Pharmacology & Therapeutics 1 Flashcards
1
Q
What are the 3 principle efferent outputs from the CNS?
A
Autonomic: responsible for involuntary control, accounts for the innervation of the exocrine glands, smooth muscle, cardiac muscle and is involved in metabolism and host defenceSomatic: it is the innervation of the muscle, including the diaphragm and respiratory musclesNeuroendocrine: this system is responsible for growth metabolism, reproduction, development , salt & water balance and host defence
2
Q
What are the basic branches of the ANS?
A
Sympathetic: fight and flight Parasympathetic: rest and digest
3
Q
How does the ANS target the eye?
A
Sympathetic: Dilation of the pupil Parasympathetic: Constriction of the pupil Contraction of the ciliary muscle
4
Q
How does the ANS target the salivary glands?
A
Sympathetic: Thick, viscous secretion Parasympathetic: Copious, watery secretion
5
Q
How does the ANS target the trachea and bronchioles?
A
Sympathetic: Dilates Parasympathetic: Constriction
6
Q
How does the ANS target the skin?
A
Sympathetic: Piloerection Sympathetic cholinergic: Increased sweating
7
Q
How does the ANS target the liver?
A
Sympathetic: Glycogenolysis and gluconeogenesis
8
Q
How does the ANS target the heart?
A
Sympathetic: Increase in rate and contractility Parasympathetic: Decrease in rate and contractility
9
Q
How does the ANS target adipose tissue?
A
Sympathetic: Lipolysis
10
Q
How does the ANS target the gastrointestinal system?
A
Sympathetic: Decrease in motility and tone Sphincter contraction Parasympathetic: Increase in motility and tone Increase in secretions
11
Q
How does the ANS target to kidney?
A
Sympathetic: Increased renin secretion
12
Q
How does the ANS target the ureters and bladder?
A
Sympathetic: Relaxes detrusor; constriction of trigone and sphincter Parasympathetic: Contraction of detrusor Relaxation of trigone and sphincter
13
Q
How does the ANS target the blood vessels?
A
Sympathetic: (skeletal muscle)Dilation (skin, mucous membranes, splanchnic area) constriction
14
Q
What are the characteristics of the parasympathetic nervous system?
A
- Cranial sacral outflow - Long pre-ganglionic fibre - Short post-ganglionic fibre - Ganglia tend to lie within the innervated tissue - Only neurotransmitter involved is Ach, therefore all cholinergic synapses
15
Q
What are the characteristics of the sympathetic nervous system?
A
- Thoracolumbar outflow - Short pre-ganglionic fibre - Long post-ganglionic fibre - Ganglia form just outside spinal cord in the paravertebral chains
16
Q
What do postganglionic fibres of the SNS to effector organs release?
A
Noradrenaline
17
Q
What to postganglionic fibres of the SNS which innervate sweat glands release?
A
Ach
18
Q
What do preganglionic fibres of the sympathetic nervous system release?
A
Ach
19
Q
In which cases do preganglionic fibres of the SNS release noradrenaline?
A
Some preganglionic fibres innervate the adrenal medulla
20
Q
What is the enteric nervous system?
A
The local nervous system of the digestive tract which consists of the submucosal and myenteric plexus
21
Q
What is the somatic nervous system?
A
Consists of one long motor neurone, with Ach release to the skeletal muscle
22
Q
What are the types of Ach receptors?
A
Nicotinic and muscaranic receptors
23
Q
What are the characteristics of nicotinic receptors?
A
- Membrane bound receptors that are present at autonomic ganglia - Type 1 ionotrophic receptors therefore they produce rapid responses via iron channel opening - Stimulated by nicotine and acetylcholine - Blocked by hexamethonium
24
Q
What are the characteristics of muscarinic receptors?
A
- Tend to be found in the effectors organs which are innervated by post-ganglionic parasympahetic fibres which mediate effector responses - Type 2 G-protein coupled receptors therefore require generation of 2nd messenger molecules. This means the responses are slower. - Stimulated by muscarine and acetylcholine - Blocked by atropine
25
What are the subtypes of muscarinic cholinoreceptors?
M1- founds in neural tissues M2- found in cardiac tissues M3- found in exocrine and smooth muscle
26
What are the subtypes of adrenoreceptors?
Alpha 1 Alpha 2 Beta 1 Beta 2
27
What is the process of amine transmitter synthesis?
1) The precursor is taken up into the pre-synaptic nerve terminal 2) The precursor is enzymatically converted into the active transmitter and then packaged into vesicles 3) Follow pre-synaptic nerve terminal depolarisation, the vesicles fuse and release the transmitter into the synapse 4) The transmitter then binds with the receptor on the effector cel; where it is broken down and the degradation products are taken back up into the nerve terminal
28
What is the precursor for acetyl choline synthesis?
Acetyl CoA & choline
29
Which enzyme is responsible for the conversion during acetyl choline synthesis?
Choline acetyl transferase
30
Which enzyme is responsible for enzymatic degradation during acetyl choline degradation?
Acetylcholine esterase
31
What is the process of noradrenaline synthesis?
- The precursor is tyrosine - Tyrosine is then hydroxylased into DOPA by tyrosine hydroxylase - DOPA is then decarboxylated to form dopamine which is then packaged into vesicles - In the vesicle, dopamine is hydroxylased to form noradrenaline by dopamine beta hydroxylase - NA is released from the vesicle
32
What are the two uptake systems for noradenaline?
1) Neural reuptake & degradation by MAO-A to form secondary metabolites 2) Extraneural uptake and degradation via COMT
33
What is pharmacology?
The science of the properties of drugs and their side effects on the body
34
What is pharmacokinetics?
The study of how drugs are handled within the body, including their absorption, distribution, metabolisation and excretion This concerns: - How drug concentration changes with time - How drugs pass across cell membranes - How often drugs should be given - What the effect of long-term administration may be - How drugs interact with each other
35
What is pharmacodynamics?
The interactions of drugs with cells and their mechanism of action on the body. It involves - How drugs bind to cells - Uptake of drugs into cells - Intracellular metabolism of drugs
36
What is a drug?
A chemical that affects the physiological function in a specific way
37
What are drug target sites?
Protein complexes key to drug mechanism of action
38
When a drug is administered, what are the target sites that it must interact with?
1) Cell receptors 2) Ion channels 3) Transport systems 4) Enzymes
39
What are cell receptors?
Proteins which usually sit within cell membranes thus exposing an active site waiting to be activating by neurotransmitters or hormones
40
How are the different families of cell receptors differentiated between?
On the basis of protein structure of the receptors and the biochemical/transduction system the receptor interacts with with in the cell
41
What are the different types of cell receptors?
Type 1: Ionotrophic (ligand-gates channels) Type 2: Metabotrophic (G-protein couples Type 3: Kinase-linked Type 3: Intracellular steroid type
42
What are the characteristics of ionotrophic cell receptors?
Location: Membrane Effector: Channel Coupling: Direct Speed: Millisecond Example: Nicotinic Ach receptor
43
What are the characteristics of metabotrophic cell receptors?
Location: Membrane Effector: Enzyme or channel Coupling: G-protein Speed: Seconds Example: Muscarinic Ach receptor
44
What are the characteristics of kinase-linked cell receptors?
Location: Membrane Effector: Enzyme Coupling: Direct or indirect Speed: Minutes Example: Insulin receptor
45
What are the characteristics of intracellular steroid type cell receptors?
Location: Intracellular Effector: Gene transcription Coupling: Via DNA Speed: Hours Examples: Steroid/thyroid receptors
46
What is an agonist?
A drug or other substance that acts on the cell receptor to activate it, initiating a response. E.g. Acetylcholine (at acetylcholine receptors) and nicotine
47
What are antagonists?
A drug or other substance that binds to the cell receptor without activating it. It blocks the receptor active site and therefore inhibits the normal response
48
What are the shapes of a normal dose-resposne curve and a log dose-response curve?
Normal: hyperbolic Log: sigmoidal
49
What are the different types of ion channels?
Voltage sensitive: the channel opens in response to a change in membrane potential e.g. Ca2+ channels (VSCC) Receptor linked: channel opens in response to the activation of a receptors. e.g. choline activates NAChR, which in turns opens an ion channel
50
Which types of drugs might interact with on or both types of ion channels?
- Local anaesthetics: they interact with or block sensitive Na+ channels on pain conduction neurones in order to reduce the perception of pain - Calcium channel blockers- e.g. Nitradipine; very useful in the treatment of CV disorders for example as anti-hypersentives and anti-angine drugs
51
What are transport systems?
Specific carrier molecules that transport substances against their concentration gradients. They are energy dependent.
52
What are examples of transport systems?
- Glucose transporter in hepatocutes - Neurotransmitter transport e.g. active reuptake of noradrenaline into nerve terminals in the sympathetic nervous systems - Na+/K+ ATPase
53
How do tricyclic anti-depressants interact with transport system?
- Used in clinical depression the Na5HT transporter in the brain is not fully functional - Tricyclic anti-depressants slow down the postsynaptic reuptake of NA into the nerve terminals which prolongs the effect of NA
54
How do cardiac glycosides interact with transport systems?
- Acts to slow down the NA/K ATPase which leads to an increase in intracellular Na+. - Useful in cardiac failure, as the increase in intracellular Na+ results in an increased force of contraction e.g. Digoxin
55
How do drugs interact with enzymes?
Enzyme inhibitors: act to slow enzyme function False substrate: act to subvert normal pathways by introducing a new substrate Prodrugs: drugs which interact with an enzyme component which then has an effect of the body
56
Give an example of an enzyme inhibitor
Neostigmine- an anticholinesterase which slows down the rate of degradation of acetylcholine which enhamces its action
57
Give an example of a false substrate
Methyldopa- an antihypertensive drug which subverts the normal noradrenaline synthesis pathways by introducing a different precursor leading to local vasodilation
58
Give an example of a prodrug
Chloral hydrate is converted to the active trichloroethanol
59
What mediates the unwanted effects of paracetamol?
Enzymes
60
What are examples of non-specific drug action, in which drug action is mediated solely by their own physiochemical properties and not the 4 main drug target sites?
- General anaesthetics: interact with synaptic transmission in the brain - Antacids: used in the treatment of indigestion, dyspepsia and symptoms of ulceration - Osmotic purgatives/ laxatives- actis to draw water into the large intestine causing softening/expansion of faeces and promotion of excretion
61
Give an example of a plasma protein binding site
Albumin- acts to allow the storage of drugs in the body in a protein bound form. It allows the transport of the drug but does not mediate any action of the drug
62
What is affinity?
The strength of the drug binding to the receptor
63
What is efficacy?
The ability of the drug to induce a response in the receptor post-binding
64
What is potency?
The powerfulness of a drug, depending on its affinity and efficacy
65
What is a full agonist?
An agonist which has the ability to induce a max response in tissue post-binding
66
What is a partial agonist?
An agonist which can only produce a partial response in tissue, and in conjunction with a full agonist may act with antagonist activity
67
What is selectivity?
The preference of a drug for a receptor
68
What is the structure-activity relationship?
Refers to the fact that the activity of a drug is related to the structure of the drug which means small changes in the structure may produce large effects on its action
69
What is receptor reserve?
The fact that in many tissues, not all receptors need to be occupied in order to achieve the maximal tissue response
70
What are competitive antagonists?
They bind to the same site as the agonist which reduced the number of agonist molecules which can bind to the receptor leading to a reduced normal agonist response They are surmountable- increasing the concentration of the agonist, a competitive antagonist block can be overcome
71
What are irreversible antagonists?
They bind tightly either to the same site as the agonist or at a different site to the agonist. They are insurmountable, meaning maximal normal response cannot be achieved regardless of whether the concentration of the agonist is increased further
72
What are the 4 main types of drug antagonists?
1) Receptors blockade 2) Physiological antagonism 3) Chemical antagonism 4) Pharmacokinetic antagonism
73
What is physiological antagonism?
Drugs may act on different receptors in the same tissue to induce the opposite effect. E.g. noradrenaline acts to induce vascular constriction. Blood pressure increases. Whereas, histamine acts on different receptors to induce vascular dilation and bloop pressure reduction.
74
What is chemical antagonism?
Where two drugs interact in solution E.g. chelating agents, dimercaprol, useful in treatment for heavy metal poisoning
75
What is pharmacokinetic antagonism?
Antagonists act to reduce the concentration of the active drug at the site of action. Pharmacokinetic antagonism occurs in different ways: - Decrease absorption - Increase metabolism - Increase excretion
76
Give an example of pharmacokinetic antagonism
Barbiturate interaction with warfarin - Barbiturates are good enzyme inducers so if they are administered repeatedly, the metabolising system within the liver increases - This can pose a problem with co-administrering another drug which is metabolised b the same enzymes. This leads to this enzymes activity being reduced.
77
What is drug tolerance?
The gradual reduction in responsiveness to a particular drug, following repeated administration
78
Which factors can influence drug tolerance ?
1) Pharmacokinetic factors - increase the rate of metabolism of the drug i.e. enzyme inducing e.g. barbiturates and alcohol 2) Loss of receptors- by membrane endocytosis which leads to receptor 'down-regulation' e.g. beta- adrenoreceptors 3) Receptor desensitisation- the receptor remains on the cell surface but undergoes a conformational change meaning that it can no longer bind with an effective response e.g. nitotinic acetyl CoA receptr at the neuromuscular junction 4) Exhaustion of mediator stores- with repeated stimulation of a system, any required mediator stores may be exhausting meaning tissue response is reduced e.g. amphetamines 5) Physiological adaption- a homeostatic response to the effect of a drug in which the body tries to keep effects within a set range.
79
What is the journey of a drug through the body?
Formulate Administration Distribution Metabolism Excretion
80
How can administration routes be categorised?
Enteral: routes include sublingal, buccal, oral and rectal - these routes are considered to easier and patients can self-administer these drugs Parenteral: routes include intravenous, intramuscular, subcutaneous, percutaneous and inhalation - these are more invasive routes and are usually administered by a medical professional (exceptions would be asthmatics and diabetics)
81
What are the advantages and disadvantages of the oral route of administration?
Advantages: Permits self medication Does not require very sterile preparations Lower incidence of anaphylactic shock Capacity to prevent complete absorption (vomiting) Disadvantages: Inappropriate for drugs which - are easily altered in stomach acid - undergo extensive 'first pass' metabolism Requires patient compliance
82
What are the advantages and disadvantages of the intravenous route of administration?
Advantages: Rapid onset of action Avoids poor absorption/ destruction of the GI tract Permits care control of blood levels Disadvantages: Slow injection necessary Higher incidence of anaphylactic shock Possible complications include embolism, phlebitis and pain
83
What are the advantages and disadvantages of inhalation for administering drugs?
Advantages: Is ideal for particles, gases, volatile liquids and aerosols There is an large surface area available due to alveolar membranes Simple diffusion mechanism and phagocytosis Disadvantages: Possible localised effect within the lungs
84
What are the advantages and disadvantages of the intramuscular route of administration?
Advantages: Relatively high blood flow which increases during exercise Enable the depot theory Disadvantages: Possible infection and nerve damage (more common in the gluteal region)
85
What are the advantages and disadvantages of the subcutaneous route of administration?
Advantages: Local administration so dissemination can be minimised Enable depot theory Disadvantages: Pain Abscess Tissue Necrosis
86
What are the advantages of the percutaneous route of administration?
Advantages: Local application and action Lipid soluble compounds diffuse readily Disadvantages: Local irritation and skin reactions Alteration of skin structure (e.g. steroids)
87
How do drugs cross different barriers (membranes)?
1) Passive diffusion 2) Facilitated diffusion 3) Active transport 4) Pinocytosis 5) Filtration 6) Paracellular transport
88
Via which two ways do drug molecules move around the body?
Bulk flow transfer- in the bloodstream Diffusional transfer- molecule by molecule over short distances
89
Why do drugs exist in ionised (polar) and non-ionised (non-polar) forms?
Most drugs are either weak acids or weak bases
90
What is the PH partition hypothesis?
Drugs are absorbed when they are in their unionised state, therefore the rate of absorption is dependent on the amount of drug that is present in an unionised form
91
What factors influence drug distribution?
- Regional blood flow - Extracellular binding (plasma-protein binding) - Capillary permeability (tissue alterations- renal, hepatic, brain/CNS), placental) - Localisation in tissues
92
How are drugs excreted in the kidneys?
Responsible for the elimination of most drugs 1) Glomerulus: drug-protein complexes are not filtered 2) Proximal tubule: active secretion of acids and bases 3) Proximal and distal tubules: lipid soluble drugs are reabsorbed
93
Why might treatment with intravenous sodium bicarbonate increase aspirin excretion?
I.V sodium bicarbonate will increase the pH of urine. Increased urine pH ionises the aspirin which makes it less lipid soluble and therefore less reabsorbed from the tubule. Its rate of excretion is therefore increased
94
What is enterohepatic cycling?
Where the drug/metabolite is excreted into the gut (via the bile) but is then reabsorbed and taken back to the liver to be excreted again
95
What can enterohepatic cycling lead to?
Drug persistence
96
Aside from the major 2 routes (kidney and liver) of drug excretion, what other routes exist?
Lungs Skin Gastrointestinal secretions Saliva Sweat Milk Genital Secretions
97
What is bioavailability?
The proportion of the administered drug that is available within the body to exert its pharmacological effect
98
What is the apparent volume of distribution?
The volume in which a drug appears to be when it is distributed - it is an indicator of the pattern of distribution
99
What is biological half-life?
The time taken for the concentration of a drug (in blood/plasma) to fall to half its original value
100
What is clearance?
Blood plasma clearance is the volume of blood plasma that has been cleared of a drug in a unit time
101
What type of molecule are usually xenobiotics?
Lipophilic
102
What is the purpose of metabolism?
It tends to reduce or eliminate pharmacological/toxicological activity. Metabolism converts lipophilic chemical to polar derivatives
103
What is the major organ of drug metabolism?
The liver. Hepatic 'first pass' metabolism can be extensive
104
What are the 3 types of metabolic changes?
Phase 1 Phase 2 Excretion
105
What occurs during Phase I reactions of metabolism?
- Oxidation/reduction creates new functional groups and hydrolysis unmasks them. - Functional groups serve as a point of attachment for Phase II reactions. - Phase 1 reactions often inactivate chemicals. - The reactions can activate chemicals such as in the cases involving prodrugs -There is little change in the polarity of the drug after phase I metabolism - Can produce toxic metabolites - Often generate a biologically inactive product
106
Where is the cytochrome P450 enzyme predominantly found?
Liver
107
What is an important role of cytochrome P450?
Important enzyme in Phase I oxidising reactions
108
How do oxidation reactions in Phase I metabolism usually begin?
With a hydroxylation step catalysed by the P450 system
109
What are the reactions and their enzymes that are involves in Phase II metabolism?
Glucuronidation (glucuronyl transferase) Methylation (methyl transferase) Sulphation (sulphotransferase) Acetylation (acetyl transferase) Glutathione (glutathione-s-tranferase) Aminoacid conjugation (acyl transferase)
110
What are the characteristics of Phase II metabolism reactions?
- The conjugate is almost always pharmacologically inactive - Less lipid soluble - Easier to excrete
111
What is the conjugating agent and target functional groups in glucuronidation?
Conjugating agent: UDP- glucuronic acid Target functional groups: -OH, -COOH, -NH2, -SH
112
What is the conjugating agent and target functional groups in acetylation?
Conjugating agent: Acetyl CoA Target functional groups: -OH, -NH2
113
What are the conjugating agents and target functional groups in amino acid conjugation?
Conjugating agents: Glycine, Glutamine, Taurine Target functional groups: -COOH
114
What is the conjugating agent and target functional groups in methylation?
Conjugating agent: S-adenosyl-methionine Target functional group: -OH, -NH2
115
What is the conjugating agent and target functional groups in suplhation?
Conjugating agent: 3'-phosphoadenosine-5'-phosphosulphate Target functional group: -OH, -NH2
116
What is the conjugating agent and target functional groups in Glutathione conjugation?
Conjugating agent: Glutathione Target function group: electrophiles
117
What is the high energy intermediate forms in glucuronidation?
UDP-glucoronate
118
What acts as an energy rich donor in sulfation?
PAPS
119
Why is drug metabolism important?
- The biological half-life of a chemical is decreased - The duration of exposure is reduce - The accumulation of the compound in the body is avoided - The potency/duration of the biological activity of the chemical can be altered - The pharmacology/toxicology of the drug can be governed by its metabolism
120
What are cholinomimetric drugs?
They mimic activation of the parasympathetic nervous system?
121
What are muscarinic effects
- Effects that can be replicated by muscarine and can be abolished by low doses of the antagonist atropine - Muscarinic actions correspond to those of parasympathetic stimulation
122
What can happen with larger doses of acetylcholine after an atropine blockade of muscarinic actions?
Acetylcholine can induce effects similar to those caused by nicotine
123
What are the subtypes of muscarinic receptors?
3 main subtypes:- M1: salivary glands, stomach, CNS M2: heart M3: salivary glands, bronchial/visceral smooth muscle, sweat glands, eye M4/M5: CNS
124
