Receptor-mediated activation of a G protein and the resultant effector interaction The Major G-Protein Families need ta Yarnoam iv Masuho et al.; Cell; 2020 BY subunit] G-alpha Protein TubunitDirect Actions / Indirect Actions protein (target/effector cellular activation Gs L subunit binds = cause Activates adenylyl cyclase ↑ Camp Conc. A. AP. Potential excitability ↑ synaptic trans. Gi ↓ subunit binds = cause Inhibits adenylyl cyclase ↓ Camp conc. ↓ A P.. Potential ↓ synaptic trans. Go called o because i t has no target Go Inhibits Ca2+ channels, Activates K+ channels · protein (2 subunit does not do anything this effect Go causes/produces causes F poly o f binds BlY subunit = Gq Activates phospholipase C G12/13 Motility/contractility machinery (e.g. Rho activation) Transmembrane G-protein coupled receptors (GPCRs) reaction Zin The subtype of Gα protein that is activated often determines which effector the G protein will activate Common Gα subunits are Gαs and Gαi which stimulate or inhibit adenylyl cyclase Gαq stimulates phospholipase C GPCR Signaling Convergence open an = conc meanin A limited number of mechanisms are used to transduce intracellular signal cascades. In some cases, this allows for convergence, where two different receptors have opposite effects that tend to negate one another in the cell. Transmembrane Receptors with Enzymatic Cytosolic Domain ProteSure. Major types of transmembrane receptors with enzymatic cytosolic domains. Phosphylation A. Receptor tyrosine kinases (e.g. the insulin receptor) B. Receptor tyrosine phosphatases. (e.g. immune system receptor tyrosine phosphatases). C. Nonreceptor tyrosine kinases. De-phosphorylation D. Receptor serine/threonine kinases. (e.g. TGF-β receptor superfamily) E. Receptor guanylyl cyclases. (e.g. B-type natriuretic peptide receptor)  Intracellular Receptors Lipophilic molecule binding to an intracellular transcription factor. A. Small lipophilic molecules can diffuse through the plasma membrane and bind to intracellular transcription factors. B. Ligand binding triggers a conformational change in the receptor (and often, as shown here, dissociation of a chaperone repressor protein) that leads to transport of the ligand–receptor complex into the nucleus. In the nucleus, the ligand–receptor complex typically dimerizes. C. The dimerized ligand–receptor complex binds to DNA and may then recruit coactivators or corepressors. These complexes alter the rate of gene transcription, leading to a change (either up or down) in cellular protein expression. Receptor Type: Intracellular Receptors Pharmacodynamics ↓ Drug-Recept on Pharmacodynamics - A term used to describe the effects of a drug on the body. These effects are typically described in quantitative terms. Factors involved include molecular interactions by which pharmacologic agents exert their effects AND integration of these molecular actions into an effect on the organism as a whole. It is important to describe the effects of a drug quantitatively in order to determine appropriate dose ranges for patients, as well as to compare the potency, efficacy, and safety of one drug to that of another. Pharmacokinetics - Factors that influence whether a drug is successfully able to cross the physiologic barriers that limit the access of foreign substances to the body: Absorption, Distribution, Metabolism, Elimination (ADME) Pharmacodynamics – Ligand/Receptor Interactions Tissue specific receptor expression expression * which gene specific protein requires I ·. of release ↓ Uhlen et al.; Science, 2015 Cell-type specific genetic expression in the nervous system ! future drugsthat targea = https://celltypes.brain-map.org/ Pharmacodynamics describe Different ways to Drugs Agonists > - ligand-receptor interaction Full Agonist - Activates receptor with maximal efficacy ex : endogenous molecules Partial Agonist - Activates receptor but not with maximal efficacy Inverse Agonist - Inactivates constitutively active receptor Antagonist > blocks - the being recepter ac tive from Competitive antagonist - Binds reversibly to active site of receptor; competes with agonist binding to this site Non-competitive active site antagonist - Binds irreversibly to active site of receptor; prevents agonist binding to this site Allosteric Modulators indirectly influencing receptors Positive Allosteric Modulator (PAM) - also known as allosteric enhancers or potentiators, induce an amplification of the effect of the primary ligand. Has no function by itself, requires agonist to have an effect Negative Allosteric Modulator (NAM) - Allosteric Antagonists - Binds reversibly or irreversibly to site other than active site of receptor; prevents conformational change required for receptor activation by agonist Pharmacodynamics Therapeutics in neuropharmacology are rarely specific or rational ↳ bindsg speci t. receptors S Drug-Receptor Binding Curves konPetworkise sible interactore e ogo nices L+R LR Kd = koff/kon ↓ free ↓ tree koff ↓ bound ligand receptor ligand receptor [h] = free liganc Receptor [R] = free [L] total = [L] + [LR] [R] total = [R] + [LR] [L][R] Ro = [R] to t a l Kd = [LR] A. Linear graphs of drug–receptor binding for two drugs with different values of Kd. B. Semilogarithmic graphs of the same drug– receptor binding. Kd is the equilibrium dissociation constant for a given drug–receptor interaction—a lower Kd lower the Ra = affinity indicates a tighter drug–receptor interaction If (higher affinity). morepotentanta a higher binding Kd corresponds to the ligand concentration at affinity. which 50% of the receptors are bound = R + otal (occupied) by ligand. [L] is the concentration of free (unbound) ligand (drug), [LR] is the concentration of ligand–receptor complexes, and [Ro] is the total concentration of occupied and unoccupied receptors. total  Practice Question: Ask stions to bind? : can you find a drug I. DO that they binds to a receptor (binding bound affinity( to Metric = Kd : 50 % 1. ligand recepter ? 2. Does the drug do anything concintration metric = Elso : effective to t re a t a disease ?. 3 can we use this drug metric = ED50 : effective closing (Howieng) 4. side effects ? Drug > metric TD5o effects - = toxicity · lethalitity effects -> metric = LD50 You are characterizing a newly developed drug and performing a binding affinity assay. This assay consists of a target receptor concentration of 250 nM, and total drug concentration of 100 nM. You find under these conditions that 30% of the drug binds to the target receptor. Receptor *wasso 23 d Using this information, please calculate an estimate of the drug-receptor equilibrium dissociation constant (Kd): o necessar z = Receptor complex R L+ R = L F - LR = fraction x total bound - = 0. 30 x 100nM 100 LR = 30nM all conc. must the same be in F u n i ts =R (Fonzom 5 & drugconcentrate to hp - = en 0. 1 AB 100nm = L + 30nM 250 nM = R + 30nM L = 70nm R = 220mM Dose-Response Curves Dose–response curves demonstrate the effect of a drug as a function of its concentration. EC50 is the potency of the drug, or the concentration at which the drug elicits 50% of its maximal effect. [L] is drug concentration, E is effect, Emax is efficacy, and EC50 is potency. amore Active ↓ Higher Potency (EC50) = the concentration at which the drug elicits 50% of its maximal response Efficacy (Emax) = is the maximal response (produced by the drug Y comparing drug to endogenous drug. ***Potency and efficacy are not intrinsically related—a drug can be extremely potent but have little efficacy, and vice versa*** Drug-receptor vs. dose-response curves Drug–receptor binding curves and a dose–response curves are not necessarily equal In the absence of spare receptors, there often exists a close correlation between a = Shiftentratio drug– receptor binding curve and a dose–response curve—the binding of additional drug to the receptor causes an incremental increase in response, and EC50 is approximately equal to Kd. binding > - = efficacy. In situations with spare receptors, however, a half-maximal response is elicited when less than half of all receptors are occupied (the term spare implies that occupation of every receptor with drug is not necessary to elicit a full response). Receptor-dose responses with spare receptors Example: GPCR Signaling is activated as the Recepter different as long many - by T ligand it can produce requires Amplification = only effect responses- Amplification to produce huge recepters some Maximal cellular response possible even without full receptor activation Dose-Response Curves a modification o I fulloni fullgonist mat partis Full and partial agonist dose- response curves partial t Various alkyl derivatives of trimethylammonium all stimulate muscarinic acetylcholine (ACh) receptors to cause muscle contraction in the gut, but they produce different maximal responses, even when all receptors are occupied. more efficacy Agonists that produce only a partial response, such as the heptyl and octyl derivatives, are called partial agonists. Partial Agonist more p o te n t = requires less conc. Partial agonists may be more or less potent than full agonists (e.g. Buprenorphine vs. Morphine) Quantal dose-response curves rese Quantal dose–response curves demonstrate the average effect of a drug, as a function of its ther's used dish concentration, in a population of individuals. a ↓ peri Quantal dose–response relationships are useful for predicting the effects of a drug when it is administered to a population of individuals and for determining population-based toxic doses and lethal doses. These doses are called the ED50 (dose at which 50% of subjects exhibit a therapeutic response 1 if you to a high enough will trigger to a drug), TD50 (dose at which 50% of subjects - concentration you · ideally you wa n t these possible lethality. experience a toxic response), and LD50 (dose at which 50% of subjects die). as as fa rapart Drug Safety Measurements: wantswant a Therapeutic Index (TI) = TD50/ED50 ↓ ↓ unitsunits would index safer/better theraputic = High the drug. we Pharmacodynamics Summary of agonist and antagonist action ↓ does  Antagonist Classification 4 I he e sTo ste againsthas bind targeting is antagonist Me agonistitea factors. covalent binding oncea.. ↑ wins-binding affinity - and concentration GPCR that Stimulate - is Gs coupled you Camp concintration see up go. Pharmacodynamics Types of receptor antagonists. Differences between agonist (active) site and allosteric antagonists: A. The unbound inactive receptor. B. The receptor activated by agonist. Note the conformational change induced in the receptor by agonist binding, for example, the opening of a transmembrane ion channel. C. Agonist site antagonists bind to the receptor's agonist site but do not activate the receptor; these agents block agonist binding to the receptor. D. Allosteric antagonists bind to an allosteric site (different from the agonist site) and thereby prevent receptor activation, even when the agonist is bound to the receptor. Pharmacodynamics ↓ agrise inverse opposite Shift I right-ward *youcanoutcompetenagmonist Antagonist effects on the agonist dose–response relationship. Competitive and noncompetitive antagonists have different effects on potency (the concentration of agonist that causes a half-maximal response) and efficacy (the maximal response to an agonist). A. A competitive antagonist reduces the potency of an agonist, without affecting max efficacy being agonist efficacy. is what activated B. A noncompetitive antagonist reduces I conca the efficacy of an agonist. As shown here, no matterte most allosteric noncompetitive In etos ed antagonists do not affect agonist potency. Pharmacodynamics confirm it a helps his or noncompetitive competive Antagonist Effect of a noncompetitive antagonist on the agonist dose–response curve in the presence of spare receptors. In a system without spare receptors, a noncompetitive antagonist causes efficacy to decrease at all concentrations of the antagonist In a system with spare receptors, however, potency is decreased see a but efficacy is unaffected at low concentrations of the antagonist, f because a sufficient number of unoccupied receptors is available to generate a maximal response. As increasing concentrations of antagonist bind noncompetitively to more and more receptors, the antagonist eventually occupies all of the “spare” receptors, and efficacy is also reduced. Pharmacodynamics – Special Considerations: Drug Tolerance - ! of antagonism type Interchangable / Drug Tolerance = Receptor Desensitization - Receptor Sensitization = Enhancement of drug effect through a receptor Receptor Desensitization = Diminishing drug effect through a receptor Drug Tolerance = Repeated administration of the same dose of drug resulting in a diminishing effect over time Drug Tolerance inactivation Receptor Sensitization/Desensitization F -Phosphy a proms. Mechanisms: 1) Modify Existing Receptors ↑makethecons prostationreceptor 2) Change Receptor Numbers F Onespterdrymeet Desensitization Mechanisms: Receptor Inactivation Freducethereceptors line phosphy froma Receptor Down-Regulation the F changes numbera endocytosis (Sequestration and Degradation) Decreased Receptor transcription - cell usually receptorsadayo a produces 5 7 I or less more maaeas cells abaling to reinsertion Agonist Day 1 Agonist Day 30 - kind of like a non-competitive antagonism Agonist Concentration Pharmacokinetics Drug absorption, distribution, metabolism, and excretion (ADME). – Administration/Absorption – Distribution Neuropharmacology special considerations: The Blood Brain Barrier Binding (Pharmacodynamics) – Metabolism – Excretion/Elimination Pharmacokinetics Drug absorption, distribution, metabolism, and excretion (ADME). The basic principles of pharmacokinetics affect the amount of free drug that ultimately reaches the target site. To elicit an effect on its target, a drug must be absorbed and then distributed to its target before being metabolized and excreted. At all times, free drug in the systemic circulation is in equilibrium with tissue reservoirs, plasma proteins, and the ? target site (which usually consists of How yougetoe ↓ receptors) dependsonente Only the fraction of drug that binds to specific receptors will have a pharmacologic effect. Note that metabolism of drug can result in both inactive and active metabolites; Active metabolites may also exert a pharmacologic effect, either on the target receptors or sometimes on other receptors. Pharmacokinetics Administration - Routes Oral (Enteral) Parenteral Subcutaneous Intramuscular Intravenous Intrathecal Other Inhalation Topical / Transdermal  Pharmacokinetics Absorption- the process by which drugs pass from the external world into the bloodstream Factors that effect absorption: Concentration ↑ fastestrue a Ionization Lipophilicity - D Administration Method Howmuche bed measurement ↓ Administration method determines drug time to peak [drug] of free blood in the cell ↳ ↓ Intravenous administration (IV) ↓ samekenetic Intramuscular administration (IM) metabolism Subcutaneous administration (SC) Oral administration (PO) Note: Blood concentration is not the same as brain concentration Pharmacokinetics Drug distribution and elimination after intravenous administration. Immediately after intravenous administration of a drug, the plasma drug ↓ concentration declines rapidly as the drug Rapid decreasegetting distributed distributes from the vascular compartment to other body compartments. This rapid decline is followed by a slower decline as the drug is metabolized and excreted from the body. Both drug distribution and elimination display first- order kinetics, as demonstrated by linear kinetics on a semilogarithmic plot.  Pharmacokinetics Ideal closing giveA close the IST close to produce fast effect Z not takin enough to produce an effect. noterapoect Therapeutic, subtherapeutic, and toxic drug dosing. From a clinical perspective, the goal of most drug-dosing regimens is to maintain the drug at concentrations within the therapeutic range (referred to as the “therapeutic window”).  Pharmacokinetics ds a peoplemetabolize ↓ Saturation kinetics and drug toxicity. Drug elimination typically follows first-order Fluctuations in steady-state drug Michaelis-Menten kinetics, increasing as the concentration depend on dosing frequency. plasma drug concentration increases. The same average steady-state plasma drug At optimal dosing, the steady-state plasma drug concentration can be achieved using a variety of concentration remains within the therapeutic different drug doses and dosing intervals. range (bottom curve). If these peaks and troughs fall above or below the However, excessive drug dosing may saturate boundaries of the therapeutic window (as in the the body’s capacity to eliminate the drug, for infrequent large-dose regimen), then clinical example, by overwhelming the hepatic outcome can be adversely affected. cytochrome P450 enzyme system (top curve). Pharmacokinetics I ↳ notgoina  Pharmacokinetics Absorption- the process by which drugs pass from the external world into the bloodstream Factors that effect absorption: Concentration Ionization PH/PhA Lipophilicity # How well the drugcan cros enter e for m= Idepronated lost it resulting an drug has , species in a negatively charged ↑ protonated form-drug has gained a HT , becoming positively inAcidic conditions charged. dominating. Absorption  ↓ Stomach HA-H + + A HAA- Neura X lipid bilayer blood Pharmacokinetics % X V blood PH 7 form = log ↑ 103-100 1 = 4 + log - 3 = low PH High 103 = ↑ X at pH1 HA(deprotonated trapped in the A cell and i s i n traping layer F cross pl once i t. t o beA b l e blood for m going pH trapping across lipid is The blood becomes more drug through way ionized and can't pass pass back through than A the lipid bilayer bilayers Henderson-Hasslebeck Equation pKa = pH at which 50% of drug is in ionized form if phaXpH the molecule is m o re protonated If pl >Pha the molecule i s more deprotonated [A-] pH = pKa + log [HA] [HA] pha = pH + log SA] [A ] - = PhA CHAT *** Non-ionized drugs cross lipid membranes more favorably *** HA: Example drug with pKa = 4 Practice Question: Some brands of over-the-counter (OTC) analgesics contain aspirin, a weak organic acid with a pKa of 3.5, and antacids, such as bicarbonate salts. Assume that the antacid component in an OTC analgesic preparation temporarily elevates stomach pH to 3.5. - low = High absorption f some higher drugs h ave a lower absoption 2 or 1 rate at low or high pha's veutra e (( 50 pha Y..... - ) Phatlog. V pH = He form 100 " low absorption highhigh A PH l ow low = PH absorption Q: What is the aspirin deprotonated/protonated chemistry ratio in the stomach at pH 3.5? XpH = PKAX 112 of protonated the deprotonated drug ,a w i ll will b e be PH = Pha + log3 I a = 1 2 deprotonated I : I natio "la protonated Q: What is the aspirin deprotonated/protonated chemistry ratio in the intestine at pH 5.5? PH Pha log [ = + more a deprotonated 5. 5 = 3 5. + log2 1- 102 C= - = 100 100 : I CHA] [A - ] Q: Which compartment is aspirin absorbed more favorably into the bloodstream: stomach or intestine? Stomach because ionized / charged , anything will be less absorbed time (has a harder crossing the bilayer  Distribution What happens after a drug enters the blood? Rapid distribution of the drug – every minute the heart pumps roughly a volume equivalent to that of the total blood – Psychoactive drugs quickly get distributed evenly throughout not only the blood, but tissues too. Distribution  Drug Distribution Via the Circulatory System 1st pass metabolism ↓ absorbed into blood · ↑ focus on these ↓ Julian, 2004. A primer of Drug Action. Worth, pg 14. Distribution The Blood Brain Barrier 7m u st cross to access to get cerebral Spinal Distribution into Brain Parenchyma Alic Drug molecule Distribution Blood Brain Barrier,Julian, 2004. A primer of Drug Action. Worth, pg 20. The Blood Brain Barrier Evans Blue Dye – Assessment of functional blood brain barrier a abcormal linning the the ↓ of Vascular is the Vascular the blood brain barrier stone I - toke-disruption S locate & Experimental and Translational Stroke Medicine; 2012; 4(1):6 The Blood Brain Barrier ↓ Capilaries cause the barrier ↓ loser organization Features of capillaries in the central nervous system o In the periphery, capillary endothelial cells have gaps (termed fenestrae) between them and use intracellular pinocytotic vesicles to facilitate the transcapillary transport of fluid and soluble molecules. o In contrast, CNS vessels are sealed by tight junctions between the endothelial cells. The cells have fewer pinocytotic ↓ tighter vesicles and are surrounded by struc ture lack fenestra pericytes and astroglial processes. around endoth ↑ coverage. Cells o Capillary endothelial cells in the CNS have more mitochondria than those in peripheral vessels o These mitochondria may reflect the ! layer add of cellular support energy requirements necessary for CNS endothelial cell ↓ endothelial cells to transport certain molecules into the CNS and transport other molecules out of the CNS. Peripheral Capillary D plasma can pass not WbC through or FbC ↳ and release s u b s an Peripheral Capillary features Endothelial Fenestra Incomplete coverage by pericyte processes Abundant pinocytotic vesicles http://medcell.med.yale.edu/systems_cell_biology/blood_vessels_lab.php Brain Capillary Brain Capillary features Endothelial Tight Junctions mitochondria ↳ Ensheathed by pericyte lot of lipids and astrocyte processes ↓ drugs wh high lipophilicity Endothelial cells have few can the BBP cross pinocytotic vesicles Endothelial cells have an enrichment of mitochondria Endothelial cells abundantly express transport proteins (active transport) un expression genetic level The Blood Brain Barrier Barar et al., Bioimpacts, 6(4), 225-248; 2016 The Blood Brain Barrier transport · proteins A l l ow in the and keep nutrients to get out drugs Simple diffusion In this process, small, partially water-soluble solutes pass freely through a membrane bilayer, driven by their concentration gradient across the membrane. This process is also called passive diffusion. Passive transport requireor ins In this process, protein channels or carrier proteins facilitate the transport of substrates down their concentration gradient. The Blood Brain Barrier Blood Brain Barrier Active Transport Primary active transport Energy of hydrolysis of adenosine triphosphate (ATP) is used to transport solutes against their concentration gradients; e.g. Na+/K+- ATPase Secondary and tertiary active anioe transport organic o re Coupling primary active transport to transport other molecules across the membrane Na+/K+-ATPase Bicarbonate (HCO3−)/Na+ Symporter Bicarbonate / organic anion (OA−) antiporter. The Blood Brain Barrier -very liphophilic makes i t into the brain very. easily lipid outliers loving. I molecules both h ave active transport ↳ A properties. & even though they h ave A lipophilicity,theycanta Recognized by recognized bytransporters eeporter o in At to be pumped Cuptake transporters un 1 all have passive transport properties water loving molecules 50150 H2o and oil , share F it with drug and let i t Separate wherever the drug is deter mines i ts lipophilicity. ***In general, there is a correlation between the oil/water partition coefficient of a compound and its ability to enter the brain*** The Blood Brain Barrier organic anion transpor ters Uptake and Efflux Transporters Major transporters of drugs and endogenous compounds abundantly expressed in certain cell types: Intestine Kidney Liver Blood–brain barrier endothelial cells Uptake transporters (Blue) Efflux transporters (Red) The Blood Brain Barrier Important blood brain barrier proteins Hexose transporter - facilitated diffusion – uptake of glucose (e.g.Glut1) Efflux transporters Multiple drug resistance (MDR) transporters, or multidrug multi drug restarters resistance proteins (MRP) ↓ Uptake transporters - Organic Anion anythinggengine Transporting Polypeptide (OATP) Family Facilitate the uptake of large hydrophobic and amphiphilic organic compounds, (e.g. bile acids, thyroid hormones, steroids) Metabolic blood–brain barrier - maintained by enzymes that metabolize compounds transported into CNS endothelial cells  The Blood Brain Barrier is Dynamic peripheral 1. fenstra ra instra wraps around endoth Cells.. ↓ #. 2 pericyte. 2 A pericyte coverage coverage support. 3 Astrocyte. 3 no Astrocytes 4. pinocytosis fo r activee sport 4. ↑ pinocytosis fo r energy 5 1 Mitochondria I 5. Mitochondria. as Itactiveransport 6 ↓ Active transport. 6. 1 Y Sometimes the BBB needs to be broken down sick t o a l l ow When were Whe's in and then rebuild i t when we re not sick (dynamic Blood–Brain Barrier Dynamics to Maintain Brain Homeostasis; Segarra et al. Trends in Neurosciences, 2021 Pharmacokinetics MET