All of Pharmacology (1-10) Flashcards
1
Q
A
2
Q
What are the principal target organs of the ANS?
A
3
Q
Name two examples of organs/systems that are only innervates by the sympathetic Nervous system
A
E.g.
- Blood vessels
- Skin
- Liver
- Kidneys
4
Q
Name one example of and organ that is innervated by both, sympathetic and parasympathetic NS and describe their respective effect
A
Pupils
- SNS: dilation
- PNS: Constriction
Trachea:
- SNS: dilation
- PNS: constriction
GI:
- SNS: inhibitory (less motility and secretion)
- PNS: exitory (more motilty and secretion
5
Q
What are the neurotransmitters of the parasympathetic NS? Which receptors do they bind to?
A
PNS uses Acetlycholine (ACh) as transmitter
- Binds to nicotinic receptors after (long) pre-ganglionic fibre
- Binds to Muscarenic receptors after post-ganglionic fibre in target organ
(First Nicotin than mucus)
6
Q
What type of receptor is the nicotinic receptor?
A
They are Ionotropic (Type 1) receptors
7
Q
What is an Ionotropic receptor?
A
A receptor that opens/closes an ion chanel as reaction to a ligand binding
8
Q
What type or receptor is a muscarenic acetylchline receptor?
A
It is G-Protein coupled (Type 2)
9
Q
Which Neurotransmitters does the SNS use?
A
- ACh after (short) preganglionic fibres
- Noradrenaline
- Adrenaline / Noradrenaline produced by adrenals
- (Sometimes ACh e.g. in sweat glands)
18
Q
Describe the synthesis + degradation of Acetyloecholine
A
- Acetyle CoA + Choline combined by Choline acetyl transferase
- Packed into vesicles + excreted when Ca2+ influx
- Broken down by Acetylecholine esterase in Choline + Acetate
- Reuptake into cell
19
Q
Describe the synthesis of Noradrenaline
A
- Tyrosine —> Tyrosine Hydroxilase —>
- DOPA —> DOPA decarboxylase —>
- Dopamine (transported into vesicles) —> Dopamine ß hydroxylase —>
- Noradrenaline
20
Q
How is Noradrenaline degraded?
A
Reuptaken in pre- or post-synaptic cell, degraded via
- Monoamine oxidase A (MAO-A) (in mitochondria)
- COMT (Catechol-O-methyltransferase)
21
Q
Which receptors does the SNS generally uses
A
- Nicotinic ACh receptor
- adrenergic receptors (adrenoceptors) (Noradrenaline/Adrenaline)
- Muscarenic (when ACh as neurotransmitter at target organ)
22
Q
Wich sub-types of Muscarenic receptors are there?
Where do they occur and what do they controll?
A
5 Sub-types
- M1: Neural (e.g. in Forebrain for memory)
- M2: Cardiac (to decrease heart rate and contractility force)
- M3: Exocrine + Smooth muscle (decreased SM contration, increases secretion
4+5 less easy to classify
- M4 – Periphery: prejunctional nerve endings (inhibitory)
- M5 – Striatal dopamine release
23
Q
What does the M1 Muscarinic achetylcholine receptor do?
A
Involved in neural parts (e.g. memory in forebrain)
24
Q
Which sub-type of muscarinic acetylcholine receptor can be found primarily in the Brain?
A
M1
25
Q
Which sub-type of muscarinic acetylcholine receptor can be found primarily in the Heart?
A
M2
26
Q
Which sub-type of muscarinic acetylcholine receptor can be found primarily in exocrine glands and Smooth muscle?
A
M3
27
Q
What type of receptor are adrenoreceptors?
A
G-protein coupled receptors (Type2)
28
Q
Which questions can be asked to discribe a pharmacodinamic action of drugs?
A
- What is the drug target?
* e.g. a1 adrenergic receptor - Where is the drug target?
* on SM tissue - What is the end result of the interaction?
* Vasoconstriction
29
Q
Describe the synthesis + degradation of Acetyloecholine
A
- Acetyle CoA + Choline combined by Choline acetyl transferase
- Packed into vesicles + excreted when Ca2+ influx
- Broken down by Acetylecholine esterase in Choline + Acetate
- Reuptake into cell
30
Q
Describe the synthesis of Noradrenaline
A
- Tyrosine —> Tyrosine Hydroxilase —>
- DOPA —> DOPA decarboxylase —>
- Dopamine (transported into vesicles) —> Dopamine ß hydroxylase —>
- Noradrenaline
31
Q
How is Noradrenaline degraded?
A
Reuptaken in pre- or post-synaptic cell, degraded via
- Monoamine oxidase A (MAO-A) (in mitochondria)
- COMT (Catechol-O-methyltransferase)
32
Q
What does Pharmacokinetics discribe?
A
What the body does to/with the drug
33
Wht does Pharmacodynamics discribe?
What the drug does the the body (what the effect is)
34
What are the prinicpal target sited of drugs?
**Proteins:**
* Receptors
* Ion channels
* Transport systems
* Enzymes
35
Which signals does a receptor respond to?
* Neurotransmitters
* Hormones
36
Where are receptors located
Type 1-3: in cell membrane (usually)
Type 4: intracellular steroid receptors
37
Which Sub-Types of Receptors are there?
1. Type 1: ionotropic (ion channel linked)
2. Type 2: G-protein coupled
3. Type 3: Kinase linked
4. Type 4: intracellular steroid receptors
38
What are the characteristics of a Type 1 receptor?
Ionotropic receptors (ion channel coupled)
* very fast response (milli sec.)
* e.g. nAChR, GABA
40
Whar are the characteristics of a Type 2 receptor?
G-protein coupled --\> set off intracellular messenger system
* seconds of response
* e.g. ß1 adrenergic receptor in heart
41
What are the characteristics of a **Type 3** receptor?
**Kinase linked**
* response within minutes
* e.g. insulin, Growth factor
42
Whar are the characteristics of Type 4 receptors?
Intracellular steroid hormones
* regulate DNA transcription
* response within hours
44
Which type of receptor is an ionotrypic receptor?
Type 1
48
Which signals does an ion chanel respond to?
Which example drugs target ion channels?
1. Change in voltage (voltage gated)
2. Receptor binding (Receptor linked)
e.g. Local Anesthetics, Calcium channel blockers
49
How can transport systems be exploited as drug target?
By blocking transport systems that transport substanced against their concentration gradient ( are specific for substance + ATP dependant)
* e.g. Neurotransmitter uptake (blocking of reuptake of Noradrenaline used in antidepressants)
50
In which ways can drugs target Ezymes?
1. **Enzyme inhibitors**
* inhibit enzyme action and slows reaction down
2. **False substrate**
* Derivate von enzym substaten lassen "False transmitters" entstehen (e.g. Methylnoradrenaline from Methyldopa which has a less powerful effect)
3. **Produgs**
* umwandlung des Medikaments durch Enzym
51
What is a False transmitter? What is a true transmitter?
False transmitter: Transmitter that closely immitates the action of a transmitter but act a bit different
* e.g. **Methyldopa (False transmitter)** giving Methylnoradrenaline binding weaker to target --\> causing muscle relaxation
* DOPA would be the **true transmitter**
52
What are Non-specific drug actions?
Drugs that work via theit physiochemical properties
* anitacids (bases)
* osmotic purgatives (abführmittel)
53
What is an agonist?
Something that enhances receptor action
54
What is an antagonist?
Something that blocks/ decreased receptor action
55
Which factors does the potency of a drug depend on?
1. **Affinity** --\> how strong/easy does the drug bind to the target
2. **Efficacy** --\> how strong is the effect of the drug on the target
56
What is the Affinity of a Drug?
How strongly/easy the drug binds to its target
57
Descibe/draw a dose-response curve of a full agonist in comparison to a partial agonist
58
Describe /draw how a log- dose response curve of a full agonist with high efficacy, full agonist with low efficacy and partial agonist would look like
59
What is teh effecacy of a drug?
How strong the effect is on the target
(e.g. conformatin change in receptor)
60
What are the characteristics of a full agoinst?
It binds to and activate a receptor with the **maximum response that an agonist can elicit** at the receptor
61
Whar are the charcteristics of a partial agonist?
Bind to and activate the receptor but only have a partial efficacy in comparison to full agonist
--\> can have antagonist property in presence of a full agonist
62
What is the selectivity of a drug?
How selective the drug is to its target (will be overlap, often resulting in side-effects)
63
How would a log dose response curve look like in presence of
* agonist alone
* with competitve agonist
* with irreversible agonist
64
What does the structure-activity relationship descibe?
Small changes in structure can have major effects on results (because of lock-and key modell)
67
How efficiant are antagonist?
Not at all --\> have affinity but no efficacy (don't do anything)
68
What two types of Antagonists are there?
1. **Competitive**
* same binding site as substrate
* Shifts Dose-response curve to the right
* surmountable (überwindbar bei hohen Substratkonenztrationen)
2. **Irreversible**
* different binding site or binds tighly
* --\> incativate enzyme/receptor
69
What are the characteristivs of competitive antagonist binding?
Competitive
* same binding site as substrate
* Shifts Dose-response curve to the right
* surmountable (überwindbar bei hohen Substratkonenztrationen)
70
What are the characteristics of irreversible antagonsit binding?
Irreversible
* different binding site or binds tighly
* --\> incativate enzyme/receptor
* insurmountable (unüberwindbar bei hohen Substratkonzentration)
72
Explain the concept of receptor blockage antagonism
Competitive binding or Irreversible binding
73
Through which mechanisms can a drug act as an antagonist?
1. **Receptor blockage**
* competitive
* irreversible
2. **Physiological antagonism**
* opposite effect in same tissue
3. **Chemical antagonism**
* reduces concentration of agonist by forming chemical complexes
4. **Pharmacokinietic antagonism**
* reduce concentration by: decreasing absorbtio, increasing metabolism/excretion
74
Explain the conecegt of physiological antagonism
A drug has the opposite effect as the agonist in the same tissue
e.g. Noradrenaline is an antagonist of histamine in blood vessel (dilation vs. constriction)
75
Explain the conept of chemical antagonism
Antagonist reduces concentration by reducing formin chemical complex with agonist
e.g. Dimercaprol with heavy metals
76
Explain the concept of pharmacokinetic antagonism
decrease concentration of agonist at site of action by
* decreasing absorbtion
* increasing excretion
* increasing metabolism
77
What is drug tolerance?
A gradual decrease to drug afer longer time of administration
78
Which concepts can lead to drug tolerance?
1. Pharmacokinetic factors
* adaptive increase in metabolism (e.g. enzymes)
2. Receptor loss/increase
3. Change in receptor (desensitisation)
4. Exhaution of mediator store
5. Physiological adaption (to side effects)
79
Explain the concept of pharmacokinetic in drug tolerance
Ther ecan be an adaptive increase in drug metabolites etc. e.g. enzmyes
80
Explain the concept of receptor loss/increase with drug tolerance
Receptors can be lossed by plasma endocytosis
less receptors ---\> less action
81
What happens at receptor desensitzation in drug tolerances?
Conformation change in receptor leading to desensitization
82
Explain the concept or exhaution of mediator site in the context of drug tolerance
E.g. Amphitamines cause release of amines
--\> Amine storages get exhaused --\> can't be released
83
Explain the concept of physiological adaptation in the context of drug tolerance
it is a homeostatic response
often a tolerance to the drug side effects
84
What is pharmacokinetics?
The way of a drug through the body + what the body does to it
85
What is the significance of pharmacokinetics?
It determines the does of the drug that is available to the tissue
86
Which steps does a drug in the body undergo from Administration to removal?
**A** bsorbtion
**D** istribution
**M** etabolism
**E** xcretion
87
What are the different routes a drug can be administered?
...
89
Explain systemic and local administration
Systemic: entrire organism
Local: specific tissue of organism
90
What is enternal and parenternal administration of drugs?
Enternal: via GI tract
Parenternal: without GI tract
91
How do drugs move around in the body?
1. Bulk flow transfer
* bloodstream, lymph
2. Diffustion transfer
* molecule by moelcule over a short distance
92
Through which mechanisms do drugs cross cell membranes?
93
What kind of molecules can cross via the following routes? Which one is the least important?
Diffusion: Fat soluble molecules (or very small)
Diffusion through aqueous pores: small watersolube molecules ---\> barly any drug --\> least important
Active transport: the rest
94
Why do drugs have to pass aqueous and lipid compartments?
Aqueous: to move around e.g. in bloodstream, lymph , extracellulra, intracellular fluid
Lipid: To reach their target (to cross membranes)
95
How does the Handerson Hasselbach equation look like to determine, how the ration between Ionised and unionised forms of bases/acids look like when pka and pH are known?
98
Which chemical feature do most drugs have in common? Why?
They are either weak acids or bases
--\> can be ionised and unionised, depending on the environment (often therefore polar and non-polar)
99
How does capillary permeability influence drug distribution?
* Fat soluble: can cross all membranes, into all tissues (even blood-brain barrier)
* Water soluble: often rely on transport emchanisms /pores --\> will me distributed more unevenly (and more in capillaries with large gaps)
101
Which factors influence drug distribution?
* Regional blood flow
* Extracellular binding (plasma protein)
* Capillary permeability
* Localisation in tissues
* Solibility (e.g. general anestetics are very fat soluble --\> large proportion will be in fat even though only very little blood flow to it)
102
How does regional blood flow influence distribution of drugs?
Highly metabolically active tissues have more blood flow + denser capillary networks (can change e.g. with exercise in skeletal muscle)
103
How does extrcellular binding of drugs influence their distribution (passage of membranes)
Extracellular binding to plasma proteins
* determines availability e.g. if 95% is bound --\> only 5% are able to cross membranes
104
What happens during phase one of drug metabolism?
Which reactions take place to let this happen?
Adding/unmasking a reactive group to the drug (increasing polarity)
* most reactions are **oxidations** (ofter start with hydroxylation)
* But also: **redeuction, hydrolisis**
106
Which characteristics can the metabolite have that is formed after Phase one of the drug metabolism?
107
How does localisation in tissues influence drug distribution?
Fat: 15% body weight, but 2% blood supply
## Footnote
Very fat soluble drugs – 75% partitioned in fat at equilibrium
--\> disproportional high amounts of drugs in fat tissue (e.g. general anestetics)
108
What happens during phase 2 of drug metabolism?
What are common reactions?
**Add a water soluble conjugate to the reactive group**
there will be a conjugate and a conjugative agent
Recations involve
* Glucoronidation (most common)
* Sulfation
* Glutathionine conjugation
Less common:
* Acetylation
* Methylation
* Aminoacid conjugation
109
What is the most common reaction in phase 2 of drug metabolism?
What are its characteristics?
Glucoronidation
low affinity/high capacity – more likely to occur at high drug dosages
110
What is an example of a phase 2 drug high affinity low capacity metabolism?
Sulfation --\> More likely to occur at low drug dosages
111
In which drug metabolism phase does glutathiodine conjugation take place? What does it require? What might be the problem with it?
Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate
--\> But electropiles are extremely reactive
When overdosing --\> no glutathiodine available --\> electrophile might cause tissue damage
112
What is the aim of metabolism of a drug?
Why is that so?
To make the drug more water soluble for easier excretion
1. no diffusion back into bloodstream once in kidney nephron
2. more drug in bloodstream (less in tissue) hence more excretion
113
Why are most drugs rather fat soluble?
To get into tissues (be able to cross cell membranes)
114
How are drugs excreted in the kidney?
Which factor influence each step?
1. **Glumerular filtration**
* size dependant
2. **Active secretion**
* dependant on available transporters + transport mechanisms
3. **Passive reabsorbtion**
* urine pH (--\> determines ionisation) + drug characteristics, state of metabolism (fat soluble drugs just diffuse back into systemic circulation)
115
What are the two phases in drug metabolism? What are their respective aims
* **Phase 1:** introduce(add/unmask) a reactive group to the drug (to increase polarity)
* **Phae 2:** add a water soluble conjugate to the reactive group
116
How does the Enterohepatic cycling influence drug excretion?
Recycling of drugs can significantly increase half life and concentration of drugs!
118
Which is the most common enzyme to oxidise drugs in phase 1 of drug metabolism?
What are its characteristics
**Cytochrome P450**
* 57 enzymes (each do different drugs)
* has low specifity
120
What is a prodrug?
A drug that is activated by Phase 1 of drug metabolism (not active at administration)
125
Why is drug metabolism important? (What are the overall aims - not on a chemical level)
* The biological half-life of the chemical is decreased.
* The duration of exposure is reduced.
* Accumulation of the compound in the body is avoided.
* Potency/duration of the biological activity of the chemical can be altered.
* The pharmacology/ toxicology of the drug can be governed by its metabolism.
126
Through which main organ systems are drugs excreted?
Mainly via the
* kidney
* liver
128
How does drug excretion via the liver work?
1. Diffusion from sinusoids into hepativ tissue (via discontinuous capillaries/ diffusion through cells)
2. Active transport (or fat soluble --\> diffusion) into bile
3. Excretion via bile
--\> Mint the Enterohepatic cycling! (reabsorbtion)
130
Other than the kidney and liver: Through which routes can drugs also be excreted?
* lungs
* skin
* gastrointestinal secretions
* saliva
* sweat
* milk
* genital secretions
131
Define Bioavailability
Proportion of the administered drug that is available within the body to exert its pharmacological effect
(dependant on absorbtion + distribution???)
132
Define **Apparent volume distribution**
The volume in which a drug appears to be distributed
- an indicator of the pattern of distribution
133
Define **Biological half life**
Time taken for the concentration of drug (in blood/plasma) to fall to half its original value
(linked to metabolism/excretion)
134
Define **Clearance (**pharmacokinetics)
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)
135
Where are the Cytochrome P450 enzymes located?
Primarily in the Smooth ER (in liver but also in other tissues)
136
Which factors does Oxitation reaction in Phase 1 metabolism require?
Requires
* NADPH (as co-enzyme)
* often molecular oxygen
137
Glutathione is a tripeptide consisting of:
* Glycin
* Cystein (with thiol group)
* Glutamic acid
138
What is the enzyme and co-substrate needed for Sulphation reaction?
Sulphation
* sulphotransferase
* 3’phosphoadenosyl-5’-phosphosulphate (PAPS)
139
Which enzyme and co-substrate are needed for Glucoronidation?
Glucoronidation
* Enzyme: UDP-glucuronosyltransferase
* Co-substrate: UDP-glucuronic acid (UDP-GA)
143
Which Enzyme and Co-enzyme is needed for Glutathione conjugation reactions?
Glutathiodine conjugation
* for electrophilic substraties (often produced by phase I oxidation)
* Co-substrate: Glutathione
* Enzyme needed: Glutathione-S-transferase
144
Which Phase 2 Metabolism reactions does Paracetamol undergo?
1. 40-60% sulfation
2. 20-30% glucoronidation
3. 10% Glutathione conjugation --\> neutralisation of NAPQI
145
How could you treat a Paracetamol overdose?
Oral/I.V. N-acetylcysteine
* promote synthesis of GSH (Glutathione)
* more capacity for metabolism of Paracetamol
* needed for conjugation of NAPQI and for protection of protein thiols
146
What kind of drug is Atropine?
It is a kompetitive Muscarinic receptor antagonist
147
What does muscarine do?
Agonist of the Muscarinic receptor
--\> Stimmulation (not broken down by Ach-esterase)
* tears
* saliva
* miosis
* sweating etc.
148
Where are the M1 muscarenic achetylcholine receptors loacted?
Which secound messenger system do they activatie?
•M1:
* Salivary glands
* Stomach
* CNS
Activate Gq-Protein: exitory
* IP3 + DAG (--\> increases Ca2+ influx)
149
Where are the M2 muscarenic achetylcholine receptors loacted?
Which secound messenger system do they activatie?
•M2: **Heart**
* are **inhibitory**
Activate Gi-protein
* **downregulation of cAMP**
150
Where are the M3 muscarenic achetylcholine receptors loacted?
Which secound messenger system do they activatie?
M3:
* Salivary glands
* Bronchial/visceral SM
* Sweat glands
* Eye
Are exitory: Activate Gq protein
* increase in IP3 and DAG
151
What are the structural features of the Muscarinic receptor?
Has **7 transmembrane regions**
connencted to loop + G-protein in the inside
153
What are the effects of muscarinic exitation in the eye?
**Contraction of the ciliary muscle**: accommodation for near vision
**Contraction of the sphincter pupillae** (circular muscle of the iris): Constricts pupil (miosis) and improves drainage of intraocular fluid
**Lacrimation** (tears)
154
What is the effect of contraction of the spincter puppilare?
How can this be used in glaucoma treatment?
Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage
--\> reducing intra-ocular pressure
--\> in some form of glaucoma, iris is deformed, blocking fluid drainage and hence increasing intraoccular pressure
155
What are the effects of muscarinic stimmulation on the heart?
156
Explain the structure of a nicotinic receptor
* Ionotropic receptor
* Has 5 subunites (alpha-epsylon)
* Binding property is determines by the combination of Subunits
* •Effects of ACh relatively weak
160
Which effect does Ach has on the vasculature?
No direct PNS innervation but has M3 receptors:
* stimmulation causing endothelial NO release
* SM relaxation
161
Which effect does parasympathetic innervation has on the non-vascular smooth muscle?
--\> Constriction:
* **Lung:** Bronchoconstriction
* **Gut:** Increased peristalsis (motility)
* **Bladder**: Increased bladder emptying
162
Which effect does stimmulation of muscarinic Ach receptor have on excretions?
Exitory:
* Salivation
* •Increased bronchial secretions
* •Increased gastro-intestinal secretions (including gastric HCl production)
* •Increased sweating (SNS-mediated)
163
What directly acting cholinomimetic drugs are there?
1. Alkaloids (Pilocarpine)
2. Choline esters (Bethanechol)
164
What are the characteristics of Pilocarpine?
What kind of drug is it?
It is a non-selective muscarenic agonist
--\> good lipid solubility
--\> half life around 3-4h
165
What is the clinical use of pilocarpine?
Mostly used for local treatment of glaucoma
(non-selective muscarenic agonist)
166
What are possible side effects of pilocarpine? Why?
* Blurred vision (--\> PNS stimmulation of eye)
* sweating (SNS stimmulation)
* gastro-intestinal disturbance and pain
* hypotension
* respiratory distress
--\> all others: PNS stimmulation
167
What kind of drug is Bethanechol?
What are its characteristics?
M3 Acetylcholinereceptor selective agonist
* no degradation
* orally active (can be orally given)
* half life: 3-4h
168
What is the clinical use of Bethanechol?
To assist bladder emptying and enhance gastric motility
169
What are the side effects of Bethanechol administration?
* Sweating
* imparied vision
* bradycardia
* hypotension
* respiratory distress
170
What is the function of Acetylcholinesterase?
Where is it found?
Break down ACh to acetate and choline
* found in all cholinergic synapses
* very fast and highly selective
171
What is the function of Butyrylcholinesterase?
Where is it found?
What are its characteristics?
* Break down ACH
* found in plasma and most tissues, not in synapse --\> reason for low ACh plasma levels
* •Broad substrate specificity - hydrolyses other esters e.g. suxamethonium
* Genetic variation
172
What happens at a low, medium and high dose of cholinesterase inhibitors?
Low dose
* Enhanced muscarinic activity (see above)
Moderate dose
* Further enhancement of muscarinic activity
* Increased transmission at ALL autonomic ganglia (nAChRs)
High dose (toxic)
* Depolarising block at autonomic ganglia & NMJ (see PT9 NMJ lecture) --\> too much fiering --\> receptors shout down --\> paralysis
173
Which drug is a reversibel Anticholinesterase drug?
Why is it reversible?
Physostigmine and Neostigmine
* competitive inhibitor --\> binds to active side
* Donates Carbamyl group that blocks the receptor
* Carbamyl group removed by slow hydrolysis (mins rather than msecs)
174
What is physiostigme?
What are its characteristics?
A reversibele indirectly cholinomimetic drug
* reversibly blocks Cholinesterase (get freed again after minutes)
* Primarily acts on postganglionic parasympathetic synapse
* Half life about 30m
175
What is the clinical use of physiosigme?
Clinical use:
* Glaucoma treatment
* To treat atropine poisoning (particularly in children)
176
What kind of drugs are irreversibel Anticholinesterase Drugs?
How do they act?
1. **ecothiopate (**only one with clinical use)
2. dyflos, parathion and sarin used as pestisides or chemical weapons
React with enzyme active side
* Make a stable block, resistant to hydrolysis
* --\> recovery may require production of new enzymes
177
What is Ecothiopate?
Potent inhibitor of acetylcholinesterase
--\> Slow reactivation of the enzyme by hydrolysis takes several days
178
What is the clinical use of Ecothiopate?
Irreversible anticholinesterase inhibitor
Used in treatment of glaucoma
* prolonged effect in fluid drainage
179
What are the side effect of Ecothiopate?
* Sweating
* blurred vision
* GI pain
* bradycardia
* hypotension
* Respiratory problems
--\> PNS stimmulation
180
What are the effect of Anicholinestases in the CNS?
Non-polar Anticholinesterases can cross BBB
Low doses
* exitation with possibility of convulsions (Krämpfe)
High dose:
Unconsciousness, respiratory depression, death
181
What are possible treatments for Organophosphate Poisonings?
Organophsphate = irreversible anticholinesterase
Can be treated via
* Atropine (Muscarenic antagonist)
* Parlidoxime within first hours --\> displaces the bound organophsphate from enzyme
182
What is pharmacology?
It it the science of chemicals that potentially could benefit patietns
183
What is the difference between a drug and a medicine?
A drug is the chemical which should have its effect
A medicine is a dosage form of the drug but also contains excipients (zusätze)
184
What is the functio of exipents in a medicine?
* to improve its chemical and biological stability
* to increase its acceptability to the patient by improving its flavour, fragrance or appearance
* To make it able to grab e.g. the pill (increase size)
* to increase its bioavilibility
185
What involves the process called formulation?
The process of making a medicine (with excipients) containing a drug
186
What are the advantages and disadvantages of oral administration of a medicine?
_Advantage_
* It permits self-medication
* It does not require rigorously sterile preparations
* The incidence of anaphylactic shock is lower (than intravenous)
* There is the capacity to prevent complete absorption (vomiting, lavage).
_Disadvantage_
It is inappropriate for drugs which:
* are labile in acid pH of stomach or otherwise degraded
* or undergo extensive ‘first-pass’ metabolism,
It requires patient compliance.
187
What are the advantages and disadvantages of IV administration of drugs?
Advantage
* rapid onset of action
* avoids poor absorption from, and destruction within, the g.i. tract permits careful control of blood levels
Disadvantages
* slow injection necessary (to avoid toxic bolus) higher incidence of anaphylactic shock
* trained personnel required
* complications possible; embolism, phlebitis, pai
188
What are the advantages and disadvantages of inhalation/ administration of a drug via the lungs?
_Advantages_
* ideal for small molecules, particles, gases, volatile liquids, aerosols
* enormous surface area presented by alveolar membranes
* simple diffusion, also phagocytic cells clear particles
_Disadvantages_
* possible localised effect within lung (unless this is desired)
189
What are the advantages and disadvanatages of IM administration of a drug?
Advantages
* relatively high blood flow, increased during exercise enables DEPOT THERAPY (prolonged absorption from pellet, microcrystalline suspension or solution in oily vehicle).
Disadvantages
* possible infection and nerve damage (especially in gluteal region)
190
What are the advantages and disadvantages of a subcutaneous administratio of a drug?
_Advantages_
* Local administration, dissemination can be minimised for local effect
* enables DEPOT THERAPY (as for intramuscular above)
_Disadvantages_
* pain, abscess, tissue necrosis
191
What are the advantages and disadvantages of percutaneous (across the skin) administration of a drug?
_Advantages_
* local application and action
* lipid soluble compounds diffuse rapidly (may be assisted by vehicles)
_Disadvantages_
* local irritation and skin reactions
* alteration of skin structure (e.g. steroids – subcutaneous adipose tissue)
192
What is bioavailibility?
The amount of a drug contained in a medicine that enters the systemic circulation in an unchanged form after administration of the product
193
How do each of the following influene bioavailibitly of a drug?
1. the physicochemical characteristics of the drug (ionisation in gut)
2. gastrointestinal pH
3. whether or not the drug is passively or actively transported
4. gastrointestinal motility
5. particle size of the drug
6. physicochemical interaction between drug and gut contents (e.g. chemical interaction between calcium and tetracycline antibiotics)
* the physicochemical characteristics of the drug (ionisation in gut)
* gastrointestinal pH
--\> diffusion of ver membrane
* whether or not the drug is passively or actively transported
--\> might rely on transport mechanisms (can be genetically different)
* gastrointestinal motility
* particle size of the drug
--\> Smaller Particle, higher motility= more/faster absorbtion
physicochemical interaction between drug and gut contents (e.g. chemical interaction between calcium and tetracycline antibiotics)
194
Does the measurement of bioavailability always reflect the effectiveness of a drug?
No, some durgs can be effective without having a high bioavailability
Also, some drugs have to be metabolised to be effective --\> would potentially have low bioavilibilty (because of its definition)
195
What is the therapeutic index/therapeutic window?
The range of mount of drug that can be administered between
* Lower end: its usefullness
* Upper end: its toxicity
196
Name examples of how a drug can be altered in the presystemic metabolism/ first pass metabolism)
* the microbes within the gut lumen
* enzymes present in the gut wall
* enzymes in the liver
197
Under what circumstances could a drug, which undergoes 100% first pass metabolism, be therapeutically useful?
Either
* target side is berfore first pass site (e.g. Intestinal target after oral use)
* administration without going to liver (e.g. iv, sublingual)
* Metabolism required to make drug usefull
198
What is bioequivalence?
evidence that the new ‘generic’ product behaves sufficiently similar to the existing one to be substituted for it without causing clinical problems
--\> otherwie coule be different e.g. because of excipients
199
What are Nicotinic receptor antagonists also called?
Ganglion blocking drugs
--\> Block transmission of whole autonomic devision at ganglion
200
Explain the mechanism of action, effect and use of Hexamethonium
Nicotinic receptor antagonist, first ever antihypertensive drug!
--\> Ion channel block
* creates a use-dependant block
Effect:
* loss of function of the dominant autonomic NS
* e.g. at rest : increased HR, bronchodilation, hypotension --\> vasodilation + less retention in Kidney
Also:
* pupil dilation (light sensitivity)
* constipation
* no bladder emptiying
* --\> too unspecific, no clinical use anymore
201
What is a use-dependant block?
The more a channel/recptor etc, is used, the stronger its blocke
--\> At high usage--\> high blocking
e.g. at Ion channel blockers, where Ion channels need to be open (working) for blocking to go into channel and create effect
202
Explain the mechanism of action, effect and use of Trimetaphon
Trimetaphon: Nicotinic receptor antagonist
* receptor blocking antagonist
* half life of around 30 min
* effects same as Hexamethonium (dominant autonomic System functions are lost)
Used in controll of BP during surgery (as single dose shot)
203
Name two Nicotinic receptor antagonists (including their mechanism of action and effect
Hexamethonium
* ion channel blocker
* 1st ever hypertensive drug (no clinical use anymore)
Trimetaphon
* receptor blocker
* t1/2= 30min
* used in controll of BP during surgery
Effect:
* loss of function of dominant Autonomic system
* at high dosage: blocking of NMJ --\> paralysis (many poisons)
204
What is the clinical use of Nicotinic receptor antagonists?
Barely any clinical use:
* drugs are too messy, too many side effects because all autonimic functions are blocked + interference with NMJ
Ony use
Trimetaphon to controll BP during surgery
205
What are the side effects of Nicotinic antagonist drugs?
Too messy: interfer with many systems
E.g. somatic (NMJ) --\> used in animal poisons (alpha-bungarotoxin) leading to parlaysis
But also:
* hypotension
* light senstitivity
* constipation
* no bladder emptying
* etc.
206
What are the effects of Atropine and Hyoscine on the CNS?
Why?
Atropine;
* Normal dose – Little effect
* Toxic dose - Mild restlessness --\>Agitation (normal effect of M-antagonists)
* (Less M1 selective)
Hyoscine;
* Normal dose – Sedation, amnesia
* Toxic dose – CNS depression or paradoxical CNS excitation (associated with pain)
* (Greater permeation into CNS. Influence at therapeutic dose)
--\> Difference not yet fully understood, probably because Hyoscine more lipophilic --\> BBB maybe more M1 selective
207
What is the mechanism of action and use of **Tropicamide**
**Tropicamide**
Muscarenic receptor antagonist
Causing **pupil dilatio**n (relaxation of Spincter Pupillae) --\> Mydriasis and blurred vision (**paralysis of ciliary muscle of eye**)
* Used for examination of the retina
208
Explain the clinical use of Muscarenic receptor antagonists in Anestehetic premedication
Hyoscine
Causes **sedation**
* blocks bronchioconstrition --\> dilation (good for e.g. inhaled anesthetics)
* blocks glandular secretions (good e.g. to prevent aspiration of saliva)
* Blocks HR reduction (good because anesthetics generally decrease HR --\> prevention of bradycardia)
209
Explain the clinical use of Hyoscine
Used as **hyoscine patch** in motion sickness
## Footnote
Normally: Auditory signals + visual sicknes are combined and when missmatch: transport to vomiting centre
When blocked: **Pathway to vomiting centre blocked** --\> prevention of motion sickness
210
Explain the use of Muscarenic antagonists in Parkinsons disese
Problem in Parkinsons is: **too little Dopamine**
this can't be changed but **amount of dopamine receptor can be increased** --\> less dopamine needed for same effect
* Dopamine receptor is downregulated by M4 activity
* When blocking M4 --\> less downregulation --\> **More Dopamine receptors**
213
What are the side effects of Muscarenic Receptor Antagonists?
* Heat intolerance --\> no thermoregulation via sweating
* Dry --\> decreased secretions
* Blind --\> Cyclopegia (cillary muscle paralysis)
* Mad --\> CNS disturbance
214
Which drug would be used to treat Atropine poisoning?
Preferably: Physiostime --\> reversible Anti-cholinesterase drug
Atropine: Blocks Muscarenic receptors (kompetitevely)
Physiostigme --\> increases dose of available ACh
215
Explain the effect of Botolinum Toxin on the body
Extremely dangerous (only low dose required)
Blocks release of ACh out of vesicles
--\> (by interfering with SNARE complex)
--\> Paralysis of everythingn
217
Explain the clinical use of muscarenic antatgonists in respiratory disease
Which drug is commonly used to achive this?
Blocking of Bronchioconstriction --\> Bronchiodilation
* e.g. **Ipratropium Bromide**
* Atropine
218
Explain the clinical use of a Muscarenic antagonist in GI conditions such as Irritatable bowl syndrome
IBS: movement of GI tract causes pain
(Usually M3 selective antagonists)
With antagonist:
* Slows GI tract down
* motility and tone
* secretions
* --\> reduction of symptoms of IBS
222
What are the clinical uses of Muscareninc antagonists?
* Preanesthesia medication
* Motion sickness
* Astmah/Airway disease
* GI disturbances
* Prakinsons
* Ophtalmology
223
Where are a1 adrenoreceptors located?
What is their second messenger mechanism and prinicpal effect?
Alpha 1 receptors:
* Eye (contraction of iris dilator muscle)
* vasoconstriction (SM constriction)
* excretion of nose
* contraction of ureter--\> holding urine
**--\> Exitory via**
PLC into IP3 and DAG
224
Where are alpha 2 adrenorecpetors commonly found?
What is their secound messenger system and principal effect?
Usually inhibitory --\> decerease of cAMP
* regulation in CNS
* reduction of aqueous humor production in ciliary body
226
Where are ß2 adrenoreceptors located?
What is their 2nd messenger system
Bronchios/Airway
Vessels --\> **causing vasodilation**
uterine smooth muscle
increase in cAMP
227
How would you medically treat an anaphylactic shock?
What are the (desired) effects?
Adrenaline (non-selective adrenoreceptor agonist) e.g. in Epipen
It counteracts the problems associated with too much histamine release:
* ß2--\> Bronchiodilation
* ß1 --\> tachycardia
* a1 --\> vasoconstriction
* Might bind to ß receptors on mast cells and supresses the release of mediator cells
--\> to increase BP and maintain breathing
228
What do you use adrenaline for? (as drug)
1. Anaphylactic shock
2. Emergency Astmah + acute bronchspasm (ß2)
3. Cardiogenic shock (ß1)
4. Maintaining BP during spinal anestehsia (a1)
5. Prolonging effect during local anesthesia (a1)
230
Where are ß1 receptors located?
What is their secound messenger system?
Heart --\> icrease heart rate + force of contraction
Kideny--\> increase renin --\> increase reabsorbtion
Messenger System: increase in **cAMP**
231
Which drug is a a1 selective agonist?
More or less selective:
## Footnote
**Phenylephrine**
235
What are the side effects of Adrenaline use?
When might this be problematic?
* Reduces and thickened secretions
* Tremor (skeletal muslce)
* CVS effects
* tachycardia, palpitation, arrythmias
* vasoconstriction (cold extremities)+ high BP
* at overdose: cerebral haemorrhage and pulmonary oedema
* (Minimal CNS and GI effects)
Overall: not too severe, only in elderly patients of with underyling condition (e.g. heart problems)
236
What are COMT and MAO?
Where are they situated
Both enzymes that break down Adrenaline/Noradrenaline
Catechol-O-Methyltransferase --\> More peripheral
MAO --\>Monoaminooxidase = More in CNS
238
What is the mechanism of action and the clinical use of Phenylephrine?
It is a (more or less) a1 selective adreno agonist
It is more resistant than Adrenlaine to COMT --\> longer there than Adrealine itself
* vasoconstriction
* Mydriasis
* Nasal decongestant (abschwellendes Mittel)
* vasoconstriction --\> less fluid production
239
Which drug is used as a a2 adrenergic agonist?
Clonidine
--\> a2 receptors are inhibitory!
* **Glaucoma** (decrease of humous production due to stimmulation of a2 receptor)
* Treatment in hypertension and migrane
* Reduction of sympathetic tone (by reducing sympathetic outflow via binding to a2 receptors in brainstem that then reduce signaling --\< presynaptic inhibition of Noradrenline release)
240
What are the clinical uses for Clonidine?
More or less selective a2 adrenoreceptor agonist
a2 receptors are inhibitory!
* Treatment of **Glaucoma** (decrease of humous production due to stimmulation of a2 receptor)
* Treatment in **hypertension and migrane**
* **Reduction of sympathetic tone** (by reducing sympathetic outflow via binding to a2 receptors in brainstem that then reduce signaling --\< presynaptic inhibition of Noradrenline release)
241
What is the clinicl use of Salbutamol?
Explain the mechanism of action and unwanted effects
Salbutamol --\> increase in cAMP --\> increase in PKA
* Main use in astmah
* side effects
* Cardiac--\> increase in BP, tachycardia, arrythmias
* hyperglycaemia
* tremor, restlessness
242
Which adrenorecepors controll vascular tone in the brain?
ß2 receptors--\> would not want vasoconstriction to the brain
243
What is an example of a adrenergic ß receptor selective drug?
Isoprenaline
* more resistant to break down by MAO (central effects) and uptake 1 than Adrenaline
244
When would you use Isoprenaline as medication?
What is the problem with the use of isoprnaline?
It is a adrenergic ß receptor selective agonsit (ß1=ß2)
Used in:
* Cardiogenic shock
* Acute heart failure
* MI
Can be problematic: (especially in e.g. Astmah medication when patients would always get refelx tachycardia)
* stimmulation of ß2 receptors causes vasodilation
* --\> drop in BP
* Causing reflex tachycardia (via Baroreceptors)
245
What is a adrenergic ß1 receptor selective drug?
Dobutamine
246
What is the clinical use and characteristics of Dobutamine?
Used in
* cardiogenic shock
* (because of short half life of 2 min)
--\> but does not have refelx tachycardia (like isoprenaline
247
Name a adrenergic ß2 receptor selective drug?
Salbutamol
248
What is the clinicl use of Salbutamol?
Explain the mechanism of action and unwanted effects
Salbutamol --\> increase in cAMP --\> increase in PKA
* Main use in astmah
* side effects
* Cardiac--\> increase in BP, tachycardia, arrythmias
* hyperglycaemia
* tremor, restlessness
249
How are eye infections normally treated?
Allergy+ conditions that cause inflammation: corticosterids (antiinflammatory drugs)
Actue infections: dependant on cause: antibacterials, antifungals, antivirals
In severe cases: systemic treatment
250
What is constriction and what is dilation of the pupil?
Constriction: Miosis
Dilation:Mydriasis
251
Which drug types are used to induce mydriasis?
Name an example
Normally antimuscarenic agents are used
e.g. atropine, tropicamide
252
How would you medically induce miosis?
What is the drug type and name examples
Obtained with muscarenic agonists (e.g. pilocarpine)
253
What are the effects of tropicamide on
* pupil diameter
* accomodation
Tropicamide is a Muscarenic receptor antagonist
* It dilates the pupil --\> relaxation of the constrictor pupillae
* Inpaires near vision (accomondation) --\> relaxation of the ciliary muscle) (poit of focus is further away)
254
What is the clinical use of tropicamide?
Muscarenic receptor antagonist--\>
Use in diagnostics of the **retina+ lens** because of **pupil dilation**
255
Explain the effects of pilocarpine on accomodation and pupil diameter
Pilocarpine is a muscarenic receptor agonist causes
* constriction of the ciliary muscle --\> very near accomodation
* constriction of the constrictor pupillae --\> small pupil diameter
256
What is the clinical use of pilocarpine?
It increasing aqueous outflow --\> used in glaucoma treatment
257
How does the sympathetic NS influence occular function?
* Dilation pupillae
* aqueous humor production via
* stimmulation of ß2 --\> stimmulates production
* also a1 in cillary muscle (vasoconstriction) --\> inhibiton of production
* a2 --\> inhibiton of production
* Vasoconstrictoon of blood to retina??
258
How can a sympathomimetic drug be used in the tratment of glaucoma?
If it is alpha selective: reduces blood flow (a1) and inhibits formation of aqueous humor (a2)
259
How can a ß-blocker be used in the treatment of glaucoma?
Antagonises the ß2-adrenoreceptors in the eye
--\> decrease of aqueous humor production
260
Explain the administration of drugs to the eye in terms of local and systemic effects
It is not easy to get drugs into the eye (local administration) but once they are in, they easily get into body (because of high vasculisation)
261
Explain the mechanism by which opioids induce miosis
Heroin in stimulating the nerve (CNIII --\> normally inhibited by GABA --\> heroin is switching off GABA (physiologically done by endorphins)) and therefore causes stimmulation of the PNS --\> miosis
262
Explain the mechanism of action of the prostaglandin analogue Latanoprost in the treatment of glaucoma
Increases drainiage via clearing of the venous drainage channels (no function via the pupil)
263
Explain the use of Carbonic anhydase inhibitors like Acetazolamide in the treatment of glaucoma
It directly stops ß receptor from producing aqueous humor (by blockign enzyme that produces aqueous humor)
264
Explain the role of alopha 2 adrenoreceptors in Noradrenaline release
As soon as Noradrenaline is released into the synapse it binds to alpha 1+2 receptors
1. Alpha 1: effect of Noradrenaline (vasoconstriction)
2. Alpha 2: negative feedback on Noradrenaline release in presynaptic neuron to ensure short acting action of Noradrenaline
266
Explain the effects and mechanisms of action in the clinical use of ß-Blockers
ß Blockers
* Reduce blood volume (ß1 on kidney Via less Renin--\> Aldosterone production)
* Reduce TPR (less Renin --\> less Vasocontriction as AGTII response)
* Reduce CO (ß1 on heart: reduced cAMP leading to redcued HR+ Force of Contraction)
* Minor effect: blockage of presynaptic ß receptors leading to a reduced NA release
267
What is Propanolol?
It is a non-selective ß antagonist (equal afinity for ß1+2 receptors)
268
What is Atenolol?
It is a ß1 "selective" antagonist
269
What is Carvedilol?
Mixed b and a blockers
•a1 blockade gives additional vasodilator properties
270
Which different ß Blocker classes are there?
Name examples for each class
1. Non selective (ß1+2)
* Propanolol
2. Cardio-selective
* Atenolol
3. Mixed ß-a- blockers
* Cervedilol
4. Other
* Nebivolol: also potentiates NO
* Sotalol: also inhibits K+ channels
271
Which drug class of SNS antagonists is commonly used in the chronical treatment of hypertension?
ß-Blockers
276
What are the side effects of Beta-blockers
1+2 are the major concerns
1. Bronchoconstriction (no pure slectivity for ß1)--\> might not be tolerated by astmathics (ß2 activity)
2. Hypoglycaemia --\> might not be toleareated by Diabetics
* masking of hypoglycaemic symptoms
* Inhibits glycogen break down in liver (ß2)
3. Cardiac failure (some SNS activity required for heart)
4. Cold extremitis (no cutaneous ß2 mediated vasodilation)
5. Fatigue (reduced CO+ reduced muscle blood flow (ß2 antagonism))
6. Bad dreams
277
Which group of patients might not tolerate ß-blockers?
1. Astmatics (inhibitionof ß2-mediated bronchiodilation)
2. Diabetics (risk of hypoglycaemia --\> inhibition ß-2 mediated glycogen break down and release)
3. Cardiac failure --\> loss of SNS innervation to the heart which keeps the heart running
278
What is the clinical use for alpha blockers?
Limited use in treament of hypertension
279
Name 2 alpha-blockers and explain their mechanism of action, effect and use
1. Phenotolamine
* used in reduceing phaeochomocytoma-induced hypertension
* alpha-non selective antagonist
2. Prazosin
* limited BP lowering effect
* only used in combination with other hypertensive drugs
280
What is Phenotolamine?
When is it used?
It is a non-selective adrenergic alpha antagonist
Used in management of phaechromycytoma-induced hypertension
281
What is prazosin?
What is its clinical use?
It is a alpha1 selective adrenergic antagonist
* used in hypertension treatment (in combination with other hpyertensive drugs due to limited effects)
282
What are the side-effects of alpha-blocker?
Side effect mainly GI tracts
* reduces SNS innervation to gut --\> leading to increased gut activity
* diarreah etc.
283
Explain the mechnism of action of Methyldopa
It is a false substrate for DOPA-methyltransferase that gets converted into **alpha-methylnoradrenaline**
**Alpha-methylnoradrenaline** is a **false transmitter resulting in**
* Increased selectivity for alpha2 receptors
* Decreased sensitivity for alpha1+ß receptors
* Decreased break down by MAO
--\> Higher concentration of alpha-methylnoradrenaline in synapse with high A2 affinity
**--\> Decreased SNS activtity--\> hypotension**
284
Which drug can be used as a false transmitter in the treatment of hypertensoion?
Methyldopa
* Mmimics DOPA
* Gets transfered to the false transmitter **alpha-methylnoradrenaline**
285
Explain the use of SNS antagonists in the treatment of Glaucoma
Target: ß1 receptors on cliary body --\> reduction in production of aqueous humor (ß-blockers)
286
What is the clinical use of Methyldopa?
Used to treat Hypertension
* linked to Kidney disease
* linked to CNS + cerebrovascular disease
287
What are the (main) side effects of the use of Methyldopa?
Many side effects because it interferes with almost whole SNS
--\> Mainly
* **Hypotension**: Very potent anti-hypertensive drug
* Dry mouth
288
Ich which clinical conditions could you use SNS antagonists as a treatment?
1. In Hypertension
2. In Arrythmias
3. In Angina
4. In Glaucoma
289
Explain the use of SNS antagonists in the treatment of Arrythmias
Mainly Propanolol
* blocks the ß1 receptors in heart
* --\> slows heart rate --\> giving heart more time to fill
290
Explain the use of SNS antagonists in Angina Pectoris
There are two ways of treating Angina:
1. Increasing the Oxygen availibility to the Myocardium
2. Decreasing the Oxygen demand of the Myocardium --\> ß Blockers (less work for heart muscles)
291
What kind of drug groups can be differentated within the neuromuscular blocking drugs?
What are the drugs for each?
1. Non-depolarising (competittive antagonist)
2. Or depolarising (agnoist) Suxaemethonium = succinylcholine
292
What is succinylcholine?
The same drug as suxamethonium
--\> action at the Motor end plate AP initiasation
293
What is the mechanism of action of suxamethonium?
It is a muscular ACh receptor agonist
It causes an
* overstimmulation causing
* extended depolerisation --\> fasciculations
* Leading to shut down of receptors --\> depolerisation block (phase 1)
294
What is the mechanims of action of Tubocurarine?
How much of is is needed to get an effect (on molecular level)
Is a competittive nictinic AChR antagoist
--\> 70-80% must be blocked to achieve flaccid paralisis
295
What is flaccid paralsisi?
Paralysis due to reduced muscle tone
296
What are FASCICULATIONS?
Twitching of muscles due to overstimmulation and hence generation of AP
297
What is the effect of suxamethonium?
Extended depolerisation on the muscular end plate --\> (ACh agonist)
Causes overstimmulation
* fasciculations
Shut down of receptors
* causes flaccid paralysis
**No interference with conciousness and no analgesic effect**
298
What is the effect of Tubocuranine?
Flaccid paralysis in following order
1. of the extrinsic eye muscles causing double vision
2. Small muscles of face, limbs, larynx
3. Respiratory muscles
(Also recoverers in reverse order)
**No analgesic or nor interference with conciousness**
300
What is the clinical use of Tubocurarine?
What do you always have to provide when administering tubocurarine?
1. Relaxation of skeletal muscle during surgical operations--\> reduces dose of required anesthetic (reduces risk)
2. Permits artificial ventilation
**Always assist ventilation!**
301
What is the clinical use of suxamehtonium?
What do always need to provide when administering it?
* To allow endotracheal intubation
* Relaxation for Electroconvulsive therapy (ECT)
* used in very severe deppression
* provide electric impulses over brain
**Always assist ventilation**
302
Explain the pharmacokinetic administration and properties of Suxamethonium
* IV administration (highly charged)
* short action (about 5 min)
* Metabolised by pseudo-cholinesterases (cholinesterase is too selevtiv efor ACh) in plasma and liver
303
Explain the pharmacokinetic properties and route of administration of Tubocurarine
* IV adminstration (highly charged)
* long paralytic action (1-2h)
* does not cross BBB or placenta
* not metabolised
* excretion 70% via kidney, 30% via bile (important in renal/ hepatic disfunction)
304
How could you treat an overdosation of Tubocurarine?
because it is a competitive antagonist--\> effects can be reversed by increased ACh
1. Neostigme (Anticholinesterases)
2. (In combination with Atropine to not cause overstimmulation of muscarenic receptors)
305
What are the side effects of Tubocurarine?
It is a muscular nicotinicAChR antagonist--\> only limited selectivity for muscular nicotinic R
Occuring side effects are because of Ganglion bloockage and histamine release (because of basic properties of Tubocurarine)
1. Hypotension
2. Tachycardia (may trigger arrythmias)
* Reflex
* inhibition of vagal ganglia (less PNS to heart)
3. Bronchospasm + excessive bonchiosecretion (histamine release)
4. Apnoe --\> always assist respiration
306
What are the side effects of suxamehtonium?
* Post-opperative **muscle pains**
* **Bradycardia** (direct muscarenic action on heart --\> for prevention Atropine is normally given as pre-medication)
* **Hyperkalaemia**
* Expecially in patients with soft-tissue injury or burns --\> nerve damage--\> no innervation to these tissues --\> receptor upregulation
* When receptors are stimmulated--\> More NA+ inflow + **K+ outlow**
* **Migh trigger arrythmias, cardiac arrest**
* increase in **Intra-occular pressure**
* avoid in eye injuries and glaucoma
307
What is atrarium?
What is its mechanism of action, use, side effects?
It is just like Tubocurarine a competitive NMJ antagoinst
--\> Use: just like Tubocurarine atratium has just a different duration of action
308
What kind of drug groups can be differentated within the neuromuscular blocking drugs?
What are the drugs for each?
1. Non-depolarising (competittive antagonist)
2. Or depolarising (agnoist) Suxaemethonium = succinylcholine
309
What is succinylcholine?
The same drug as suxamethonium
--\> action at the Motor end plate AP initiasation
310
What is the mechanism of action of suxamethonium?
It is a muscular ACh receptor agonist
It causes an
* overstimmulation causing
* extended depolerisation --\> fasciculations
* Leading to shut down of receptors --\> depolerisation block (phase 1)
311
What is the mechanims of action of Tubocurarine?
How much of is is needed to get an effect (on molecular level)
Is a competittive nictinic AChR antagoist
--\> 70-80% must be blocked to achieve flaccid paralisis
312
What is flaccid paralsisi?
Paralysis due to reduced muscle tone
313
What are FASCICULATIONS?
Twitching of muscles due to overstimmulation and hence generation of AP
314
What is the effect of suxamethonium?
Extended depolerisation on the muscular end plate --\> (ACh agonist)
Causes overstimmulation
* fasciculations
Shut down of receptors
* causes flaccid paralysis
**No interference with conciousness and no analgesic effect**
315
What is the effect of Tubocuranine?
Flaccid paralysis in following order
1. of the extrinsic eye muscles causing double vision
2. Small muscles of face, limbs, larynx
3. Respiratory muscles
(Also recoverers in reverse order)
**No analgesic or nor interference with conciousness**
317
What is the clinical use of Tubocurarine?
What do you always have to provide when administering tubocurarine?
1. Relaxation of skeletal muscle during surgical operations--\> reduces dose of required anesthetic (reduces risk)
2. Permits artificial ventilation
**Always assist ventilation!**
318
What is the clinical use of suxamehtonium?
What do always need to provide when administering it?
* To allow endotracheal intubation
* Relaxation for Electroconvulsive therapy (ECT)
* used in very severe deppression
* provide electric impulses over brain
**Always assist ventilation**
319
Explain the pharmacokinetic administration and properties of Suxamethonium
* IV administration (highly charged)
* short action (about 5 min)
* Metabolised by pseudo-cholinesterases (cholinesterase is too selevtiv efor ACh) in plasma and liver
320
Explain the pharmacokinetic properties and route of administration of Tubocurarine
* IV adminstration (highly charged)
* long paralytic action (1-2h)
* does not cross BBB or placenta
* not metabolised
* excretion 70% via kidney, 30% via bile (important in renal/ hepatic disfunction)
321
How could you treat an overdosation of Tubocurarine?
because it is a competitive antagonist--\> effects can be reversed by increased ACh
1. Neostigme (Anticholinesterases)
2. (In combination with Atropine to not cause overstimmulation of muscarenic receptors)
322
What are the side effects of Tubocurarine?
It is a muscular nicotinicAChR antagonist--\> only limited selectivity for muscular nicotinic R
Occuring side effects are because of Ganglion bloockage and histamine release (because of basic properties of Tubocurarine)
1. Hypotension
2. Tachycardia (may trigger arrythmias)
* Reflex
* inhibition of vagal ganglia (less PNS to heart)
3. Bronchospasm + excessive bonchiosecretion (histamine release)
4. Apnoe --\> always assist respiration
323
What are the side effects of suxamehtonium?
* Post-opperative **muscle pains**
* **Bradycardia** (direct muscarenic action on heart --\> for prevention Atropine is normally given as pre-medication)
* **Hyperkalaemia**
* Expecially in patients with soft-tissue injury or burns --\> nerve damage--\> no innervation to these tissues --\> receptor upregulation
* When receptors are stimmulated--\> More NA+ inflow + **K+ outlow**
* **Migh trigger arrythmias, cardiac arrest**
* increase in **Intra-occular pressure**
* avoid in eye injuries and glaucoma
324
What is atrarium?
What is its mechanism of action, use, side effects?
It is just like Tubocurarine a competitive NMJ antagoinst
--\> Use: just like Tubocurarine atratium has just a different duration of action
