1 CHOLINOMIMETIC DRUGS

2 RHS - 366
3
4 Cholinomimetic Drugs
5 (Parasympathomimetic Drug
6

7  Parasympathetic nerves use ACh as a neurotransmitter.

8  Cholinomimetic drugs mimic the action of ACh at its receptors.

9  Knowledge of distribution of receptor subtypes (muscarinic or nicotinic)
10 helps in predicting drug response.
11 

Cholinergic site Receptor subtype

Neuroeffector
Muscarinic
junctions
Ganglionic synapses Nicotinic

12

13Classification of Cholinomimetics:
14
151. Direct-acting (receptor agonists)
16  Muscarinic receptors
17  Nicotinic receptors
18
192.Indirect-acting (cholinesterase inhibitors)
20  Reversible
21  Irreversible
22Direct-acting Cholinergic Receptor Agonists:
 1
2A) Muscarinic receptor agonists:
3
4Drugs that mimic ACh at neuroeffector junctions of PNS
5
6Mechanisms:
7Cholinergic receptors are coupled to G proteins (in tramembrane transducers that
8regulate second messengers):
9
10  Agonist ----> increase in cGMP ----> activation of IP3, DAG cascade
11  DAG opens smooth muscle Ca2+ channels
12  IP3 ----> release of Ca2+ from sarcoplasmic reticulum
13  Agonist selectivity is determined by muscarinic receptor subtype and G
14 protein in cell.
15

16Types of direct acting muscarinic receptor agonists:

17
18A) Esters of choline (eg. acetylcholine, pilocarpine, carbachol, bethanechol chloride)
19  Poorly absorbed
20  Susceptibility to hydrolysis by cholinesterase affects duration of action
21b) Alkaloids (eg. muscarine)
22  Well absorbed, not used clinically
23  Mushroom poisoning (Amanita muscaria)
24
25
261. Acetylcholine
27  Highly susceptible to hydrolysis
28  IV bolus lasts 5-20 seconds
29  Limited use in topical application in ophthalmology
30
312. Pilocarpine
32  Acts on smooth muscles of eye to constrict the pupil
33 (miosis).
 1  Used to treat glaucoma.
2  Contracts ciliary muscles by stimulating muscarinic
3 Receptors.
4  Penetration (15-30 min) and long duration (8 hrs).
5  Increased aqueous outflow.
6
73. Carbachol
8  Carbamyl ester of choline.
9  Used mainly in ophthalmology for cataract surgery
10 (causes rapid miosis).
11  Decreases intraocular pressure by opening drainage
12 angle of anterior chamber of eye.
13  Used in glaucoma (when resistant to pilocarpine or
14 physostigmine).
15
164. Bethanechol Chloride
17  Choline ester
18  Persistent effects because it is resistant to cholinesterases
19  Selectively stimulates urinary and gastrointestinal tracts
20  Facilitates emptying of neurogenic bladder in patients after surgery or
21 parturition or with spinal cord injury.
22
23
24
25B) Nicotinic receptor agonist
26  Natural alkaloid found in tobacco which mimics the effects of ACh at
27 nicotinic receptors at
28  Autonomic ganglionic synapses (both SNS & PNS)
29  Skeletal neuromuscular junctions
30  Nicotine still used in some insecticides
31
32Mechanism:
33
34  Activates nicotinic receptor (transmembrane polypeptide comprised of
35 cation-selective ion channel subunits
 1
2 Nicotinic agonists
3
4 Conformational change in receptor
5
6 Opens cation channels
7
8 Na+/K+ diffusion into cell
9
10 Depolarization of nerve cell or neuromuscular endplate
11 
12Clinical
use:
13  No therapeutic action but important for its toxicity
14  Available as a transdermal patch or as chewing gum
15  Used as an aid in cessation of smoking
16
17Toxicity:
18  Both stimulant and depressant (affects both SNS & PNS ganglia).
19  Stimulates nicotinic receptors in CNS ----> mild alerting action.
20  Also acts centrally ----> tremor & convulsions.
21  Can increase or decrease HR.
22  Increased respiratory rate.
23  Vomiting due to activation of chemoreceptor trigger zone.
24  Larger doses ----> CNS and respiratory depression by muscle endplate
25 depolarization blockade
26
272.
Indirect-acting Cholinomimetic Drugs
28Characteristics:
29  Anticholinesterase drugs ie. inhibitors of ACh metabolism.
30  Similar effects to direct-acting cholinomimetics.
31
32Mechanism:
33  Normally ACh is rapidly degraded in cholinergic synapse.
34  (T1/2=40ms)
 1

3
4  Acting cholinomimetics block the enzymatic hydrolysis of acetylcholine ---->
5 increases local concentrations of Ach consequently effect of ACh is
6 amplified, leading to muscarinic or nicotinic effects, depending on the
7 organ.
8  Effect can be therapeutic or life threatening

9 Classification

10
11
12A)

13Reversible Inhibitors
14  All are poorly absorbed from conjunctiva, skin & lungs except physostigmine
15 which is well absorbed from all sites.
16  Used topically in eye.
17  More commonly used clinically than organophosphates.
18
19Quaternary alcohols
20  Bind reversibly to active site of ACh esterase and prevents access by Ach.
21  No covalent bond between enzyme inhibitor complex , so short T1/2 (2-10
22 min), eg. Edrophonium.
 1
2  Carbamate esters
3  Two step hydrolysis like Ach.
4  But the covalent bond of carbamylated enzyme is more resistant to hydration
5 (T1/2=30-60 min)
6 eg. neostigmine, physostigmine
7
8Clinical use:
9Primary target organs of anticholinesterase drugs:
10  eye
11  Skeletal muscle
12  Neuromuscular junctions
13  Gastrointestinal tract
14  Urinary tract
15  Respiratory tract
16  Heart
17Effects are similar to direct acting cholinergic agonists
18
19Major uses in treatment of:
20  Glaucoma
21  Myasthenia gravis
22  Stimulation of gastrointestinal and urinary tract motility (eg. neostigmine)
23 -same effects as with agonists.
24  Reversal of neuromuscular blockade.
25  Atropine poisoning
26
27A) Glaucoma:
28  An ocular disease caused by increased intraocular pressure due to
29 inadequate drainage of aqueous humour at filtration angle ----> damage to
30 the retina & optic nerve.
31  Intraocular pressure is determined by the balance between fluid input &
32 drainage out of the globe.
33  Aqueous humour produced by ciliary epithelium and drained at the filtration
34 angle of the anterior chamber.
35
 1

4Therapy:
5  Objective: increase outflow & decrease production of aqueous humour by
6 local treatment with:
7
81. Muscarinic cholinomimetics
9  Direct-acting: pilocarpine, carbachol
10  Indirect-acting: physostigmine ----> contracting the smooth muscle of iris
11 sphincter (contraction of pupil) ----> contraction of ciliary muscle ----> iris
12 pulled from angle of anterior chamber ----> widening the filtration angle and
13 opening the trabecular network ----> increased outflow of aqueous humour
14 ----> decreased intraocular pressure.
15
162. Adrenoceptor agonists: eg. Epinephrine
17  ----> contraction of dilator muscle of iris ----> increased aqueous outflow.
18  Used mainly for treatment of closed angle glaucoma along with surgery.
19
203. B- adrenoceptor blockers: eg. Timolol
21  ----> decreased production of aqueous humour by ciliary epithelium
22
23B) Myasthenia gravis
24  Autoimmune disease resulting in destruction of nicotinic receptors ---->
25 progressive weakness, fatigue, difficulty speaking & swallowing
26 Resembles neuromuscular block by curare.
27  Treated with indirect acting cholinesterase inhibitors (eg neostigmine) ---->
28 increased strength of contraction of muscles
29
30c) Reversal of neuromuscular blockade
 1  Short-acting cholinesterase inhibitors (eg. neostigmine, edrophonium Cl)
2 ----> increased ACh concentration which then competes with neuromuscular
3 blocker for nicotinic receptors.

4B) Irreversible Inhibitors

5  Organophosphates (Parathion, malathion).

6Mechanism:
7  Act by covalently phosphorylating the hydroxyl group of serine on
8 cholinesterase.
9  A few organophosphate pesticides are selective in toxicity to insects e.g.
10 malathion is rapidly metabolized by plasma esterases .: safer

11
12  Aging occurs when an alkyl or alkoxy group is lost
13 ----> increased strength of phosphorus-enzyme bond
14 ----> stable enzyme-inhibitor complex which is difficult to split
15  Before aging occurs patients can be treated with strong nucleophiles eg.
16 pralidoxime which breaks the phosphorus-enzyme complex and regenerates
17 the enzyme.
18
19Signsof Toxicity:
20A) Mild exposure:
21  Pupillary constriction.
22  Tightness of the chest.
23  Watery discharge from the nose.
24  Wheezing
25
26B) Severe exposure (see DUMBELS):
27  More intensified symptoms
28  Visual disturbances
29  Muscle fasciculation
30  Bronchoconstriction & pulmonary edema
31  Pronounced muscle weakness
 1  Shallow respiration
2  Vomiting and diarrhea
3  CNS effects, anxiety, headache, tremor, seizures, depression.
4  Death
5

9DUMBELS:
DIARR
D
10 HEA
URINA
U
TION
12  Treatment: Muscarinic blocking
drugs, e.g. MIOSI atropine
13 M
S
14 BRON
15 CHOC
16 Overview of B ONST Therapeutic
17 Applications of RICTI Cholinomimetic Drugs
Tissue ON Effect Use/drug
EXCIT
Muscarinic agonists ATION
 Eye (skel.
E contraction of ciliary  Glaucoma
 GI tract musc.
m./sphincter m. of iris (pilocarpine)
&
 increased peristalsis,  Paralytic ileus
 Urinary CNS)
sphincter relaxation (bethanechol Cl)
bladder LACRI
 increased contraction of  Urinary
L MATI
detrusor
ON m./sphincter retention
relaxation (bethanechol Cl)
SALIV
ATION
S ,
SWEA
TING
 ACh esterase inhibitors
 Skeletal m.  increased muscle  Myasthenia
activity gravis
 Eye (neostigmine)
 similar to agonists
 Glaucoma
(physostigmine)
1
2
3

8 ADRENERGIC RECEPTORS
9 RHS-366
10
11 :Alpha adrenoceptors .1
12
13.Alpha1: postsynaptic, mediate mainly vasoconstriction
14
15.Alpha2: presynaptic or postsynaptic
16
17.Presynaptic: mediate negative feedback on NE release
18
19Postsynaptic: central or peripheral
20
 1Central tractus solitarius : stimulation causes reduction in central sympathetic
2.discharge and fall of blood pressure
3
4Peripheral postsynaptic receptors mediate inhibition of adenyl cyclase in platelets
5.and lipocytes
6
7:Beta adrenoceptors: postsynaptic .2
8
9.B1: present mainly in the heart causing its stimulation
10
11B2: causes bronchodilatation, uterine relaxation, skeletal and coronary
12.vasodilatation
13
14Presynaptic B1: facilitate NE release
15
16
17:Alpha adrenoceptor agonists
18Alpha1 + Alpha2: epinephrine, norepinephrine ِ
19Alpha1: phenylephrine, methoxamine
20.Alpha2: clonidine, alpha-methyl NE
21
22 :Alpha adrenoceptor antagonists
23 .Alpha1 + Alpha2: phentolamine
24 .Alpha1: prazosin
25.Alpha2: yohimbine
26
27:B- adrenoceptor agonists
28 .B1 + B2: isoproterenol, epinephrine ِ
29 .B1: NE, dobutamine, pronalterol
30 .B2: salbutamol, terbutaline, albuterol
31
32 :Beta adrenoceptor antagonists
33 .B1 + B2: propranolol, timolol, nadolol
34 .B1: atenolol, metoprolol, acebutolol
35 .B2: butoxamine
 1 .N.B. labetalol blocks both alpha and beta-adrenoceptors
2
3:Steps of synthesis of catecholamines and drugs affecting them
4
5Phenylalanine by phenylalanine hydroxylase to tyrosine -1
6
7Tyrosine by tyrosine hydroxylase to Dopa. This step is inhibited by alpha-methyl -2
8.tyrosine and 3-iodotyrosine
9
10Dopa by aromatic L-amino acid decarboxylase to dopamine. This step is inhibited by -3
11.alpha-methyldopa, carbidopa and benserazide
12
13Dopamine by dopamine B-hydroxylase to norepinephrine. This step is inhibited by -4
14.disulfiram
15
16Norepinephrine by N-methyl transferase to epinephrine. This step is inhibited by -5
17 .glucocorticoids
18
19:Fate of catecholamines
20
21:Enzymatic catabolism of circulating CAs
22
23Norepinephrine by COMT to normetanephrine-1
24
25.Epinephrine by COMT to metanephrine-2
26
27Both normetanephrine and metanephrine by MAO to 3-methoxy 4-hydroxy mandelic -3
28.aldehyde
29
30methoxy 4-hydroxy mandelic aldehyde to vanillyl mandelic acid (VMA) and 3- -3 -4
31methoxy, 4-hydroxy phenylglycol (MOPEG)
32
33
34:Enzymatic catabolism of neuronal CAs
35
 1 .Both norepinephrine and epinephrine by MAO to 3,4-dihydroxy mandelc aldehyde-1
2
3dihydroxy mandelc aldehyde is converted to 3,4-dihydroxy mandelic acid (DOMA) -3,4 -2
4.and then by COMT to vanillyl mandelic acid (VMA)
5
6dihydroxy mandelc aldehyde is converted to 3,4-dihydroxy phenylglycol (DOPEG) -3,4 -3
7.and then by COMT to 3-methoxy, 4-hydroxy phenylglycol (MOPEG)
8
9:Uptake of catecholamines
10.Neuronal uptake (uptake I): prevented by cocaine -1
11.Granular uptake: prevented by reserpine -2
12Non-neuronal uptake (uptake II) prevented by glucocorticoids anf phenoxybenzamine -3
13
14:Types of MAO isoenzymes
15.MAO-A: in peripheral tissues, inhibited selectively by clorgyline -1
16.MAO-B: in brain, inhibited selectively by deprenyl -2
17Non-selective MAOIs include hydrazines (e.g. iproniazid) and non-hydrazines -3
18(tranylcypromine)
19
20
21:Molecular mechanism of action of CAs
22B-receptor stimulation results in activation of adenyl cyclase with increased -1
23.intracellular c-AMP
24Alpha1-receptor activation increases intracellular calcium through activation of -2
25phospholipase-C
26Alpha2-receptor activation inhibits adenylate cyclase and decreases intracellular c-AMP -3
27
28 :Functions of alpha1-adrenoceptors
29.Vasoconstriction -1
30.Mydriasis -2
31.Decrease gut motility -3
32.Contraction of pregnant uterus -4
33.Ejaculation -5
34
35
 1:Functions of B-adrenoceptors
2.B1: stimulation of all properties of the heart, increase lipolysis and rennin release
3B2: Coronary and skeletal vasodilatation, bronchodilatation, relaxation of pregnant uterus,
4.decrease gut motility, inhibition of of mast cell degranulation
5
6
7
8Metabolic actions of CAs
9Alpha1: increase hepatic glycogenolysis, hyperkalemia -1
10.Alpha2: decrease lipolysis, rennin secretion, insulin release -2
11.B1: increase lipolysis and rennin secretion -3
12B2: increase hepatic glycogenolysis and insulin release, hypokalemia -4
13
14
15:Reversal effect of epinephrine on blood pressure
16IVI of epinephrine leads to rapid rise of blood pressure (alpha1-action). When an alpha
17adrenoceptor blocker is given the vasodilator effect (B2-action) of epinephrine is
18unmasked resulting in a drop of blood pressure. This reversal effect does not occur with
19.pure alpha-agonists
20
21:Epinephrine, norepinephrine and isoproterenol on HR
22.Epinephrine and isoproterenol increase HR (positive chronotropic) due to B1-action
23Norepinephrine causes reflex bradycardia secondary to increase in mean arterial BP
24
25:Main therapeutic uses of epinephrine
26Anaphylactic shock .1
27Cardiac arrest .2
28Acute bronchial asthma .3
29with local anesthetics .4
30Topical hemostatic .5
31
32:Selective B2 agonists
33 :Advantages
34Less toxic effects on the heart .1
35Effective orally and by inhalation .2
 1.Longer duration of action .3
2:Therapeutic uses
3Bronchial asthma as salbutamol and terbutaline .1
4Premature labor as retodrine -2
5Peripheral vascular disease as isoxsuprine .3
6:Adverse reactions
7Skeletal muscle tremors .1
8Nervousness and weakness .2
9Tachyphylaxis and hypoxemia may occur with excessive use .3
10
11
12
13
14
15
16Compare between Dopamine and Dobutamine
DOPAMINE Dobutamine

Agonist to dopamine receptors, B1 and alpha .1 .Selective B1-agonist .1

adrenoceptors

Causes release of NE .2
Does not release NE .2
Chronotropic and arrhythmogenic .3
Much less .3
.Given by IV infusion .4

Given by IV infusion .4

17
18
19Adverse reactions of ephedrine and amphetamine
Ephedrine Amphetamine
 CNS stimulation .1
Palpitation and tachycardia .2
Urinary retention .3
Tachyphylaxis .4
CNS stimulation and .1
excitement, acute psychosis
Dependence, anorexia .2
Weight loss .3
Palpitation, tachycardia .4
Arrhythmias, hypertension .5
.and hyperpyrexia

1
2
3
4
5
6
7
8Cardiovascular uses of sympathomimetics
9Shock states following AMI as Dopamine or dobutamine .1
10Shock state following sympathectomy as alpha agonists .2
11.Complete heart block and cardiac arrest as isoproterenol or epinephrine .3
12Congestive heart failure as dobutamine, prenalterol .4
13Nasal decongestants as naphazoline, xylometazoline .5
14Local haemostatic as epinephrine .6
15.Peripheral vascular disease as isoxsuprine, nylidrin .7
16
17Classification of B-adrenoceptor blockers
18:Cardioselective B-blockers
19Atenolol, Acebutolol and Metoprolol .1
20.Less liable to cause bronchospasm or Raynaud's phenomenon .2
21with minimal effects upon renal plasma flow or metabolic responses to hypoglycemia .3
22:B-blockers with intrinsic sympathomimetic activity
23Pindolol, Oxprenolol, alprenolol .1
24They have limited effect on HR, A-V conduction, myocardial contractility, peripheral .2
25blood flow, bronchomotor tone and plasma lipids
26:Lipophilic B-blockers
27.Propranolol, Timolol, Alprenolol .1
 1Well absorbed from the GIT .2
2Extensive hepatic metabolism .3
3Shorter half-life (3-5 hour) .4
4.Cross Blood Brain Barrier .4
5:Hydrophilic B-blockers
6Nadolol, Atenolol .1
7Less well absorbed .2
8Elimination primarily by the kidney .3
9Longer half life (7-14 hours) .4
10Do not cross BBB .5
11
12Beta blockers as antihypertensives
13.Negative inotropic and chronotropic action .1
14.Inhibition of rennin secretion by the kidney .2
15.Reconditioning of baroreceptors .3
16.Decrease central sympathetic outflow .4
17.Decrease NE release .5
18.Formation of vasodilator PG .6
19
20Beneficial effects of B-blockers in angina pectoris
21Reduction of myocardial oxygen demand by decrease in heart rate, systolic BP and .1
22.contractility. Decrease lipolysis and free fatty acid utilization
23Increase of oxygen supply by prolongation of diastolic coronary perfusion time, shift of .2
24.subepicardial to subendocardial coronary blood flow and inhibition of platelet aggregation
25
26:Therapeutic uses of B-adrenoceptor blockers
27.Hypertension .1
28.Ischemic heart disease (angina pectoris and acute phase of myocardial infarction) .2
29.Arrhythmias .3
30Hypertrophic obstructive cardiomyopathy .4
31.Migraine prophylaxis .5
32.Open angle glaucoma .6
33.Hyperthyroidism .7
34Pheochromocytoma (+ alpha blocker) .8
35.GI bleeding in hepatic cirrhosis .9
 1
2:Adverse reactions of B-adrenoceptor blockers
3:B1-mediated
4Cardiac failure .1
5Bradycardia .2
6A-V block .3
7Hypotension .4
8
9B2-mediated
10Bronchospasm .1
11Prolongation of insulin hypoglycemia .2
12Intermittent claudication .3
13Cold extremeties .4
14Fatigue .5
15Reduced blood flow to liver and kidney .6
16Abrupt cessation after prolonged therapy can lead to dysrhythmias, hypertension, and
17.worsening of angina
18
19Other side effects: night mares, mental depression, increase in plasma triglycerides and
20decrease HDL
21
22Characteristic features and uses of Labetalol
23Selective alpha1 blocker and non-selective B-blocker .1
24.Has a rapid antihypertensive effect .2
25Used for emergency control of severe hypertension, pheochromocytoma, hypertensive .3
26.response during abrupt withdrawal of clonidine
27
28General therapeutic uses of alpha-adrenergic blockers
29Essential hypertension .1
30Pheochromocytoma .2
31Peripheral vascular disease .3
32Shock associated with severe vasospasm .4
33Toxicity of alpha-agonists .5
34Urinary obstruction .6
35
1Prazosin
2Selective postsynaptic alpha-1 adrenoceptor blocker .1
3.Used in essential hypertension, severe CHF, and Raynaud's vasospasm .2
4Adverse reactions include dose-related postural hypotension (first-dose phenomenon), .3
5dizziness, sodium and water retention on chronic use, tachycardia occurs much less than
6with the non-selective alpha blockers
7
8:Therapeutic uses of ergot alkaloids
9Migraine attack as ergotamine and dihydroergotamine .1
10Migraine prophylaxis as methysergide .2
11Postpartum hemorrhage (ergonovine and methylergonovine .3
12Senile cerebral insufficiency (dihydroergotoxine) .4
135. Bromocriptine is used to suppress lactation, amenorrhoea-galactorr
14
15

16 ALPHA AND BETA ADRENERGIC

17 RECEPTOR AGONISTS
18 RHS-366
19

20 ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS

21History:

22A. Finklemann in 1930 stimulated the sympathetic input to rabbit intestine and
23found a decrease in spontaneous movements. Perfusate did the same thing to a 2nd
24piece of intestine. Effects mimicked by "adrenaline".

25B. Von Euler 1946 demonstrated that NE, not EPI is the main endogenous
26catecholamine in sympathetically innervated tissue.
 1C. The study of the sympathetic nervous system is important from a clinical
2perspective. The SNS is involved in controlling heart rate, contractility, blood
3pressure, vasomotor tone, carbohydrate and fatty acid metabolism etc. Stimulation of
4the SNS occurs in response to physical activity, psychological stress, allergies etc.
5Drugs influencing the SNS are used in treatment of hypertension, shock, cardiac
6failure and arrhythmias, asthma and emphysema, allergies and anaphylaxis.

7D.There are three major catecholamines: NE, EPI, and DA naturally found in the
8body. EPI and NE mediate the response of the sympathoadrenal system to activation,
9and are also found in the CNS. DA is primarily a CNS neurotransmitter.

10

11

12

13I. Sympathomimetic amines have 7 major classes of action

14A. A peripheral excitatory action: i.e. on smooth muscles of blood vessels supplying skin.

15B. A peripheral inhibitory action: i.e. on smooth muscles of gut, bronchioles, and blood
16vessels supplying skeletal muscle.

17C. A cardiac excitatory action: i.e. positive chronotropic, dromotropic, and inotropic
18effects.

19D. Metabolic actions: i.e. enhanced glycogenolysis and lipolysis.

20E. Endocrine actions: i.e. modulation of secretion of insulin

21F. CNS actions: i.e. increased wakefulness and inhibition of appetite.

22G. Presynaptic actions: i.e. inhibition of release of NE, NPY, and ACh at autonomic nerve
23terminals by activation of alpha 2 receptors.

24 Enhanced release of ACh by activation of presynaptic alpha 2 receptors on somatic motor

25neurons. Enhanced release of NE, and NPY by activation of Beta 2 receptors.
1

Classification of adrenergic receptor agonists (sympathomimetic amines) or

drugs that produce sympathomimetic-like effects.

5
 1

2II. Pharmacology of Epinephrine

3

4A. Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1, 2, & 3) receptors,
5therefore, its effects on target organs are complex.

7B. Effects of EPI on blood pressure are dose dependent.

8 1. When given in large doses intravenously, EPI gives a rapid increase in blood pressure.
9As the response wanes, the mean pressure falls below normal before returning to control
10levels. The pressor effects are due to A) the positive inotropic effect of EPI, B) the positive
11chronotropic effect, and C) vasoconstriction in many vascular beds. The depressor effect is
12due to the activation of vasodilator beta 2 receptors in the vasculature perfusing skeletal
13muscle. This effect is not seen initially because it is overwhelmed by the vasoconstrictive
14effect of alpha 1 receptors on vascular smooth muscle at other sites, however
15vasoconstriction is lost as the concentration of EPI goes down, but the beta 2 mediated
16vasodilatory effect is retained. If you pretreat a person with an alpha adrenergic receptor
17blocker, one sees the so-called epinephrine reversal effect i.e. the unopposed effect of the
18beta 2 receptors causes a pronounced decrease in total peripheral resistance, and means
19blood pressure falls in response to EPI.

23

242. When given in small doses, there is little or no effect on the mean blood pressure
25because the increase in blood pressure resulting from increased heart rate and contractility
26is counteracted by the decrease in total peripheral resistance due to vasodilation in blood
27vessels perfusing skeletal muscle. You will recall that these beta 2 receptors have a lower
28threshold to activation than alpha 1 receptors, therefore the net effect of low doses of EPI
29is vasodilation.

30
 13.When EPI causes an increase in mean arterial pressure (High doses); it activates a
2compensatory vagal baroreceptor mediated bradycardia which also helps to return blood
3pressure toward normal.

5C. Effects of EPI on vascular smooth muscle are variable, resulting in a substantial
6redistribution of blood flow. That is, EPI causes a marked reduction of blood flow through
7the skin by activating its alpha 1 receptors, while simultaneously redistributing flow
8through the muscles by causing vasodilation there through the activation of Beta 2
9receptors. This has obvious utility in survival of the organism by preparing it for fight or
10flight. EPI can reduce renal blood flow by 40% in doses that do not affect mean blood
11pressure. Effects of EPI on Cerebral Circulation. No significant constrictor action on
12cerebral blood vessels. If you think about it, it is a lucky thing that the blood flow to the
13brain is not restricted during responses to stressors.

14

15D. Effects of EPI on Cardiac Muscle are mediated primarily by beta 1 receptors, although
16Beta 2 and alpha receptors are also present in the heart. As indicated before, EPI has a
17powerful chronotropic and inotropic effect. EPI reduces the time for systole and makes it
18more powerful without decreasing the duration of diastole. The latter effect occurs
19because EPI also increases the rate of relaxation of ventricular muscle. Cardiac output is
20enhanced and the work of the heart and its oxygen consumption are markedly increased.
21Cardiac efficiency (work done relative to oxygen consumption) is lessened! The
22chronotropic action of EPI is due to its ability to accelerate the slow depolarization of
23pacemaker cells of the SA node that takes place during diastole. Large doses may provoke
24cardiac arrhythmias. Large doses of EPI, or long term elevation of plasma catecholamines
25damages the myocardium. This may in part explain the beneficial effects of beta blockers
26in heart failure.

27

28

29
 1E. Effects of EPI on Other Smooth Muscles. In general GI muscle is relaxed and resting
2tone and peristaltic movements are reduced. This is due to the inhibitory effect of beta 2
3receptors, and possibly also due to inhibition of release of ACh by activation of inhibitory
4presynaptic alpha 2 receptors on cholinergic nerve terminals. The response of the uterus is
5variable depending on phase of the sexual cycle, state of gestation, and dose of the drug.
6During the last month of pregnancy, EPI inhibits uterine tone and contractions, by
7activating beta 2 receptors. As a result, selective beta 2 agonists are used to delay the onset
8of premature labor. Bronchial smooth muscle is powerfully relaxed by EPI via activation
9of Beta 2 receptors. Selective beta 2 agonists are used in the treatment of asthma. Epi
10relaxes the detrusor muscle of the bladder by activating beta receptors, and contracts the
11trigone and sphincter muscles due to alpha agonist effects. The result is urinary retention.

13

14F. Metabolic effects of EPI:

151.Glycogenolysis via activation of beta 2 receptors, results in an increase in blood

16glucose.

172. Lipolysis via activation of beta 3 receptors, results in an increase in the concentration of
18free fatty acids in blood.

193.Insulin secretion is inhibited by alpha 2 receptors, and increased by beta 2 receptors, but
20inhibition predominates in man.

214. EPI promotes a fall in plasma K due to enhanced uptake of K into skeletal muscle via
22an action on Beta 2 receptors. This action has been exploited in the management of
23hyperkalemia.

24

25

26

27
 1G. Absorption and fate of EPI

21. Absorption of EPI as well as other catecholamines from GI tract is negligible due to
3rapid conjugation and oxidation in the intestinal mucosa of the GI tract and liver.
4Subcutaneous absorption slows due to vasoconstriction. Inhaled effects largely restricted
5to the respiratory tract in low doses. Larger doses can give systemic effects, including
6arrhythmias. The liver which is rich in both COMT and MAO destroys most circulating
7EPI.

8H. Toxicity and contraindications

91. EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness, headache,
10tremor, weakness, dizziness, etc. Hyperthyroid and hypertensive patients are particularly
11susceptible.

122. More serious reactions include cardiac arrhythmias, including fatal ventricular
13arrhythmias when EPI is given to a patient anesthetized with halogenated hydrocarbon
14anesthetics such as halothane. Also cerebral hemorrhage due to severe hypertension has
15occurred. Use of EPI in patients receiving nonselective Beta blockers is contraindicated
16because the unopposed actions of EPI on vascular alpha 1 receptors can lead to severe
17hypertension and cerebral hemorrhage.

18I. Therapeutic uses of EPI

191. Relief of bronchospasm

202. Relief of hypersensitivity reactions and anaphylaxis

213. To prolong the duration of action of local anesthetics.

224. As a topical haemostatic to control superficial bleeding from skin and mucosa

235. To restore cardiac rhythm in patients with cardiac arrest.

25
 1III. Pharmacology of Norepinephrine

3A. Cardiovascular effects of NE

41. NE is a potent agonist at alpha and Beta 1 receptors, and has little action on beta 2
5receptors, therefore when given by intravenous infusion of low doses; NE causes a
6pronounced increase in total peripheral resistance (i.e. because there is no opposing Beta 2
7mediated vasodilation). This is combined with its direct inotropic effect on the heart to
8cause a substantial increase in mean blood pressure, and a reflex mediated bradycardia. In
9contrast to EPI, pretreatment with an alpha 1 antagonist will block the pressor effects of
10NE, but will not cause reversal to a depressor effect. Since the effects of NE are mainly on
11alpha and Beta 1 receptors, indirectly acting sympathomimetics which act by releasing NE
12have predominantly alpha mediated and cardiac effects.

13B. Other responses to NE are not prominent in Man.

14

15C. Toxicity

161. The toxic effects of NE are like those of EPI, except they are less pronounced and less
17frequently seen i.e. anxiety, headache, palpitations, etc. In toxic doses, can get severe
18hypertension. NE, like EPI is contraindicated in anesthesia with drugs that sensitize the
19heart to the arrhythmic effects of catecholamines such as halothane. Accidental
20extravasation of NE during attempted intravenous infusion can cause local anoxic necrosis
21and impaired circulation through the limb. In pregnant females, NE should not be used
22because it stimulates alpha 1 receptors in the uterus that cause contraction.

23

24

25

26
 1D. Therapeutic uses

2Currently very little therapeutic use. Sometimes used as a cardiac stimulant in cardiogenic
3or septicemic shock.

6IV. Pharmacology of Dopamine

7
8A. Cardiovascular effects

91.At low doses DA activate D 1 receptors in renal, mesenteric, and coronary vascular
10beds. This leads to vasodilation. Increased flow through renal blood vessels is useful in
11cardiogenic and septicemic shock when perfusion of vital organs is compromised. DA
12activates Beta 1 receptors at higher concentrations leading to a positive inotropic effect.
13Total peripheral resistance is usually unchanged, although at higher concentrations DA can
14cause activation of alpha 1 receptors mediating vasoconstriction.

15B. Toxicity

161.Toxicity of high doses of DA is similar to that noted above for NE. Since the drug has
17an extremely short half life in plasma, DA toxicity usually disappear quickly if the
18administration is terminated.

19C. Therapeutic uses

201. Useful in treatment of severe congestive heart failure, particularly in patients with
21oliguria or impaired renal function. DA is also useful in the treatment of cardiogenic and
22septic shock in patients with reduced renal function.
23C. DA Agonists

24 1. Fenoldopam is a rapidly acting vasodilator which is used for acute control of

25severe hypertension. It is a D1 receptor agonist as well as an alpha 2 agonist. It does not
26affect alpha 1 or beta receptors. The half life of fenoldopam is 10 minutes.
 1V. Pharmacology of Isoproterenol

2A. Cardiovascular effects

31.ISO is primarily a beta receptor agonist, therefore intravenous infusion of ISO leads to a
4substantial reduction of total peripheral resistance. Simultaneously, ISO causes a direct
5inotropic and chronotropic effect on the heart. The net result is a reduction in mean
6pressure.

7B. Actions on other smooth muscles.

81. ISO relaxes almost all varieties of smooth muscle, but particularly bronchial and GI
9smooth muscle. Its effectiveness in asthma may also be due to inhibition of the release of
10histamine by activation of Beta 2 receptors.

11C. Metabolic effects

121. ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also strongly
13releases insulin by activating Beta 2 receptors.

14D. Metabolism

151. Primarily by COMT, not MAO. Mainly in the liver.

16E. Toxicity

171. Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily.

18F. Therapeutic uses

191. Used in emergencies to stimulate heart rate in patients with bradycardia or heart block.
20Its use in asthma and shock has been discontinued due to development of more selective
21sympathomimetics.

23
 1VI. Pharmacology of Dobutamine

3A. The mechanisms of action of dobutamine are complex. It is given as the racemic
4mixture. The l-isomer is a potent agonist at alpha 1 receptors, while the d-isomer is a
5potent alpha 1 antagonist. Both isomers are beta receptor agonists with greater selectivity
6for Beta 1 than beta 2 receptors. The net result of administration of the racemic mixture is
7more or less selective Beta agonist effects.

8B. Cardiovascular effects

91. Total peripheral resistance is not much affected, presumably by the counterbalancing
10effects of beta 2 agonist mediated vasodilation, and alpha 1 agonist mediated
11vasoconstriction. Dobutamine has a prominent inotropic effect on the heart, without
12much of a chronotropic effect. The explanation for this is unclear. Like other inotropic
13agents, dobutamine may potentially increase the size of a myocardial infarct by increasing
14oxygen demand.

15C. Toxicity is like isoproterenol, esp. arrhythmias

16D. Not effective orally. Given by I.V. route, however its half life in plasma is two minutes,
17therefore it must be given by a continuous infusion. After a few days, tolerance develops
18to its effects. This has led to short term use repeated intermittently.

19E. Therapeutic Uses

202. Used in the short term treatment of congestive heart failure or acute myocardial
21infarctions, because of its inotropic effect, and because it does not increase heart rate and
22has minimal effects on blood pressure. These effects minimize the increased oxygen
23demands on the failing heart muscle.

25

26

27
 1VII Pharmacology of Selective Beta 2 Agonists

2
3A. These compounds are mainly utilized for treatment of asthma. Their advantage over
4non-selective beta agonists is that they do not cause undesired cardiovascular effects by
5stimulating beta 1 receptors of the heart.

6B. Metaproterenol, Terbutaline, Albuterol, Pirbuterol are structural analogues of the

7catecholamines which have been modified so that they are not substrates of COMT and are
8poor substrates for MAO. These results in a longer duration of action compared to
9catecholamines and vary from 3 to 6 hours when administered by inhalation.

10C. Formoterol is a selective Beta 2 agonist with similarities to the above agents, however
11it has the advantages a rapid onset of action (minutes) and a long duration (12 hours).

12D. Salmeterol is another long acting Beta 2 agonist however it has a slow onset of action,
13therefore it is not useful for acute asthmatic attacks. It may also have anti-inflammatory
14activity.

15D. Ritodrine is a selective Beta 2 agonist which was developed as a uterine relaxant. It is
16used to delay the onset of premature labor. Other beta 2 agonists have been used for the
17same purpose in Europe. While these drugs can delay the onset of birth, they may not have
18any significant effect in reducing perinatal mortality and may increase maternal morbidity.
19Nifedepine ( a calcium channel blocker: NOT a beta 2 blocker) caused longer
20postponement of delivery, fewer maternal side effects, and fewer admissions to the
21neonatal intensive care unit.

22E. Adverse effects of Beta 2 agonists

231. Skeletal muscle tremor is the most common adverse side effect. This may be due to the
24presence of Beta 2 receptors in skeletal muscle, which when activated, cause twitches and
25tremor. Tolerance generally develops to this side effect.

262. Restlessness, apprehension, anxiety

273.Tachycardia may occur possibly secondary to beta 2 receptor mediated vasodilation. In

28patients with heart disease particularly, can see arrhythmias.
 14. Increased glycogenolysis

25.Some recent epidemiological studies suggest that regular use of Beta 2 agonists may
3actually cause increased bronchial hyper reactivity and deterioration in the control of
4asthma. In patients requiring regular use of these drugs, strong consideration should be
5given to the use of additional or alternative therapies, such as use of inhaled
6glucocorticoids.

10

11

12

13

14

15

16

17

18

19

20

21

22

23VIII. Pharmacology of Alpha 1 Agonists

25A. Phenylephrine and Methoxamine

 11. Primarily directly acting vasoconstrictors by activating alpha 1 receptors. The resulting
2hypertension results in a prominent reflex bradycardia. They are used in the treatment of
3atrial tachycardia to terminate the arrhythmia by causing a reflex bradycardia.
4Phenylephrine is also used as a nasal decongestant and mydriatic. They are not
5metabolized by COMT, therefore they also have a longer duration of action than the
6catecholamines.

8B. Mephentermine and Metaraminol

91. These drugs have two effects: a) They are directly acting alpha 1 agonists, and b) they
10are indirectly acting sympathomimetics i.e. they cause the release of endogenous
11norepinephrine. The direct effect on alpha 1 receptors mediates vasoconstriction and an
12increased blood pressure. The indirect effect of released NE on the heart is a positive
13inotropic and chronotropic action that also increases blood pressure. This results in a reflex
14bradycardia. Both drugs are administered intravenously. Adverse effects are due to CNS
15stimulation, excessive increases in blood pressure, and arrhythmias. They are used in the
16treatment of the hypotension which is frequently associated with spinal anesthesia.
17Metaraminol is also used in the termination of paroxysmal atrial tachycardia, particularly
18in patients with existing hypotension.

19

20C. Midodrine
211. It is an orally effective alpha 1 agonist which is a prodrug. Its activity is due to
22metabolism to desglymidodrine. Sometimes used in patients with autonomic insufficiency
23and postural hypotension.

24

25IX. Pharmacology of Alpha 2 Agonists

27A. Introduction
 11. Selective alpha 2 agonists are used primarily for the treatment of hypertension. Their
2efficacy is somewhat surprising since many blood vessels, especially those of the skin and
3mucosa, contain post-synaptic alpha 2 receptors that mediate vasoconstriction. Indeed
4clonidine, the prototype alpha 2 agonist drug which we will consider was originally
5developed as a nasal decongestant because of its ability to cause vasoconstriction of blood
6vessels in the nasal mucosa. The capacity of alpha 2 agonists to lower blood pressure
7results from their CNS effect, possibly from the activation of alpha 2 receptors in the
8medulla that diminish centrally mediated sympathetic outflow.

10B. Pharmacology of Clonidine

121. Pharmacological effects

13a.Intravenous clonidine can cause a transient rise in blood pressure due to its ability to
14cause vasoconstriction via an alpha 2 agonist effect on vascular smooth muscle of skin and
15mucosa. This is followed by a decreased blood pressure due presumably to activation of
16CNS alpha 2 receptors, resulting in a decreased central outflow of impulses in the
17sympathetic nervous system, although this is an area of intense current research interest,
18and some evidence suggests that different mechanisms may be more important. Some of
19the antihypertensive effect of clonidine may also be due to diminished release of NE at
20sympathetic postganglionic nerve terminals due to activation of presynaptic alpha 2
21receptors. Clonidine also stimulates parasympathetic outflow and causes slowing of the
22heart.

23

24

25

262. Pharmacokinetics

27a.Clonidine is well absorbed orally, and is nearly 100% bioavailability. The mean half life
28of the drug in plasma is about 12 hours. It is excreted in an unchanged form by the kidney,
29and its half life can increase dramatically in the presence of impaired renal function. A
 1transdermaldelivery system is available in which the drug is released at a constant rate for
2about a week. Three or four days are required to achieve steady state concentrations.

43. Adverse effects

5a.The major adverse effects of clonidine are dry mouth, and sedation. Other effects
6include bradycardia, and sexual dysfunction. About 20% of patients develop a contact
7dermatitis to the transdermal delivery system. In patients with long term therapy with
8clonidine, abrupt discontinuation is associated with development of a withdrawal
9syndrome and potentially life threatening hypertension.

10

114. Therapeutic uses

12a. The major use of clonidine is in the treatment of hypertension.

13b.Clonidine is useful in the management of withdrawal symptoms seen in addicts after

14withdrawal from opiates, alcohol, and tobacco. This may be due to its ability to suppress
15sympathomimetic symptoms of withdrawal.

16c.Clonidine is useful in the diagnosis of hypertension due to pheochromocytoma. In

17primary hypertension, clonidine causes a marked reduction in circulating levels of
18norepinephrine. This is not seen if the cause of hypertension is pheochromocytoma.

19d. Apraclonidine and Brimonidine are structural analogues of clonidine (i.e. alpha 2
20agonists) which are used topically in the treatment of glaucoma by decreasing the rate of
21synthesis of aqueous humor. Brimonidine also acts by enhancing the outflow of aqueous
22humor. Its efficacy in reducing intraocular pressure is equivalent to timolol.

24C. Pharmacology of Guanfacine and Guanabenz

 11. Guanfacine and guanabenz are alpha 2 receptor agonists which are also believed to
2lower blood pressure by activation of central sites. Their pharmacological effects and side
3effects are quite similar to clonidine. Guanfacine has a longer mean half life in plasma
4than clonidine (12-24 hrs).

10

11

12

13

14

15

16

17

18

19

20

21X. Miscellaneous Adrenergic Agonist Drugs

22
23A. Amphetamine
 11. Amphetamine is an indirectly acting sympathomimetic which causes release of NE from
2adrenergic nerve endings, and also blocks its reuptake into the cytoplasm of the nerve
3terminal. As such it has potent peripheral effects on alpha 1 & 2 receptors, and Beta 1, but
4not beta 2 receptors. It is also a potent CNS stimulant which is orally effective.

52.Cardiovascular effects of amphetamine include increased blood pressure, and reflex

6bradycardia. In larger doses see cardiac arrhythmias.

73.Other smooth muscles respond to amphetamine as they do to previously described

8sympathomimetics. The contractile effect on the sphincter of the urinary bladder is
9particularly pronounced and has been used for the treatment of incontinence.

104. Amphetamine is one of the most potent sympathomimetic amines in stimulating the
11CNS. The d-isomer is 3 to 4 times more potent than the l-isomer. CNS effects include
12increased wakefulness and alertness; decreased sense of fatigue; elevation of mood, with
13increased initiative, self-confidence, and ability to concentrate; elation and euphoria;
14depressed appetite; physical performance in athletes is improved; performance of simple
15mental tasks is improved, however although more work is accomplished, the number of
16errors increases. The most striking improvement with amphetamine occurs when
17performance is reduced by fatigue and lack of sleep. The behavioral effects of
18amphetamine depend both on the dose and the mental state or personality of the
19individual. Prolonged use or high doses are nearly always followed by depression and
20fatigue. Tolerance develops to the appetite suppressant effects rapidly. Amphetamine
21stimulates the respiratory center. When respiration is depressed by centrally acting drugs,
22amphetamine can stimulate respiration.

23

24

25

265.Toxicity includes: restlessness, dizziness, tremor, irritability, insomnia, confusion,

27assaultiveness, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or
28homicidal tendencies. The psychotic effects of amphetamine, including vivid hallucination
29and paranoid delusions, which are often mistaken for schizophrenia is the most common
 1serious effect, and can be elicited in any individual taking sufficient quantities of
2amphetamine for a long period of time. Cardiovascular effects are common and include
3cardiac arrhythmias, hypertension or hypotension, and circulatory collapse. GI symptoms
4include dry mouth, nausea, vomiting, and diarrhea. Fatal poisoning usually terminates in
5convulsions, stroke, and coma. Repeated use leads to the development of tolerance and
6psychological dependence.

8 6.Therapeutic uses include treatment of narcolepsy, obesity, and attention-deficit

9 hyperactivity disorder.

10

117. Methamphetamine, in low doses, has prominent CNS effects like amphetamine,
12without significant peripheral actions. It has a high potential for abuse. It is used
13principally for its central effects which are more pronounced than amphetamine.
14Methylphenidate is a mild CNS stimulant whose pharmacological properties is
15essentially the same as amphetamine but which may not lead to as much motor activation.
16Pemoline is another CNS stimulant which has minimal cardiovascular effects. It is used in
17the treatment of attention-deficit hyperactivity disorder and is given once daily due to its
18long half-life.

20

21

22

23

24B. Ephedrine

251. Ephedrine is an alkaloid isolated from the plant Ephedrine sinica. Extracts of this plant
26have been used in Chinese herbal medicine for at least 2000 years. Ephedrine has both
27directly- and indirectly- mediated sympathomimetic effects. That is, it stimulates both
 1alpha and beta receptors, and it causes release of NE. Ephedrine was the first
2sympathomimetic drug which was effective orally. Its spectrum of effects is similar to
3EPI, another sympathomimetic with both alpha and beta agonist effects, however it has a
4longer duration of effect. In addition it has CNS effects similar to amphetamine, but less
5intense. In the past it was used as a CNS stimulant for treatment of narcolepsy, and as a
6bronchodilator in asthma. More selective agents have replaced ephedrine.

9C. Ethylnorepinephrine

101.It is primarily a beta agonist with some alpha agonist effects. It is administered IM or
11SC to cause bronchiolar dilation as well as vasoconstriction in the bronchioles, which
12reduces bronchial congestion.

13D.Oral sympathomimetics used primarily for relief of nasal congestion include

14phenylephrine, pseudoephedrine, and phenylpropanolamine.

15E.Topical sympathomimetics used primarily as nasal decongestants or mydriatics include

16naphazoline, tetrahydrozoline, and oxymetazoline. and xylometazoline

18

19

20

21

22XI. A Summary of Therapeutic Uses of Sympathomimetics

23A. Uses that relate to vascular effects of sympathomimetics

241.Control of superficial hemorrhage, i.e. in facial, oropharyngeal, and nasopharyngeal

25surgery. EPI
 12. Decongestion of mucous membranes.

2a. Usually get temporary relief, but it is often followed by a rebound swelling.

33. To prolong the duration of action of local anesthetics: EPI

44. in the treatment of hypotension and shock.

5a.Use controversial because autoregulatory phenomena usually cause intense sympathetic

6activation and sympathomimetics may compromise perfusion of vital organs. DA!

7B. Uses that relate to CNS effects of sympathomimetics

81. Narcolepsy (amphetamines)

92. Weight Reduction (amphetamines)

103. Attention deficit-hyperactivity disorder (amphetamines, methylphenidate)

11C. Uses for cardiac effects

121. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia.

132. Epinephrine used in emergency treatment of cardiac arrest.

143. DA is useful in the treatment of cardiogenic or septicemic shock especially in patients

15with compromised renal function.

16

17

18

19D. Uses in allergic reactions

 11. Epinephrine is the drug of choice to reverse the manifestations of serious acute
2hypersensitivity reactions due both to its cardiovascular effects and its ability to suppress
3release of histamine.

42. Asthma is preferentially treated with selective beta 2 agonists (Metaproterenol,

5terbutaline, albuterol).

7E. Uses in ophthalmology

81.Sympathomimetics cause mydriasis i.e. phenylephrine and epi. These two drugs also
9cause a reduction in intraocular pressure in wide angle glaucoma.

10F. Uses in obstetrics

111. Beta 2 agonist (Ritodrine) blocks onset of premature labor by inhibiting contractility of
12uterus

13G. Nasal decongestion

14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
 1 Uptake of catecholamines:
2

3 1) Neuronal Uptake:
4 Adrenergic neurons have a high capacity of actively taking up noradrenaline from the
5 extracellular fluid to the cytoplasm resulting in a fall of the transmitter concentration at
6 the receptor sites. This neuronal uptake process or Uptake 1 is both stereo- and structure
7 selective. It has a higher affinity for L-than for D-forms, and for noradrenaline twice as
8 much as for adrenaline.
9
10 Uptake1 is probably the most important mechanism in terminating the action of
11 neuronally released noradrenaline. Drugs that inhibit uptake-1 potentiate the response to
12 sympathetic stimulation and to exogenously administered noradrenaline and adrenaline.
13 Such drugs include cocaine, guanethidine and tricyclic antidepressants as desipramine
14
15 2) Granular uptake:
16 The noradrenaline taken up into the cytoplasmic pool may also be actively transported
17 into the storage vesicles or granules, a process described as granular uptake. Inhibitors
18 of uptake1, have little effect on this process whereas resepine has little effect on
19 uptake1 but is a potent inhibitor of granular uptake
20
21 3) Extraneuronal uptake:
22 Some peripheral tissues as cardiac muscle and smooth muscle of the intestine and blood
23 vessels may also take up circulating catecholamines especially when their concentration
24 becomes relatively high. This extraneuronal uptake or uptake2 has different
25 characteristics from uptake1 and is suggested to play a role in inactivating circulating
26 catecholamines
27
28
29
30
31
32
33
1 ADRENOCEPTOR ANTAGONISTS
2 RHS-366
3
4

5Alpha-Adrenoceptor
6Antagonists (Alpha-

7Blockers) 

8 General Pharmacology

9These drugs block the effect of sympathetic

10nerves on blood vessels by binding to alpha-
11adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as
12competitive antagonists to the binding of norepinephrine that is released by sympathetic
13nerves synapsing on smooth muscle. Therefore, sometimes these drugs are referred to as
14sympatholytics because they antagonize sympathetic activity. Some alpha-blockers are
15non-competitive (e.g., phenoxybenzamine), which greatly prolongs their action.

16Vascular smooth muscle has two primary types of alpha-adrenoceptors: alpha1 (a1) and
17alpha2 (a2). The a1-adrenoceptors are located on the vascular smooth muscle.  In contrast,
18a2-adrenoceptors are located on the sympathetic nerve terminals as well as on vascular
19smooth muscle. Smooth muscle (postjunctional) a1 and a2-adrenoceptors are linked to a
20Gq-protein, which activates smooth muscle contraction through the IP3 signal transduction
21pathway. Prejunctional a2-adrenoceptors located on the sympathetic nerve terminals serve
22as a negative feedback mechanism for norepinephrine release.

23a1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine

24to the smooth muscle receptors. Non-selective a1 and a2-adrenoceptor antagonists block
25postjunctional a1 and a2-adrenoceptors, which causes vasodilation; however, the blocking
26of prejunctional a2-adrenoceptors leads to increased release of norepinephrine, which
27attenuates the effectiveness of the a1 and a2-postjunctional adrenoceptor blockade.
1Furthermore, blocking a2-prejunctional adrenoceptors in the heart can lead to increases in
2heart rate and contractility due to the enhanced release of norepinephrine that binds to
3beta1-adrenoceptors.

4Alpha-blockers dilate both arteries and veins because both vessel types are innervated by
5sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the
6arterial resistance vessels. Because most blood vessels have some degree of sympathetic
7tone under basal conditions, these drugs are effective dilators. They are even more
8effective under conditions of elevated sympathetic activity (e.g., during stress) or during
9pathologic increases in circulating catecholamines caused by an adrenal gland tumor
10(pheochromocytoma).

11Therapeutic Uses

12Alpha-blockers, especially a1-adrenoceptor antagonists, are useful in the treatment of

13primary hypertension, although their use is not as widespread as other antihypertensive
14drugs. The non-selective antagonists are usually reserve for use in hypertensive
15emergencies caused by a pheochromocytoma. This hypertensive condition, which is most
16commonly caused by an adrenal gland tumor that secretes large amounts of
17catecholamines, can be managed by non-selective alpha-blockers (in conjunction with
18beta-blockade to blunt the reflex tachycardia) until the tumor can be surgically removed.

19Specific Drugs

20Newer alpha-blockers used in treating hypertension are relatively selective a1-adrenoceptor

21antagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs
22are non-selective antagonists (e.g., phentolamine, phenoxybenzamine). (Go to
23www.rxlist.com for specific drug information)

24Side Effects and Contraindications

25The most common side effects are related directly to alpha-adrenoceptor blockade. These
26side effects include dizziness, orthostatic hypotension (due to loss of reflex
27vasoconstriction upon standing), nasal congestion (due to dilation of nasal mucosal
28arterioles), headache, and reflex tachycardia (especially with non-selective alpha-
29blockers). Fluid retention is also a problem that can be rectified by use of a diuretic in
 1conjunction with the alpha-blocker. Alpha blockers have not been shown to be beneficial
2in heart failure or angina, and should not be used in these conditions.

3
4

5 BETA ADRENOCEPTOR ANTAGONISTS

6Pharmacology

7Beta blockers block the action of endogenous catecholamines (epinephrine (adrenaline)

8and norepinephrine (noradrenaline) in particular), on β-adrenergic receptors, part of the
9sympathetic nervous system which mediates the "fight or flight" response.

10There are three known types of beta receptor, designated β1, β2 and β3. β1-Adrenergic
11receptors are located mainly in the heart and in the kidneys. β2-Adrenergic receptors are
12located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle,
13and skeletal muscle. β3-receptors are located in fat cells.

14β-Receptor antagonism

15Stimulation of β1 receptors by epinephrine induces a positive chronotropic and inotropic

16effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation
17of β1 receptors on the kidney causes renin release. Stimulation of β2 receptors induces
18smooth muscle relaxation (resulting in vasodilation and bronchodilation amongst other
19actions), induces tremor in skeletal muscle, and increases glycogenolysis in the liver and
20skeletal muscle. Stimulation of β3 receptors induces lipolysis.

21Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have
22minimal effect on resting subjects. That is, they reduce the effect of excitement/physical
23exertion on heart rate and force of contraction, dilation of blood vessels and opening of
24bronchi, and also reduce tremor and breakdown of glycogen.

25It
is therefore expected that non-selective beta blockers have an antihypertensive effect.
26The antihypertensive mechanism appears to involve: reduction in cardiac output (due to
1negative chronotropic and inotropic effects), reduction in renin release from the kidneys,
2and a central nervous system effect to reduce sympathetic activity.

3Antianginal effects result from negative chronotropic and inotropic effects, which decrease
4cardiac workload and oxygen demand.

5The antiarrhythmic effects of beta blockers arise from sympathetic nervous system
6blockade – resulting in depression of sinus node function and atrioventricular node
7conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional
8antiarrhythmic properties and prolongs action potential duration through potassium
9channel blockade.

10Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone
11via the renin angiotensin aldosterone system with a resultant decrease in blood pressure
12due to decreased sodium and water retention.

13Intrinsic sympathomimetic activity

14Some beta blockers (e.g. oxprenolol and pindolol) exhibit intrinsic sympathomimetic
15activity (ISA). These agents are capable of exerting low level agonist activity at the β-
16adrenergic receptor while simultaneously acting as a receptor site antagonist. These
17agents, therefore, may be useful in individuals exhibiting excessive bradycardia with
18sustained beta blocker therapy.

19Agents with ISA are not used in post-myocardial infarction as they have not been
20demonstrated to be beneficial. They may also be less effective than other beta blockers in
[3]
21the management of angina and tachyarrhythmia.

22α1-Receptor antagonism

23Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both β- and
24α1-adrenergic receptors, which provides additional arteriolar vasodilating action.

25Other effects

26Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep
[4]
27disturbance caused by some agents. Beta blockers protect against social anxiety:
 1"Improvement of physical symptoms has been demonstrated with beta-blockers such as
2propranolol; however, these effects are limited to the social anxiety experienced in
[5]
3performance situations." Beta blockers can impair the relaxation of bronchial muscle
4(mediated by beta-2) and so should be avoided by asthmatics.

5Clinical use

6Large differences exist in the pharmacology of agents within the class, thus not all beta
7blockers are used for all indications listed below.

8Indications for beta blockers include:

9  Hypertension
10  Angina
11  Mitral valve prolapse
12  Cardiac arrhythmia
13  Congestive heart failure
14  Myocardial infarction
15  Glaucoma
16  Migraine prophylaxis
17  Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
18  Essential tremor
19  Phaeochromocytoma, in conjunction with α-blocker

20Congestive heart failure

21Although beta blockers were once contraindicated in congestive heart failure, as they have
22the potential to worsen the condition, studies in the late 1990s showed their positive
[6] [7] [8]
23effects on morbidity and mortality in congestive heart failure. Bisoprolol, carvedilol
24and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE
25inhibitor and diuretic therapy in congestive heart failure.

26The beta blockers are a benefit due to the reduction of the heart rate which will lower the
27myocardial energy expenditure. This is turns prolongs the diastolic filling and lengthens
[9]
28coronary perfusion. Beta blockers have also been a benefit to improving the ejection
29fraction of the heart despite an initial reduction in it.
1Trialshave shown that Beta blockers reduce the absolute risk of death by 4.5% over a 13
2month period. As well as reducing the risk of mortality, the number of hospital visits and
3hospitalizations were also reduced in the trials.

4Anxiety and performance enhancement

5Some people, particularly musicians, use beta blockers to avoid stage fright and tremor
6during public performance and auditions. The physiological symptoms of the fight/flight
7response associated with performance anxiety and panic (pounding heart, cold/clammy
8hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling
9anxious individuals to concentrate on the task at hand. Officially, beta blockers are not
[10]
10approved for anxiolytic use by the U.S. Food and Drug Administration.

11Since they lower heart rate and reduce tremor, beta blockers have been used by some
12Olympic marksmen to enhance performance, though beta blockers are banned by the
[11]
13International Olympic Committee (IOC). Although they have no recognisable benefit to
14most sports, it is acknowledged that they are beneficial to sports such as archery and
15shooting.

16Adverse effects

17Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea,
18diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome,
19bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision,
20decreased concentration, hallucinations, insomnia, nightmares, clinical depression, sexual
21dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed
22α1/β-antagonist therapy is also commonly associated with orthostatic hypotension.
[3]
23Carvedilol therapy is commonly associated with edema.

24Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares,

25depression) are more common in agents with greater lipid solubility, which are able to
26cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less
27common in agents with greater aqueous solubility.

28Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm,

29peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common
 1withβ1-selective (often termed "cardioselective") agents, however receptor selectivity
2diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula
3densa inhibits renin release, thus decreasing the release of aldosterone. This causes
4hyponatremia and hyperkalemia.

5A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a
6patient's risk of developing diabetes whilst ACE inhibitors and Angiotensin II receptor
[12]
7antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.
8Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics
[13]
9and beta-blockers as first-line treatment of hypertension due to the risk of diabetes.

10Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha
11adrenergic stimulant overdose. The blockade of only beta receptors increases
12hypertension, reduces coronary blood flow, left ventricular function, and cardiac output
13and tissue perfusion by means of leaving the alpha adrenergic system stimulation
[14]
14unopposed. The appropriate antihypertensive drugs to administer during hypertensive
15crisis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like
16furosemide and alpha blockers like phentolamine.

17

18

19Examples of beta blockers

20
21
22Dichloroisoprenaline, the first beta blocker.

23Non-selective agents

24  Alprenolol
25  Carteolol
26  Levobunolol
27  Mepindolol
28  Metipranolol
29  Nadolol
 1  Oxprenolol
2  Penbutolol
3  Pindolol
4  Propranolol
5  Sotalol
6  Timolol

7β1-Selective agents

8  Acebutolol
9  Atenolol
10  Betaxolol
11  Bisoprolol[16]
12  Esmolol
13  Metoprolol
14  Nebivolol

15Mixed α1/β-adrenergic antagonists

16  Carvedilol
17  Celiprolol
18  Labetalol

19β2-Selective agents

20  Butaxamine (weak α-adrenergic agonist activity

21

22

23Side Effects / Health Consequences

24  Low Blood Pressure

25  Slow Heart Rate
26  Impaired Circulation
27  Loss of Sleep
 1  Heart Failure
2  Asthma
3  Depression
4  Sexual Dysfunction
5  Nausea
6  Headaches
7  Dizziness
8  Muscle Cramps

9Pharmacological differences

10  Agents with intrinsic sympathomimetic action (ISA)

11 o Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol
12  Agents with greater aqueous solubility
13 o Atenolol, celiprolol, nadolol, sotalol
14  Agents with membrane stabilising activity
15 o Acebutolol, betaxolol, pindolol, propranolol
16  Agents with antioxidant effect
17 o Carvedilol
18 o Nebivolol

19Indication differences

20  Agents specifically indicated for cardiac arrhythmia

21 o Esmolol, sotalol
22  Agents specifically indicated for congestive heart failure
23 o Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol
24  Agents specifically indicated for glaucoma
25 o Betaxolol, carteolol, levobunolol, metipranolol, timolol
26  Agents specifically indicated for myocardial infarction
27 o Atenolol, metoprolol, propranolol
28  Agents specifically indicated for migraine prophylaxis
29 o Timolol, propranolol
 1 Propranolol is the only agent indicated for control of tremor, portal hypertension and
2 esophageal variceal bleeding, and used in conjunction with α-blocker therapy in
3 phaeochromocytoma
4
5
6
7
8

9Neuromuscular-blocking drugs

10Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular

11junction, causing paralysis of the affected skeletal muscles. This is accomplished either by
12acting presynaptically via the inhibition of acetylcholine (ACh) synthesis or release, or by
13acting postsynaptically at the acetylcholine receptor. While there are drugs that act
14presynaptically (such as botulin toxin and tetrodotoxin), the clinically-relevant drugs work
15postsynaptically.

16Clinically, neuromuscular block is used as an adjunct to anesthesia to induce paralysis, so

17that surgery, especially intra-abdominal and intra-thoracic surgeries, can be carried out
18with fewer complications. Because neuromuscular block may paralyze muscles required
19for breathing, mechanical ventilation should be available to maintain adequate respiration.

20

21Classification

22These drugs fall into two groups:

23Non-depolarizing blocking agents: These agents constitute the majority of the clinically-
24relevant neuromuscular blockers. They act by blocking the binding of ACh to its receptors,
25and in some cases, they also directly block the ionotropic activity of the ACh receptors

26Depolarizing blocking agents: These agents act by depolarizing the plasma membrane of
27the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to
28further stimulation by ACh.
 1Non-depolarizing blocking agents

2All of these agents act as competitive antagonists against acetylcholine at the site of
3postsynaptic acetylcholine receptors.

4Tubocurarine, found in curare of the South American plant genus Strychnos, is the
5prototypical non-depolarizing neuromuscular blocker. It has a slow onset (>5 min) and a
6long duration of action (1-2 hours). Side effects include hypotension, which is partially
7explained by its effect of increasing histamine release, a vasodilator,as well as its effect of
8blocking autonomic ganglia. It is excreted in the urine.

9This drug needs to block about 70-80% of the Ach receptors for neuromuscular
10conduction to fail, and hence, for effective blockade to occur. At this stage, end-plate
11potentials (EPPs) can still be detected, but are too small the reach the threshold potential
12needed for activation of muscle fiber contraction.

13

14Depolarizing blocking agents

15Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle
16fiber, similar to acetylcholine. However, these agents are more resistant to degradation by
17acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus
18more persistently depolarize the muscle fibers. This differs from acetylcholine, which is
19rapidly degraded and only transiently depolarizes the muscle.

20There are two phases to the depolarizing block. During phase I (depolarizing phase), they
21cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle
22fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing
23phase) sets in and the muscle is no longer responsive to acetylcholine released by the
24motoneurons. At this point, full neuromuscular block has been achieved.

25The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the

26only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of
27action (5-10 minutes) because of hydrolysis by various cholinesterases. Succinylcholine
28was originally known as diacetylcholine because structurally it is composed of two
 1acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but
2rarely, used in clinical practice.

4Comparison of drugs

5The main difference is in the reversal of these two types of neuromuscular-blocking drugs.

6  Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs.

7 Since they are competitive antagonists at the ACh receptor so can be reversed
8 by increases in ACh.
9  The depolarizing blockers already have ACh-like actions, so these agents will
10 have prolonged effect under the influence of acetylcholinesterase inhibitors.
11 The administration of depolarizing blockers will initially exhibit fasciculations
12 (a sudden twitch just before paralysis occurs). This is due to the depolarization
13 of the muscle. Also, post-operative pain is associated with depolarizing
14 blockers.

15The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently-high
16frequencies of electrical stimulation.

17  Non-depolarizing blockers will have this effect on patients.

18  Depolarizing blockers will not.

19Adverse effects

20Since these drugs may cause paralysis of the diaphragm, mechanical ventilation should be
21at hand to provide respiration.

22Additionally, these drugs may exhibit cardiovascular effects, since they are not fully
23selective for the nicotinic receptor and hence may have effects on muscarinic receptors.If
24nicotonic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs
25may cause autonomic symptoms. Additionally, neuromuscular blockers may facilitate
26histamine release, which causes hypotension, flushing, and tachycardia.
 1In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts ofpotassium from
2muscle fibers. This puts the patient at risk for life-threatening complications, such as hyperkalemia and cardiac
3arrhythmias. Certain drugs such as aminoglycoside antibiotics and polymyxin and some
4fluoroquinolones

5
6
7
nglionic
8 Transmission
imary
9 Pathway
10 Most autonomic ganglions (Para and Sym) work in the following way. The pre-ganglionic nerve terminal relea
11 ACh which activates a nicotinic receptor (Rc) on the autonomic ganglia, producing a fast excitatory potential,
12 stimulating transmission through the post-ganglionic nerve terminal.
13
14 HEXAMETHONIUM or C6 is the prototype nicotinic Rc antagonist that blocks ganglionic transmission. It does
15 in a competitive fashion meaning that if you give a cholinesterase inhibitor, you can build up the level of ACh in
16 the presence of hexamethonuim and override it’s blockade.
17
Secondary
18 Pathway
19 Found in certain ganglia such as the SA node
20
21 ACh released from a pre-ganglionic nerve ending, acts on a nicotinic Rc, produces a fast excitatory potential,
22 is blocked by HEXAMETHONIUM, just as in the primary pathway.**But, there are also slow excitatory and slow
23 inhibitory potentials being produced.
24
25 The slow excitatory pot. arises when ACh that is released from the pre-ganglionic terminal activates a muscari
26 – 1 (M1) Rc on the ganglia. This can be blocked be the specific M1 Rc antagonist PIRENZEPINE.
27 PIRENZEPINE may eventually be introduced for the treatment of peptic ulcer. The slow excitatory potential ca
28 also be blocked by the non-specific muscarinic antagonist ATROPINE, which blocks the transmission of ACh a
29 all muscarinic Rc sites.
30
31 The slow inhibitory potential arises from the pre-ganglionic release of ACh acting on the muscarinic 2 (M2) Rc
32 a SIF cell (small intensely fluorescent) or interneuron. There is dopamine in the interneuron which, when
33 released, activates a dopaminergic Rc on the ganglia to produce the slow inhibitory potential. The slow inhibito
34 potential is important because the drug METACLOPRAMIDE that blocks the inhibitory action of dopamine on t
35 ganglia leading to activation of the post-ganglionic nerve terminal. This drug is used in the treatment of gastric
36 atony
37
38 There is a difference between the gastric atony therapeutic drugs METACLOPRAMIDE and the muscarinic Rc
39 agonist BETHANECHOL. BETHANECHOL stimulates intestinal motility, but also stimulates HCl secretion. For
40 some unknown reason, METACLOPRAMIDE does not stimulate acid secretion when it stimulates intestinal
41 motility. Therefore, METACLOPRAMIDE is a good choice for treatment of patients with peptic ulcers and with
42 gastric atony.
 1
2 Summary: To achieve complete blockade of the ganglia, you would need HEXAMETHONIUM to block the act
3 of ACh at the nicotinic Rc and ATROPINE to block the action of ACh at the muscarinic 1 and 2 Rc.
4
anglionic
5 Stimulants
6

NICOTINE--low
7 dose stimulant
8 Activates nicotinic Rc on autonomic ganglia, stimulating transmission through both parasympathetic and
9 sympathetic ganglia.
10
11 It does so only in low doses, because in high doses, it causes ganglionic blockade by desensitization of the
12 ganglionic Rc. Because it can cause desensitization of Rc’s, it is considered a very dangerous drug. For
13 example, if the Rc’s at the neuromuscular junction are desensitized, respiration will become impaired. Also,
14 desensitization of the Rc’s in the medulla oblongata impairs respiration centrally.
15
16 NICOTINE is considered a non-selective nicotinic Rc agonist because it binds a variety of nicotinic receptors.
17 will activate nicotinic Rc’s at motor end plates (causing muscle fasciculations), on the adrenal medulla (causin
18 Epi and NE release), and in the CNS.
19

NICOTINE’S
20 effects on a new smoker

21
Cardiovascular
22 – similar to a sympatho-adrenal activation (fight or flight)
23 Initial effect - increase in BP:
24  Increase total peripheral resistance (TPR) – due to increase in sympathetic tone of arterioles
25  Increase cardiac output (CO) – due to increase in sympathetic tone in venules
26  Increase ventricular contraction - remember only sym innervation to ventricles
27  Remember that arterioles, venules and ventricle are only innervated by the sympathetic system
28
29 Secondary effect - decrease in BP:
30  the release of NE and Epi by the adrenal medulla
31  the action of Epi on β2 Rc’s in skeletal muscle beds, causing dilation.
32
33
34 Tertiary effect - increase in BP:
35  The Epi then acts on the arteriole smooth muscle α1 Rcs, the ventricle and SA node β1 Rcs and the vein α
36 Rcs to produce constriction and, therefore, increase BP.
37
***HR
38 in response to nicotine is unpredictable***
39
Respiration
40
41 Activates chemoreceptors to increase respiration
42 Stimulates the medulla oblongata centrally to increase respiration
 1
2
3
4Gastrointestinal tract
5 increase in GI motility and in HCl secretion
6 Parasympathetic has dominant tone in G.I. tract
7
8Central actions
9 Causes nausea and/or vomiting when acting at the chemoreceptor trigger zone (doesn’t have to cross BBB to
10 activate trigger zone)
11 Causes release of antidiuretic hormone, causes water retention
12
Dangers
13 of NICOTINE:
14 Ganglionic blocker at high doses cause paralysis of respiratory muscles and inhibition of the medulla oblongata,
15 leading to respiratory distress
16 Absorbed across skin, placenta, blood brain barrier, and gets into nursing mothers’ milk easily.
17 In the case of an overdose, treatments include syrup of ipecac and activated charcoal to absorb the nicotine.
18
Ch19
administered
20 IV at high doses along with an AChE inhibitor
can
21 cause ganglionic stimulation
at22low doses, ACh has trouble getting to nicotinic receptors on autonomic ganglion but no trouble reaching the
muscarinic
23 receptors on smooth muscle.

24
MPP
25 (dimethylphenylpiperazinium ion)
26
Only
27 stimulates ganglionic transmission. It does NOT cause Rc desensitization, therefore, it does not cause ganglion
blockade
28 at high doses.
29
Specific
30 for nicotinic Rc on autonomic ganglia and at the adrenal medulla. It does not act at the neuromuscular junct
31
Cardiovascular
32 effects – basically same as nicotine

33 increase TPR

34 increase ventricular contraction

35 increase venous return

36 increase blood pressure

37 reflex bradycardia in response to elevation of blood pressure – this is the difference between DMPP and
38 NICOTINE effects

39 parasym tone is dominant at SA node, so parasym outflow to that site is increased to achieve the reflex bradycar

40 stimulates transmission through the vagus by increasing the release of ACh to SA node

41 baroceptors sense high BP so two things happen to give the overall effect of decreased HR: 1) Increase Para
42 activity @ SA node – slowing HR, 2) Decrease Sym tone with high BP
 Adrenal
1 Medulla - acts to stimulate Epi and NE release (same as NICOTINE) resulting in a slight decrease in BP wh
Epi
2 hits the skeletal muscle beds and β2 Rc, followed by and increase in BP when NE and Epi hit the α 1 and β1 Rc a
over
3 the body
4
anglionic
5 Blocking Drugs
6
cological
7 actions will depend on which division of the autonomic nervous sys
dominates
8 in controlling an organ function.
9
Parasym
10 dominates at SA node therefore use of a ganglionic blocker will lead to tachycardia by removing the inhibit
tone.
11
12
Magnitude
13 of response to the drug will depend on tone at the time of administration
14
Giving
15 a standing person a ganglionic blocker will cause them to faint because you are blocking the dominating
sympathetic
16 innervation to the veins that return blood to the heart.
17
Giving
18 a reclined person the same drug will have a much smaller effect because the sym innervation on the veins is
much
19 less in a reclined individual.
20
Blockers
21 abolish autonomic reflexes, impairing one’s ability to maintain homeostasis (can’t sweat, salivate, or mainta
BP).
22 For example, because parasym innervation dominates in pupil constriction, taking a ganglionic blocker will bloc
parasympathetics
23 causing pupils not to constrict in bright sunlight.
24
ominating
25 systems
26
mpathetic
27
28 TPR – arteriolar smooth muscle
29 Venous return – cardiac output
30 Ventricular
31 Sweat glands
32
Parasympathetic
33
34 SA node – dominating parasym innervation, when blocked, usually causes tachycardia, but it can sometimes
35 cause bradycardia. Bradycardia results when an individual has an elevated heart rate at the time the ganglionic
36 blocker is given. This occurs because at elevated heart rates, the sym tone is greater than the parasym tone;
37 therefore, the ganglionic blocker blocks the dominating sym tone, resulting in a decrease in heart rate.
38 Pupil size – ganglionic blocker causes mydriasis
39 Accomodation – blocker causes the individual to only be able to see objects that are distant
40 GI motility and HCl secretion – a blocker will decrease HCl secretion and slow GI motility
41 PROPANTHELINE and METHANTHELINE (both anti-muscarinic drugs) are ganglionic blockers with
42 ATROPINE-like action and are used in the treatment of peptic ulcer (not too useful because histamine is th
43 major cause of HCl release, and drugs that specifically block the H 2 histamine Rc are now availableà fewer
44 unwanted side effects)
 1 Bladder function – ganglionic blocker causes urinary retention
 2 Salivation – blocker causes dry mouth
oth3
 4 Para & Sym in sexual function. Ganglionic blocker will cause impotence because para=erection and
5 sym=ejaculation
6
cal7 uses of ganglionic blockers – because of side-effects, their use is extremely limited
 8 acute dissecting aortic aneurysm to decrease blood pressure and to decrease blood flow to the site of the tear by
9 blocking sympathetics
10 hypertensive crises – advantageous to block autonomic reflexes
11
12Specific ganglionic blockers
13

14HEXAMETHONIUM – C6
15 1)positively charged
16 2)long duration of action
17 3) not well-absorbed therefore won’t cross blood brain barrier so it will not cause central side-effects
18 4) rarely used today
19

20MECAMYLAMINE
21 1) long duration
22 2) differs from HEXAMETHONIUM in that it is not charged so it is absorbed better, but it will cross the blood
23 brain barrier and cause central side effects
24

25TRIMETHAPHAN
26 1) positively charged
27 2) used more than the other two blockers because short duration of action
28 3) must be given IV (orally inactivates)
29 4) lowers blood pressure by causing ganglionic blockade and by releasing
30 histamine which causes vasodilation
31 5) someone with asthma will not want TRIMETHAPHAN because it will aggrevate the condition so
32 HEXAMETHONIUM would be better choice.
33
34
35
e36effects
37 Constipation
38 Orthostatic hypotension
39 Tachycardia
40 Photophobia
41 Blurred vision
42 Impotence
1 Dry mouth
2 Increased body temp. – can’t sweat when hot
3 Delay gastric emptying – important if taking another drug simultaneously that must get into the duodenum to be
4 absorbed. The drug that must be absorbed in the duodenum would have delayed action since it is stuck in the
5 stomach and may also build up to toxic level in the stomach.
6 Tolerance develops when treating hypertension. The blockers withdraw sym stim to the arterioles so less NE is
7 released onto the α1 Rc of arterioles. This causes the Rc’s to increase in number to compensate for the decrease
8 NE. As the number increases, the drug loses its effectiveness.
9 Tolerance also may develop because the slow excitatory Rc M1 may take over transmission as the fast excitator
10 pot is being blocked.
11

13
14
15
1
2
3