Week 3 Flashcards
Functions of membrane potential
Source of energy (production of ATP in mitochondria, influx of glucose, Ca2+, motility)
Changes in membrane potential are basis for action potentials and thus for cell communication
Origin of membrane potential
Asymmetric cation distribution, Na-K-ATPase, charge neutrality
Ionic Permeability Model
Potassium is higher in the cells, but it leaks down concentration gradient, chemical force balances electrostatic force when net flux of K ions is 0; Use Goldman-Hodgkin Katz equation to calculate equilibrium potentials
Equivalent Circuit Model
Lipid bilayer is a capacitor; Ion channels are conductors; Equilibrium potentials are batteries; Resting potential can be calculated via Kirchoff’s Law
Alterations in Membrane Potential
Diffusion restriction, blocking Na/K ATPase, action potentials, changes in membrane potential lead to calcium influx into the cytoplasm
General Properties and Categories of ion transport proteins
Transport Proteins
Channels- proteins that form pores through which solutes pass
Carriers- transmembrane protiens that bind to small molecules carry them and release them
ex. transporters, ATPase
Channels
Ion-specific channels- specialized for ion permeability ex. ligand dependent, voltage dependent
Non-specific channels- allow many kinds of molecules to pass through
ex. gap junction, alpha toxin
Primary Drug Receptor Types and examples
Intracellular receptor ex. steroid receptors
Transmembrane receptor with intrinsic enzyme activity (EGF receptor)
Transmembrane receptor with auxillary enzyme (cytokine receptor)
Ligand- or voltage-gated ion channel
GPCR
Drug Classes by Action
Agonists
They directly interact with receptors to produce biological reponse
Full, Partial, and inverse agonists
Drug Classes by Action
Antagonists
Chemical, Physiological, Pharmacological (ligands that bind but do not activate receptor)
Orthosteric and Allosteric Antagonists
Types of Receptors
Intracellular receptors, enzyme linked receptors (intrinsic or associated activity), ligand and voltage gated ion channels, G Protein- coupled receptors
Ligand and Voltage Gated Ion Channels
Cys-loop receptor (pentameric) - GABA
Ionotropic glutamate (tentrameric)- NMDA
Ionotropic ATP receptors (trimeric)- P2X
Drug desensitization
Receptor-mediated: loss of receptor function, decrease in receptor number
Non receptor-mediated: decoupling of receptor and signalling machinery, reduction in drug concentration, physiological adaptation
3 factors important in controlling drug transport across membrane
Membrane as barriers
Specialized transport mechanisms
Physio-chemical properties of drugs
Physio-chemical properties of drug transport
Non-ionized form of drugs are more lipid soluble which will preferentially penetrate lipid bilater membranes
Log(acid/base)= pKa- pH
Different routes of drug administration and bioavailability
- Oral- 1st pass effect diminishes bioavailabiliy
- Rectal- 50% of lower rectal area drains directly into systemic circulation bypassing liver
- Parenteral- Intravenous, intramusuclar, subcutaneous
- Intrathecal- directly into CSF from blood and into brain cells
- Inhalation
- Topical application- Skin or mucous membrane, sublingual (behind the tongue)
Factors affecting oral absorption
Direct Interaction- Drug may be destroyed by gastric pH
Inhibition of drug metabolism in the gut- GFJ irreversible inhibition of CYP3A4
Inhibition of transport process- GFJ reversible inhibition of OATP
Generic vs name-brand drugs
Generic drug needs to meet three criteria to be substituted as brand-name:
• Pharmaceutical equivalent: same active ingredients, identical in strength or concentration, same dosage form, and same route of administration.
• Bioequivalence: when two pharmaceutical equivalent drugs produce the same rates and extents of bioavailability of the same active ingredient, they are considered to be bioequivalent. Pharmaceutical equivalent drugs might not be bioequivalent, however: differences in crystal form, particle size, and manufacture processes could affect pharmaceutical phase and hence the rate of extent of drug absorption, especially for oral administration. A generic drug must conform to 80 to 125 of bioequivalence of the brand-name drug, but it may not be identically formulated
• Effectiveness and safety for intended use
Phases of oral administration:
Pharmaceutical phase
Pharmacokinetic phase
Pharmacodynamic phase
Disintegration of dosage form, dissolution of active ingredients
Absorption, distribtution, metabolism, excretion
Drug-receptor interaction, drug-drug interaction, individual sensitivity
Midazolam (and other zolams)
Phase I- CYP3A4; Phase II- glucuronide metabolism
Cimetidine
Competitive inhibitor of histamine at the H2 receptor; inhibits all CYPs (AKA is metabolized by most CYPs) except for CYP2E1; relieves heartburn
Ethanol dehydrogenase
Uses and induces CYP2E1 to faciliate toxic acetaminophen toxicity; St. John’s Wort induces CYP2E1
Acetaminophen
Inhibits COX
Inactivated phase II by sulfation via sulfotrasnferases and glucuronidation via UDP glucuronyl transferase (all benzodiazepines)
Phase I CYP2E1 and CYP3A4 converts acetaminophen into NAPQI and depletes GSH pool
Glomerular Filtration
3 layer barrier- fenestaeted epithelium, porous glomerular basement membrane, and podocyte with negatively charged glycoproteins; albumin does not pass
Tubular secretion
Occurs in proximal tubules; Basolateral side has SLC22 transporters and apical side has ABC and SLC transporters (OCT’s and OAT”s), SLC transporters are nonspecific, important for drug-drug interactions
Passive tubular reabsorption
Distal tubule, net movement is absorptive due to concentration of urine and ionized/non-ionized balance;lipids are reabsorbed while polar compounds are excreted
Second route of drug excretion
Drug is transported to hepatocytes to be metabolized mainly via passive diffusion or via transporters; Drug and its metabolites are actively pumped out into the bile
Basic Principles of chemical synaptic transmission
Synthesis+Storage: choline + acetyl coA= ACh
Release: stimulation of motor nerves produces ACh
Mimicry- exogenous ACh achieves same effect
Pharmacological parallels- curare (which inhibits ACh) abolishes transmission
Termination- cholinesterase
Other events of neuromuscular transmission and important presynaptic proteins
ACh receptors concentrated at end plate, ACh release activates non-selective cation channel of muscle membrane and then voltage-dependent sodium channel opens to propagage action potential
Fusion machine- connects the vesicle membrane through the nerve terminal cytoplasm to the calcium channels in the plasma membrane with calcium sensors on snares
Lambert-Eaton Myasthenic Syndrome
Myasthenia Gravis
Reduced number of P/Q type calcium channels (presynaptic) in the nerve ending
Postsyaptic deficit of many nicotinic ACh receptors due to autoimmune reaction
Botulinum toxin
Reduced calcium sensitivity in secretory apparatus due to Snap-25 cleavage which affects the calcium sensor synaptotagmin, exocytosis impaired despite vesicle accumulation
Used to treat blepharospasm, ocular disorders, facelifts, hemifacial spasms, laryngeal problems,musician’s cramp
CYP3A4
Most popular/promiscuous CYP
Metabolizes warfarin, midazolam, diazepam (into two active drugs)
Inhibited by flavonoids and induced by St John’s wort and echinacea
CYP2D6
Most polymorphic
Metabolizes metoprolol, Opioids (codeine), Tricyclic antidepressants
CYP2C19
Polymorphic, proton pump inhibitors, NSAIDS, (15%-25% of Asians are poor metabolizers)
Ginkgo induces this CYP
Major differences beween ester-type and amide type local anesthetics
Refers to the group that connects the aromatic/amine
Factors affecting action: lipid solubility, pKa, pH of medium
Metabolism- ester type rapidly hydrolyzed by plasma pseudocholinesterase; amide type metabolized by liver P450
Neutral vs. Charged Local Anesthetics
Neutral form crosses membrane, Increase pH to get more uncharged across the membrane into axoplasm and vice versa
Sodium channel blocking action: channel state dependent blocking action
Anesthetic binds to the inner cavity created by 4 S6 segments of the alpha subunit, reduces sodium conductivity and amplitude of action potential
Use dependent block
Binding affinity is greatest when sodium channel is in open state, repetitive stimulation is necessary to achieve blockade
Frequency dependent block
Increase in frequency of stimulation prevents anesthetic from escaping binding site; pronounced in diseased settings in which the tissue is more likely to be depolarized
Adverse actions of local anesthetics
Generally due to excessive blood concentrations of drug
CNS- light headednes, shivering, seizures; treated with benzodiazepines (GABA agonist)
Cardiovascular- myocardial suppression, vasodilation, cardiac arrest; treated with intralipid
Methemoglobinemia- when heme iron is oxidized due to local anesthetic leading to hypoxia; treatment- methylene blue
Allergic reaction- to P-aminobenzoic, bronchospasm, uticaria (hives)
Enterohepatic Recirculation
Glucuronide conjugates of drugs gets cleaved by beta-glucuronidases leading to reabsorption and reduced systemic drug concentrations by localizing all of the drug in the liver
Blood brain barrier
Anatomical Barriers- small EC space, no fenestra, tight junctions, astrocytes
Biochemical Barrier- Drug efflux pumps
