Midterm II - Topic 19,20,21 Flashcards
19: PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM: 20: PARASYMPATHETIC NERVOUS SYSTEM: 21: SYMPATHETIC NERVOUS SYSTEM
1
Q
19: PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM:
- SYMPATHETIC NERVOUS SYSTEM
A
- “Fight or flight”.
- Reaction of the body to emergency situations,
- short-term stress.
- Operating adrenaline and noradrenaline.
2
Q
19: PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM:
* Parasympathetic nervous system:
A
- “Rest and digest”.
- Regaining health, energy, and nutritional supplies.
- The neurotransmitter will be acetylcholine.
3
Q
Synthesis of catecholamines:
A
PRECURSOR = Phenylalanine
L-DOPA = decarboxylated to form Dopamine.
–> This will form Noradrenaline via beta hydroxylation
–> With the transferring of a methyl group,
= forms Adrenaline
(the difference between the two being that noradrenaline is lacking a methyl group).
4
Q
Synthesis of Acetylcholine:
A
CONTAINS= quaternary nitrogen + acetate group.
NEED = choline
= Taken up from the synaptic cleft and the acetyl group donor also.
5
Q
What kind of function will be influenced by the parasympathetic and sympathetic nervous system?
- PARASYMPATHETIC NERVOUS SYSTEM
A
If the parasympathetic nervous system/parasympathomimetic is stimulated because it is rest and digest,
- More secretion e.g. gastric, intestinal fluid etc.
- Bowel movement
- constriction of the pupils.
6
Q
What kind of function will be influenced by the parasympathetic and sympathetic nervous system?
- SYMPATHETIC NERVOUS SYSTEM
A
Sympathetic nervous system stimulated = almost opposite effect.
- The heart will pump faster (positive chronotropic effect),
- dilation of the pupils,
- lower gastric secretion,
- bowel movement will be limited because you would like to fight.
7
Q
Parasympathetiic nervous system use…?
A
CHOLINERGIC TRANSMITTERS
= ACETYL CHOLINE
8
Q
Sympathetiic nervous system use…?
A
NORADRENALINE TRANSMITTERS
9
Q
Peripheral nervous system:
Can be broken up into?
A
- Somatic nervous system,
- Sympathetic nervous system, and
- Parasympathetic nervous system.
10
Q
Parasympathetic and sympathetic nervous system:
How does it act?
A
- Pre-ganglion - Transmits Acetylcholine(PS+S nervous system)
- Post-ganglion
- Release NORADRENALINE - SYMPATHETIC NS
- Release ACETYL CHOLINE - PARASYMPATHETIS NS
Acetylcholine - binds to nicotinic acetylcholine receptors however, these two systems will differ because (postganglion)
The noradrenalin will bind to different receptors:
- alpha-1,
- alpha-2,
- beta-1, or
- beta-2 receptors.
The acetylcholine (PS) will bind to Muscarine receptors (postganglionic neurons)
11
Q
The target organs of the Parasympethetic and sympathetic nervous systems?
A
- Smooth muscle,
- glands
- cardiac muscle.
12
Q
PERIPHERAL NERVOUS SYSTEM
- Somatic nervous system:
A
- Non-depolarising muscle relaxants =
- ATRACURIUM,
- PANCURONIUM,
- VECURONIUM,
- ROCURONIUM etc.
- Mechanisms of action = competitive antagonists of nicotinic acetylcholine receptors.
- NO pre-ganglia or ganglion, there is only a post-ganglion which will release acetylcholine.
- The target organ of this nervous system is skeletal muscle.
13
Q
Somatic Nervous system
Mechanism of action
A
Competitive antagonists of nicotinic acetylcholine receptors.
14
Q
Somatic nervous system
Ganglions??
A
NO pre-ganglia or ganglion,
Only post-ganglion - Release ACETYLCHOLINE.
15
Q
Somatic Nervous system
Target organs
A
Skeletal muscle.
16
Q
If you apply the non-depolarising muscle relaxant Curare (Indian poison), can you influence the Parasympathetic nervous system?
- Why?
A
It will not have any effect on this nervous system.
There are nicotinic receptors but there is a difference in the subunits.
That is why if you add Curare to the NS, the parasympathetic nervous system will not be able to stop it.
You cannot influence this nervous system based on the different subunits. Nicotinic acetylcholine receptor is a Na+ channel so if the sodium is transported into the cell, depolarisation will occur.
17
Q
What kind of receptor is Muscarinic acetylcholine receptors
A
G-protein-coupled receptors.
18
Q
How does the G-Protein cascade get activated?
A
Ach binds to the Ach receptors and the G-protein cascade is activated.
19
Q
How many different Muscarine acetyl subtypes(receprors) exist?
Which can we influence pharmacologically?
A
5 different subtypes (receptors).
Pharmacologically, we can mainly influence:
- M1
- M2
- M3
20
Q
What is this?
Fill in blanc spaces
A
This is a signalling cascade
A = Acetylcholine
B= Muscarinic Acetylcholine Receptor
C = G-Protein
1= ADENYL CYCLASE
2= PHOSPHOLIPASE C
3= K+ Channels
21
Q
In which different organs can we find muscarinic receptors?
M1, M2 and M3
A
M2 in the heart
M1 and M3 in the EYE and many glands and have a connection with VASODILATION
22
Q
Is the blood vessels innervated by the parasympathetic NS?
How does it achieve vasodilation?
A
- NOT innervated by the parasympathetic nervous system
- Vasodilation can be achieved via NO (nitrogen oxide).
- NO will dilate the vessels rather than the PS nerve ending.
- This is different in the sympathetic nervous system which does innervate the blood vessels.
23
Q
What does “SLUDGE” stand for?
A
“SLUDGE” =
- salivation,
- lacrimation,
- urination,
- digestion,
- gastro-intestinal upset and pain, and
- emesis.
24
Q
If you stimulate muscarinic receptors (PS NS) what will be the result?
A
- Bradycardia (negative chronotropic effect i.e. slow down the heart).
- Bronchoconstriction – cannot therapeutically be used.
- Miosis – can therapeutically be used in cases of glaucoma.
- Salivation
- Vomiting, diarrhea – can therapeutically be used for bowel atony..
- Urination – can therapeutically be used for urinary bladder atony.
i.e. we would consider stimulating the parasympathetic nervous system in some cases of treatment.
25
**_Drugs acting on the parasympathetic nervous system:_**
***_A. Parasympathomimetics:_*** stimulate the **parasympathetic nervous system:** **cholinergic drug** =
* **acetylcholine,**
* **parasympathetic stimulants,**
* **acetylcholine receptor agonists.**
1. **Direct Parasympathomimetics**
2. **Indirect Parasympathomimetics**
**B. Parasympatholytics:**
26
Drugs acting on the parasympathetic nervous system:
* *_Pharmacological Effects:_*
27
Parasympathomimetics
* *_Pharmacological Effects:_*
1. *_EYE_*
* The pupil will be constricted by reducing the intraocular pressure which can be useful in cases of **glaucoma.**
28
Parasympathomimetics
Pharmacological Effects:
EYE
In case of KSC - Dry eye disease
* In keratoconjunctivitis sicca (KCS = dry eye disease i.e. it is an **auto-immune disease**)
* **Lacrimal gland cannot produce enough fluid**,
* Apply **parasympathomimetics**, you can **moisturize the eye** by **increasing lacrimal secretion**
29
Parasympathomimetics
Pharmacological Effects:
EYE
**Problems when treating KCS**
**Auto-immune disease = symptomatic treatment** rather than preventative treatment.
If you want to **treat KCS,** you can diagnose it via the **Schirmer test** which **measures the amount of fluid secreted in the eye**.
When it is a **low amount = KCS (usually associated with dogs)**.
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What should you treat KCS with?
* In cases of KCS, you can try and **add ointments,**
* M**ainly administer immunosuppressants** e.g. **glucocorticoids** (corneal laceration present or not?),
* **CYCLOSPORINE,**
* **TACROLIMUS**, because again, it is an **auto-immune disease.**
31
Parasympathomimetics
Pharmacological effect
Heart
* **Negative chronotropic effect** (slow down the heart). Therapeutically, this will not be made use of.
* There are **no inotropic effects** – parasympathomimetic drugs do **not influence the level of contractions of the heart.**
* **Vasodilation via NO** - nitrogen monoxide (rather than parasympathetic innervation).
32
Parasympathomimetics
Pharmacological effects
**GI- Tract**
* **Secretion** enhanced
* **Peristalsis** and the **Bowel movemen**t will be **increased**
* i.e. **smooth muscle contraction.**
* **Vomiting**
* **Diarrhea**
* **Glandular hyperfunction**
33
Parasympathomimetics
Pharmacological effects
**_Respiratory Tract:_**
1. **Bronchoconstriction**
2. increased **bronchial secretion**
= **parasympathomimetics are completely contraindicated in asthmatic cases.**
34
Parasympathomimetics
Pharmacological effects
**_Urinary Tract:_**
Useful if you would like to **relax the sphincter** and **constrict the bladder** to **allow for urination.**
35
Parasympathomimetics
What is **_Direct parasympathomimetics:_**
These will **directly stimulate the ACh-receptors.**
36
Parasympathomimetics
What are the **different drugs** used for **direct parasympathomimetic**
1. **Acetylcholine:**
2. **Carbachol:**
3. **Bethanechol:**
4. **Methacholine:**
5. **Pilocarpine:**
37
_Direct parasympathomimetics:_
_USAGE OF **ACETYLCHOLINE**_
**Acetylcholine***_:_*
* **Therapeutically**, this **cannot be used =** **very short half-life!**
* It is **non-specific** and **non-selective.**
38
Direct parasympathomimetics:
**_USAGE OF CARBACHOL_**
**_Carbachol:_**
* It is old and obsolete.
* Used to **treat glaucoma** - **eye drops**.
* Applied in the **uterus** = **remove content** in the case of **metritis** (intrauterine tablet).
* It is **non-specific** to **M-ACh receptors**
* **Several side effects**.
* It used to be used as a **laxative in pigs** - **emesis.**
39
Direct parasympathomimetics:
**_USAGE OF BETHANECHOL_**
**_Bethanechol:_** (Human).
* **M-ACh-specific** i.e. it has **less side effects.**
* Causes the **induction of intestinal peristalsis after operations.**
* Useful in **urinary bladder atony** (veterinary use also).
* **Spinal trauma** = sometimes the **urinary bladder cannot function appropriately** = **Bethanechol**= **induce urination.**
40
Direct parasympathomimetics:
**_USAGE OF METHACHOLINE_**
**_Methacholine: (Human)._**
* **Theoretical indication** & **Practical indication.**
* **M-ACh-specific.**
* **Theoretically =** **cardiovascular system** for **atrial fibrillatio**n
* **Practically** it is **NOT**
* Useful in **ergot-toxicosis---\> gangrene blood vessels**
* i.e. **serious vasoconstriction**.
* **Methacholine helps by causing vasodilation.**
41
Direct parasympathomimetics:
**_USAGE OF PILOCARPINE_**
**_Pilocarpine:_**
* **Natural alkaloid.**
* Used in **glaucoma**
* (**miosis** can be seen approx. 15 minutes later which **lowers the intraocular pressure**)
* **KCS**
* (**increasing the amount of tears from the lacrimal gland**).
* **Improves salivation mildly.**
42
Parasympathomimetics
What is **_Indirect parasympathomimetics:_**
* **Inhibit the ACh-esterase enzyme** = **lowers the degradation** of **ACh**
* ****i.e. **increases** the **amount of ACh.**
* **Various N-ACh and M-ACh effects** & **side effects.**
* Primarily on the **nicotinic-ACh receptors and**
* furthermore on the **muscarinic-ACh receptors** and,
* also on the **ACh receptors in the CNS.**
43
INDIRECT PARASYMPATHOMIMETICS
Where can the blockage happen?
The blockage can happen as serine residues.
You can find serine in the ACh-esterase which contains a hydroxyl group.
These agents can block the ACh-esterase because they will esterify the serine OH group.
This means that ACh-esterase will not be available towards ACh binding. These are reversible, this means that it can be controlled i.e. regulated.
44
INDIRECT PARASYMPATHOMIMETICS
What will happen to the blockage if you add **ORGANOPHOSPHATES**
* **Bind** to **ACh-esterase for a longer period.**
* NOT GOOD
* **Excessive cholinergic sign of tremors and convulsions.**
* This depends on the **severity of the organophosphate-toxicosis.**
* **1st sign of this toxicosis---\>** binding to ACh-esterases= \>
* Increase in **ACh** = **PARASYMPATHOMIMETIC EFFECT**
* **Salivation,**
* **Diarrhoea,**
* **Vomiting**,
* if **severe**,
* **tremors**,
* **convulsions**,
* **Seizures** --\> Increase in **temperature** --\> **Death**.
45
INDIRECT PARASYMPATHOMIMETICS
Why would we apply **organophosphates**?
It can be used against:
1. **parasite infestation**
2. **ectoparasites**
3. **insecticides**
46
PARASYMPATHOMIMETICS
What are the **INDIRECT PARASYMPATHOMIMETIC** drugs
1. **Physostigmine:**
2. **Neostigmine:**
1. **Pyridostigmine**
2. **Edrophonium: TENSILON**
3. **Organophosphates:**
47
INDIRECT PARASYMPATHOMIMETICS
***_PHYSOSTIGMINE in general_***
***_Physostigmine:_***
* **Lipophilic molecule** with a **Tertiary nitrogen structure**
* Causes **hallucination.**
* **Systematically**, we **require a quaternary nitrogen structure.**
* This is useful in the form of **eye drops** i.e. **locally** and **topically** but **NOT systematically.**
* Used to **treat glaucoma,**
* However, it has a **tolerance**
* ie. when you apply the drug, there will be a certain biological effect.
* After a while, you have to increase the dose to have that same biological effect/response.
* **Very fast = TACHYPHYLAXIS**.
* **Very small therapeutic index systematically**
* ****but is **used in ATROPINE POISONING**
* Atropine is a parasympatholytic which c**rosses the blood-brain barrie**r i.e. for treatment, we need a **parasympathomimetic that also crosses** the blood-brain barrier – **Physostigmine.**
48
INDIRECT PARASYMPATHOMIMETICS
_***NEOSTIGMINE** in general*_
***_NEOSTIGMINE:_***
* This structure has **quaternary nitrogen**
* = **good** --\> **not cross the blood-brain barrier**
* i.e. it is **not as lipophilic.**
* **It can be used systematically = Because NO** effect on the **CNS**.
* Useful as **eye drops**
* **Safer systematically** (injected IV or IM)
* Very **low oral absorption.**
* **The therapeutic indication** = **MYASTHENIA GRAVIS**
* **An auto-immune disease =** **antibodies against the ACh receptors** = causes **paralysis of all muscles.**
* **This is very difficult to treat, even symptomatically.**
* **Due to the myasthenia gravis**,
* **ACh receptor will be damaged**
* **= lower chance of the Neostigmine to bind.**
* **Suspends the action of nondepolarizing muscle relaxants**
* because they are **competitive antagonists** of the **receptor**,
* **Administering parasympathomimetic restores the function of the skeletal muscle**
* **Increases intestinal motility**
* **Induces emesis.**
49
INDIRECT PARASYMPATHOMIMETICS
**_PYRIDOSTIGMINE in general_**
**_PYRIDOSTIGMINE_**
* Q**uaternary nitrogen structure,**
* making it **less lipophilic.**
* **Advantage over Neostigmine**
* You can apply it **orally**.
* It is the first drug that can be **applied systematically and orally.**
* **Best bioavailability (3-8%).**
* **Lasts for a longer period**
* Used to **treat MYASTHENIA GRAVIS**
* **Increases intestinal motility.**
50
INDIRECT PARASYMPATHOMIMETICS
**_EDROPHONIUM in general_**
**_Edrophonium:_ TENSILON**
* **Difference between edrophonium & pyridostigmine/neostigmine**
* is that this one will have a short action
* i.e. **you cannot treat MYASTHENIA GRAVIS**
* Only useful to **test the patient**
* ****because if it is applied, the effect will only last for 15 minutes and after that time, the patient will worsen.
* N**ot used to treat the patient** but to **DIAGNOSE it (Tensilon-test)**.
* It causes **inhibition in the neuromuscular junction.**
* This action is **suspended by diffusion (5-15 minutes).**
51
INDIRECT PARASYMPATHOMIMETICS
**_ORGANOPHOSPHATE in general_**
**_Organophosphates:_**
* **Irreversible inhibition of AChE.**
* **Good to use as an ectoparasiticide** (e.g. diazinon).
* It is **very difficult to treat organophosphate toxicosi**s
* But **ATROPINE** and **PRALIDOXIME** (parasympatholytics) can help.
* **ECHOTHIOPATE =** Organophosphate used in human therapy to treat **GLAUCOMA** but **only as eye drops.**
* **ATROPINE** has a **very narrow therapeutic index,** and its dosage is 0.01-0.02 mg/kg however, **when treating organophosphate toxicosis = Y**ou can administer **0.1mg/kg.**
* If the dose is administered in other cases= **Can kill the animal.**
* **PRALIDOXIME** is an **AChE activator** (another example of this is **OBIDOXIME**).
* Be careful when administering this drug as
* **You must be within hours of the toxicosis!!**
* **If you wait a day, it will not work.**
52
PARASYMPATHETIC NERVOUS SYSTEM
## Footnote
***_Parasympatholytics:_***
***_Parasympatholytics:_***
* **Anticholinergic drugs** (**muscarinic-receptor antagonists**).
1. *_**Atropine**:_*
* Tropane-alkaloid. On the WHO essential drug list.
1. Datura stramonium,
2. Atropa belladonna,
3. Hyoscyamus niger.
53
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
54
PARASYMPATHIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
**_Pharmacological effects_**
**_EYE_**
**_Eye:_**
* **Cycloplegia** is the **paralysis of the ciliary muscle of the eye**
* Causes **lack of accommodation/accommodation disturbances**.
* Causes the **ciliary body to spasm and cause pain**.
* **Atropine** helps to get rid of that pain by
* **Alleviating the spasms of the ciliary muscle**.
* It helps in **inner eye inflammation**
* Only a **symptomatic treatment** rather than a causative treatment.
* Atropine and its derivative **causes mydriasis**
* which causes the **pupil to dilate**
* **V**ia the **inhibition of the m. constrictor pupillae**
* And **stimulation of the m. dilator pupillae.**
* **Dilation of the pupil causes light sensitivity**.
* It is **NOT used in cases of GLAUCOMA**.
* **Dilating the pupil** can be **useful for eye examinations**
* ****however, we would NOT use ATROPINE for this
* It has a **very long-lasting effect** **on the healthy eye** (a shorter-lasting effect on damaged eyes).
* Instead, we **use TROPICAMIDE or HOMATROPINE** **(atropine derivatives)** as they have a **shorter half-life.**
* It can also prevent the development of **SYNECHIAE**.
* This is an **accumulation of fibrin in the eye**,
* **Causing the iris to connect** to
* either the **cornea** (anterior synechiae)
* or to the **lens** (posterior synechiae).
* **You cannot stop the fibrin but by dilating the pupil,** we shorten the connection of the iris, breaking the binding to either the cornea or the lens.
55
PARASYMPATHIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
Pharmacological effects
**_HEART_**
**_Heart:_** (cardiovascular system).
* Causes **tachycardia** (acceleration of the heart)
* by lifting the **cholinergic blockade** of the heart (n. vagus).
* This is an effect we can make use of e.g.
* in **pre-medication.**
* It is not necessary but sometimes **atropine** can be used however, **GLYCOPYRROLATE** is better.
56
PARASYMPATHIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
Pharmacological effects
**_BRONCHI_**
**_Bronchi:_**
* **Bronchodilation** (relaxing bronchial smooth muscle) and
* **Decreased mucus secretion,**
* this is what **makes it a good pre-medication for surgeries.**
57
PARASYMPATHIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
Pharmacological effects
**_GI-TRACT_**
**_GI Tract:_**
* It will **decrease the gastric secretion** and **salivation**.
* This is **good for pre-medication for surgeries.**
* The **transit time increases**,
* **Causes constipation.**
* **Stomach-acid decreases** in **small doses.**
58
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
*_Therapeutic indications:_*
* SHORT ACTING **atropine derivatives** (homatropine, tropicamide)
* for **diagnostic purposes**
* e.g. eye examinations.
* LONG ACTING **atropine**
* for the prevention of **SYNECHIAE**.
59
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
**_Premedication_**
*_**Premedication**:_*
* **We have to pre-medicate with parasympatholytics:**
1. as we would like to **decrease secretion**.
2. The other purpose is that, when we have an **anesthetic** e.g. **Fentanyl**, the heart will slow down **(bradycardia).**
* The **parasympatholytics help to accelerate the heart** (**tachycardia**).
* When considering this, you **must be aware of the agent that has been administered in connection with the anesthesia**
* ****e.g. if you have applied an **alpha-2 agonist** with the anesthesia, **vasoconstriction will occur** and if this is present **together with tachycardia,**
* = **exhaustion of the heart**.
* If you would like to **antagonize bradycardia**, you must be aware of **whether or not vasoconstriction is present.**
**The solution to this is that we ONLY use parasympatholytics as a premedication if there is severe bradycardia on the heart.**
60
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
**Atropine VS Glycopyrrolate:**
***_Atropine Vs Glycopyrrolate:_***
CARDIOVASCULAR EFFECT
* If you apply **atropine,**
* The **cardiovascular effect** will last for **20-30 minutes,**
* If you apply **glycopyrrolate,**
* The **cardiovascular effect** will last for **2-3 minutes**.
BOWEL ACTIVITY
* If you apply **atropine**, it will just **minimize the bowel activity for 1.5 hours**
* **Glycopyrrolate** will **inhibit bowel activity for up to 7 hours.**
* ****Because of these issues, we would **NOT** like to administer glycopyrrolate to **HORSES as it will cause COLIC.**
SAFETY
* **Glycopyrrolate** is **much safer** when **considering cardiovascular issues** and also **CNS effects** as it **does not cross the blood-brain barrier** whereas atropine does.
61
## Footnote
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
***_Bronchodilation:_***
***_Bronchodilation:_***
* This can be applicable in cases of **asthma** which we can see frequently in **cats**.
* **In horses, asthma is called RAO** (recurrent airway obstruction) = **COPD** (chronic obstructive pulmonary disease).
* It is seen **less frequently in dogs as canine chronic bronchitis**
* **Asthma in humans.**
**IPATROPINE** is better to use in these cases than **atropine**
* Because it has a **quaternary nitrogen structure,**
* = means that it **cannot cross the blood-brain barrier.**
* It is in an **inhalation form.**
62
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
***_Antidiarrheals:_***
*_Antidiarrheals:_*
* It will d**ecrease secretion and bowel movement**
* i.e. **atropine is used for obstipation**,
* meaning it is **useful in cases of diarrhea.**
* It **inhibits peristalsis and segmental contractions.**
* The recommendation is **BENZETHIMIDE**
* as in **ruminants**, it will **block bowel motility** and **stop the secretion at the same time.**
* **Morphine derivatives in connection with diarrhea**
* They will **influence the longitudinal movements (peristalsis).**
* It will **not have a negative effect on segmental contraction.**
* This is good and is why we use **morphine derivatives instead of atropine.**
63
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
***_Antispasmodics:_***
***_Antispasmodics:_***
* Parasympatholytics are **useful in spasms**,
* especially **BUSCOPAN (BUTYL-SCOPOLAMINE)**.
* This is very **effective in the intestine**
* **used in cases of colic in horses.**
64
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
***_Parkinson-disease:_***
***_Parkinson-disease:_***
* In Parkinson’s, the
* **Dopamine levels are very low** and the
* **ACh is very high.**
* The **first-line treatment** is to **administer dopamine derivatives**
* e.g. **LEVODOPA**
* (not dopamine itself as it will immediately be decomposed).
* **Levodopa** will **not be decomposed by decarboxylase**
* It is able to **reach the brain.**
* This is only a **substitution therapy** because we are **substituting dopamine**.
* The problem is that the **dopamine-producing nerves are depleted.**
* If you see the **symptoms of Parkinson's**,
* it usually means that **90% of the neurons are obsolete already.**
* Parkinson's patients have **hypersalivation,** and **parasympatholytics are useful for this issue.**
65
66
PARASYMPATHETIC NERVOUS SYSTEM
PARASYMPATHOLYTICS
**_Toxicity_**
***_Toxicity:_***
* This drugs has a very **low therapeutic index**,
* meaning it is **very toxic.**
* It is very **easy to overdose on** **it**.
* **In rabbits,** we do **not see as much of sensitivity to atropine.**
* **Enzyme atropine** can be **found in the rabbit’s body**.
* **Horses are extremely sensitive to atropine.**
67
Summary
PARASYMPATHOLYTIC DRUGS
1. *_Atropine:_*
2. *_Glycopyrrolate:_*
3. *_Homatropine_*:
4. *_Tropicamide:_*
5. *_Ipratropium:_*
6. *_Benzetimide:_*
7. *_Butyl-scopolamine:_*
68
SUMMARY
PARASYMPATHOLYTIC DRUGS
*_Atropine:_*
* The main drug,
* highly toxic,
* can cross the BBB.
* Used in organophosphate toxicosis,
* uveitis (synechiae),
* asthma.
69
SUMMARY
PARASYMPATHOLYTIC DRUGS
**Glycopyrrolate:**
* Not in Hungary,
* very low BBB-penetration,
* used in premedication,
* not used in eye examinations.
70
SUMMARY
PARASYMPATHOLYTIC DRUGS
**Homatropine:**
Diagnostic eye examination.
71
SUMMARY
PARASYMPATHOLYTIC DRUGS
**Tropicamide**:
**Diagnostic eye examination.**
72
SUMMARY
PARASYMPATHOLYTIC DRUGS
Ipratropium:
* Safe,
* very low BBB-penetration.
* COPD,
* asthma.
73
SUMMARY
PARASYMPATHOLYTIC DRUGS
Benzetimide:
* anti-diarrheal
* but morphine derivatives are better.
74
SUMMARY
PARASYMPATHOLYTIC DRUGS
**Butyl-scopolamine:**
**Used in horses with colic.**
75
***_SYMPATHETIC NERVOUS SYSTEM:_***
The neurotransmitter released from
* **Alpha preganglionic neurons** of SNS = **ACETYLCHOLINE**
* **Postganglionic neurons** = Release **NORADRENALINE.**
76
SYMPATHETIC NERVOUS SYSTEM:
## Footnote
**Postganglionic site**
**Which receptors are involved**
* ɑ1-receptors
* ɑ2-receptors
* β1-receptors
* β2-receptors
* β3-receptors
77
SYMPATHETIC NERVOUS SYSTEM:
Postganglionic site
***_ɑ1-receptors:_***
***_ɑ1-receptors:_***
* When **stimulated, they cause vasoconstriction.**
* If you would like to **reduce the blood pressure**,
* we would use **alpha-1-antagonists** to do so,
* this is a **therapeutic/practical use**
* i.e. **alpha-1-blockers are anti-hypertensive.**
* **Stimulation** will also cause **pupil dilation** but therapeutically, this is not made use of.
* **Pupil dilation** is just a **side effect of their use.**
78
SYMPATHETIC NERVOUS SYSTEM:
Postganglionic site
ɑ2-receptors:
***_ɑ2-receptors:_***
Alpha-2-agonists e.g.
1. **XYLAZINE,**
2. **DETOMIDINE,**
3. **MEDETOMIDINE**.
* These are used as a **hypnosedative agent.**
* Their **mechanism of action =**
* **Inhibit the neurotransmitter release of noradrenaline.**
* **Noradrenaline** would usually be released into the synaptic cleft but when we administer **xylazine**,
* it will **bind to the alpha-2-receptors** and **block that release.**
* These receptors can be found both **post- and pre-synaptically.**
* It causes **hypnosedation** along with **various side effects** such as .... - due to .......
* **Bloating -** blocking of the **GI motility,**
* **Hyperglycemia -** reduction of insulin secretion
* **bowel atony.**
79
SYMPATHETIC NERVOUS SYSTEM:
Postganglionic site
***_β1-receptors:_***
***_β1-receptors:_***
* The main site = **heart.**
* If they are stimulated,
* **Heart** will be accelerated (**tachycardia**)
* **Increase the contractility of the heart** i.e.
* beta-1-agonists have a **positive chronotropic** (accelerate the heart), and a
* **positive inotropic effec**t (enhance contractility).
* **Beta-1-antagonists,** as well as alpha-1-antagonists, are **antihypertensive agents.**
80
SYMPATHETIC NERVOUS SYSTEM:
Postganglionic site
β2-receptors:
***_β2-receptors:_***
* These are situated in the **bronchi**, **uterus**, and **blood vessels.**
* **Therapeutically**, they are used (as a beta-2-mimetic) to
* i**nhibit bronchoconstriction** (via bronchodilation) i.e.
* **asthma**.
* They are also used for **uterus relaxation**.
* The beta-2-agonists have a **vasodilating effect** on the **smooth** **muscles** i.e.
* **blood vessels**, however, we do **not use them as vasodilators.**
81
SYMPATHETIC NERVOUS SYSTEM:
Postganglionic site
β3-receptors:
***_β3-receptors:_***
* **The beta-2-agonist should not be used as a gross promoter.**
* If these are used, they will have an **influence on the beta-3-receptors**
* i.e. you can **influence the quality of the meat.**
* These **agonists are used to improve the quality** of the meat however, they will **reduce the fat content** and are **not tolerated.**
82
**_Drugs acting on the sympathetic nervous system:_**
***_Talking about Sympathomimetics - What is mentioned_***
1. ***_Pharmacological effect:_***
2. ***_Non-specific sympathomimetics:_***
3. ***_Specific sympathomimetics:_***
4. ***_Beta-2 agonists:_***
5. **Alpha-1-agonists**
6. ***_Alpha-2-agonists:_***
83
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
* *_Pharmacological effect: Overview_*
1. **_Heart:_** Cardiovascular system.
2. **_GI system:_** Smooth muscle relaxation,
3. **_Respiratory system:_** Bronchodilation,
4. **_Urinary bladder:_** Increased sphincter-constriction
5. **_Eye:_** Mydriasis (iris radial muscles),
84
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
* *_Pharmacological effect:_*
1. **_Heart:_**
**_Heart:_**
* **Cardiovascular system.**
* If we stimulate the **beta-1-receptors** =
* **positive chronotropic**
* **positive inotropic** effect.
* If we stimulate the **alpha-1-receptors** =
* **vasoconstriction**
* If we stimulate the **beta-2-receptors** =
* we will cause **vasodilation.**
85
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
* *_Pharmacological effect:_*
**_GI system:_**
**_GI system:_**
* Smooth muscle relaxation,
* GI atony.
* Theoretical importance, not really used therapeutically for GI Tract.
86
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
* *_Pharmacological effect:_*
**_Respiratory system:_**
**_Respiratory system:_**
* **Bronchodilation**, **decreased bronchial secretion.**
* Useful in **treating asthma.**
* If you would like to treat asthma,
* **you cannot do this without using a short-acting beta-2-agonist.**
87
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
*_Pharmacological effect:_*
**_Urinary bladder:_**
**_Urinary bladder:_**
* **Increased sphincter-constriction** (alpha-1-receptor).
* In the **case of neutering,**
* Animal can end up with **incontinence** (leakage of urine).
* To treat this incontinence, you can add **oestrogen derivatives** and **PHENYLPROPANOLAMINE** which is an **alpha-1-agonist.**
88
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
* *_Pharmacological effect:_*
**_Eye:_**
* **Mydriasis** (iris radial muscles),
* **increase in aqueous humor production.**
* It is **not used in the case of glaucoma.**
****
* When treating **glaucoma**,
* we want to **reduce the intraocular pressure** and to do this,
* we **decrease the aqueous humor production**
* which will aid in **opening the Schlemm channel**
* **where the fluid can be removed easily.**
= **This is how intraocular pressure inside the eye is lowered**.
* In order to do this = **Block the sympathetic nervous system**.
89
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
*_Non-specific sympathomimetics:_*
1. **Adrenaline**
2. **Noradrenaline**
3. **Dopamine**
90
**Drugs acting on the sympathetic nervous system:**
***_Sympathomimetics:_***
***Non-specific sympathomimetics:***
***1. Adrenaline***
***_Adrenaline:_* (epinephrine)**
* Stimulate:
* Beta-receptors
* Alpha-1-receptors in a higher dose.
* The dose is 0.1-0.5 mg/animal
(Ca, Fe: 0.02 mg/kg intratracheal i/v).
* It is injected **intra cardically** if you would like to **treat cardiac stop.**
* It can also be **injected i/v** but, this method is faster.
* INDICATION=
* **Cardiac stop**
* **Severe bronchoconstriction** (asthma, but we have better treatments),
* **Anaphylaxis** (anaphylactic shock)
* where we can also use:
* glucocorticoids
* antihistamines,
* local vasoconstriction (hemorrhages)
* because adrenaline can **act on alpha-1-receptors**, and it can **prolong the action of local anaesthetics** e.g. **LIDOCAINE** by preventing it from being absorbed as quickly.
* **Lidocaine is an antiarrhythmic agent,** but it can **promote** **arrhythmia.**
* **Adrenaline will prolong its effect** and also **causes vasoconstriction =** **lowers the absorption of the lidocaine.**
91
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
*_Non-specific sympathomimetics:_*
***_Noradrenaline:_***
***_Noradrenaline:_***
* It will stimulate
* **beta-1 and**
* **alpha-1 receptors.**
* It is mainly used **therapeutically** to **reduce hypertension** i.e.
* **elevates the blood pressure.**
* It is **injected i/v** to do so.
92
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
*_Non-specific sympathomimetics:_*
***_Dopamine:_***
***_Dopamine:_***
* The action of this drug is **dependent on the dose**
**= i.e. dosages are important.**
* _Its **low dose**_ of 2-5 μg/kg/min, acts on the **dopamine-1-receptors** in **the kidney.**
* ****Its **effect** is that you can **enhance the blood circulation** (perfusion) of the **kidney**,
* = Useful in cases of **babesiosis** or **ethylene glycol (antifreeze) poisoning.**
* **_Its medium dose_** of 5-10 μg/kg/min, acts on the **beta-1-receptors** of the **heart**.
* This leads to higher **tachycardia** (heart rate) and
* an **increase in the blood pressure**.
* **_Its high dose_** of 10-20 μg/kg/min acts on the **alpha-1-receptors** (pressor).
* The pressor effect is when the **alpha-1-receptors are stimulated** and lead to a **lowered perfusion of the kidney** i.e.
* **if the low dose is highered significantly, you can end up with the opposite effect.**
93
**_Drugs acting on the sympathetic nervous system:_**
***_Sympathomimetics:_***
***_Specific sympathomimetic drugs are?_***
1. ***_Dobutamine_*:**
* **Beta-2-receptor stimulator**.
* C**ardiac effect** - **positive chronotropic** and **inotropic effect.**
* This **injected i/v in cases of cardiogenic shock.**
1. ***_Isoproterenol:_***
* **Not fully specific** as it will **stimulate beta-1 and beta-2 receptors.**
* This causes:
* **acceleration of the heart,**
* **bronchodilation**, and the
* **increase of the oxygen** being **transported to the skeletal muscles** via the blood vessels.
* Therapeutic importance is not very relevant.
94
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
***_Beta-2 agonists:_***
***_Beta-2 agonists:_***
* **Therapeutic indication** is:
* **bronchodilation** in **asthmatic patients** and
* **uterus relaxant.**
* It is useful if you would like to:
* **manipulate the foetus** or
* **avoid premature birth.**
**Beta-2 selectivity:**
Clenbuterol = 4:1,
Salbutamol = 650:1,
**Salmeterol = 50000:1 i.e.**
* **Most specific** of the three is **salmeterol**
* because the **higher the ratio**,
* **Lower the cardiac effect.**
* Salmeterol will have an **effect mainly on the beta-2-receptors** and you will **not affect the beta-1-receptors.**
* If you have **2 asthmatic patients** with a **high blood pressure** and add **clenbuterol to one** and **salmeterol to the other**,
= **Asthma will be relieved in both** due to the
* Action on the **beta-2-receptors** but at the same time in **clenbuterol**, the beta-1-receptors will also be stimulated
* i.e. the blood pressure will further increase.
* **This is why it is better to use salmeterol**. All in all, you will have **less of a side effect** e.g.
* **tremor and excitation, when using salmeterol.**
*_**Indications**:_*
* Horse RAO,
* feline asthma,
* bronchitis,
* bronchopneumonia,
* tracheal hypoplasia,
* tracheal collapse.
***_Dosages:_***
* **Clenbuterol**: horse = 1-3 μg/kg PO
* **Salmeterol**: 100-200 μ/cat, 360-720 μ/horse.
95
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
**Name Beta-2 agonists:**
Beta-2 agonists:
1. CLENBUTEROL,
2. SALBUTAMOL,
3. TERBUTALINE,
4. SALMETEROL,
5. ISOXSUPRINE etc.
96
97
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
***_Alpha-1-agonists:_***
***_Alpha-1-agonists:_***
* If we stimulate the **alpha-1-receptors** we end up with **vasoconstriction.**
* This can be **good when used topically** e.g. in
* **nasal congestion**
* **Blood vessels are constricted inside the nose** and **make more room for air.**
98
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
**Name Alpha 1 agonists**
1. **PHENYLEPHRINE:**
2. **XYLOMETAZOLINE, OXYMETAZOLINE, NAPHAZOLINE, TETRYZOLINE:**
3. **PHENYLPROPANOLAMINE:**
4. **EPHEDRINE:**
99
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
Specific sympathomimetic
Alpha-1-agonists:
**PHENYLEPHRINE**
**PHENYLEPHRINE:**
* **Used rarely**.
* Act on the **alpha-1-receptors** to cause **vasoconstriction**.
* It is **used locally** in cases of **allergies** and **colds** and
* **Used systematically** in cases of **hypotension** and **shock** (not relevant).
100
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
Specific sympathomimetic
Alpha-1-agonists:
**XYLOMETAZOLINE, OXYMETAZOLINE, NAPHAZOLINE, TETRYZOLINE:**
**XYLOMETAZOLINE, OXYMETAZOLINE, NAPHAZOLINE, TETRYZOLINE:**
* Also act on the **alpha-1-receptors** to cause **vasoconstriction**
* Used **locally**.
* **Tetryzoline administered as eye drops**
* **constrict the blood vessels**
* **Stop the redness in your eye**
* It will **dry out the eye.**
101
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
Specific sympathomimetic
**Alpha-1-agonists:**
**PHENYLPROPANOLAMINE:**
**PHENYLPROPANOLAMINE:**
* It is used with **estrogen derivatives** to **treat incontinence in bitches post-neutering.**
* Act on the **alpha-1-receptors** to cause **urinary bladder sphincter constriction.**
* It is administered **orally** on an **empty stomach.**
* It has **many side effects.**
102
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
Specific sympathomimetic
**Alpha-1-agonists:**
**EPHEDRINE:**
**EPHEDRINE:**
* It can be used as **oral administration** for **incontinence**,
* but it has a CNS effect i.e.
* it is a mild amphetamine (a psychostimulant).
* Non-specific,
* Direct,
* Indirect effects.
* It causes **tachyphylaxis** (a faster developing tolerance).
* Usually, tolerance can occur within **weeks** but, with **tachyphylaxis, tolerance can occur within hours or days i.e.**
* it must **increase the dosage in order to achieve a similar effect.**
103
Drugs acting on the sympathetic nervous system:
Sympathomimetics:
Specific sympathomimetic
**Alpha-2-agonists:**
***_Alpha-2-agonists:_***
* *_**Sedatohypnotics**:_*
1. **XYLAZINE,**
2. **DETOMIDINE,**
3. **MEDETOMIDINE,**
4. **ROMIFIDINE.**
104
## Footnote
**_Drugs acting on the sympathetic nervous system:_**
**_Sympatholythics_**
***_Sympatholytics:_*** Block the sympathetic nervous system.
1. ***_Non-specific alpha-antagonists:_***
* ***__***Used for **urethra sphincter relaxation.**
2. ***_Alpha-1-antagonists:_***
3. ***_Alpha-2-antagonist:_***
4. ***_Non-specific beta-antagonists:_***
* The main indication is to **treat**
* **hypertension**,
* **arrhythmia**, and
* **hyperthyroidism**.
5. ***_Specific beta-1-antagonists_***
105
Drugs acting on the sympathetic nervous system:
Sympatholythics
***_Non-specific alpha-antagonists:_***
***_Non-specific alpha-antagonists:_***
* Used for **urethra sphincter relaxation**.
* **Therapeutically** used if there are **urinary difficulties.**
* These are also used in cases of **pheochromocytoma.**
* This is when there is a **benign tumor** in the **medulla** and the **final result is a hypertensive crisis.**
* If you apply 1. or 2. you can treat this high blood pressure.
1. **PHENOXYBENZAMINE:** long duration of action.
2. **PHENTOLAMINE**
3. **TOLAZOLINE**
106
Drugs acting on the sympathetic nervous system:
Sympatholythics
***_Alpha-1-antagonists:_***
***_Alpha-1-antagonists:_***
1. **PRAZOSIN:**
* ****Used to **treat hypertension** by **causing vasodilation** and
* can **reduce the blood pressure.**
1. **DOXAZOSIN**: Used for **urethra sphincter relaxation.**
107
Drugs acting on the sympathetic nervous system:
Sympatholythics
***_Alpha-2-antagonist:_***
1. **ATIPAMEZOLE:** Used in cases of overdose.
2. **YOHIMBINE**
108
Drugs acting on the sympathetic nervous system:
Sympatholythics
***_Non-specific beta-antagonists:_***
*_Non-specific beta-antagonists:_*
The **main indication** is to **treat**
* **hypertension**,
* **arrhythmia**, and
* **hyperthyroidism**.
109
Drugs acting on the sympathetic nervous system:
Sympatholythics
Non-specific beta-antagonists:
**PROPRANOLOL**:
* Acts on **beta-1 and beta-2-receptors**.
* Its **main indication** is to **treat high blood pressure.**
* With this treatment, it will also **cause bronchoconstriction** due to **stimulation of the beta-2-receptor**s i.e.
* if you have a **patient with asthma,** it will **induce an asthmatic attack as it is non-specific**.
* For treating **asthma**, use a **specific beta antagonist instead.**
110
Drugs acting on the sympathetic nervous system:
Sympatholythics
**Non-specific beta-antagonists:**
**TIMOLOL:**
* **Indication** (other than **hypertension**) is as **eye drops in cases of glaucoma.**
* Not only will it **reduce the aqueous humor production**, but it will also
* **Open the Schlemm channel** to **allow for the outflow** of fluid .
111
Drugs acting on the sympathetic nervous system:
Sympatholythics
***_Specific beta-1-antagonists_***
*_Specific beta-1-antagonists:_*
1. **METOPROLOL**
2. **ATENOLOL**
