Intro & Autonomic pharmacology Flashcards
(86 cards)
0
Q
What are pharmacodynamics?
A
What the drug does to the body.
1
Q
What are Pharmacokinetics?
A
They determine what the body does to the drug, absorption, metabolism, distribution, excretion.
2
Q
What is enterohepatic recirculation?
A
Drug is released into the gastrointestinal tract in the bile and a proportion of it may then be reabsorbed from the GIT.
3
Q
Describe First order kinetics
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The rate of drug elimination changes and is proportional to the drug concentration.
4
Q
What is Zero order Kinetics?
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The rate at which drug concentration changes is constant and independent of drug concentration. The rate of elimination is fixed. (bad)
5
Q
Describe ion trapping
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Most drugs are weak acids or bases. Non ionised drug moves across cell membranes more readily. the local pH environment may lead to an ion trapping effect. Degree of ionisation depends on the ppH and pKa of the drug.
6
Q
What is the First pass effect?
A
Generally refers to removal of a percentage of the drug as it passes through the liver via the portal circulation - before it reaches the systemic circulation.
7
Q
What Is Bioavailability?
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Defines the extent to which an administered dose of a drug enters the systemic circulation intact. Referred to as F.
8
Q
Describe plasma protein binding.
A
Certain drugs bind highly to plasma proteins. Binding is reversible. Bound dug does not move across membranes. Bound drug acts as a reservoir. Albumin is the main plasma protein that drugs bind to. Binding in excess of 80% is considered high. Bound Drug tends to stay centrally and bound drug cannot be filtered by the kidney but carrier mediated transport is not affected. Hypoalbuminaemia may increase free drug. Uraemia may increase free drug.
9
Q
What is the Volume of Distribution?
A
The amount of tissue to which the drug distributes is directly related to the plasma drug concentration. It is calculated Vd = Dose/ Co. Co is the peak plasma drug concentration after equilibrium is achieved and before elimination has begun.
10
Q
Name the Phase I and phase II reactions.
A
Phase I- hydrolysis, reduction, oxidation. (make a drug more reactive.)
Phase II - Acetylation, glucuronidation, conjugation to AAs e. cysteine, glycine. (adds a side chain to make more easily excreted)
11
Q
Describe Enzyme inducers & give an example
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Enhance their own metabolism and that of other drugs by inducig hepatic microsomal enzymes. Eg diazepam, phenylbutazone
12
Q
Describe Enzyme inhibitors and give an example
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Reduce their own rate of metabolism and that of some other drugs by inhibiting Hepatic microsomal enzymes (mixed function oxidases). e.g Cimetidine, chloramphenicol.
13
Q
Describe Species differences in Phase II reactions
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Cats are deficient in glucuronyl transferase - they have a limited ability to perform glucuronidation.
Dogs have a limited capacity to perform acetylation.
14
Q
What is Clearance?
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Defined as the volume of blood cleared of the drug by all elimination processes per unit time and is measured in ml/min. It will encompass biotransformation as well as elimination processes.
15
Q
What is Steady State?
A
Where the levels of drug remain stable or consistent from dose to dose. 95% SS is achieved after 5 half lives. 99% is achieved after 7 half lives.
16
Q
Describe Pharmacodynamics
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Drug action - describes the interaction of the drug with its receptor. Drug effect - the subsequent chain of events caused by the drug receptor interaction.
17
Q
What is an Agonist?
A
An agonist is a drug that binds to a physiological receptor and mimics the effect of the endogenous ligand. Full agonists can achieve maximal response even if not all the receptors are occupied. partial agonists are incapable of achieving maximal response even if all the receptors are occupied.
18
Q
What is Affinity?
A
The tendency of the ligand to bind to the receptor
19
Q
What is Efficacy?
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A term used to describe how good the drug is at eliciting a particular response e.g partial agonists have less efficacy than full agonists.
20
Q
Describe Potency
A
It is a relative term. Often used to compare two drugs and compares the concentration required to elicit the same response.
21
Q
What are Antagonists
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They can have affinity but have no intrinsic activity. They may be competitive (reversible) OR non competitive (the antagonism cannot be overcome by increasing amount of agonist).
22
Q
What is Selectivity
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Often drugs produce more than one effect. Selectivity defines the capacity to preferentially produce one particular effect.
23
Q
What is specificity?
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An absolute term - ultimate selectivity. A drug with specificity tends to only act on one particular receptor type.
24
What is the therapeutic index?
The ratio of the dose giving an undesired effect over the dose required to give the desired effect.
25
Describe Receptor Desensitisation
When a receptor is exposed to a ligand the response may reach a peak and then despite the continued presence of the ligand begin to fall off. There is rapid recovery once the ligand is removed. The receptor number remains the same.
26
Describe receptor down-regulation
Slower in onset and recovery than desensitisation. The receptors become internalised and degraded within the cell. Tyrosine kinase receptors are prone to this.
27
Describe the Neurotransmitters of the SNS
Acetylcholine - preganglionic neurotransmitter.
Noradrenaline - postganglionic neurotransmitter
Adrenal medulla chromaffin cells release adrenaline
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What are the functions of the SNS?
Mydriasis, positive chronotropic effect, positive inotropic effect, vasoconstriction or dilation depending on receptors, increased dromotropic effect, bronchodilation, decreased gastric motility, increased sphincter tone, glycogenolysis, gluconeogenesis.
29
Describe Noradrenaline
Synthesised in the nerve terminal from tyrosine, it is stored in vesicles until an action potential induces the release. It undergoes reuptake and enzymatic degradation and has an effect on alpha and B adrenoceptors.
30
Describe Alpha 1 adrenoceptors
They are widely distributed throughout the body. They couple mainly to Gq. The second messenger system usually involves the activation of phospholipase C leading to the formation of IP3 and diacylglycerol. IP3 induces the release of intracellular calcium from the SR and DAG activates protein kinase C.
31
Describe Alpha 2 adrenoceptors.
Couple to Gi and Go. They inhibit adenylyl cyclase and thus decrease cAMP. They also inhibit voltage gated calcium channels and activate Ca2+ dependent K channels.
32
Describe B1 Adrenoceptors
Couple mainly to Gs. Stimulation of adenylyl cyclase which increases cAMP and this in turn increases protein kinase A. Found mainly in the heart. Activation leads to increased force of contraction, conduction and increased rate of impulse formation.
33
Describe B2 Adrenoceptors
Mediate activity through Gs and Gi. They can stimulate or inhibit cAMP production. The main effects are vascular smooth muscle relaxation, bronchodilation and stabilisation of respiratory mast cells.
34
Describe the Parasympathetic nervous system
It has cranial and sacral outflows. Its axons of the presynaptic fibres synapse in or near the organ innervated (long preganglionic, short post ganglionic fibres). The PNS has a more localised effect. Acetylcholine ACh is the pre and post synaptic neurotransmitter.
35
Describe the actions of acetylcholine
ACh synthesis requires the enzyme choline acetyltransferase. Acetylcholine esterase rapidly degrades ACh. ACh acts at nicotinic and muscarinic receptors.
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PNS: Function - rest & digest
Cardiovascular system - decreased rate, decreased conduction, decreased force of contraction, vasodilation - ACh induces NO release which causes vascular smooth m. to relax, Increased gastrointestinal motility & increased secretion. Contraction of the detrusor muscle, urethral peristalsis, relaxation of sphincters, miosis, bronchoconstriction, secretion decreased.
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Describe nicotinic Receptors
Ligand gated ion channels. They increase permeability to Sodium and potassium which depolarises the cell. There are two types, Nm and Nn. Nm are found on skeletal muscle. Nn are found in ganglia.
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Describe Muscarinic Agonists
Also called parasympathomimetics - made up of two groups.
1. synthetic choline esters and ACh. - The presence of the ester groups makes the compounds susceptible to AChE.
2. Naturally occurring cholinomimetic alkaloids
39
Describe the Choline Esters (muscarinic Agonists)
ACh, methacholine, bethanecol, carbachol. ACh itself is too rapidly degraded by AChe to be useful. Methacholine - mainly muscarinic, main effect on CVS. Bethanecol and carbachol - resistant to AChE. Both drugs effect GI tract.
40
Describe the Cholinomimetic alkaloids (Muscarinic agonists)
Muscarine, pilocarpine and arecoline. Pilocarpine has dominant muscarinic activity. It is used as a solution applied topically to the eye. Used for the treatment of glaucoma. Contraindacated in uveitis.
41
Describe the Acetylcholinesterase inhibitors
Reversible (neostigmine) or Irreversible (organophosphates). They have a cholinergic effect initially but prolonged depolarisation may have the opposite effect. They may also act as direct agonists or antagonists. Solubility and volatility contribute to effects/toxicity They are used with eye, skeletal and Gi tract. Edrophonium chloride is used for the reversal of non depolarising muscle relaxants and the diagnosis of myasthenia gravis.
42
Describe the Muscarinic Antagonists
Competitive antagonists for ACh at muscarinic receptors. They have a limited effect at the neuromuscular junction or in ganglionic transmission. They have a similar structure to ACh but bulkier aromatic group in place of acetyl group. Atropine and scopolamine, glycopyrronium, ipratopium, tropicamide.
43
Describe Atropine (muscarinic antagonist)
Can be given i/m, i/v, s/c. Metabolised in the liver and also excreted by kidneys. Ionised at physiological pH yet crosses the gut, conjunctival sac and blood brain barrier. Premedicant to decrease salivation. Not recommended in horse. GI motility reduced.
44
Describe Scopolamine (muscarinic antagonist)
A naturally occuring agent, used for drying secretions, decreases vomiting, contained in buscopan, has antiemetic properties.
45
Describe Ganglionic blockers
Trimpetaphan and hexamethonium. Have profound effects including hypotension and loss of cardiovascular reflexes. Not really used in veterinary medicine.
46
Describe adrenaline (non selective agonists in SNS)
Act at both a- and b- adrenoceptors. Increases heart rate and force of contraction, induces vasoconstriction, used for cardiac arrest and anaphylaxis, taken up by nerve terminals and non neuronal tissue and metabolised by MAO and COMT respectively.
47
Describe the effects of Dopamine
Neurotransmitter - subtypes of receptor D1-D5. D1 Receptors are found in the renal vasculature. Stimulation by low doses of dopamine leads to increase in intracellular cAMP. Induces a vasodilation, increased renal perfusion and filtration, prevention and management of acute renal failure. Dopamine at higher doses can induce vasoconstriction through vascular a1-adrenoceptors.
48
Describe phenylpropanolamine (propalin)
Has alpha antagonist properties. Its most important use is in the treatment of urinary incontinence in the bitch. It is administered orally. IT has also been used as a nasal decongestant. Has tyramine like activity in that it induces the release of NA from the nerve terminal.
49
Describe the uses of Clenbuterol (a B2 selective agonist)
Used to induce bronchodilation, uterine relaxation, treatment of COPD, given orally or intravenously, can induce vasodilation and tachycardia, has a growth promotant effect,
50
Describe the a1 selective agonists
They will induce vasoconstriction and can increase force of myocardial contraction. Phenylephrine is used in occular preparations to induce mydriasis.
51
Describe the a2 adrenoceptor agonists
central sedative effects eg clonidine and detomidine.
52
What are the uses of A1 antagonists
They cause vasodilation, such as prazosin, terazosin. Phenoxybenzamine is an irreversible a-antagonist having a predominant a1-adrenoceptor blocking effect. It has been used in the treatment of laminitis.
53
What are the uses of a-2 antagonist drugs?
Used to reverse sedation induced by the alpha 2 agonist drugs. Examples are yohimbine and atipamezole.
54
Describe Muscarinic Receptors in the PNS
They are G protein coupled receptors, with fie subtypes, M1-M5.
M1- Ganglia, activate PLC leading to IP3 and DAG formation.
M2 - In the heart, Inhibit Adenylyl cyclase and open K+ Channels.
M3- Smooth m. and glandular tissue, Activate PLC
M4- Inhibit Adenylyl cyclase, CNS.
M5 - Activate PLC
55
What is the Enteric Nervous system?
Third division of the Autonomic nervous system - it consists of intrinsic nerve plexuses of the GI tract. Cell bodies lie in the intramural plexuses in the intestinal wall. Sympathetic and parasympathetic fibres terminate on enteric neurones modulating the function. A large number of neuropeptides participate in effects including 5-HT.
56
What are the three main drug types used on the parasympathetic nervous system?
Muscarinic agonists, acetylcholinesterase inhibitors, muscarinic antagonists.
57
Describe the Muscarinic agonists
Made up of 1) The choline esters and ACh. (presence of the ester group makes the compounds susceptible to AChE.)
And 2) The naturally occurring cholinomimetic alkaloids.
58
What are the choline esters? (muscarinic agonists)
E.g ACh, metacholine, bethanecol, carbachol. ACh itself is too rapidly degraded by AChE to be clinically useful. Methacholine has slower degradation by AChe than ACh - main effect on CVS. Bethanecol and carbachol are resistant to AChE. Both drugs have GI tract effect. Bethanecol mainly muscarinic effect. Carbachol has some nicotinic action contributing to the release of ACh from the nerve terminals. Have been used to induce gastric motility. Carbachol also used topically to induce miosis.
59
Describe the cholinomimetic alkaloids with examples
Pilocarpine - dominant muscarinic activity, used as a solution applied topically to the eye to induce miosis, used for the treatment of gluacoma. (opens drainage angle of aqeous humor by constricting lense). Other exampls, muscarine, arecoline.
60
What are the Acetylcholinesterase inhibitors?
Reversible - AChEL - e.g physostigmine, neostigmine, edrophonium and pyridostigmine. Irreversible AChEl - organophosphates e.g parathion, fenthion, malathion. Have a cholinergic effect initially but prolonged depolarisation may have the opposite effect.
61
Describe potential toxicity of the acetylcholinesterase inhibitors.
Factors that contribute to the effects/toxicity of these agents are - volatility and solubility, which determine how easily they are absorbed and how widely they are distributed in the body, whether they are irreversible or reversible. Sarin, tobun and soman were used as nrve gases - volatile, lipid soluble and almost completely irreversibl.
62
What are the main uses of acetylcholinesterase Inhibitors
Have a cholinergic effect. Main uses are in connection with the eye, skeletal muscle and gastrointestinal tract. Edrophonium chloride is a very short acting compound used for reversal of non-depolarising muscle relaxants. Used for diagnosis of myasthenia Gravis. Given by slow intravenous injection - rapid onset and short duration of action.
63
What is neostigmine?
A acetylcholinesterase inhibitors. Has a cholinergic effect. Moderate duration of action - reversal of non depolarising muscle relaxants - treatment of myasthenia gravis, can be given orally or intravenously. Oral administration for the treatment of M gravis is TID and the dose is reduced as required.
64
What is the use of pyridostigmine?
Also of moderate duration, treatment of myasthenia gravis, Orally BID, half life about 4 hours, intravenously half life about 2 hours.
65
Describe the toxicity seen with acetylcholinesterase inhibitors
Due to excess cholinergic effects - salivation, muscle tremor, defecation, miosis, collapse, antimuscarinic agents always needed to hand (Atropine).
66
Describe the muscarinic antagonists
Competative antagonists for ACh at muscarinic receptors. They have a limited effect at the neuromuscular junction or in ganglionic transmission. They have a similar structure to ACh but bulkier aromatic group in place of the acetyl group. Atropine and scopolamine are naturally occurring. (atropine, scoolamine ,glycopyrroonium, ipratopium, tropicamide, cyclopentolate.)
67
What are The main uses of Atropine?
Can be given I/m, I/v, S/c and P/o. It is metabolised in the liver and also excreted by the kidneys. It is a tertiary amine - ionised at physiological pH yet crosses the gut, conjunctival sac and blood brain barrier. Its uses are as a Premedicant to decrease salivation. Not recommended in the horse - gastric motility is reduced and can cause central excitation. It has an antispasmodic effect in the gut and also decreases gastric secretion. Used for treatment of organophosphate toxicity. Dilation of the pupil for examination. Used to increase heart rate. Used with AChEl to prevent side effects from muscarinic stimulation when these agents are used to reverse neuromuscular blockade. CNS stimulation can be a problem in the horse, constipation, tachycaria, urinary retention, AChE inhibitors can be used to treat toxicity.
68
What are the main uses of scopolamine?
Used for drying secretions. Contained in the antispasmodic buscopan together with the dipyrone metamizole. It has antiemetic properies.
69
What are the main sues of glycopyrronium bromide? (muscarinic antagonists)
A synthetic agent, does not cross the placenta or the blood brain barrier, less CNS effects and useful in caesarian sections, less tachycardias, used in occular surgery to prevent vagal stimulation.
70
What are the main uses of Ipratopium bromide?
-Bronchodilation in horses - inhalation, poor absorption therefore minimal side effects - quaternary ammonium structure.
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What effect would muscarinic antagonists have on the eye?
Dilation of the pupil and relaxation of the ciliary muscles
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What are Nicotinic Antagonists?
Nm receptors are located on the skeletal muscle. Nn receptors are located in the autonomic ganglia. Several agents can discriminate between the two types of nicotinic receptors. Since agents acting at the nicotinic receptors in the ganglia will have parasympatholytic and sympatholytic actions, not really used.
73
What are Ganglionic Blockers?
Include hexamethonium and trimpetaphan. They have profound effects including hypotension and loss of cardiovascular reflexes. Not really used except trimetaphan in anaesthesia to induce a controlled hypotension.
74
Describe Epinephrine/adrenaline
Acts at both a and B adrenoceptors. It increases heart rate and force of contraction - induces vasoconstriction. Used for cardiac arrest and anaphylaxis. Taken up by nerve terminals and non neuronal tissue and metabolised by MAO and COMT respectively.
75
What is Isporenaline?
A non selective B adrenergic agonist. Not often used. It has positive inotropic and chronotropic effects. It can induce arrhythmias and in severe cases myocardial necrosis. It is not taken up by nerve terminals but metabolised by COMT in the liver.
76
Describe the effects of dopamine?
A neurotransmitter - effects on subtypes f receptor (D1-D5). D1 receptors are found in the renal vasculature. Stimulation by low doses of dopamine leads to increase in intracellular cAMP. Induces a vasodilation. It causes an increase in renal perfusion and filtration. Prevention and management of acute renal failure. Dopamine at higher doses can induce vasoconstriction through vascular a1 adrenoceptors.
77
What is phenylpropanolamine and what is it used for?
It has a-agonist properties. Its most important use is in the treatment of urinary incontinence in the bitch. Administered orally. Can induce hyperexcitability. It has tyramine like activity in that it induces the release of NA from the nerve terminal.
78
What is the main effects of the B1 agonists?
Primarily Cardiac effects and increase heart rate and force of contraction. E.g Dobutamine - used frequently in equine anaesthesia to maintain a mean arterial pressure. Used in acute cardiac crisis for inotropic support. Administered by intravenous infusion due to a short half life and rapid metabolism.
79
What is the main use of the B2 agonists?
Used to induce Bronchodilation. They also cause uterine relaxation and have been used as growth promotors. E.g clenbuterol causes bronchodilation, uterine relaxation, used in the treatment of COPD in horses. Given orally or intravenously, can induce vasodilation and tachycardia. It has a growth promotant effect and a repartitioning agent. Causes hypertrophy of muscle fibres, protein deposition and lipolysis in adipose cells.
80
What is Terbutaline?
It is used as a bronchodilator. It has more cardiac side effects. It can be used as an alternative to propantheline in the medican management of cnduction disturbances. It is administered orally. (A B2 Agonist)
81
What is Isoxuprine?
Used in the treatment of navicularr diseases, it induces vasodilation. Can also decrease uterine contraction and delay parturition. This can be desirable if C section. Tocolytic effect can be reversed with oxytocin.
82
What is the main effect of the A1-adrenoceptor agonists?
They will induce vasoconstriction and can increase the force of myocardial contraction. Phenylephrine and methoxamine are two examples.Phenylephrine is used in occular preparations to induce mydriasis.
83
What are the a2 adrenoceptor agonists used for?
Most important in veterinary medicine for their central sedative effects e.g xylazine, medetomidine and detomidine. Clonidine is used for diagnosis of growth hormone deficiency since it stimulates the release of GHRF.
84
What is the main use of the Alpha Antagonists?
The a1 antagonists cause vasodilation and include drugs such as Prazosin, terazosin and alfuzasin. Phenoxybenzamine is an irreversible a-antagonist having predominant a1 adrenoceptor blocking effect. Has been used in the treatment of laminitis to induce vasodilation. Also been used to treat urinary retention by antagonising the A1 adrenoceptors in the bladder. Prazosin is used in the treatment of certain urinary conditions.
85
What is the main use of the alpha 2 antagonists
Used to reverse sedation induced by the alpha 2 agonist drugs. Exmaples are yohimbine and atipamezole.
