PHARM; Lecture 4, 5 and 6 - Pharmacokinetics, Drug metabolism and Cholinomimetics Flashcards
1
Q
How does a drug need to be presented to achieve its effect?
A
Suitable formulation at appropriate site of administration where it is then absorbed and distributed throughout the body
2
Q
What is ADME?
A
The journey of the drug throughout the body: Administration, Absorption, Distribution, Metabolism, Excretion, Removal
3
Q
What are the routes drug takes during administration?
A
4
Q
Why is administration important?
A
Depending on where it is administered, determines the functionality of the drug - e.g. If taken down GI and not absorbed then it is just excreted
5
Q
Is inhalation effective and how?
A
Quite effective as it is directly absorbed into the bloodstream but some (specifically very volatile drugs) are exhaled back out
6
Q
What is local administration?
A
Restricted to one area of the organism
7
Q
What is systemic administration?
A
Affects the entire organism
8
Q
Are the following local or systemic administration: Salbutamol, Cannabis, Aspirin, Antacid, nicotine
A
Salbutamol (L&s), Cannabis (S), Aspirin (S), nicotine (S), Antacid (L)
9
Q
What is enteral administration?
A
G-I administration, where it can be absorbed orally, buccal, sub-lingual. Easiest way to admin a drug
10
Q
What is parenteral administration?
A
Outside of GI tract
11
Q
How do drugs enter the systemic circulation?
A
NB: intraperitoneal vs intravenous are nearly as good as each other.
12
Q
What is the slowest administration method?
A
Intramuscular
13
Q
What is the fastest administration method?
A
Intravenous
14
Q
How do drugs move around the body?
A
Bulk flow transfer (bloodstream) OR diffusional transfer (molecule by molecule across short distance). Drugs traverse both aqueous and lipid environments
15
Q
What is the difference between compartments and barriers in drug transport?
A
Compartments are aqueous and barriers are lipid
16
Q
How do drugs cross barriers?
A
Diffuse through lipids and use carrier molecules
17
Q
Why do drugs have the ability to be charged?
A
They are mostly either weak acids or weak bases - so exist in ionised or non-ionised forms depending on surrounding pH
18
Q
What is the pH partition hypothesis? (Using aspirin as example)
A
Predominantly in stomach is uncharged (L) so is predominantly absorbed here (rapid). In the intestine it is predominantly in the ionised form (R) which can diffuse across the cell membrane (slow).
19
Q
What is an enteric coating?
A
It is a sugar coating around the drug to prevent dissolving/absorption in the stomach
20
Q
What is ion trapping?
A
Blood pH causes drug to become ionised which causes it to be trapped in the blood but due to dynamic equilibrium a slow amount of non-ionised is being formed steadily so it becomes a slow release drug
21
Q
Which factors affect drug distribution?
A
Regional blood flow (perfusion of tissue dictates how quickly the drug will flow through it). Extracellular binding (once drug is bound by protein it is slowly released and that dictates how quickly the drug acts -DE) Capillary permeability (tissue alterations - renal, hepatic) Localisation in tissues (prefer lipid)
22
Q
How can strenuous exercise affect drug distribution?
A
Strenuous exercise changes blood flow/perfusion to certain tissues thus how quickly the drug acts on certain tissues
23
Q
How does extracellular binding affect drug distribution?
A
If it is bound too tightly then dose must be thought out
24
Q
How does capillary permeability affect distribution?
A
Ionised drugs have the ability to move through the pores in the capillary. Dependent on organ we’re looking at
25
Where do drugs localise when drug reaches equilibrium in system?
75% in fatty tissue
26
What are the two major routes of drug excretion in humans?
Kidneys (eliminates most drugs) and liver (concentrated in bile forming large molecular weight conjugates - excreting through faeces)
27
How do kidneys excrete drugs?
Not filtered in the glomerulus so are actively secreted in proximal tubule (acids and bases) and proximal/distal tubules (lipid soluble drugs reabsorbed)
28
Why might treatment with IV Na bicarbonate increase aspirin excretion?
Increased urine pH ionizes the aspirin making it less lipid soluble and less reabsorbed from the tubule, increasing its rate of excretion
29
How are drugs excreted via the liver?
Large drugs are excreted through bike due to kidney/liver not being able to handle it. Active transport systems move drugs into bile (with bile acids and glucuronides)
30
What are some other routes of drug excretion?
Lungs (breathe out volatile molecules), skin, GI secretions, saliva, sweat, milk, genital secretions
31
What is a problem of the bile excretion route for drugs?
Enterohepatic circulation means that when the drug is excreted into bile it is then reabsorbed, taken to liver and reabsorbed again increasing persistence of drug in the body
32
How can we predict time course of drug action?
By considering all of the pharmacokinetic processes
33
What are the terms associated with pharmacokinetic processes?
Bioavailability, apparent volume of distribution, biological half life, clearance
34
What is bioavailability?
Proportion of admin drug that is available within the body to exert its pharmacological effect
35
What is the apparent volume of distribution?
Volume in which a drug appears to be distributed (indicating pattern of distribution)
36
What is the biological half-life?
Time taken for the conc of drug (blood/plasma) to fall to half its original value
37
What is clearance?
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time. (Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)
38
Which of the following drugs would be least likely to penetrate lipid membranes? a)Ionised drug b)Non-ionised drug c)Protein bound drug d)Lipophilic drug e)Hydrophilic drug
A
39
What does metabolism do to xenobiotics?
Tends to reduce/eliminate pharmacological/toxicological activity and converts lipophilic chemicals to polar derivatives
40
What is a main site of drug metabolism and what is a major complication in this organ?
Liver - major organ where hepatic first pass can be extensive (body can metabolise and remove the drug in the first pass of the liver where it is rendered useless if drug target was somewhere after the liver - need to be manufactured to pass by the liver if needed)
41
Where else does drug metabolism occur?
Gut, kidneys, skin, brain etc
42
What are the types of metabolic change?
Phase I, II and excretion
43
What reactions occur in phase I and what is the purpose?
Redox, hydrolysis - add a functional group to the drug that is accessible for phase II
44
What reactions occur in phase II (with enzymes) and what is the purpose?
Glucuronidation, Acetylation, Amino acid conjugation, Sulphation, Methylation, Glutathione conjugation - add on large polar group to drug
45
What are cytochrome p450 enzyme systems?
Important in phase I oxidising reactions and it is involved in metabolism of most drugs - multiple isozymes (57) involved in drug metabolism with certain drugs inhibiting or inducing CYP450 system
46
Where are cytochrome p450 ES found?
Predominantly in the liver
47
What kind of reactions can CYP450 system do?
Oxidises drugs via a cycle of reactions
48
What can occur during Phase I reactions?
Can inactivate chemicals but can also activate them (prodrugs) - after reactions, little change in polarity of drug
49
Give examples of oxidative reactions with aliphatic and aromatic compounds
Pentobarbitone is a sleep-inducing hypnotic and when hydroxylated becomes inactive. Acetanilide is a prodrug but it is toxic causing problems in the blood
50
Give examples of oxidation reactions with n-demethylation and o-demethylation
Can also form di-Demeth groups when both methyl groups are removed.
51
Give examples of oxidation reactions with n-oxidation and alcohol oxidation
Amine oxides are very polar, lipophilic so can be absorbed at all. (NOT P450 but FMO3 which is defective in \>3% causing people to smell like fish). Ethanol metabolised not by P450 but cytoplasmic alcohol DH (zero order kinetics)
52
Give examples of reduction and hydrolytic reactions
Red: frequently occurs in gut. Hydrolysis form acid and amide byproducts
53
Summarise phase I including reactions and purpose.
Prepares drug for phase II metabolism introducing a functional group -\> generating biologically inactive product, with little effect on drug polarity - sometimes produces toxic metabolites
54
What are the enzymes in phase II with their targets and name of the reaction?
All conjugating agents are high energy intermediates
55
Give an example of glucuronidation
Ibuprofen product is polar so can be excreted - most important/common reaction
56
Give an example of acetylation
It's an adaptable reaction which is quite common
57
Give an example of methylation
Amphetamines use the metabolism of NA to A
58
Give an example of sulphation
Paracetamol is very lipophilic but the derivative is soluble so can be excreted in urine
59
Give an example of conjugation with glutathione
Removes toxic materials making them harmless (large tripeptide (glycine, glutamine and cysteine), adding to xenobiotic removing the chloride group - excreted in bile due to large molecular weight)
60
Summarise phase II including reactions and purpose
Conjugation reactions utilising the functional groups from the Phase I reaction; includes glucuronidation, sulphation, acetylation, methylation, conjugation with amino acids and glutathione. High energy intermediate involved.
61
Why is drug metabolism important?
Biological half life of chemical is decreased, duration of exposure reduced, accumulation of compound in body is avoided, potency/duration of the biological activity of the chemical can be altered, pharmacology/toxicology of the drug can be governed by its metabolism
62
What is a cholinomimetic?
Drug that mimics act of ACh in the body in the PNS
63
What are the subtypes of muscarinic receptors and where are they located?
M1: salivary glands, stomach, CNS. M2: heart. M3: salivary glands, bronchial/visceral SM, sweat glands, eye. M4/5: CNS
64
What are the functions of muscarinic receptors?
All but M2 are excitatory (M2 is inhibitory) and all are G-protein coupled receptors. M1, 3 and 5 use IP3 and DAG with Gq. M2 and 4 use cAMP with Gi.
65
What are the subtypes of nicotinic receptors, what type are they and is ACH effective?
Ligand gated ion channels with 5 subunits (alpha-epsilon) with the combination determining ligand binding properties of receptor. Muscle type has 2A, 1B, 1D, 1E. Ganglion type has 2A and 3B (similar to CNS). ACh effects are relatively weak
66
What are the muscarinic cholinergic targets located?
67
What are the muscarinic effects on the eye?
Contraction of ciliary muscle (for near vision), contraction of sphincter pupillae which constructs pupil and improves drainage of intraocular fluid, lacrimation (tears)
68
What are the muscarinic effect on the heart?
M2 in the atria and nodes which decreases cAMP, decreasing Ca2+ entry and CO, increasing K+ efflux and decreases HR
69
What are the muscarinic effect on vasculature?
Most vessels don't have PSNS innervation so ACh acts on vascular endothelial cells to stimulate NO release via M3
70
What are the muscarinic effect on CVS?
Decreased HR, CO and vasodilation leading to sharp drop in BP
71
What are the muscarinic effect on non-vascular SM?
Responds oppositely to vascular muscle, so contracts - lung: bronchoconstriction, gut: increased peristalsis, bladder: increased bladder emptying
72
What are the muscarinic effect on exocrine glands?
Salivation, increased bronchial secretions, increased G-I secretions (inc. gastric HCl production), increased sweating (SNS-mediated)
73
What are the main muscarinic effect on body (summary)?
Decreased HR, BP; increased sweating; difficulty breathing; bladder contraction; GI pain; increased salivation and tears
74
What are directly acting cholinomimetic drugs?
Typical agonists: choline esters (bethanechol - selective muscarinic agonist), alkaloids (pilocarpine -selective muscarinic agonist)
75
What is pilocarpine (derived, type, use, side effects)?
Derived from South American pilocarpus plant, non-selective muscarinic agonist with good lipid solubility, t1/2: 3-4hrs - useful in ophthalmology as local treatment for glaucoma. Side effects: sweating, blurred vision, GI disturbance/pain, hypotension, resp distress
76
What is bethanechol (derived, use, side effects)?
Minor modification of ACh, producing M3 AChR selective agonist; resistant to degradation, orally active and with limited access to the brain (t1/2=3-4hrs); mainly used to assist bladder emptying and to enhance gastric motility; SE: sweating, impaired vision, nausea, bradycardia, hypotension, respiratory difficulty
77
What are indirectly acting cholinomimetic drugs?
Increase effect of normal PSNS nerve stimulation - reversible anticholinesterase (physostigmine, neostigmine, donepezil) and irreversible anticholinesterases (ecothiopate, dyflos, sarin)
78
What are cholinesterase enzymes?
2 types with different distribution, substrate specificity and function: acetylcholinesterase and butyrylcholinesterase
79
What is acetylcholinesterase?
Found in all cholinergic synapses (P and CNS) with very rapid action (hydrolysis) and highly selective for ACh
80
What is butyrylcholinesterase?
Found in plasma and most tissues but not cholinergic synapses. Broad substrate specificity hydrolysing other esters (suxamethonium). Principal reason for low plasma ACh and shows genetic variation.
81
What are the effects of cholinesterase inhibitors?
Low dose enhances muscarinic activity. Moderate dose enhances muscarinic activity and increases transmission at all autonomic ganglia. High dose is toxic as depolarising block at autonomic ganglia and NMJ.
82
How do reversible anticholinesterase drugs work?
Compete with ACh for active site on cholinesterase enzyme - donates carbamyl group to enzyme, blocking the active site and preventing the ACh from binding.
83
What is physostigmine? (Derived, use, side effects)
3ry amine from calabar beans - acts as postganglionic PSNS synapse. Used in treatment of glaucoma aiding intraocular fluid drainage and atropine poisoning (mainly in children)
84
What are irreversible anticholinesterase drugs?
Organophosphate compounds - rapidly react with enzyme active site, leaving large blocking group, which is stable and resistant to hydrolysis with recovery requiring production of new enzymes.- most used for insecticides and nerve gas
85
What is ecothiopate? (Derived, use, side effects)
Potent inhibitor of AChE with slow reactivation of enzymes by hydrolysis taking several days - used as eye drops in treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action -\> systemic SE: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
86
How do anticholinesterase drugs affect the CNS?
Non-polar anticholinesterases can cross the blood brain barrier with low doses causing excitation with possibility of convulsions and high doses causing unconsciousness, resp depression, death
87
What is first order kinetics?
Rate of elimination of a drug where amount of drug decreases at a proportional rate to conc of remaining drug in body
88
What is 1st order kinetics dependent upon?
Concentration of drug at any given time and applies to most drugs in clinical use
89
What is zero order kinetics?
x
90
What are xenobiotics?
Usually lipophilic
91
Give some examples of organophosphate compounds.
Ecothiopate, dyflos, parathion, sarin
92
What drugs are used to treat Alzheimer's?
Donepezil and tacrine - ACh is important in memory
93
How do anticholinesterase drugs work to help Alzheimer's?
Potentiation of central cholinergic transmission relieves AD symptoms but doesn't affect degeneration
94
How can you treat organophosphate poisoning?
Accidental exposure to organophosphates can cause severe toxicity due to increased mus arinic activity, CNS excitation, depolarising NM block -\> treated with atropine, artificial respiration, pralidoxime
95
What is the function of cholinomimetics?
Decrease HR and CO, increase exocrine gland activity and non-vascular SM contractility, causes miosis
96
What can occur due to a high dose of cholinomimetics?
Activates PSNS and all autonomic ganglia, causing depolarising blockade of nAChRs
97
Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system? A: All autonomic synapses B: Pre- and post-ganglionic parasympathetic synapses C: Pre- and post-ganglionic sympathetic synapses D: Post-ganglionic parasympathetic synapses only E: Pre-ganglionic sympathetic synapses only
B
98
Anticholinesterase drugs can be used to treat which of the following conditions? A: Asthma B: Glaucoma C: Hypotension D: Motion Sickness E: Peptic Ulcer Disease
B
99
How is glaucoma caused?
Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via canals of Schlemm, reducing intra-ocular pressure (this doesn't happen in glaucoma)
100
T, F, T, T, F
101
T, T, F, T, F
