Intro 7.5 - 10.5 Flashcards
PHARMACOKINETIC PRINCIPLES:
Inactive precursor. They need to be activated by passing through the liver
Prodrug
PHARMACOKINETIC PRINCIPLES:
Must be administered and converted to the active drug by biologic process inside the bodyz
Prodrug
PHARMACOKINETIC PRINCIPLES:
T/F: To reach its receptors and bring about biologic effect. A drug molecule (eg, sedative) must travel from the site of administration (eg, gastrointestinal tract) to the site of action (eg, brain)
True
PHARMACOKINETIC PRINCIPLES:
2 Movements of Drugs in the Body
Permeation
Water and Lipid Soluble Drugs
5 Permeation
- Movement of drug molecules into and within the biologic environment
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Movement of molecules through the watery
extracellular and intracellular spaces
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
Occurs within the LARGER aqueous compartments of the body (eg: interstitial space, cytosol, etc.) and across epithelial membrane tight junctions and the endothelial lining of blood vessels
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
The capillaries of the brain, testes, and some other tissues have no pores that permit aqueous diffusion.
○ They may also contain high concentrations of drug export pumps (MDR pump molecules).
○ Hence, they are protected or “sanctuary” sites from many circulating drugs.
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
can permit molecules as large as MW 20,000 - 30,000
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
Membranes of capillaries with small water filled pores. Passive process
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
Driven by the concentration gradient of the permeating drug
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
A downhill movement (Governed by Fick’s law)
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Aqueous diffusion
Aqueous diffusion:
Fick’s Law Formula
Rate = C1 - C2 x Permeability coefficient / Thickness x Area
C1 - higher conc
C2 - lower conc
Movement of molecules through membranes and other lipid structures
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Lipid diffusion
Most important factor for drug permeation because of the large number of lipid barriers that separate the compartments of
the body
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Lipid diffusion
Aside from Aqueous diffusion, it is also passive process and governed by Fick’s law
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Lipid Diffusion
Drugs transported across barriers by mechanisms
that carry similar endogenous substances: Amino acid, peptides, glucose
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Transport by special carriers
Special carrier molecules function for:
- substances important in cell function;
- too large or too insoluble in lipids to diffuse passively through membranes ○ eg: peptides, amino acids, and glucose.
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Transport by special carriers
Capacity is limited and not governed by Fick’s law
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Transport by special carriers
2 types of TRANSPORT BY SPECIAL CARRIERS
Active Transport
Facilitated diffusion
What type of Transport by Special Carrier is this:
Needs energy and is against a concentration gradient
- Active Transport
- Facilitated diffusion
Active Transport
What type of Transport by Special Carrier is this:
No energy required and is downhill
- Active Transport
- Facilitated diffusion
Facilitated diffusion
The 2 types of Transport by special carriers (Active Transport and Facilitated Diffusion) are ____, _____, ____.
(SIS)
Selective
Inhibitable
Saturable
5 Transport molecules important in pharmacology:
- NET (norepinephrine transporter)
- SERT (serotonin)
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
WHAT TRANSPORT MOLECULE IS THIS:
Physiologic function: reuptake from synapse
- NET (norepinephrine transporter)
- SERT (serotonin)
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
- NET (norepinephrine transporter)
- SERT (serotonin)
WHAT TRANSPORT MOLECULE IS THIS:
Pharmacologic Significance: Target of cocaine and some tricyclic antidepressants
- NET (norepinephrine transporter)
- SERT (serotonin)
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
NET (norepinephrine transporter)
WHAT TRANSPORT MOLECULE IS THIS:
Pharmacologic Significance: Target of selective serotonin reuptake inhibitors and some tricyclic antidepressants
- NET (norepinephrine transporter)
- SERT (serotonin reuptake transsporter))
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
SERT (serotonin reuptake transsporter))
WHAT TRANSPORT MOLECULE IS THIS:
Physiologic Function: Transport of dopamine and norepinephrine into adrenergic vesicles in nerve endings
- NET (norepinephrine transporter)
- SERT (serotonin reuptake transsporter))
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
VMAT (vesicular monoamine transporter)
WHAT TRANSPORT MOLECULE IS THIS:
Pharmacologic Significance: Target of reserpine and tetrabenazine
- NET (norepinephrine transporter)
- SERT (serotonin reuptake transsporter))
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
VMAT (vesicular monoamine transporter)
WHAT TRANSPORT MOLECULE IS THIS:
Pharmacologic Significance: Increased expression confers resistance to certain anticancer drugs; inhibition increases blood levels of digoxin
- NET (norepinephrine transporter)
- SERT (serotonin reuptake transsporter))
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
MDR1 (multidrug resistance protein - 1)
WHAT TRANSPORT MOLECULE IS THIS:
Physiologic Function: Transport of many xenobiotics out of cells
- NET (norepinephrine transporter)
- SERT (serotonin reuptake transsporter))
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
MDR1 (multidrug resistance protein - 1)
WHAT TRANSPORT MOLECULE IS THIS:
Pharmacologic Significance: Confers resistance to certain anticancer and antifungal drugs
- NET (norepinephrine transporter)
- SERT (serotonin reuptake transsporter))
- VMAT (vesicular monoamine transporter)
- MDR1 (multidrug resistance protein - 1)
- MRP1 (multidrug resistance-asso ciated protein - 1)
MRP1 (multidrug resistance-asso ciated protein - 1)
Binding to specialized components (receptors) on
cell membranes
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Endocytosis
Internalization by infolding of the area of the
membrane and contents of the vesicle are
subsequently released into the cytoplasm
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Endocytosis
the process by which the substance is bound at a cell-surface receptor, engulfed by the cell membrane, and carried into the cell by pinching off of the newly formed vesicle inside the membrane.
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Endocytosis
Substance can be released into the cytosol by breakdown of the vesicle
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Endocytosis
Permits very large or very lipid-insoluble chemicals to enter the cell: B12 with intrinsic factor, Iron with transferrin
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Endocytosis
Reverse process
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Exocytosis
Expulsion (or secretion) of membrane-encapsulated material from the cell: Neurotransmitters
○ Aqueous diffusion
○ Lipid diffusion
○ Transport by special carriers
○ Endocytosis
○ Exocytosis
Exocytosis
Predicts the movement of molecules across a barrier
FICK’S LAW OF DIFFUSION
FICK’S LAW OF DIFFUSION:
Drug absorption is faster in organs with larger surface areas (eg, _______) than from organs with smaller absorbing areas (eg, ______)
MAS MAKAPAL, MAS MABAGAL
small intestine; stomach
FICK’S LAW OF DIFFUSION:
Drug absorption is faster from organs with (thick/thin)
membrane barriers (eg, lungs) than those with thick barriers (eg, skin)
thin membrane barriers
The passive flux of molecules down a concentration gradient is governed by _____.
Fick’s law
FICK’S LAW OF DIFFUSION:
measure of the mobility of the drug in medium of the
diffusion path
- Permeability coefficient
- Thickness
- area
Permeability coefficient
FICK’S LAW OF DIFFUSION:
(length of the diffusion path). Is inversely proportional but the area is directly proportional. THE BIGGER THE AREA, FASTER TO ABSORB
- Permeability coefficient
- Thickness
- Area
Thickness
FICK’S LAW OF DIFFUSION:
cross-sectional area of the diffusion path
- Permeability coefficient
- Thickness
- Area
area
WATER AND LIPID SOLUBLE DRUGS
polar; they follow the water diffusion
- Water soluble
- Lipid soluble
Water soluble
WATER AND LIPID SOLUBLE DRUGS
Pag maliit, they can go to the paracellular.
They can diffuse in between cells
- Water soluble
- Lipid soluble
Water soluble
WATER AND LIPID SOLUBLE DRUGS
Pag maliit, they can go to the paracellular.
They can diffuse in between cells
- Water soluble
- Lipid soluble
Water soluble
WATER AND LIPID SOLUBLE DRUGS
non polar; they follow the lipid diffusion
- Water soluble
- Lipid soluble
Lipid soluble
WATER AND LIPID SOLUBLE DRUGS
non polar; they follow the lipid diffusion
- Water soluble
- Lipid soluble
Lipid soluble
WATER AND LIPID SOLUBLE DRUGS
They can traverse in cell membrane
because the cell membrane is lipid bilayer.
- Water soluble
- Lipid soluble
Lipid soluble
WATER AND LIPID SOLUBLE DRUGS:
Aqueous solubility of a drug is a function of the
electrostatic charge (degree of ionization, polarity)
of the molecule.
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
AQUEOUS DIFFUSION
WATER AND LIPID SOLUBLE DRUGS:
Water molecules are attracted to charged drug
molecules forming an aqueous shell around them
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
AQUEOUS DIFFUSION
WATER AND LIPID SOLUBLE DRUGS:
Lipid solubility of a molecule is inversely proportional to its charge
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
AQUEOUS DIFFUSION
WATER AND LIPID SOLUBLE DRUGS:
Many drugs are weak bases or weak acids
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
LIPID DIFFUSION
WATER AND LIPID SOLUBLE DRUGS:
pH of the medium determines the fraction of molecules charged (ionized) versus uncharged
(nonionized)
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
LIPID DIFFUSION
WATER AND LIPID SOLUBLE DRUGS:
Fraction of molecules in the ionized state can be
predicted by means of the H - H equation
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
LIPID DIFFUSION
WATER AND LIPID SOLUBLE DRUGS:
Hendersson - Hasselbach equation (H - H
equation): log (protonated) / (unprotonated) = pka -pH
Protonated means associated with a proton (a
hydrogen ion)
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
LIPID DIFFUSION
LIPID DIFFUSION:
T/F: Weak acid has PKA
True
LIPID DIFFUSION:
T/F: Some of our drugs are weak acid and weak base
True
LIPID DIFFUSION:
T/F: If weak acid and weak bases, some of them clings
on to their hydrogen. Pag walang charge, non polar (lipid soluble). Pag may charge, lipid INsoluble (polar)
True
LIPID DIFFUSION:
T/F: Strong acid and strong bases will be separated in a solution because it will ionized
True
WATER AND LIPID SOLUBLE DRUGS:
Some of our drugs are weak acid and weak base
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
IONIZATION OF WEAK ACIDS AND WEAK BASES
WATER AND LIPID SOLUBLE DRUGS:
The electrostatic charge of an ionized molecule attracts water dipoles —> polar, relatively water-soluble and lipid-insoluble complex
- AQUEOUS DIFFUSION
- LIPID DIFFUSION
- IONIZATION OF WEAK ACIDS AND WEAK BASES
IONIZATION OF WEAK ACIDS AND WEAK BASES
IONIZATION OF WEAK ACIDS AND WEAK BASES:
T/F: Because lipid diffusion depends on relatively high lipid solubility, ionization of drugs may reduce their ability to permeate membranes. A very large percentage of the drugs in use are weak acids or weak bases;
True
IONIZATION OF WEAK ACIDS AND WEAK BASES:
T/F: Some of our drugs are weak acid and weak base
True`
IONIZATION OF WEAK ACIDS AND WEAK BASES:
T/F: Pag walang charge, non polar. Pag may charge, lipid INsoluble (polar). If uncharged, IT CAN’T pass through (only traverse)
True
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Neutral molecule that can form a cation (+ charged) by combining with a proton (hydrogen ion)
- Weak Base
- Weak Acid
Weak base
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Ionized, more polar, more water soluble when they are protonated. Pag acidic ang weak base,
- Weak Base
- Weak Acid
Weak Base
IONIZATION OF WEAK ACIDS AND WEAK BASES:
can accommodate a proton so pag acidic ang weak base they become positively charged since they absorb the Hydrogen
- Weak Base
- Weak Acid
Weak Base
IONIZATION OF WEAK ACIDS AND WEAK BASES:
When it is positive in an acidic environment they are water-soluble.
- Weak Base
- Weak Acid
Weak base
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Neutral molecule that can
reversibly dissociate into an anion (- charged) and a proton ( hydrogen ion)
- Weak Base
- Weak Acid
Weak acid
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Not ionized, less polar, less water soluble when they are protonated
- Weak Base
- Weak Acid
Weak acid
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Weak Acid: T/F
pag acidic yung environment, dadami ang hydrogen, it will hold to their hydrogen so it is uncharged. Protonated weak acid is uncharged
True
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Weak Acid: T/F
If alkaline environment, they release there proton, they become negatively charge. If negatively charge polar, you are water soluble, you stay in the water
True
IONIZATION OF WEAK ACIDS AND WEAK BASES:
Weak Acid: T/F
The protonated form of a weak acid is the neutral, more lipid-soluble form
True
IONIZATION OF WEAK ACIDS AND WEAK BASES:
RNH3+ ⇔ RNH2 + H+
Which part of the equation is Protonated weak base (charged, more water-soluble)
RNH3+
IONIZATION OF WEAK ACIDS AND WEAK BASES:
RNH3+ ⇔ RNH2 + H+
Which part of the equation is Unprotonated weak base (uncharged, more lipid-soluble)
RNH2
IONIZATION OF WEAK ACIDS AND WEAK BASES:
RNH3+ ⇔ RNH2 + H+
Which part of the equation is proton
H+
IONIZATION OF WEAK ACIDS AND WEAK BASES:
RCOOH ⇔ RCOO- + H+
Which part of the equation is Protonated weak acid (uncharged, more water-soluble)
RCOOH
IONIZATION OF WEAK ACIDS AND WEAK BASES:
RCOOH ⇔ RCOO- + H+
Which part of the equation is Unprotonated weak acid (charged, more water-soluble)
RCOO-
IONIZATION OF WEAK ACIDS AND WEAK BASES:
More of a weak acid will be in the lipid-soluble form at (acid/basic) pH, while more of a weak base will be in lipid soluble form at alkaline pH
Acid