Pharmacokinetics and Pharmacodynamics Flashcards
Define ligand
A molecule that binds to the receptor ( e.g ACH)
Define receptor
the molecular target for a drug (e.g ACH receptor)
Define agonist
a molecule that activates a receptor
Define antagonist
blocks or reduces agonist mediated responses
Name some facts about ligands
-exogenous vs endogenous
-might be a drug, neurotransmitter, hormone
-can act on different receptors
-synthetic vs natural
Define targeting within context to pharmacology
a molecule, usually a protein, that is accessed by a drug to produce a therapeutic effect
What is a “ideal” drug?
-Desirable pharmacological action
-acceptable side effects
-reach its target in the right conc at the right time
-remain at the site of action for sufficient time
-be rapidly and completely removed from the body when no longer needed
What properties effect drug-receptor binding?
-physio chemical properties (electrostatic charges)
-steric properties (physical structure)
Define affinity
how well the ligand e.g agonist binds to receptor
What are the links between genetic variation and pharmacology?
-drug targets are often proteins
-protein is encoded in the genome
-genetic variation in drug reception is possible
-genetic variation in proteins involved in cellular processes is possible
-genetic variation in enzymes that process/ inactivate drugs
-genetic variation could lead to differences in the way people respond to any given drug
Define pharmacogenomics
the way an individual’s genetics attributes affect response to therapeutic drugs
Where are oxytocin receptors found?
-mammary glands myoepithelial cells
-uterus myometrium
-mesolimbic pathway
What are the targets for drug action?
-most drugs initially work by binding to a protein
-proteins sub serve important roles-physiological regulation
common protein targets include: receptors, ion channels, carrier molecules, enzymes
Give an example of receptors as a target for drug acton
-endogenous ligand (ACh) activates
-exogenous agonist drug (nicotine activates)
-antagonist- e.g curare inactivates receptor
Describe G protein linked trans-membrane receptor
-ligand binds
-alters receptor conformation
-activation of intracellular second messenger cascade
-diverse intracellular effects-cellular excitability
-modulation of other ion channels
-down regulation of G protein linked receptors
Describe the structure of ion channels as a target for drug action
-complex membrane proteins- actual physical pore
-molecular sensitivity filter-specific substrates
-e.g cl-, Na+, K+, Ca++
Describe the structure/ function of carrier proteins as a target for drug action
-facilitators for transport
-active transport
-facilitated diffusion
-inhibitors or false substrates are common drug types
Name some enzymes that are a target for drug action
-cyclooxygenase
-thromboxane and prostaglandins
-pain, inflammation, clotting
-aspirin
Describe false substrate and pro drug production
false substrate- abnormal metabolite produced
pro drug- active drug produced
What are the broad families of drugs that interact with enzymes?
-enzyme inhibitors
-false substrates
-prodrugs
Why is drug specificity important?
-no drugs act with complete specificity
-non-specific interactions are very possible
-a drug may be preferentially bind to a relevant target
-more likelihood of non-specific interaction becoming significant with larger doses
What 4 proccesses determine the time of onset and duration of drug action in the body?
Absorption
distribution
metabolism
excretion
describes the disposition of the drug
Define absorption
process by which drug reaches the systemic circulation
What is absorption affected by?
-route of administration
-permeation-the absorption process
-regardless of route of administration, drugs must be in solution to be absorbed
what’s the difference between enteral administration and parenteral adminosttraion?
enteral:
-Via gut
-oral/buccal/rectal
parenteral:
-Not via gut
-e.g injections/topical
pros and cons of enteral routes
-oral ingestion-gut absorption
-low infection risk
-very simple (self administered)
-harsh environment-stomach/duodenum
-first pass metabolism
Describe first pass metabolism
can be lost via:
-excretion
-interstitial wall, interstitial lumen
-metabolism through the gut
-metabolism through the lungs or liver
-leads to reduced bioavailability
-FPM avoided by drug into a region of gut that does not drain into hepatic portal vein
Pros and cons of topical
-local effects
-low systemic effects
-limited first pass metabolism
-suited to slow continuous, long period administration
-risk of systemic absorption (direct absorption to blood)
-low infection risk
-proccess of lipid permeation so drug must be:
lipid soluble, small molecular size,use a carrier molecule- usually irritant to increase absorptions
Name different types of injection
Intravascular (IV, IA) – drug enters directly into the blood stream
Intramuscular (IM) – drug injected into skeletal muscle
Subcutaneous (SC) – drug absorbed from subcutaneous tissue
Dermal (ID) – dermal vascular layer
Depot injection - for slow-release formulations
Pros and cons of injections
-infection risk
-rapid bioavailability for IV/IA
-targeting risks
-avoid first pass metabolism
define bioavailability
the proportion of active drug that reaches the systemic circulation and is free to bind to its target
-its affected by administration route and formulation e.g enteric coating
-not a measure of how effective the drug is
What factors affect distribution?
-protein binding
-blood flow
-membrane permeation/tissue solubility
Describe distribution in regards to protein binding
-partly bound to plasma proteins and partly in plasma water
-binding is usually reversible
-dynamic equilibrium for most drugs
-only the unbound fraction can cross membranes or bind to receptors
Describe what the unbound drug in the plasma may do
-diffuse through capillary walls
-produce a pharmacological effect
-be metabolised/excreted
-subtle changes in binding can have profound effects
-may be a particular problem in the elderly, malnourished patients
Describe distribution of drug through blood flow
-primarily through circulation system
-tissue perfusion rate per tissue-important
List the main tissue perfusion rates that effect the distribution of a drug
lung- 1000
brain-56
gut-300
bone/cartilage/fat - 3
all ml min-1 per 100g
describe lipophilicity
-charged molecules, ions, ionised molecules diffuse less efficiently
-uncharged, non ionised drugs have better access to membrane bound compartments
Describe why metabolism is important for drugs
-metabolism typically inactivates drugs
-liver is key organ involved
-kidneys, intestines, lungs, plasma, skin and placenta also involved
-metabolic rate can determine the duration of drug action
-pro-drug activation
-little or no activity until they undergo metabolic activation (codeine, L-dopa, gabapentin enacarbil)
What are the two phases of metabolism?
Phase I - produces toxic metabolites (oxidation,hydroxylation, dealkylation, deamination)
Phase II -converts toxins to soluble metabolites for excretion (conjugation)
-Phase II can precede phase I, Phase II can occur in the absence of phase I
What can phase I of metabolism chemical reactions change?
-polarisation of the substance
-increase water solubility
-reduce pharmacological activity
-may activate pro-drugs
cytochrome p450
cyp3A- can metabolise 50-60% of all known drugs
What can phase II of metabolism chemical reactions change?
-making it water soluble
-biologically inactive
-converting the drug/toxin by covalently joining them to other molecules
Define conjugation
adding of an endogenous substance
Describe excretion via the kidney/renal route (main route)
-filtration
-only unbound drugs/metabolites can be processed via glomerular filtration
-PCT cells actively secrete into nephron
-reabsorption of lipophilic drugs, unionised at urine PH
-other routes: biliary, salivary ,breast milk, sweat and tears
describe biliary excretion/ principal excretory route
-hepatocyte uptake
-bile
-duodenum
-excretion in faeces
but gut bacteria can convert drug to original form, drug can be reabsorbed across intestinal wall, re circulate in the blood, be metabolised in liver again and resecreted into bile. (enterohepatic circulation)
What is half life in regards to drugs?
time taken to decrease plasma concentration to 50%
